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Treatment Guidelines for Medicine and Primary Care 2006 Edition New Treatment Guidelines Paul D. Chan, MD Margaret T. Johnson, MD Current Clinical Strategies Publish- ing Purchasers of this book may download the digital book and updates for Palm, Pocket PC, Windows and Macintosh. The digital books can be downloaded at the Current Clinical Strategies Publishing Internet site: Copyright © 2006 by Current Clinical Strategies Publish- ing. All rights reserved. This book, or any parts thereof, may not be reproduced or stored in an information retrieval network without the permission of the publisher. Current Clinical Strategies is a registered trademark of Current Clinical Strategies Publishing Inc. The reader is advised to consult the drug package insert and other references before using any therapeutic agent. No warranty exists, expressed or implied, for errors and omissions in this text. Current Clinical Strategies Publishing 27071 Cabot Road Laguna Hills, California 92653 Phone: 800-331-8227 or 949-348-8404 Fax: 800-965-9420 or 949-348-8405 E-mail: [email protected] Printed in USA ISBN 1929622-69-4 Cardiovascular Disorders Acute Coronary Syndromes (ST- Segment Elevation MI, Non-ST-Seg- ment Elevation MI, and Unstable An- gina) Acute myocardial infarction (AMI) and unstable angina are part of a spectrum known as the acute coronary syndromes (ACS), which have in common a ruptured atheromatous plaque. Plaque rupture results in platelet activation, adhe- sion, and aggregation, leading to partial or total occlusion of the artery. These syndromes include ST-segment elevation MI, non- ST-segment elevation MI, and unstable angina. The ECG presentation of ACS includes ST-segment elevation infarc- tion, ST-segment depression (including non–Q-wave MI and unstable angina), and nondiagnostic ST-segment and T- wave abnormalities. Patients with ST-segment elevation MI require immediate reperfusion, mechanically or pharmaco- logically. The clinical presentation of myocardial ischemia is most often acute chest pain or discomfort. I. Characteristics of chest pain and associated symp- toms A. Ischemic chest pain can be characterized by the the OPQRST mnemonic. Symptoms associated with the highest relative risk of myocardial infarction (MI) include radiation to an upper extremity, particularly when there is radiation to both arms, and pain associated with diaphoresis or with nausea and vomiting. The patient should be asked if current pain is reminiscent of prior MI. 1. Onset. Ischemic pain is typically gradual in onset, although the intensity of the discomfort may wax and wane. 2. Provocation and palliation. Ischemic pain is gener- ally provoked by an activity. Ischemic pain does not change with respiration or position. It may or may not respond to nitroglycerin. 3. Quality. Ischemic pain is often characterized more as a discomfort than pain, and it may be difficult to describe. The patient may describe the pain as squeezing, tightness, pressure, constriction, crushing, strangling, burning, heartburn, fullness in the chest, band-like sensation, knot in the center of the chest, lump in throat, ache, heavy weight on chest. It is usually not described as sharp, fleeting, knife-like, stabbing, or pins and needles-like. The patient may place his clenched fist in the center of the chest, which is known as the "Levine sign." 4. Radiation. Ischemic pain often radiates to other parts of the body including the upper abdomen (epigastrium), shoulders, arms (upper and forearm), wrist, fingers, neck and throat, lower jaw and teeth (but not upper jaw), and not infrequently to the back (specifically the interscapular region). Pain radiating to the upper extremities is highly suggestive of ischemic pain. 5. Site. Ischemic pain is not felt in one specific spot, but rather it is a diffuse discomfort that may be difficult to localize. The patient often indicates the entire chest, rather than localizing it to a specific area by pointing a single finger. 6. Time course. Angina is usually brief (two to five minutes) and is relieved by rest or with nitroglycerin. In comparison, patients with an acute coronary syndrome (ACS) may have chest pain at rest, and the duration is variable but generally lasts longer than 30 minutes. Classic anginal pain lasting more than 20 minutes is particularly suggestive of an ACS. 7. Associated symptoms. Ischemic pain is often associated with is shortness of breath, which may reflect pulmonary congestion. Other symptoms may include belching, nausea, indigestion, vomiting, diaphoresis, dizziness, lightheadedness, clamminess, and fatigue. Elderly women and diabetics are more likely to present with such "atypical" symptoms in lieu of classic chest pain. B. Characteristics of nonischemic chest discomfort: 1. Pleuritic pain, sharp or knife-like pain related to respiratory movements or cough. 2. Primary or sole location in the mid or lower abdominal region. 3. Any discomfort localized with one finger. 4. Any discomfort reproduced by movement or palpa- tion. 5. Constant pain lasting for days. 6. Fleeting pains lasting for a few seconds or less. 7. Pain radiating into the lower extremities or above the mandible. C. Some patients with ACS present with atypical types of chest pain. Acute ischemia is diagnosed in 22 percent of patients who present with sharp or stabbing pain and 13 percent who presented with pleuritic-type pain. D. Atypical symptoms. Some patients with acute coro- nary syndrome (ACS) present with atypical symptoms rather than chest pain. One-third have no chest pain on presentation to the hospital. These patients often present with symptoms such as dyspnea alone, nausea and/or vomiting, palpitations, syncope, or cardiac arrest. They are more likely to be older, diabetic, and women. E. Additional history and exam 1. Historical features increasing likelihood of ACS a. Patients with a prior history of coronary heart disease (CHD) have a significantly increased risk of recurrent ischemic events. b. A prior history of other vascular disease is associ- ated with a risk of cardiac ischemic events compa- rable to that seen with a prior history of CHD. c. Risk factors for CHD, including especially age, sex, diabetes, hypertension, hyperlipidemia, and cigarette smoking. d. Recent cocaine use. 2. Focused physical exam a. Responsiveness, airway, breathing and circulation. b. Evidence of systemic hypoperfusion (hypotension; tachycardia; impaired cognition; cool, clammy, pale, ashen skin). Cardiogenic shock complicating acute MI requires aggressive evaluation and management. c. Ventricular arrhythmias. Sustained ventricular tachyarrhythmias in the periinfarction period must be treated immediately because of their deleteri- ous effect on cardiac output, possible exacerbation of myocardial ischemia, and the risk of deteriora- tion into VF. d. Evidence of heart failure (jugular venous disten- tion, rales, S3 gallop, hypotension, tachycardia). e. A screening neurologic examination should be performed to assess for focal lesions or cognitive deficits that might preclude safe use of thrombo- lytic therapy. Differential diagnosis of severe or prolonged chest pain Myocardial infarction Unstable angina Aortic dissection Gastrointestinal disease (esophagitis, esophageal spasm, peptic ulcer disease, biliary colic, pancreatitis) Pericarditis Chest-wall pain (musculoskeletal or neurologic) Pulmonary disease (pulmonary embolism, pneumonia, pleurisy, pneumothorax) Psychogenic hyperventilation syndrome f. Exam findings increasing likelihood of MI. Findings on physical examination associated with significantly increased risk of myocardial infarction are hypotension (systolic blood pres- sure <80) and signs of pump failure (ie, new or worsening pulmonary crackles, new S3, new or worsening MR murmur). II.Immediate management A. During the initial assessment phase, the following steps should be accomplished for any patient with significant risk of ACS: 1. Airway, breathing, and circulation assessed 2. 12-lead ECG obtained 3. Resuscitation equipment brought nearby 4. Cardiac monitor attached 5. Oxygen given 6. IV access and blood work obtained 7. Aspirin 162 to 325 mg given 8. Nitrates and morphine given (unless contraindi- cated) B. Twelve-lead ECG should be obtained in all patients with possible coronary ischemia. The 12-lead ECG provides the basis for initial diagnosis and manage- ment. The initial ECG is often not diagnostic in patients with ACS. The ECG should be repeated at 5 to 10 minute intervals, if the initial ECG is not diagnostic but the patient remains symptomatic and there is a high clinical suspicion for MI. C. Cardiac monitoring should be initiated with emer- gency resuscitation equipment (including a defibrillator and airway equipment) nearby. D. Supplemental oxygen should be initiated to maintain oxygen saturation above 90 percent. E. Intravenous access should be established, with blood drawn for initial laboratory work, including cardiac biomarkers. F. Aspirin should be given to all patients at a dose of 162 to 325 mg to chew and swallow, unless there is a compelling contraindication (eg, history of anaphylactic reaction) or it has been taken prior to presentation. G. Sublingual nitroglycerin should be administered at a dose of 0.4 mg every five minutes for a total of three doses, after which an assessment should be made about the need for intravenous nitroglycerin. Before this is done, all men should be questioned about the use of sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis); nitrates are contraindicated if these drugs have been used in the last 24 hours (36 hours with tadalafil) because of the risk of severe hypotension. 1. Extreme care should also be taken before giving nitrates in the setting of an inferior myocardial infarction with possible involvement of the right ventricle. Nitrate use can cause severe hypotension in this setting. H. Intravenous morphine sulfate at an initial dose of 2 to 4 mg, with increments of 2 to 8 mg, repeated at 5 to 15 minute intervals, should be given for the relief of chest pain and anxiety. III. ECG-based management of the Four major ischemic syndromes A. ST elevation (Q wave) MI is manifested by Q waves that are usually preceded by hyperacute T waves and ST elevations, and followed by T wave inversions. Clinically significant ST segment elevation is consid- ered to be present if it is greater than 1 mm (0.1 mV) in at least two anatomically contiguous leads. B. Non-ST elevation (Non-Q wave) MI is manifested by ST depressions or T-wave inversions without Q waves. C. Noninfarction subendocardial ischemia (classic an- gina), manifested by transient ST segment depres- sions. D. Noninfarction transmural ischemia (Prinzmetal’s variant angina) is manifested by transient ST segment elevations or paradoxical T wave normalization. E. Localization of ischemia. The anatomic location of a transmural infarct is determined by which ECG leads show ST elevation and/or increased T wave positivity: 1. Acute transmural anterior wall ischemia - one or more of the precordial leads (V1-V6) 2. Anteroseptal ischemia - leads V1 to V3 3. Apical or lateral ischemia - leads aVL and I, and leads V4 to V6 4. Inferior wall ischemia - leads II, III, and aVF 5. Right ventricular ischemia - right-sided precordial leads F. The right-sided leads V4R, V5R, and V6R should be obtained if there is evidence of inferior wall ischemia, demonstrated by ST elevation in leads II, III, and aVF. The posterior leads V7, V8, and V9 may also be helpful if there is evidence of posterior wall ischemia, as suggested by prominent R waves and ST depres- sions in leads V1 and V2. G. Serial ECGs. The initial ECG is often not diagnostic in patients with ACS. Therefore, if the initial ECG is not diagnostic, but the patient remains symptomatic and there is a high clinical suspicion for MI, it is recom- mended that the ECG be repeated at 5 to 10 minute intervals. H. LBBB or pacing. Both LBBB, which is present in 7 percent of patients with an acute MI, and pacing can interfere with the electrocardiographic diagnosis of coronary ischemia. Careful evaluation of the ECG may show some evidence of ACS in patients with these abnormalities. The clinical history and cardiac enzymes are of primary importance in diagnosing an ACS in this setting. I. ST elevation. Regardless of the presence or absence of Q waves, an ST elevation MI (STEMI) is diagnosed in the following circumstances: 1. ST segment elevation >1 mm is present in two or more anatomically contiguous leads. 2. The elevations are considered to represent ischemia and not pericarditis or left ventricular aneurysm. J. The patient should also be presumed to have an acute STEMI if the ECG shows a left bundle branch block that is not known to be old and the clinical suspicion for an ACS is high. K. Reperfusion therapy. A patient with an acute STEMI should undergo reperfusion therapy with either primary percutaneous intervention (PCI) or thrombolysis, if less than 12 hours has elapsed from the onset of symp- toms. Benefit from thrombolysis is significantly greater when given within four hours of the onset of symptoms. Primary PCI is preferred to thrombolysis when readily available. L. Antiplatelet therapy is indicated in all patients with STEMI, regardless of whether they undergo reperfusion therapy, unless an absolute contraindica- tion exists. 1. Aspirin is the preferred antiplatelet agent and should be given in a dose of 162 to 325 mg to chew and swallow as soon as possible to any patient with STEMI. 2. Clopidogrel (Plavix) is recommended in all patients treated with primary PCI and stenting. A 600 mg loading dose should begin in these patients, and primary PCI should be done within 90 minutes. Benefit from the use of clopidogrel in addition to aspirin has also been demonstrated in patients under 75 years of age undergoing thrombolysis. Patients over 75 years of age generally receive 75 mg because of the increased risk of hemorrhage. 3. Clopidogrel (300 mg loading dose followed by 75 mg once daily) is given to patients who are man- aged without reperfusion therapy in this setting based upon the benefit demonstrated in nonrevascularized patients with non-ST elevation syndromes. 4. Clopidogrel can also be given in the rare case where aspirin is contraindicated. M. Glycoprotein IIb/IIIa inhibitors. Treatment with abciximab should be started as early as possible prior to PCI, with or without stent, in patients with STEMI. N. Beta blockers should be administered to all patients with ST elevation MI without contraindications. Early intravenous use of a cardioselective agent, such as metoprolol or atenolol, is recommended: 1. Intravenous metoprolol can be given in 5 mg incre- ments by slow intravenous administration (5 mg over one to two minutes), repeated every five minutes for a total initial dose of 15 mg. Patients who tolerate this regimen should then receive oral therapy beginning 15 minutes after the last intrave- nous dose (25 to 50 mg every six hours for 48 hours) followed by a maintenance dose of 100 mg twice daily. 2. Intravenous atenolol can be given in a 5 mg dose, followed by another 5 mg, five minutes later. Pa- tients who tolerate this regimen should then receive oral therapy beginning one to two hours after the last intravenous dose (50 to 100 mg/day). 3. Esmolol (Brevibloc) (50 mcg/kg per min increasing to a maximum of 200 to 300 mcg/kg per min) can be used if an ultrashort acting beta blocker is required. O. Intravenous nitroglycerin can be given for treatment of persistent pain, congestive heart failure, or hyper- tension, provided there are no contraindications (eg, use of drugs for erectile dysfunction or right ventricular infarction). The goal of therapy is a 10 percent reduc- tion in the systolic blood pressure or a 30 percent reduction in hypertensive patients. Therapy for Non-ST Segment Myocardial Infarction and Unstable Angina Treatment Recommendations Antiplatelet agent Aspirin, 325 mg (chewable) Nitrates Sublingual nitroglycerin (Nitrostat), one tablet every 5 min for total of three tablets initially, followed by IV form (Nitro-Bid IV, Tridil) if needed Beta-blocker C IV therapy recommended for prompt response, followed by oral therapy. C Metoprolol (Lopressor), 5 mg IV every 5 min for three doses C Atenolol (Tenormin) 5 mg IV q5min x 2 doses C Esmolol (Brevibloc), initial IV dose of 50 micrograms/kg/min and adjust up to 200-300 micrograms/kg/min Heparin 80 U/kg IVP, followed by 15 U/kg/hr. Goal: aPTT 50-70 sec Enoxaparin (Lovenox) 1 mg/kg IV, followed by 1 mg/kg subcuta- neously bid Glycoprotein IIb/IIIa inhibi- tors Eptifibatide (Integrilin) or tirofiban (Aggrastat) for patients with high-risk fea- tures in whom an early invasive approach is planned Adenosine diphosphate receptor-inhibi- tor Consider clopidogrel (Plavix) therapy, 300 mg x 1, then 75 mg qd. Treatment Recommendations Cardiac catheterization Consideration of early invasive approach in patients at intermediate to high risk and those in whom conservative management has failed P. Potassium. The ACC/AHA guidelines recommend maintaining the serum potassium concentration above 4.0 meq/L in an acute MI. Maintaining a serum magne- sium concentration above 2.0 meq/L is recommended. Q. Unfractionated heparin (UFH) is given to patients with with STEMI undergoing percutaneous or surgical revascularization, and to patients undergoing thrombolysis with selective fibrinolytic agents. Low molecular weight heparin (LMWH) is an alternative to UFH in patients receiving thrombolysis provided they are younger than 75 years of age and have no renal dysfunction. Treatment Recommendations for ST-Segment Myo- cardial Infarction Supportive Care for Chest Pain • All patients should receive supplemental oxygen, 2 L/min by nasal canula, for a minimum of three hours • Two large-bore IVs should be placed Aspirin: Inclusion Clinical symptoms or suspicion of AMI Exclusion Aspirin allergy, active GI bleeding Recommenda- tion Chew and swallow one dose of160-325 mg, then orally qd Thrombolytics: Inclusion All patients with ischemic pain and ST-seg- ment elevation (>1 mm in >2 contiguous leads) within 6 hours of onset of persistent pain, age <75 years. All patients with a new bundle branch block and history suggesting acute MI. Exclusion Active internal bleeding; history of cerebrovascular accident; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; severe uncontrolled hypertension Recommenda- tion Reteplase (Retavase) 10 U IVP over 2 min x 2. Give second dose of 10 U 30 min after first dose OR Tenecteplase (TNKase): <60 kg: 30 mg IVP; 60-69 kg: 35 mg IVP; 70-79 kg: 40 mg IVP; 80-89 kg: 45 mg IVP; >90 kg: 50 mg IVP OR t-PA (Alteplase, Activase) 15 mg IV over 2 minutes, then 0.75 mg/kg (max 50 mg) IV over 30 min, followed by 0.5 mg/kg (max 35 mg) IV over 30 min. Heparin: Inclusion Administer concurrently with thrombolysis Exclusion Active internal or CNS bleeding Recommenda- tion Heparin 60 U/kg (max 4000 U) IVP, followed by 12 U/kg/hr (max 1000 U/h) continuous IV infusion x 48 hours. Maintain aPTT 50-70 seconds Beta-Blockade: Inclusion All patients with the diagnosis of AMI. Begin within 12 hours of diagnosis of AMI Exclusion Severe COPD, hypotension, bradycardia, AV block, pulmonary edema, cardiogenic shock Recommenda- tion Metoprolol (Lopressor), 5 mg IV push every 5 minutes for three doses; followed by 25 mg PO bid. Titrate up to 100 mg PO bid OR Atenolol (Tenormin), 5 mg IV, repeated in 5 minutes, followed by 50-100 mg PO qd. Nitrates: Inclusion All patients with ischemic-type chest pain Exclusion Hypotension; caution in right ventricular in- farction Recommenda- tion 0.4 mg NTG initially q 5 minutes, up to 3 doses or nitroglycerine aerosol, 1 spray sublingually every 5 minutes. IV infusion of NTG at 10-20 mcg/min, titrating upward by 5- 10 mcg/min q 5-10 minutes (max 3 mcg/kg/min). Slow or stop infusion if systolic BP <90 mm Hg ACE-Inhibitors or Angiotensin Receptor Blockers: Inclusion All patients with the diagnosis of AMI. Initiate treatment within 24 hours after AMI Exclusion Bilateral renal artery stenosis, angioedema caused by previous treatment Recommenda- tion Lisinopril (Prinivil) 2.5-5 mg qd, titrate to 10-20 mg qd. Maintain systolic BP >100 mmHg or Valsartan (Diovan) 40 mg bid, titrate to 160 mg bid IV. Non-ST elevation. Patients with coronary ischemia but who do not manifest ST elevations on ECG are consid- ered to have unstable angina (UA) or a non-ST elevation myocardial infarction (NSTEMI). UA and NSTEMI comprise part of the spectrum of ACS. A. Angina is considered unstable if it presents in any of the following three ways: 1.Rest angina, generally lasting longer than 20 minutes 2.New onset angina that markedly limits physical activity 3.Increasing angina that is more frequent, lasts longer, or occurs with less exertion than previous angina B. NSTEMI is distinguished from UA by the presence of elevated serum biomarkers. ST segment elevations and Q waves are absent in both UA and NSTEMI. Unstable angina and NSTEMI are frequently indistin- guishable initially because an elevation in serum biomarkers is usually not detectable for four to six hours after an MI, and at least 12 hours are required to detect elevations in all patients. C. Risk stratification 1.The TIMI investigators developed a 7-point risk stratifi- cation tool that predicted the risk of death, reinfarction, or urgent revascularization at 14 days after presenta- tion. This scoring system includes the following ele- ments: a. Age >65. b. Three or more cardiac risk factors. c. Aspirin use in the preceding seven days. d. Two or more anginal events in the preceding 24 hours. e. ST-segment deviation on presenting ECG. f. Increased cardiac biomarkers. g. Prior coronary artery stenosis >50 percent. 2.Patients are considered to be high risk if they have a TIMI risk score of 5 or greater (one point is given for each element) and low risk if the score is 2 or below. 3.Additional factors associated with death and reinfarction at 30 days after presentation include: a. Bradycardia or tachycardia b. Hypotension c. Signs of heart failure (new or worsening rales, MR murmur, S3 gallop) d. Sustained ventricular tachycardia D. Reperfusion. Thrombolytic therapy should not be administered to patients with UA or NSTEMI unless subsequent ECG monitoring documents ST segment elevations that persist. An aggressive approach to reperfusion using PCI is best suited for patients with a TIMI risk score >5 or possibly other high-risk features. E. Antiplatelet therapy is a cornerstone of treatment in UA and NSTEMI. 1.Aspirin is the preferred antiplatelet agent and should be given to all patients with suspected ACS. 2.Clopidogrel (300-600 mg) is indicted in patients undergoing PCI. A class IIa recommendation was given to their use in patients with high-risk features in whom PCI is not planned. F. Beta-blocker, nitroglycerin, morphine. The use of these agents in NSTEMI is similar to that in STEMI. G. Electrolyte repletion. Low electrolytes, particularly potassium and magnesium, which are associated with an increased risk of ventricular fibrillation in the setting of ACS, should be replaced. H. Heparin. The ACC/AHA guidelines recommend the use of enoxaparin in preference to unfractionated heparin in patients with UA/NSTEMI, provided there is no evidence of renal failure and CABG is not planned within 24 hours. I. Disposition of NSTEMI 1.High-risk patients have a high-risk ACS if ST seg- ment depression (>0.05 mV [0.5 mm]) is present in two or more contiguous leads and/or the TIMI risk score is >5. This patient is admitted to an intensive care unit, coronary care unit, or monitored cardiac unit depend- ing upon the persistence of symptoms and evidence of hemodynamic compromise. Those with persistent pain or hemodynamic compromise generally undergo urgent angiography and revascularization. Others with resolution of symptoms and stable hemodynamics are typically referred for early elective angiography and revascularization if appropriate. a. If there is no ST segment elevation or depression or new LBBB, regardless of the presence or ab- sence of Q waves, the patient with definite or probable ACS should still be admitted to a moni- tored care unit for further evaluation. Those pa- tients manifesting high-risk features either on presentation or during their emergency room course should be considered for early PCI. 2.Moderate-risk patient. Patients who have no ECG changes and are at moderate risk for ACS can be admitted to a chest pain observation unit, if available, for further evaluation because a small percentage (2 to 4 percent) will have an ACS. 3.Low-risk patient. Patients with no ECG changes, a TIMI risk score below 3, and no other concerning features in their presentation can be considered for early provocative testing or possible discharge with outpatient follow-up. Patients at very low risk in whom there is clear objective evidence for a non-ischemic cause of their chest pain can be discharged with outpatient follow-up. V. Cardiac biomarkers (enzymes). Serial serum biomarkers (also called cardiac enzymes) of acute myocardial damage, such as troponin T and I, creatine kinase (CK)-MB, and myoglobin, are essential for confirm- ing the diagnosis of infarction. The most commonly used are troponin T or I and CK-MB, which can be measured by rapid bedside assay. A. Sensitivity and specificity. An elevation in the serum concentration of one or more of the above markers is seen in virtually all patients with an acute MI. However, the sensitivity of these tests is relatively low until four to six hours after symptom onset. Thus, a negative test in this time period does not exclude infarction. Further- more, some patients do not show a biomarker eleva- tion for as long as 12 hours. B. Therefore, in patients who have an acute STEMI, reperfusion therapy should not await the results of cardiac biomarkers. In patients without diagnostic ST segment elevation, serial biomarker testing is per- formed after four or more hours if the initial values are indeterminate, the ECG remains nondiagnostic, and clinical suspicion remains high. Common Markers for Acute Myocardial Infarction Marker Initial Elevation After MI Mean Time to Peak Ele- vations Time to Return to Baseline Myoglobin 1-4 h 6-7 h 18-24 h CTnl 3-12 h 10-24 h 3-10 d CTnT 3-12 h 12-48 h 5-14 d CKMB 4-12 h 10-24 h 48-72 h CKMBiso 2-6 h 12 h 38 h CTnI, CTnT = troponins of cardiac myofibrils; CPK-MB, MM = tissue isoforms of creatine kinase. C. Unstable angina. Patients with cardiac biomarker elevations and unstable angina are considered to have an NSTEMI and should be treated appropriately. References, see page 360. Stable Angina Pectoris Angina pectoris is a symptom complex caused by myocardial ischemia. Stable angina refers to chest discomfort that occurs predictably and reproducibly at a certain level of exertion and is relieved with rest or nitroglycerin. Unstable angina includes new onset of chest pain, progressing effort angina, rest angina, post-myocardial infarction angina, and angina after revascularization. I. Clinical evaluation A. Important points include the following: 1. History of previous heart disease 2. Possible non-atheromatous causes of angina (eg, aortic stenosis) 3. Symptoms of systemic atherosclerosis (eg, claudication) 4. Severity and pattern of symptoms of angina 5. Risk factors for coronary heart disease, include smoking, inappropriate activity level, stress, hyperlipidemia, obesity, hypertension, and diabetes mellitus. B. Physical examination should include a cardiovascular examination, evaluation for hyperlipidemia, hyperten- sion, peripheral vascular disease, congestive heart failure, anemia, and thyroid disease. C. Laboratory studies should include an electrocardio- gram and a fasting lipid profile. Further studies may include chest films, hemoglobin, and tests for diabetes, thyroid function, and renal function. D. Exercise electrocardiography. An exercise test should be obtained for prognostic information. 1. Sensitivity of exercise electrocardiography may be reduced for patients unable to reach the level of exercise required for near maximal effort, such as: a. Patients taking beta blockers b. Patients in whom fatigue, dyspnea, or claudication symptoms develop c. Patients who cannot perform leg exercises 2. Reduced specificity may be seen in patients with abnormalities on baseline electrocardiograms, such as those taking digoxin or with left ventricular hyper- trophy or left bundle branch block. E. Noninvasive imaging, such as myocardial perfusion scintigraphy or stress echocardiography, may be indicated in patients unable to complete exercise electrocardiography. II. Medical treatment of stable angina pectoris A. Nitrates 1. Nitrates are a first-line therapy for the treatment of acute anginal symptoms. The primary anti-ischemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilation more than coronary vasodilation. Nitrates improve exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. In combination with beta-blockers or calcium channel blockers, nitrates produce greater antianginal and anti- ischemic effects. 2. Sublingual nitroglycerin remains the therapy of choice for acute anginal episodes and prophylacti- cally for activities known to elicit angina. The initial dose is 0.3 mg; one-half the dose can be used if the patient becomes hypotensive. A second dose can be taken if symptoms persist after three to five minutes. A physician should be contacted if symptoms persist after rest and three sublingual nitroglycerin tablets. 3. Chronic nitrate therapy, in the form of an oral or transdermal preparation (isosorbide dinitrate, isosorbide mononitrate, or transdermal nitroglycerin) can prevent or reduce the frequency of recurrent anginal episodes and improve exercise tolerance. However, tolerance to long-acting nitrates can develop. A 12- to 14-hour nitrate-free interval must be observed in order to avoid tolerance, and some patients have a reduced anginal threshold during this period. As a result, chronic nitrate therapy is a second-line antianginal therapy a. Isosorbide dinitrate begins with a dose of 10 mg at 8 AM, 1 PM, and 6 PM, which results in a 14-hour nitrate dose-free interval. The dose is increased to 40 mg three times daily as needed. Alternatively, isosorbide dinitrate can be taken twice daily at 8 AM and 4 PM. b. The extended-release preparation of isosorbide mononitrate, which is administered once per day, is preferable to improve compliance. The starting dose is 30 mg once daily, titrated to 120 mg once daily as needed. This preparation is useful in effort-induced angina. However, since the effect lasts only about 12 hours, nocturnal or rebound angina may occur, requiring twice-daily dosing or additional antianginal therapy. c. Transdermal nitroglycerin patches are a conve- nient way to administer nitroglycerin. The patient must remove the patch for 12 to 14 hours. Since most patients have angina with activity, the patch should be applied at 8 AM and removed at 8 PM. The initial dose of 0.2 mg per hour can be in- creased to 0.8 mg per hour. 4. Side effects. The major side effects associated with nitrate use are headache, lightheadedness, and flushing which are due to the vasodilatation. These symptoms tend to improve with time. Dosages of Nitroglycerine Preparations Prepa- ration Route of adminis- tration On- set of ac- tion , min utes Duration of action Dose Nitro- glycerin Sublingual tablet Sublingual spray Ointment Transderm- al Oral sus- tained re- lease Intravenous 2-5 2-5 2-5 30 30 2-5 15-30 min 15-30 min Up to 7 hours 8-14 hours 4-8 hours During infusion, toler- ance in 7-8 hours 0.15-0.9 mg 0.4 mg 2 per- cent, 15x15 cm (7.5 to 40 mg) 0.2-0.8 mg/hour q12h 2.5-13 mg 5-200 ug/min Isosorbi de dinitrate Sublingual Oral Spray Chewable Oral slow release Intravenous 2-5 30 2-5 2-5 30 2-5 Up to 60 min Up to 8 hours 2-3 min 2-2.25 hours Up to 8 hours During infusion, toler- ance in 7-8 hours 2.5-15 mg 5-80 mg BID or TID 1.25 mg/day 5 mg 40 mg QD or BID 1.25-5 mg/hour Isosorbi de mononitr ate, ex- tended release Oral 30 12-24 hours 20-40 mg BID 60-240 mg/day Isosorbi de mononitr ate, ex- tended release Oral 30- 60 12 hours 30-120 mg once daily Adverse Effects of Beta-blockers Bradycardia, decreased contractility, AV node conduction delay Bronchoconstriction can be induced by nonselective agents and high doses of cardioselective agents. Worsening of symptoms of peripheral vascular disease or Raynaud's phenomenon. Fatigue may be due to the reduction in cardiac output or to direct effects on the central nervous system. Central side effects include depression, nightmares, insomnia, and hallucinations. Impotence is often a problem. Beta-blockers Class Drug name Starting dose Maximal dose Cardiosel- ective Atenolol (Tenormin) 25 mg QD 100 mg QD Class Drug name Starting dose Maximal dose Cardiosel- ective Metoprolol (Lopressor) 25 mg BID 100 mg BID Metoprolol extended re- lease (Toprol XL) 50 mg qd 200 mg qd Nonselec- tive NadoIol (Corgard) 25 mg QD 240 mg QD Nonselec- tive Propranolol (Inderal) 40 mg BID 120 mg BID Intrinsic sympatho- mimetic PindoIoI (Visken) 5 mg BID 30 mg BID Alpha blocker Labetalol (Normodyne) 100 mg BID 600 mg BID B. Beta-blockers relieve anginal symptoms by competi- tively inhibiting sympathetic stimulation of the heart, reducing both heart rate and contractility. 1. Choice of agents. The cost for a one month supply of most beta-blockers is $15 to $35; propranolol costs $4 per month. 2. Lower doses of the cardioselective beta-blockers (such as atenolol and metoprolol) have the advantage of blocking beta-1-receptor mediated stimulation of the heart with lesser inhibition of the peripheral vasodilation and bronchodilation induced by the beta- 2 receptors. As a result, a long-acting cardioselective agent (atenolol or metoprolol) is preferred for the treatment of stable angina. There are no major advantages of a nonselective agent, other than the low cost of propranolol, and there are potential disad- vantages in patients with certain underlying diseases such as obstructive lung disease, asthma, peripheral vascular disease, diabetes, and depression. 3. The starting dose of atenolol (Tenormin) is 25 mg once daily, which can be increased as tolerated to a maximum of 200 mg once a day (assuming renal function is normal) until the resting heart rate is 50 to 60 beats/min and does not exceed 100 beats/min with ordinary activity. 4. The starting dose of metoprolol (Lopressor) is 25 mg BID, which can be increased to 200 mg BID as tolerated. An extended-release form of metoprolol, given once per day, can be substituted once an effective dose has been established. 5. Beta-blockers are well tolerated and extremely effec- tive in reducing anginal episodes and improving exercise tolerance. In addition, beta-blockers are the only antianginal drugs proven to prevent reinfarction and to improve survival in patients who have sus- tained an MI. 6. Achieving adequate beta blockade. Reasonable goals when titrating the dose include: a. Resting heart rate between 50 and 60 beats/min. The target heart rate for some patients with more severe angina can be <50 beats/min, as long as the bradycardia is asymptomatic and heart block does not develop. b. Patients with resting bradycardia prior to therapy can be treated with a calcium channel blocker (such as diltiazem or nifedipine), nitrates, or a drug with intrinsic sympathomimetic activity if a beta- blocker is necessary. 7. Side effects a. The most frequent side effects associated with beta-blockers include: bradycardia, conduction disturbances, bronchoconstriction, worsening of symptoms of peripheral vascular disease, fatigue, central nervous system side effects, and impo- tency. Beta-blockers should be used with caution in obstructive airways disease or peripheral vascu- lar disease and, initially at very low doses in heart failure. b. Beta-blockers should not be used in patients with vasospastic or variant (Prinzmetal) angina because they are ineffective and may induce coronary vasospasm from unopposed alpha-receptor activ- ity. C. Calcium channel blockers 1. Calcium channel blockers decrease coronary vascular resistance and increase coronary blood flow. Calcium blockers also decrease myocardial oxygen demand by reducing systemic vascular resistance and arterial pressure and a negative inotropic effect. 2. Choice of agent a. Verapamil (Calan) is a negative inotrope that also slows sinus rate and decreases AV conduction (negative chronotrope). It is a much less potent vasodilator than the dihydropyridines. b. The dihydropyridines (eg, nifedipine, nicardipine, felodipine, amlodipine) have a greater selectivity for vascular smooth muscle than for the myocardium. They are potent vasodilators with less effect on contractility and AV conduction. c. Diltiazem (Cardizem) is a modest negative inotropic and chronotropic agent and vasodilator and has intermediate effects between the dihydropyridines and verapamil. d. If a calcium channel blocker is used, long-acting diltiazem or verapamil or a second-generation dihydropyridine (amlodipine or felodipine) should be selected. Short-acting dihydropyridines, espe- cially nifedipine, should be avoided in the manage- ment of CHD because of evidence of an increase in mortality after an MI and an increase in acute MI in hypertensive patients. e. When to use. Calcium channel blockers should be used in combination with beta-blockers when initial treatment with beta-blockers is not successful. Calcium channel blockers may be a substitute for a beta-blocker when beta-blockers are contraindi- cated or cause side effects. Calcium channel blockers (eg, diltiazem at a dose of 240 to 360 mg per day) are effective in vasospastic or variant (Prinzmetal) angina; they are the preferred agents in this setting. f. Side effects include symptomatic bradycardia, heart block, worsening heart failure, constipation, flushing, headache, dizziness, and pedal edema. D. Angina that persists with monotherapy. Addition of a second drug is indicated if angina persists with monotherapy. If, for example, the patient is already taking a beta-blocker, a long-acting calcium channel blocker, particularly if the patient is also hypertensive, or a long-acting nitrate can be started. Patients who have limiting angina on two agents should receive coronary angiography and revascularization if indicated. E. General and lifestyle measures. In the absence of a contraindication, all patients should be treated with aspirin (81 mg/day [one baby aspirin] to 325 mg/day). Clopidogrel (Plavix) is an alternative when aspirin is contraindicated or not tolerated. F. Exercise program. Gradual institution of a regular aerobic exercise program should be encouraged. G. Risk factor reduction should be a central component of the management of patients with stable angina. This includes treatment of hypertension, cessation of smok- ing, lipid lowering, weight reduction, and glycemic control in diabetics. With respect to lipid lowering, a target LDL- cholesterol concentration of less than 80 mg/dL is recommended in established CHD or with CHD equiva- lents, such as diabetes mellitus. H. Exercise ECG testing should be obtained in all patients with stable angina to evaluate the efficacy of the anti- ischemic program and for prognostic information. A standard exercise ECG is preferred as the initial test in patients with a normal resting ECG who are able to exercise and are not taking digoxin. I. Coronary angiography. There are two primary indica- tions for coronary angiography followed by revascularization of appropriate lesions: 1. Angina which significantly interferes with a patient's lifestyle despite maximal tolerable medical therapy. 2. The presence of high-risk criteria on noninvasive testing, regardless of anginal severity, which indicate improved prognosis with revascularization. 3. Coronary revascularization. Despite effective medical therapy, a significant number of patients are candidates for PCI or surgical revascularization with CABG. Revascularization is also performed when the patient is active and prefers revascularization for improved quality of life compared to medical therapy. References, see page 360. Heart Failure Caused by Systolic Left Ventricular Dysfunction Over four million persons have HF in the United States. The mortality rate is 50 percent at two years and 60 to 70 percent at three years. Heart failure (HF) can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. It is characterized by dyspnea and fatigue, and signs of fluid retention. I. Classification of severity A. The classification system that is most commonly used to quantify the degree of functional limitation imposed by heart failure is the New York Heart Association (NYHA) classification. Classification of Patients with Heart Failure Caused by Left Ventricular Dysfunction New classifica- tion based on symptoms Corresponding NYHA class Asymptomatic NYHA class I Symptomatic NYHA class II/III Symptomatic with recent history of dyspnea at rest NYHA class IIIb Symptomatic with dyspnea at rest NYHA class IV B. Etiology. There are two mechanisms by which reduced cardiac output and heart failure occur: systolic dysfunc- tion and diastolic dysfunction. C. Systolic dysfunction. The most common causes of systolic dysfunction are coronary (ischemic) heart disease, idiopathic dilated cardiomyopathy, hyperten- sion, and valvular disease. Coronary disease and hypertension account for 62 and 10 percent of cases, respectively. D. Diastolic dysfunction can be induced by many of the same conditions that lead to systolic dysfunction. The most common causes are hypertension, ischemic heart disease, hypertrophic obstructive cardiomyopathy, and restrictive cardiomyopathy. II.Clinical evaluation A. There are two major classes of symptoms in HF: those due to excess fluid accumulation (dyspnea, edema, hepatic congestion, and ascites) and those due to a reduction in cardiac output (fatigue, weakness) that is most pronounced with exertion. B. Acute and subacute presentations (days to weeks) are characterized primarily by shortness of breath, at rest and/or with exertion. Also common are orthopnea, paroxysmal nocturnal dyspnea, and, with right heart failure, right upper quadrant discomfort due to acute hepatic congestion, which can be confused with acute cholecystitis. Patients with atrial and/or ventricular tachyarrhythmias may complain of palpitations with or without lightheadedness. C. Chronic presentations (months) differ in that fatigue, anorexia, bowel distension, and peripheral edema may be more pronounced than dyspnea. D. Classic exertional angina usually indicates ischemic heart disease. E. Acute heart failure after an antecedent flu-like illness suggests viral myocarditis. F. Long-standing hypertension or alcohol use suggests hypertensive or alcoholic cardiomyopathy. G. Amyloidosis should be excluded in patients who also have a history of heavy proteinuria. H. Primary valvular dysfunction should be considered in a patient with significant murmurs. I. Heart failure may be provoked or worsened by drugs, including antiarrhythmic agents such as disopyramide and flecainide; calcium channel blockers, particularly verapamil; beta-blockers; and nonsteroidal anti-inflam- matory drugs (NSAIDs). Factors Associated with Worsening Heart Failure Cardiovascular factors Superimposed ischemia or infarction Uncontrolled hypertension Unrecognized primary valvular disease Worsening secondary mitral regurgitation New onset or unctontrolled atrial fibrillation Excessive tachycardia Pulmonary embolism Systemic factors Inappropriate medications Superimposed infection Anemia Uncontrolled diabetes Thyroid dysfunction Electrolyte disorders Pregnancy Patient-related factors Medication noncompliance Dietary indiscretion Alcohol consumption Substance abuse III. Physical examination A. Patients compensate for a fall in cardiac output by increasing sympathetic outflow. This results in shunting of the cardiac output to vital organs, leading to sinus t achycardi a, di aphoresi s, and per i pheral vasoconstriction, manifested as cool, pale, and some- times cyanotic extremities. B. Volume overload. There are three major manifesta- tions of volume overload in patients with HF are pulmo- nary congestion, peripheral edema, and elevated jugular venous pressure. C. Ventricular enlargement. Ventricular chamber size can be estimated by precordial palpation. An apical impulse that is laterally displaced past the midclavicular line is usually indicative of left ventricular enlargement. Left ventricular dysfunction can also lead to sustained apical impulse which may be accompanied by a parasternal heave. D. Pulmonary hypertension. Patients with chronic heart failure often develop secondary pulmonary hyperten- sion, which can contribute to dyspnea. These patients may also complain of substernal chest pressure, typical of angina. Physical signs of pulmonary hypertension can include increased intensity of P2, a murmur of pulmonary insufficiency, and a palpable pulmonic tap. IV. Blood tests A. Recommended initial blood tests for patients with signs or symptoms of HF include: 1. A complete blood count since anemia can exacer- bate pre-existing HF. 2. Serum electrolytes and creatinine as a baseline to follow when initiating therapy with diuretics and/or angiotensin converting enzyme inhibitors. 3. Liver function tests, which may be affected by hepatic congestion. 4. Fasting blood glucose to detect underlying diabetes mellitus. (See "Heart failure in diabetes mellitus"). Laboratory Workup for Suspected Heart Failure Blood urea nitrogen Cardiac enzymes (CK-MB, troponin) Complete blood cell count Creatinine Electrolytes Liver function tests Magnesium Thyroid-stimulating hormone Urinalysis Echocardiogram Electrocardiography Impedance cardiography Atrial natriuretic peptide (ANP) Brain natriuretic peptide (BNP) B. In addition, if it is determined that dilated cardiomyopathy is responsible for HF and the cause is not apparent, several other blood tests may be war- ranted. 1. Thyroid function tests, particularly in patients over the age of 65 or in patients with atrial fibrillation. Thyrotoxicosis is associated with atrial fibrillation and hypothyroidism may present as HF. 2. Iron studies (ferritin and TIBC) to screen for heredi- tary hemochromatosis (HH). C. Other studies that may be undertaken depending upon the potential findings identified in the history and physical examination include: 1. ANA and other serologic tests for lupus. 2. Viral serologies and antimyosin antibody if myocarditis is suspected. 3. Evaluation for pheochromocytoma. 4. Thiamine, carnitine, and selenium levels. 5. Genetic testing and counseling (eg, in patients suspected of familial cardiomyopathy after obtaining a detailed family history). D. Plasma BNP. With chronic HF, atrial myocytes secrete increased amounts of atrial natriuretic peptide (ANP) and ventricular myocytes secrete both ANP and brain natriuretic peptide (BNP) in response to the high atrial and ventricular filling pressures. The plasma concentra- tions of both hormones are increased in asymptomatic and symptomatic left ventricular dysfunction, permitting their use in diagnosis. A value BNP >100 pg/mL diagno- ses HF with a sensitivity, specificity, and predictive accuracy of 90, 76, and 83 percent, respectively. E. Plasma N-pro-BNP. The active BNP hormone is cleaved from the C-terminal end of its prohormone, pro- BNP. The N-terminal fragment, N-pro-BNP, is also released into the circulation. In normal subjects, the plasma concentrations of BNP and N-pro-BNP are similar (approximately 10 pmol/L). However, in patients with LV dysfunction, plasma N-pro-BNP concentrations are approximately four-fold higher than BNP concentra- tions. V. Chest x-ray. The chest x-ray is a useful first diagnostic test, particularly in the evaluation of patients who present with dyspnea, to differentiate heart failure from primary pulmonary disease. Findings suggestive of heart failure include cardiomegaly (cardiac-to-thoracic width ratio above 50 percent), cephalization of the pulmonary vessels, Kerley B-lines, and pleural effu- sions. The cardiac size and silhouette may also reveal cardiomegaly. VI. Electrocardiogram A. The electrocardiogram may show findings that favor the presence of a specific cause of heart failure and can also detect arrhythmias such as asymptomatic ventricu- lar premature beats, runs of nonsustained ventricular tachycardia, or atrial fibrillation, which may be the cause of or exacerbate HF. B. Patients with dilated cardiomyopathy frequently have first degree AV block, left bundle branch block, left anterior fascicular block, or a nonspecific intraventricular conduction abnormality. Among the potentially diagnostic findings on ECG are: 1. Evidence of ischemic heart disease. 2. Left ventricular hypertrophy due to hypertension; a pseudo-infarct pattern may also be present. 3. Low-limb lead voltage on the surface ECG with a pseudo-infarction pattern (loss of precordial R-wave progression in leads V1-V6) can suggest an infiltrative process such as amyloidosis. 4. Low-limb lead voltage with precordial criteria for left ventricular hypertrophy is most suggestive of idio- pathic dilated cardiomyopathy. A widened QRS complex and/or a left bundle branch block pattern is also consistent with this diagnosis. 5. Heart block, that may be complete, and various types of intraventricular conduction defects are observed in patients with cardiac sarcoidosis. 6. Persistent tachycardia such as atrial fibrillation with a rapid ventricular response may lead to a car di omyopat hy ( t achycar di a- medi at ed cardiomyopathy). C. Most patients with HF due to systolic dysfunction have a significant abnormality on ECG. A normal ECG makes systolic dysfunction extremely unlikely (98 percent negative predictive value). VII. Laboratory testing A. Echocardiography. Echocardiography should be performed in all patients with new onset heart failure and can provide important information about ventricular size and function. The sensitivity and specificity echocardiography for the diagnosis of HF are as high as 80 and 100 percent, respectively. B. Detection of coronary heart disease. Most patients with HF due to ischemic cardiomyopathy have known coronary heart disease. However, occult disease is a not uncommon cause of dilated cardiomyopathy, accounting for as many as 7 percent of initially unex- plained cases. Heart failure resulting from coronary disease is usually irreversible due to myocardial infarc- tion and subsequent ventricular remodeling. However, revascularization may be of benefit in patients in whom hibernating myocardium is in part responsible for the decline in myocardial function. 1. Exercise testing should be part of the initial evalua- tion of any patient with HF. In addition to detection of ischemic heart disease, assessment of exercise capacity can be used for risk stratification and determining prognosis. With severe heart failure, measurement of the maximal oxygen uptake (VO 2 max) provides an objective estimate of the functional severity of the myocardial dysfunction. 2. Cardiac catheterization. Coronary catheterization with angiography is indicated in virtually all patients with new onset heart failure of uncertain cause, even in patients with no history of anginal symptoms and a normal exercise test. Some exceptions include patients with comorbid conditions that either render catheterization too risky or that would preclude invasive therapy. VIII. Treatment of heart failure due to systolic dysfunc- tion A. Treatment of the underlying cardiac disease 1. Hypertension is the primary cause of HF in 13 percent of patients. 2. Angiotensin converting enzyme (ACE) inhibitors, beta-blockers, and angiotensin II receptor blockers (ARBs) are the preferred antihypertensive agents because they improve survival in patients with HF. Beta-blockers can also provide anginal relief in patients with ischemic heart disease and rate control in atrial fibrillation. Beta-blocker therapy should always be initiated at very low doses. 3. Renovascular disease testing is indicated in patients in whom the history is suggestive (severe or refractory hypertension, a sudden rise in blood pressure, or repeated episodes of flash pulmonary edema). 4. Ischemic heart disease. Coronary atherosclerosis is the most common cause of cardiomyopathy, comprising 50 to 75 percent of patients with HF. All patients with ischemic heart disease should be treated medically for relief of angina and with risk- factor reduction. Myocardial revascularization with angioplasty or bypass surgery may improve symptom status, exercise capacity. Revascularization should also be considered in patients with a history of repeated episodes of acute left ventricular dysfunc- tion and flash pulmonary edema. 5. Valvular disease is the primary cause of HF in 10 to 12 percent of patients. Surgical correction of valvular disease can lead to improvement in cardiac function. 6. Other factors that can cause, or worsen, HF include alcohol abuse, cocaine abuse, obstructive sleep apnea, nutritional deficiencies, myocarditis, hemochromatosis, sarcoidosis, and rheumatologic disorders, such as systemic lupus erythematosus. Treatment Classification of Patients with Heart Failure Caused by Left Ventricular Systolic Dys- function Symptoms Pharmacology Asymptomatic ACE inhibitor or angiotensin- receptor blocker Beta blocker Symptomatic ACE inhibitor or angiotensin- receptor blocker Beta blocker Diuretic If symptoms persist: digoxin (Lanoxin) Symptomatic with recent his- tory of dyspnea at rest Diuretic ACE inhibitor or angiotensin- receptor blocker Spironolactone (Aldactone) Beta blocker Digoxin Symptomatic with dyspnea at rest Diuretic ACE inhibitor or angiotensin- receptor blocker Spironolactone (Aldactone) Digoxin Dosages of Primary Drugs Used in the Treatment of Heart Failure Drug Starting Dosage Target Dosage Drugs that decrease mortality and improve symptoms ACE inhibitors Captopril (Capoten) 6.25 mg three times daily (one-half tablet) 12.5 to 50 mg three times daily Enalapril (Vasotec) 2.5 mg twice daily 10 mg twice daily Lisinopril (Zestril) 5 mg daily 10 to 20 mg daily Ramipril (Altace) 1.25 mg twice daily 5 mg twice daily Trandolapril (Mavik) 1 mg daily 4 mg daily Angiotensin-Receptor Blockers (ARBs) Candesartan (Atacand) 4 mg bid 16 mg bid Irbesartan (Avapro) 75 mg qd 300 mg qd Losartan (Cozaar) 12.5 mg bid 50 mg bid Valsartan (Diovan) 40 mg bid 160 mg bid Telmisartan (Micardis) 20 mg qd 80 mg qd Aldosterone antagonists Spironolactone (Aldactone) 25 mg daily 25 mg daily Eplerenone (Inspra) 25 mg daily 25 mg daily Beta blockers Bisoprolol (Zebeta) 1.25 mg daily (one-fourth tablet) 10 mg daily Carvedilol (Coreg) 3.125 mg twice daily 25 to 50 mg twice daily Metoprolol tartrate (Lopressor) 12.5 mg twice daily (one-fourth tablet) 50 to 75 mg twice daily Metoprolol succinate (Toprol-XL) 12.5 mg daily (one-half tablet) 200 mg daily Drugs that treat symptoms Thiazide diuretics Drug Starting Dosage Target Dosage Hydrochlorothia- zide (Esidrex) 25 mg daily 25 to 100 mg daily Metolazone (Zaroxolyn) 2.5 mg daily 2.5 to 10 mg daily Loop diuretics Bumetanide (Bumex) 1 mg daily 1 to 10 mg once to three times daily Ethacrynic acid (Edecrin) 25 mg daily 25 to 200 mg once or twice daily Furosemide (Lasix) 40mg daily 40 to 400 mg once to three times daily Torsemide (Demadex) 20 mg daily 20 to 200 mg once or twice daily Inotrope Digoxin (Lanoxin) 0.125 mg daily 0.125 to 0.375 mg daily B. Pharmacologic therapy of heart failure 1. ACE inhibitors improve survival in patients with all severities of myocardial disease, ranging from asymptomatic left ventricular dysfunction to moderate or severe HF. All patients with asymptomatic or symptomatic left ventricular dysfunction should be started on an ACE inhibitor. Beginning therapy with low doses (eg, 2.5 mg of enalapril (Vasotec) BID or 6.25 mg of captopril (Capoten) TID) will reduce the likelihood of hypotension and azotemia. The dose is then gradually increased to a maintenance dose of 10 mg BID of enalapril, 50 mg TID of captopril, or up to 40 mg/day of lisinopril or quinapril. 2. Angiotensin II receptor blockers for the treatment of HF appear to be as effective as, or possibly slightly less effective than, ACE inhibitors. The addition of an ARB, if tolerated, to HF therapy in patients who are stable on ACE inhibitors and beta- blockers is recommended. ARB therapy should not be added to an ACE inhibitor in the immediate post- MI setting. 3. Beta-blockers carvedilol, metoprolol, and bisoprolol improve overall and event-free survival in patients with New York Heart Association (NYHA) class II to III HF and probably in class IV HF. Beta-blockers with intrinsic sympathomimetic activity (such as pindolol and acebutolol) should be avoided a. Carvedilol, metoprolol, or bisoprolol is recom- mended for all patients with symptomatic HF, unless contraindicated. b. Relative contraindications in HF include: (1) Heart rate <60 bpm. (2) Systolic arterial pressure <100 mm Hg. (3) Signs of peripheral hypoperfusion. (4) PR interval >0.24 sec. (5) Second- or third-degree atrioventricular block. (6) Severe chronic obstructive pulmonary dis- ease. (7) History of asthma. (8) Severe peripheral vascular disease. c. Prior to initiation of therapy, the patient should be stable on an ACE inhibitor and (if necessary for symptom control) digoxin and diuretics, should have no or minimal evidence of fluid retention, and should not have required recent intravenous inotropic therapy. d. Therapy should be begun at very low doses and the dose doubled at regular intervals every two to three weeks until the target dose is reached or symptoms become limiting. Initial and target doses are: (1) Carvedilol (Coreg), 3.125 mg BID and 25 to 50 mg BID (the higher dose being used in sub- jects over 85 kg). (2) Metoprolol (Toprol), 6.25 mg BID and 50 to 75 mg BID, and for extended-release metoprolol, 12.5 or 25 mg daily and 200 mg/day. (3) Bisoprolol (Ziac), 1.25 mg QD and 5 to 10 mg QD. (4) The patient should weigh himself daily and call the physician if there has been a 1 to 1.5 kg weight gain. Weight gain may be treated with diuretics, but resistant edema or more severe decompensation may require dose reduction or cessation of the beta-blocker. 4. Digoxin is given to patients with HF and systolic dysfunction to control symptoms (fatigue, dyspnea, and exercise intolerance) and, in atrial fibrillation, to control the ventricular rate. Digoxin should be started in left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] <40 percent) who continue to have symptoms despite appropriate therapy includ- ing an ACE inhibitor, beta-blocker, and, if necessary for fluid control, a diuretic. The usual daily dose is 0.125 to 0.25 mg, based upon renal function. The serum digoxin concentration should be maintained between 0.5 and 0.8 ng/mL. 5. Diuretics. Sodium and water retention lead to pulmonary and peripheral edema. a. A loop diuretic should be given to control pulmo- nary and/or peripheral edema. The most com- monly used loop diuretic is furosemide (Lasix), but some patients respond better to bumetanide (Bumex) or torsemide (Demadex) because of superior and more predictable absorption. b. The usual starting dose in outpatients with HF is 20 to 40 mg of furosemide. In patients who are volume overloaded, a reasonable goal is weight reduction of 0.5 to 1.0 kg/day. If a patient does not respond, the diuretic dose should initially be increased. c. In patients with HF and a normal glomerular filtration rate, the maximum doses are 40 to 80 mg of furosemide, 2 to 3 mg of bumetanide, or 20 to 50 mg of torsemide. In patients with renal insuffi- ciency, a higher maximum dose of 160 to 200 mg of furosemide or its equivalent can be given. d. Intravenous diuretics (either as a bolus or a continuous infusion) are more potent than their equivalent oral doses and may be required for unstable or severe disease. Thiazide diuretics can be added for a synergistic effect. e. A continuous infusion of a loop diuretic may improve diuresis and reduce toxicity when com- pared to intermittent bolus injections. Urine output is significantly greater. 6. Aldosterone antagonists. Spironolactone and eplerenone, which compete with aldosterone for the mineralocorticoid receptor, prolong survival in se- lected patients with HF. Eplerenone has greater specificity for the mineralocorticoid receptor and a lower incidence of endocrine side effects. a. Therapy should be initiated with spironolactone, and switch to eplerenone (25 to 50 mg/day) if endocrine side effects occur. The serum potas- sium should be monitored. C. Drugs that are contraindicated in HF 1. Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause a worsening of pre-existing HF because of systemic vasoconstriction. NSAID may blunt the renal effects of diuretics and may reverse the effect of angiotensin converting enzyme (ACE) inhibitors. 2. Thiazolidinediones are oral hypoglycemic agents that increase insulin sensitivity. Drugs in this class cause fluid retention, which may precipitate HF. Patients with HF who are currently taking thiazolidinediones should be carefully followed for signs and symptoms of HF, and the agent should be stopped if signs of fluid retention develop. Thiazolidinediones should not be used in patients with New York Heart Association class III or IV HF. 3. Metformin (Glucophage). Patients with HF who take metformin are at increased risk of potentially lethal lactic acidosis. Metformin is contraindicated in patients with HF. 4. Cilostazol suppresses platelet aggregation and is a direct arterial vasodilator. In patients with HF, oral phosphodiesterase inhibitors has been associated with increased mortality. HF of any severity is a contraindication to the use of cilostazol. 5. Sildenafil (Viagra) is a phosphodiesterase inhibitor that is used in the treatment of impotence. The drug is a vasodilator that can lower systemic blood pres- sure. Sildenafil may be potentially hazardous in HF. 6. Antiarrhythmic agents. Most antiarrhythmic drugs have some negative inotropic activity and can precip- itate HF. The further reduction in LV function can also impair the elimination of these drugs, resulting in drug toxicity. In addition, some antiarrhythmic drugs have a proarrhythmic effect. Amiodarone is safe and is the preferred drug to treat ventricular arrhythmias in HF D. Lifestyle modification 1. Cessation of smoking. 2. Restriction of alcohol consumption. 3. Salt restriction to 2 to 3 g of sodium per day to minimize fluid accumulation. 4. Water restriction in patients who are hyponatremic may minimize pulmonary congestion. 5. Daily weight monitoring to detect fluid accumulation before it becomes symptomatic. 6. Weight reduction in obese subjects with a goal of being within 10 percent of ideal body weight. 7. A cardiac rehabilitation program for stable patients. IX. Management of refractory HF A. Intravenous inotropes and vasodilators. Patients with decompensated HF are often hospitalized and an intravenous infusion of a positive inotropic agent and/or a vasodilator is initiated. Inotropic drugs, such as dobutamine, dopamine, milrinone, and amrinone, and vasodilators, such as nitroprusside, nitroglycerin, and nesiritide, can acutely improve hemodynamics and relieve symptoms. B. Symptomatic improvement has been demonstrated in patients after treatment with a continuous infusion of dobutamine (5 to 7.5 µg/kg per min) for three to five days. The benefit can last for 30 days or more. There is no evidence for a survival benefit, and intermittent, dobutamine may increase mortality. Use of intravenous dobutamine or milrinone is limited to the in-patient management of severe decompensated heart failure. Treatment of Acute Heart Failure/Pulmonary Edema • Oxygen therapy, 2 L/min by nasal canula • Furosemide (Lasix) 20-80 mg IV • Nitroglycerine start at 10-20 mcg/min and titrate to BP (use with caution if inferior/right ventricular infarction suspected) • Sublingual nitroglycerin 0.4 mg • Morphine sulfate 2-4 mg IV. Avoid if inferior wall MI sus- pected or if hypotensive or presence of tenuous airway • Potassium supplementation prn References, see page 360. Atrial Fibrillation Atrial fibrillation (AF) is more prevalent in men and with increasing age. AF can have adverse consequences related to a reduction in cardiac output and to atrial thrombus formation that can lead to systemic embolization. I. Classification A. Atrial fibrillation occurs in the normal heart and in the presence of organic heart disease. Classification of Atrial fibrillation: 1. Paroxysmal (ie, self-terminating) AF in which the episodes of AF generally last less than seven days (usually less than 24 hours) and may be recurrent. 2. Persistent AF fails to self-terminate and lasts for longer than seven days. Persistent AF may also be paroxysmal if it recurs after reversion. AF is consid- ered recurrent when the patient experiences two or more episodes. 3. Permanent AF is considered to be present if the arrhythmia lasts for more than one year and cardio- version either has not been attempted or has failed. 4. “Lone” AF describes paroxysmal, persistent, or permanent AF in individuals without structural heart disease. B. If the AF is secondary to cardiac surgery, pericarditis, myocardial infarction (MI), hyperthyroidism, pulmonary embolism, pulmonary disease, or other reversible causes, therapy is directed toward the underlying disease as well as the AF. II.Clinical evaluation A. History and physical examination. Associated symp- toms with AF should be sought; the clinical type or “pattern” should be defined; the onset or date of discov- ery of the AF; the frequency and duration of AF epi- sodes; any precipitating causes and modes of termina- tion of AF; the response to drug therapy; and the presence of heart disease or potentially reversible causes (eg, hyperthyroidism). B. The frequency and duration of AF episodes are deter- mined from the history. Symptoms include palpitations, weakness, dizziness, and dyspnea. However, among patients with paroxysmal AF, up to 90% of episodes are not recognized by the patient. C. Electrocardiogram is used to verify the presence of AF; identify left ventricular hypertrophy, pre-excitation, bundle branch block, or prior MI; define P-wave duration and morphology as well as other atrial arrhythmias on earlier ECGs. D. Chest x-ray may be useful in assessing the lungs, vasculature, and cardiac outline. E. Echocardiogram. The transthoracic echocardiography is required to evaluate the size of the right and left atria and the size and function of the right and left ventricles; to detect possible valvular heart disease, left ventricular hypertrophy, and pericardial disease; and to assess peak right ventricular pressure. It may also identify a left atrial thrombus, although the sensitivity is low. Transesophageal echocardiography is much more sensitive for atrial thrombi and can be used to deter- mine the need for three to four weeks of anticoagulation prior to cardioversion. F. Assessment for hyperthyroidism. A low-serum thyroid-stimulating hormone (TSH) value is found in 5.4% of patients with AF; only 1% have clinical hyperthyroidism. Measurement of serum TSH and free T4 is indicated in all patients with a first episode of AF, when the ventricular response to AF is difficult to control, or when AF recurs unexpectedly after cardiover- sion. Patients with low values (<0.5 mU/L) and normal serum free T4 probably have subclinical hyperthyroidism. G. Additional testing 1. Exercise testing is often used to assess the ade- quacy of rate control in permanent AF, to reproduce exercise-induced AF, and to evaluate for ischemic heart disease. 2. Holter monitoring or event recorders are used to identify the arrhythmia if it is intermittent and not captured on routine electrocardiography. 3. Electrophysiologic studies may be required with wide QRS complex tachycardia or a possible predisposing arrhythmia, such as atrial flutter or a paroxysmal supraventricular tachycardia. III. General treatment issues Risk-based Approach to Antithrombotic Therapy in Atrial Fibrillation Patient features Antithrombotic therapy Age <60 years No heart disease (line AF) Aspirin (325 mg per day) or no therapy Age <60 years Hear disease by no risk factors* Aspirin (325 mg per day) Age >60 years No risk factors* Aspirin (325 mg per day) Age >60 years With diabetes mellitus or CAD Oral anticoagulation (INR 2 to 3) Addition of aspirin, 81 to 162 mg/day is optional Age >75 years, espe- cially women Oral anticoagulation (INR . 2.0) Heart failure (HF) LVEF <0.35 Thyrotoxicosis Hypertension Oral anticoagulation (INR 2 to 3) Rheumatic heart disease (mitral stenosis) Prosthetic heart valves Prior thromboembolism Persistent atrial throm- bus on TEE Oral anticoagulation (INR 2.5 to 3.5 or higher may be apropriate) *Risk factors for thromboembolism include heart fail- ure, left ventricular ejection fraction (LVEF) less than 0.35, and hypertension. A. Rate control with chronic anticoagulation is recom- mended for the majority of patients with AF. B. Beta-blockers (eg, atenolol or metoprolol), diltiazem, and verapamil are recommended for rate control at both rest and exercise; digoxin is not effective during exer- cise and should be used in patients with heart failure or as a second-line agent. C. Anticoagulation should be achieved with adjusted-dose warfarin unless the patient is considered at low embolic risk or has a contraindication. Aspirin may be used in such patients. D. When rhythm control is chosen, both DC and pharma- cologic cardioversion are appropriate options. To prevent dislodgment of pre-existing thrombi, warfarin therapy should be given for three to four weeks prior to c ar di over s i on unl e s s t r ans es ophageal echocardiography demonstrates no left atrial thrombi. Anticoagulation is continued for at least one month after cardioversion to prevent de novo thrombus formation. E. After cardioversion, antiarrhythmic drugs to maintain sinus rhythm are not recommended, since the risks outweigh the benefits, except for patients with persistent symptoms during rate control that interfere with the patient’s quality of life. Recommended drugs are amiodarone, disopyramide, propafenone, and sotalol. IV. Rhythm control A. Reversion to NSR. Patients with AF of more than 48 hours duration or unknown duration may have atrial thrombi that can embolize. In such patients, cardiover- sion should be delayed until the patient has been anticoagulated at appropriate levels for three to four weeks or transesophageal echocardiography has excluded atrial thrombi. 1. DC cardioversion is indicated in patients who are hemodynamically unstable. In stable patients in whom spontaneous reversion due to correction of an underlying disease is not likely, either DC or pharma- cologic cardioversion can be performed. Electrical cardioversion is usually preferred because of greater efficacy and a low risk of proarrhythmia. The overall success rate of electrical cardioversion for AF is 75 to 93 percent and is related inversely both to the duration of AF and to left atrial size. 2. A number of antiarrhythmic drugs are more effective than placebo, converting 30 to 60 percent of patients. Evidence of efficacy is best established for dofetilide, flecainide, ibutilide, propafenone, amiodarone, and quinidine. 3. Rate control with an atrioventricular (AV) nodal blocker (beta-blocker, diltiazem, or verapamil), or (if the patient has heart failure or hypotension) digoxin should be attained before instituting a class IA drug. B. Maintenance of NSR. Only 20 to 30 percent of patients who are successfully cardioverted maintain NSR for more than one year without chronic antiarrhythmic therapy. This is more likely to occur in patients with AF for less than one year, no enlargement of the left atrium (ie, <4.0 cm), and a reversible cause of AF such as hyperthyroidism, pericarditis, pulmonary embolism, or cardiac surgery. 1. Prophylactic antiarrhythmic drug therapy is indicated only in patients who have a moderate-to-high risk for recurrence because the risks generally outweigh the benefits of maintenance antiarrhythmic drug therapy except in patients with persistent symptoms on a rate control regimen. 2. Evidence of efficacy is best for amiodarone, propafenone, disopyramide, sotalol, flecainide, and quinidine. Flecainide may be preferred in patients with no or minimal heart disease, while amiodarone is preferred in patients with a reduced left ventricular (LV) ejection fraction or heart failure and sotalol in patients with coronary heart disease. Concurrent administration of an AV nodal blocker is indicated in patients who have demonstrated a moderate-to-rapid ventricular response to AF. 3. Amiodarone is significantly more effective for mainte- nance of sinus rhythm than other antiarrhythmic drugs. Amiodarone should be used as first-line therapy in patients without heart failure. V. Rate control in chronic AF. Rapid ventricular rate in patients with AF should be prevented because of hemodynamic instability and/or symptoms. A. Rate control in AF is usually achieved by slowing AV nodal conduction with a beta-blocker, diltiazem, verapamil, or, in patients with heart failure or hypotension, digoxin. Amiodarone is also effective in patients who are not cardioverted to NSR. B. Heart rate control include: 1. Rest heart rate <80 beats/min. 2. 24-hour Holter average <100 beats/min and no heart rate >110% of the age-predicted maximum. 3. Heart rate <110 beats/min in six minute walk. C. Nonpharmacologic approaches. The medical ap- proaches to either rate or rhythm control described above are not always effective. 1. Rhythm control. Alternative methods to maintain NSR in patients who are refractory to conventional therapy include surgery, radiofrequency catheter ablation, and pacemakers. 2. Rate control. Radio-frequency AV nodal-His bundle ablation with permanent pacemaker placement or AV nodal conduction modification are nonpharmacologic therapies for achieving rate control in patients who do not respond to pharmacologic therapy. Intravenous Agents for Heart Rate Control in Atrial Fibrillation Drug Loading Dose On- set Mainte- nance Dose Major Side Effects Diltiaz em 0.25 mg/kg IV over 2 min 2–7 min 5–15 mg per hour infusion Hypotension, heart block, HF Esmol ol 0.5 mg/kg over 1 min 1 min 0.05–0.2 mg/kg/mi n Hypotension, heart block, bradycardia, asthma, HF Metopr olol 2.5–5 mg IV bolus over 2 min up to 3 doses 5 min 5 mg IV q6h Hypotension, heart block, bradycardia, asthma, HF Verap amil 0.075–0. 15 mg/kg IV over 2 min 3–5 min 5-10 mg IV q6h Hypotension, heart block, HF Digoxi n 0.25 mg IV q2h, up to 1.5 mg 2 h 0.125–0. 25 mg daily Digitalis toxic- ity, heart block, bradycardia Oral Agents for Heart Rate Control Drug Loading Dose Usual Mainte- nance Dose Major Side Ef- fects Digoxin 0.25 mg PO q2h ; up to 1.5 mg 0.125–0.3 75 mg daily Digitalis toxicity, heart block, brady- cardia Diltiaze m Ex- tended Re- lease NA 120–360 mg daily Hypotension, heart block, HF Metopr olol NA 25–100 mg BID Hypotension, heart block, bradycardia, asthma, HF Propran olol Ex- tended Re- lease NA 80–240 mg daily Hypotension, heart block, bradycardia, asthma, HF Verapa mil Ex- tended Re- lease NA 120–360 mg daily Hypotension, heart block, HF, digoxin interaction Amioda rone 800 mg daily for 1 wk 600 mg daily for 1 wk 400 mg daily for 4–6 wk 200 mg daily Pulmonary toxicity, skin discoloration, hypo or hyper- thyroidism, corneal deposits, optic neuropathy, warfa- rin interaction, proarrhythmia (QT prolongation) VI. Prevention of systemic embolization A. Anticoagulation during restoration of NSR 1. AF for more than 48 hours or unknown duration. Outpatients without a contraindication to warfarin who have been in AF for more than 48 hours should receive three to four weeks of warfarin prior to and after cardioversion. This approach is also recom- mended for patients with AF who have valvular disease, evidence of left ventricular dysfunction, recent thromboembolism, or when AF is of unknown duration, as in an asymptomatic patient. a. The recommended target INR is 2.5 (range 2.0 to 3.0). The INR should be >2.0 in the weeks before cardioversion. b. An alternative approach that eliminates the need for prolonged anticoagulation prior to cardiover- si on i s the use of transesophageal echocardiography-guided cardioversion. c. Thus, the long-term recommendations for patients who have been cardioverted to NSR but are at high risk for thromboembolism are similar to those in patients with chronic AF, even though the patients are in sinus rhythm. 2. AF for less than 48 hours. A different approach with respect to anticoagulation can be used in low-risk patients (no mitral valve disease, severe left ventricu- l ar dysf unct i on, or hi st ory of recent thromboembolism) in whom there is reasonable certainty that AF has been present for less than 48 hours. Such patients have a low risk of clinical thromboembolism if converted early (0.8%), even without screening TEE. 3. Long-term anticoagulation prior to cardioversion is not recommended in such patients, but heparin use is recommended at presentation and during the pericardioversion period. Antithrombotic Therapy in Cardioversion for Atrial Fibrillation Timing of cardioversion Anticoagulation Early cardioversion in pa- tients with atrial fibrillation for less than 48 hours Heparin during cardioversion period to achieve PTT of 50- 70 seconds. Heparin 70 U/kg load, 15 U/kg/hr drip. Early cardioversion in pa- tients with atrial fibrillation for more than 48 hours or an unknown duration, but with documented absence of atrial thrombi Heparin during cardioversion period to achieve PTT of 50- 70 seconds. Warfarin (Coumadin) for 4 weeks after cardioversion to achieve target INR of 2.0 to 3.0. Elective cardioversion in pa- tients with atrial fibrillation for more than 48 hours or an unknown duration Warfarin for 3 weeks before and 4 weeks after cardiover- sion to achieve target INR of of 2.0 to 3.0. Weight-based nomogram for intravenous heparin infusion Initial dose 80 U/kg bolus, then 18 U/kg per hour aPTT* <35 sec (<1.2 x control) 80 U/kg bolus, then increase infu- sion rate by 4 U/kg per hour aPTT 40 U/kg per hour, then increase infusion by 2 U/kg per hour aPTT No change aPTT Decrease infusion rate by 2q U/kg per hour aPTT Hold infusion 1 hour, then de- crease infusion rate by 3 U/kg per hour *aPTT = activated partial thromboplastin time 4. Current practice is to administer aspirin for a first episode of AF that converts spontaneously and warfarin for at least four weeks to all other patients. 5. Aspirin should not be considered in patients with AF of less than 48 hours duration if there is associated rheumatic mitral valve disease, severe left ventricular dysfunction, or recent thromboembolism. Such patients should be treated the same as patients with AF of longer duration: one month of oral anticoagulation with warfarin or shorter-term anticoagulation with screening TEE prior to elective electrical or pharmacologic cardioversion followed by prolonged warfarin therapy after cardioversion. B. Anticoagulation in chronic AF 1. The incidence of stroke associated with AF is 3 to 5 percent per year in the absence of anticoagulation; compared with the general population, AF signifi- cantly increases the risk of stroke (relative risk 2.4 in men and 3.0 in women). 2. The incidence of stroke is relatively low in patients with AF who are under age 65 and have no risk factors. The prevalence of stroke associated with AF increases strikingly with age and with other risk factors including diabetes, hypertension, previous stroke as clinical risk factors, and left ventricular dysfunction. The risk appears to be equivalent in chronic and paroxysmal AF. 3. Choice of antiembolism therapy. a. Patients with a CHADS2 score of 0 are at low risk of embolization (0.5% per year) and can be managed with aspirin. b. Patients with a CHADS2 score >3 are at high risk (5.3 to 6.9 percent per year) and should, in the absence of a contraindication, be treated with warfarin. c. Patients with a CHADS2 score of 1 or 2 are at intermediate risk of embolization (1.5 to 2.5 percent per year). In this group, the choice be- tween warfarin therapy and aspirin will depend upon many factors, including patient preference. 4. An INR between 2.0 and 3.0 is recommended for most patients with AF who receive warfarin therapy. A higher goal (INR between 2.5 and 3.5) is reason- able for patients at particularly high risk for embolization (eg, prior thromboembolism, rheumatic heart disease, prosthetic heart valves). An exception to the latter recommendation occurs in patients over the age of 75 who are at increased risk for major bleeding. A target INR of 1.8 to 2.5 is recommended for this age group. C. Anticoagulation in paroxysmal AF. The stroke risk appears to be equivalent in paroxysmal and chronic AF. The factors governing the choice between warfarin and aspirin therapy and the intensity of warfarin therapy are similar to patients with chronic AF. Among patients with very infrequent and short episodes of AF, any protective effect from anticoagulation may be more than offset by bleeding risk. VII. Presentation and management of recent onset AF A. Most patients with recent onset AF present with palpita- tions, a sense of the heart racing, fatigue, lightheadedness, increased urination, or mild shortness of breath. More severe symptoms and signs include dyspnea, angina, hypotension, presyncope, or infre- quently syncope. In addition, some patients present with an embolic event or the insidious onset of right-sided heart failure (peripheral edema, weight gain, and ascites). B. Indications for hospitalization 1. For the treatment of an associated medical problem, which is often the reason for the arrhythmia. 2. For elderly patients who are more safely treated for AF in hospital. 3. For patients with underlying heart disease who have hemodynamic consequences from the AF or who are at risk for a complication resulting from therapy of the arrhythmia. C. Search for an underlying cause, such as heart failure (HF), pulmonary problems, hypertension, or hyperthyroidism, and for the urgency for heart rate slowing. D. Serum should be obtained for measurement of thyroid stimulating hormone (TSH) and free T4. This should be done even if there are no symptoms suggestive of hyperthyroidism, since the risk of AF is increased up to threefold in patients with subclinical hyperthyroidism. The latter disorder is characterized by low serum TSH (<0.5 mU/L) and normal serum free T4. E. If AF appears to have been precipitated by a reversible medical problem, cardioversion should be postponed until the condition has been successfully treated, which will often lead to spontaneous reversion. If this treat- ment is to be initiated as an outpatient, anticoagulation with warfarin should be begun with cardioversion performed, if necessary, after three to four weeks of adequate anticoagulation. If the patient is to be admit- ted to the hospital for treatment of the underlying disease, it is prudent to begin heparin therapy and then institute oral warfarin. Cardioversion is again performed after three to four weeks of adequate anticoagulation if the patient does not revert to NSR. In either case, three to four weeks of adequate anticoagulation are not necessary if TEE is performed and shows no left atrial thrombus. F. Indications for urgent cardioversion 1. Active ischemia. 2. Significant hypotension, to which poor LV systolic function, diastolic dysfunction, or associated mitral or aortic valve disease may contribute. 3. Severe manifestations of HF. 4. The presence of a pre-excitation syndrome, which may lead to an extremely rapid ventricular rate. 5. In a patient who has truly urgent indications for cardioversion, the need for restoration of NSR takes precedence over the need for protection from thromboembolic risk. If feasible, the patient should still be heparinized for the cardioversion procedure. G. Initial rate control with mild-to-moderate symptoms. Most patients with acute AF do not require immediate reversion. Initial treatment directed at slowing the ventricular rate will usually result in improvement of the associated symptoms. This can be achieved with beta- blockers, calcium channel blockers (verapamil and diltiazem), or digoxin. The drug selected and the route of administration (oral versus intravenous) are dictated by the clinical presentation. 1. Digoxin is the preferred drug only in patients with AF due to HF. Digoxin can also be used in patients who cannot take or who respond inadequately to beta- blockers or calcium channel blockers. The effect of digoxin is additive to both of these drugs. 2. A beta-blocker, diltiazem, or verapamil is the pre- ferred drug in the absence of HF. Beta-blockers are particularly useful when the ventricular response increases to inappropriately high rates during exer- cise, after an acute MI, and when exercise-induced angina pectoris is also present. A calcium channel blocker is preferred in patients with chronic lung disease. The use of both a beta-blocker and calcium channel blocker should be avoided. H. Elective cardioversion. In some patients, antiarrhythmic drugs are administered prior to cardio- version to increase the chance of successful reversion and to prevent recurrence. Patients who are success- fully cardioverted generally require antiarrhythmic drugs to increase the likelihood of maintaining sinus rhythm. I. Immediate cardioversion. There is a low risk of systemic embolization if the duration of the arrhythmia is 48 hours or less and there are no associated cardiac abnormalities (mitral valve disease or LV enlargement). In such patients, electrical or pharmacologic cardiover- sion can be attempted after systemic heparinization. Aspirin should be administered for a first episode of AF that converts spontaneously and warfarin for at least four weeks to all other patients. J. Delayed cardioversion. It is preferable to anticoagulate with warfarin for three to four weeks before attempted cardioversion to allow any left atrial thrombi to resolve if: 1. The duration of AF is more than 48 hours or of unknown duration. 2. There is associated mitral valve disease or signifi- cant cardiomyopathy or HF. 3. The patient has a prior history of a thromboembolic event. 4. During this time, rate control should be maintained with an oral AV nodal blocker. The recommended target INR is 2.5 (range 2.0 to 3.0). The INR should be consistently >2.0 in the weeks before cardiover- sion. K. Role of TEE. TEE immediately prior to elective cardio- version should be considered for those patients at increased risk for left atrial thrombi (eg, rheumatic mitral valve disease, recent thromboembolism, severe LV systolic dysfunction). Among patients with AF of recent onset (but more than 48 hours) who are not being anticoagulated, an alternative approach to three to four weeks of warfarin therapy before cardioversion is TEE- based screening with cardioversion performed if no thrombi are seen. References, see page 360. Hypertension The prevalence of hypertension (systolic >140 and/or diastolic >90 mm Hg) is 32 percent in the non-Hispanic black population and 23 percent in the non-Hispanic white and Mexican-American populations. I. Definitions. The following definitions have been suggested by the seventh report of the Joint National Committee (JNC 7). Based upon the average of two or more readings at each of two or more visits after an initial screen, the following classification is used: Classification and Management of Blood Pressure for Adults Aged 18 Years or Older Initial drug therapy BP classifi- cation Sys- tolic BP Dia- stolic BP Life- style Modi- ficatio n Without compel- ling indi- cation With com- pelling indi- cations Normal <120 and <30 Encou rage Prehype rtension 120- 139 or 80-89 Yes No antihy- per- tensive drug indi- cated Drug(s) for the compel- ling indica- tions Stage 1 hyper- tension 140- 159 or 90-99 Yes Thiazide- type di- uretics for most, may con- sider ACE in- hibitor, ARB, beta blocker, CCB, or combina- tion Drug(s) for the compel- ling indica- tions Other antihyper- tensive drugs (di- uretics, ACE inhibitor, ARB, beta blocker, CCB) as needed Stage 2 hyper- tension >160 or >100 Yes 2-drug combina- tion for most (usually thiazide- type di- uretic and ACE inhibitor or ARB or beta blocker, CCB) Drug(s) for the compel- ling indica- tions Other antihyper- tensive drugs (di- uretics, ACE inhibitor, ARB, beta blocker, CCB) as needed A. The prehypertension category recognizes that the correlation between the risk of adverse outcomes (including stroke and death) and blood pressure level is a continuous variable in which there is an increased incidence of poor outcomes as the blood pressure rises, even within the previously delineated "normal" range. II. Etiology/risk factors A. Essential hypertension has been associated with a number of risk factors: 1. Hypertension is about twice as common in subjects who have one or two hypertensive parents. 2. Increased salt intake is a necessary but not a sufficient cause for hypertension. 3. There is a clear association between excess alcohol intake and hypertension. 4. Obesity and weight gain appears to be a main determinant of the rise in blood pressure (BP) that is commonly seen with aging. 5. Hypertension tends to be both more common and more severe in blacks. 6. Hypertension may be more common among those with hostile attitudes and time urgency/impatience. B. Secondary hypertension. A number of disorders may be associated with secondary hypertension. 1. Primary renal disease. Hypertension is a frequent finding in renal disease, particularly with glomerular or vascular disorders. 2. Oral contraceptives. Oral contraceptives often raise the blood pressure within the normal range but can induce overt hypertension. 3. Pheochromocytoma. About one-half of patients with pheochromocytoma have paroxysmal hyperten- sion, most of the rest have what appears to be essential hypertension. 4. Primary hyperaldosteronism. The presence of primary mineralocorticoid excess, primarily aldosterone, should be suspected in any patient with the triad of hypertension, unexplained hypokalemia and metabolic alkalosis. Some pa- tients have a normal plasma potassium concentra- tion. 5. Cushing's syndrome. Moderate diastolic hyperten- sion is a major cause of morbidity and death in patients with Cushing's syndrome. 6. Other endocrine disorders. Hypertension may be induced by hypothyroidism, hyperthyroidism, and hyperparathyroidism. 7. Sleep apnea syndrome. Disordered breathing during sleep is an independent risk factor for awake systemic hypertension. 8. Coarctation of the aorta is one of the major causes of hypertension in young children. III. Complications of hypertension A. Hypertension is the major risk factor for premature cardiovascular disease, being more common than cigarette smoking, dyslipidemia, and diabetes, the other major risk factors. B. Hypertension increases the risk of heart failure. C. Left ventricular hypertrophy is a common problem in patients with hypertension, and is associated with an enhanced incidence of heart failure, ventricular arrhythmias, death following myocardial infarction, and sudden cardiac death. D. Hypertension is the most common and most important risk factor for stroke. E. Hypertension is the most important risk factor for intracerebral hemorrhage. F. Hypertension is a risk factor for chronic renal insuffi- ciency. G. Marked elevations in blood pressure can cause an acute, life-threatening emergency. IV. Diagnosis A. Blood pressure should be measured at each office visit for patients over the age of 21. B. In the absence of end-organ damage, the diagnosis of mild hypertension should not be made until the blood pressure has been measured on at least three to six visits, spaced over a period of weeks to months. C. White-coat hypertension and ambulatory monitor- ing. Approximately 20 to 25 percent of patients with mild office hypertension (diastolic pressure 90 to 104 mm Hg) have "white-coat" or isolated office hyperten- sion in that their blood pressure is repeatedly normal when measured at home, at work, or by ambulatory blood pressure monitoring. Ambulatory monitoring can be used to confirm the presence of white-coat hyper- tension. V. Evaluation A. History. The history should search for the presence of precipitating or aggravating factors, the natural course of the blood pressure, the extent of target organ damage, and the presence of other risk factors for cardiovascular disease. B. Physical examination should evaluate for signs of end-organ damage (such as retinopathy) and for evidence of a cause of secondary hypertension. C. Laboratory testing 1. Hematocrit, urinalysis, and routine blood chemis- tries (glucose, creatinine, electrolytes). 2. Fasting (9 to 12 hours) lipid profile (total and HDL- cholesterol, triglycerides). 3. Electrocardiogram. History in the Patient with Hypertension Duration of hypertension Last known normal blood pressure Course of the blood pres- sure Prior treatment of hyper- tension Drugs: doses, side effects Intake of agents that may cause hypertension Estrogens, sympathomimetics, adre- nal steroids, excessive sodium Family history Hypertension Premature cardiovascular disease or death Familial diseases: pheochromocytoma, renal disease, diabetes, gout Symptoms of secondary cause Muscle weakness Spells of tachycardia, sweating, tremor Thinning of the skin Flank pain Symptoms of target organ damage Headaches Transient weakness or blindness Loss of visual acuity Chest pain Dyspnea Claudication Other risk factors Smoking Diabetes Dyslipidemias Physical inactivity Dietary history Sodium Alcohol Saturated fats Physical Examination in the Patient with Hyperten- sion Accurate measurement of blood pressure General appearance: distribution of body fat, skin lesions, muscle strength, alertness Funduscope Neck: palpation and auscultation of carotids, thyroid Heart: size, rhythm, sounds Lungs: rhonchi, rales Abdomen: renal masses, bruits over aorta or renal arteries, femoral pulses Extremities: peripheral pulses, edema Neurologic assessment D. Testing for renovascular hypertension. Renovascular hypertension is the most common correctable cause of secondary hypertension. It occurs in less than one percent of patients with mild hyperten- sion. In comparison, between 10 and 45 percent of white patients with severe or malignant hypertension have renal artery stenosis. 1. Signs suggesting renovascular hypertension or other cause of secondary hypertension: a. Severe or refractory hypertension, including retinal hemorrhages or papilledema; bilateral renovascular disease may be present in patients who also have a plasma creatinine above 1.5 mg/dL (132 µmol/L). b. An acute rise in blood pressure over a previously stable baseline. c. Age of onset before puberty or above 50. d. An acute elevation in the plasma creatinine concentration that is either unexplained or occurs after the institution of an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker (in the absence of an excessive reduc- tion in blood pressure). e. Moderate-to-severe hypertension in a patient with diffuse atherosclerosis or an incidentally discovered asymmetry in renal disease. A unilat- eral small kidney (<9 cm) has a 75 percent correlation with the presence of large vessel occlusive disease. f. A systolic-diastolic abdominal bruit that lateralizes to one side. g. Negative family history for hypertension. h. Moderate-to-severe hypertension in patients with recurrent episodes of acute (flash) pulmonary edema or otherwise unexplained congestive heart failure. 2. Spiral CT scanning or 3D time-of-flight MR angiography are minimally invasive diagnostic methods. Duplex Doppler ultrasonography may be useful both for diagnosis and for predicting the outcome of therapy. E. Testing for other causes of secondary hyperten- sion 1. The presence of primary renal disease is suggested by an elevated plasma creatinine concentration and/or an abnormal urinalysis. 2. Pheochromocytoma should be suspected if there are paroxysmal elevations in blood pressure, partic- ularly if associated with the triad of headache (usually pounding), palpitations, and sweating. 3. Measurement of plasma renin activity is usually performed only in patients with possible low-renin forms of hypertension, such as primary hyperaldosteronism. Otherwise unexplained hypokalemia is the primary clinical clue to the latter disorder in which the plasma aldosterone to plasma renin activity ratio is a screening test. 4. Cushing's syndrome (including that due to corticosteroid administration) is usually suggested by cushingoid facies, central obesity, ecchymoses, and muscle weakness. 5. The sleep apnea syndrome should be suspected in obese individuals who snore loudly while asleep, awake with headache, and fall asleep inappropri- ately during the day. 6. Coarctation of the aorta is characterized by de- creased or lagging peripheral pulses and a vascular bruit over the back. 7. Hypertension may be induced by both hypothyroidism and primary hyperparathyroidism, suspected because of hypercalcemia. Evaluation of Secondary Hypertension Renovascular Hypertension Captopril test: Plasma renin level before and 1 hr after captopril 25 mg. A greater than 150% increase in renin is positive Captopril renography: Renal scan before and after 25 mg MRI angiography Arteriography (DSA) Hyperaldostero nism Serum potassium Serum aldosterone and plasma renin activ- ity CT scan of adrenals Pheochromocyt oma 24 hr urine catecholamines CT scan Nuclear MIBG scan Cushing's Syn- drome Plasma cortisol Dexamethasone suppression test Hyperparathyroi dism Serum calcium Serum parathyroid hormone VI. Treatment of essential hypertension A. Benefits of blood pressure control. Antihypertensive therapy is associated with 35 to 40 percent reduction in stroke incidence; 20 to 25 percent in myocardial infarction; and more than 50 percent in heart failure. Optimal control to below 130/80 mm Hg could prevent 37 and 56 percent of coronary heart disease events. B. All patients should undergo lifestyle modification. In the absence of end-organ damage, a patient should not be labeled as having hypertension unless the blood pressure is persistently elevated after three to six visits over a several-month period. Lifestyle Modifications in the Management of Hy- pertension Modification Recommenda- tion Approximate systolic BP reduction, range * Weight reduction Maintain normal body weight (BMI), 18.5 to 24.9 kg/m 2 5 to 20 mm Hg per 10-kg weight loss Adopt DASH eat- ing plan Consume a diet rich in fruits, veg- etables, and low- fat dairy products, with a reduced content of satu- rated and total fat 8 to 14 mm Hg Dietary sodium reduction Reduce dietary sodium intake to no more than 100 meq/day (2.4 so- dium or 6 g so- dium chloride) 2 to 8 mm Hg Modification Recommenda- tion Approximate systolic BP reduction, range * Physical activity Regular aerobic physical activity, such as brisk walking (at least 30 minutes per day, most days of the week) 4 to 9 mm Hg Moderate con- sumption of alco- hol consumption Limit consump- tion to no more than 2 drinks per day in most men and no more than 1 drink per day in women 2 to 4 mm Hg C. Antihypertensive medications should be begun if the systolic pressure is persistently >140 mm Hg and/or the diastolic pressure is persistently >90 mm Hg in the office and at home despite attempted nonpharmacologic therapy. Starting with two drugs may be considered in patients with a baseline blood pressure more than 20/10 mm Hg above goal. D. In patients with diabetes or chronic renal failure, antihypertensive therapy is indicated when the systolic pressure is persistently above 130 mm Hg and/or the diastolic pressure is above 80 mm Hg. E. Patients with office hypertension, normal values at home, and no evidence of end-organ damage should undergo ambulatory blood pressure monitoring. F. Lifestyle modifications. 1. Treatment of hypertension generally begins with nonpharmacologic therapy, including dietary sodium restriction, weight reduction in the obese, avoidance of excess alcohol, and regular aerobic exercise. 2. A low-sodium diet will usually lower high blood pressure and may prevent the onset of hyperten- sion. The overall impact of moderate sodium reduction is a fall in blood pressure of 4.8/2.5 mm Hg. Dietary intake should be reduced to 100 meq/day (2.3 g of sodium or 6 g of salt). 3. Weight loss in obese individuals can lead to a significant fall in blood pressure. 4. Patients who have more than two drinks per day have a one-half to twofold increase in the inci- dence of hypertension compared to nondrinkers. 5. Aerobic exercise regimens have a beneficial effect on the systemic blood pressure. 6. Goal blood pressure a. The goal of antihypertensive therapy in patients with uncomplicated combined systolic and diastolic hypertension is a blood pressure of below 140/90 mm Hg. b. For individuals over age 65 with isolated sys- tolic hypertension (eg, a diastolic blood pres- sure below 90 mm Hg), caution is needed not to inadvertently lower the diastolic blood pres- sure to below 65 mm Hg to attain a goal sys- tolic pressure <140 mm Hg, since this level of diastolic pressure has been associated with an increased risk of stroke. c. A goal blood pressure of less than 130/80 mm Hg is recommended in patients with diabetes mellitus; and patients with slowly progressive chronic renal failure, particularly those excreting more than 1 g of protein per day. VII. Drug Therapy in Essential Hypertension A. Each of the antihypertensive agents is roughly equally effective, producing a good antihypertensive response in 30 to 50 percent of cases. B. A thiazide diuretic is recommended as initial drug therapy in most patients. African American patients generally responding better to monotherapy with a thiazide diuretic or calcium channel blocker and relatively poorly to an ACE inhibitor or beta-blocker. C. Initial therapy. The seventh Joint National Commit- tee (JNC 7) report recommends initiating therapy in uncomplicated hypertensives with a thiazide di- uretic. This recommendation applies to low doses of a thiazide diuretic (eg, 12.5 to 25 mg of hydrochloro- thiazide or chlorthalidone). This regimen is associ- ated with a low rate of metabolic complications, such as hypokalemia, glucose intolerance, and hyperuricemia. If low-dose thiazide monotherapy fails to attain goal blood pressure in uncomplicated hypertensives, an ACE inhibitor/ARB, beta-blocker, or calcium channel blocker can be sequentially added or substituted. Most often an ACE inhibi- tor/ARB, which acts synergistically with a diuretic is used. D. Indications for specific drugs. General recom- mendations for initial therapy should be amended in certain clinical settings in which specific agents offer particular benefit. Considerations for individualizing Antihypertensive Therapy Indication Antihypertensive drugs Compelling indications (major improvement in outcome independent of blood pressure) Systolic heart failure ACE inhibitor or ARB, beta blocker, diuretic, aldosterone an- tagonist Post-myocardial infarc- tion ACE inhibitor, beta blocker, aldosterone antagonist Proteinuric chronic renal failure ACE inhibitor and/or ARB High coronary disease risk Diuretic, perhaps ACE inhibitor Diabetes mellitus (no proteinuria) Diuretic, perhaps ACE inhibitor Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate con- trol Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud's syndrome Dihydropyridine calcium channel blocker Contraindications to Specific Antihypertensive Agents Indication Antihypertensive drugs Angioedema ACE inhibitor Bronchospastic disease Beta blocker Pregnancy ACE inhibitor, ARB (includes women likely to become preg- nant) Second or third degree heart block Beta blocker, nondihydropyridine calcium channel blocker May have adverse effect on comorbid conditions Depression Beta blocker, central alpha ago- nist Gout Diuretic Hyperkalemia Aldosterone antagonist, ACE in- hibitor, ARB Hyponatremia Thiazide diuretic Renovascular disease ACE inhibitor or ARB 1. Diuretics a. A low-dose thiazide diuretic provides better cardioprotection than an ACE inhibitor or a calcium channel blocker in patients with risk factors for coronary artery disease, including left ventricular hypertrophy, type 2 diabetes, previous myocardial infarction or stroke, current ci garette smoki ng habi ts, hyperlipidemia, or atherosclerotic cardiovas- cular disease. b. Diuretics should also be given for fluid control in patients with heart failure or nephrotic syndrome; these settings usually require loop diuretics. In addition, an aldosterone antago- nist is indicated in patients with advanced HF who have relatively preserved renal function and, in patients with less severe disease, for the treatment of hypokalemia. Thiazide Diuretics Drug Usual dose Hydrochlorothiazide (HCTZ, Hydrodiuril) 12.5-25 mg qd Chlorthalidone (Hygroton) 12.5-25 mg qd Chlorothiazide (Diuril) 125-500 mg qd Indapamide (Lozol) 1.25 mg qd Metolazone (Zaroxolyn) 1.25-5 mg qd 2. ACE inhibitors provide survival benefits in heart failure and myocardial infarction (particularly ST elevation) and renal benefits in proteinuric chronic renal failure. Thus, an ACE inhibitor should be used in heart failure, prior myocardial infarction, asymptomatic left ventricular dysfunc- tion, type 1 diabetics with nephropathy, and nondiabetic proteinuric chronic renal failure. The use of ACE inhibitors in these settings is inde- pendent of the need for BP control. Angiotensin-converting enzyme inhibitors Drug Usual doses Maximum dose Benazepril (Lotensin) 10-40 mg qd or divided bid 80 mg/d Captopril (Capoten) 50 mg bid-qid 450 mg/d Enalapril (Vasotec, Vasotec IV) 10-40 mg qd or divided bid 40 mg/d Fosinopril (Monopril) 20-40 mg qd or divided bid 80 mg/d Lisinopril (Prinivil, Zestril) 20-40 mg qd 40 mg/d Moexipril (Univasc) 15-30 mg qd 30 mg/d Quinapril (Accupril) 20-80 mg qd or divided bid 80 mg/d Ramipril (AItace) 5-20 mg qd or di- vided bid 20 mg/d Trandolapril (Mavik) 1-4 mg qd 8 mg/d Perindopril (Aceon) 4-8 mg qd-bid 8 mg/d 3. ARBs. The indications for and efficacy of ARBs are the same as those with ACE inhibitors. An ARB is particularly indicated in patients who do not tolerate ACE inhibitors (mostly because of cough). Angiotensin II Receptor Blockers Drug Usual dose Maximum dose Losartan (Cozaar) 50 mg qd 100 mg/d Candesartan (Atacand) 4-8 mg qd 16 mg/d Eprosartan (Teveten) 400-800 mg qd 800 mg/d Irbesartan (Avapro) 150-300 mg qd 300 mg/d Telmisartan (Micardis) 40-80 mg qd 80 mg/d Valsartan (Diovan) 80 mg qd 320 mg/d 4. Beta-blockers. A beta-blocker without intrinsic sympathomimetic activity should be given after an acute myocardial infarction and to stable patients with heart failure or asymptomatic left ventricular dysfunction (beginning with very low doses). The use of beta-blockers in these set- tings is in addition to the recommendations for ACE inhibitors in these disorders. Beta-blockers are also given for rate control in atrial fibrillation, for control of angina. Beta-blockers Drug Usual dose Maximum dose Acebutolol (Sectral) 200-800 mg/d (qd or bid) 1.2 g/d (bid) Atenolol (Tenormin) 50-100 mg qd 100 mg qd Betaxolol (Kerlone) 10 mg qd 20 mg qd Bisoprolol (Zebeta) 5 mg qd 20 mg qd Carteolol (Cartrol) 2.5 mg qd 10 mg qd Carvedilol (Coreg) 6.26-25 mg bid 100 mg/d Labetalol (Normodyne, Trandate) 100-600 mg bid 1200 mg/d Metoprolol (Toprol XL) 100-200 mg qd 400 mg qd Metoprolol (Lopressor) 100-200 mg/d (qd or bid) 450 mg/d (qd or bid) Nadolol (Corgard) 40 mg qd 320 mg/d Penbutolol(Levatol ) 20 mg qd NA Pindolol (Visken) 5 mg bid 60 mg/d Propranolol (Inderal, Inderal LA) 120-160 mg qd (LA 640 mg/d) Timolol (Blocadren) 10-20 mg bid 60 mg/d (bid) 5. Calcium channel blockers. There are no absolute indications for calcium channel blockers in hypertensive patients. Like beta- blockers, they can be given for rate control in patients with atrial fibrillation or for control of angina. Calcium channel blockers may be pre- ferred in obstructive airways disease. Calcium channel blockers Drug Dosage Diltiazem extended-release (Cardizem SR) 120-360 mg in 2 doses Diltiazem CD (Cardizem CD) 120-360 mg in 1 dose Diltiazem XR (Dilacor XR) 120-480 mg in 1 dose Verapamil (Calan) 120-480 mg in 2 or 3 doses Verapamil extended-release (Calan SR) 120-480 mg in 1 or 2 doses Verapamil HS (Covera-HS) 180-480 mg in 1 dose Dihydropyridines Amlodipine (Norvasc) 2.5-10 mg in 1 dose Felodipine (Plendil) 2.5-10 mg in 1 dose Isradipine (DynaCirc) 5-10 mg in 2 doses Isradipine extended-release (DynaCirc CR) 5-10 mg in 1 dose Nicardipine (Cardene) 60-120 mg in 3 doses Nicardipine extended-release (Cardene SR) 60-120 mg in 2 doses Nifedipine extended-release (Adalat CC, Procardia XL) 30-90 mg in 1 dose Nisoldipine (Sular) 10-60 mg in 1 dose E. Combination therapy 1. If two drugs are required, use of a low dose of a thiazide diuretic as one of the drugs increases the response rate to all other agents. By minimizing volume expansion, diuretics increase the antihypertensive effect of all other antihypertensive drugs. 2. The combination of a thiazide diuretic with a beta- blocker, an ACE inhibitor, or an ARB has a syner- gistic effect, controlling the BP in up to 85 percent of patients. An ACE inhibitor or ARB also minimizes diuretic-induced metabolic abnormalities (eg, hypokalemia, hyperuricemia and hyperlipidemia) and prevents the hypovolemia-induced increase in angiotensin II that normally limits the response to the diuretic. 3. Most drug combinations, using agents that act by different mechanisms, tend to have an additive effect. Examples include an ACE inhibitor with a diuretic or calcium channel blocker, and a beta- blocker with a vasodilator or a dihydropyridine calcium channel blocker. 4. Other combinations may not have an additive antihypertensive effect, such as the combination of an ACE inhibitor with a beta-blocker or a diuretic with a calcium channel blocker. 5. There are also combinations that have additive side effects. In particular, a beta-blocker should be used with caution in combination with verapamil and to a lesser degree diltiazem. These drugs can potentiate the cardiac depressant effect of the beta-blocker, possibly leading to bradycardia or heart block. 6. Fixed-dose combination. A wide variety of (low) dose combination preparations are available, including low doses of a diuretic with a beta-blocker, ACE inhibitor, or ARB. Combination preparations include: a. Sustained-release verapamil (180 mg) - trandolapril (2 mg). b. Atenolol (100 mg) - chlorthalidone (25 mg). c. Lisinopril (20 mg) - hydrochlorothiazide (12.5 mg). d. The three combinations were equally effective, normalizing the blood pressure or lowering the diastolic pressure by more than 10 mm Hg in 69 to 76 percent of patients. All are well tolerated. Combination Agents for Hypertension Drug Initial dose Comments Beta-Blocker/Diuretic Atenolol/chlorthalido ne (Tenoretic) 50 mg/25 mg, 1 tab qd Additive vasodilation Bisoprolol/HCTZ (Ziac) 2.5 mg/6.25 mg, 1 tab qd Metoprolol/HCTZ (Lopressor HCTZ) 100 mg/25 mg, 1 tab qd Nadolol/HCTZ (Corzide) 40 mg/5 mg, 1 tab qd Propranolol/HCTZ (Inderide LA) 80 mg/50 mg, 1 tab qd Timolol/HCTZ (Timolide) 10 mg/25 mg, 1 tab qd ACE inhibitor/Diuretic Benazepril/HCTZ (Lotensin HCT) 5 mg/6.25 mg, 1 tab qd ACE inhibitor conserves potas- sium and mag- nesium; combi- nation beneficial for CHF patients with HTN Captopril/HCTZ (Capozide) 25 mg/15 mg, 1 tab qd Enalapril/HCTZ (Vaseretic) 5 mg/12.5 mg, 1 tab qd Lisinopril/HCTZ (Zestoretic, Prinzide) 10 mg/12.5 mg, 1 tab qd Moexipril/HCTZ (Uniretic) 7.5 mg/12.5 mg, 1 tab qd ACE inhibitor/Calcium-channel blocker Benazepril/amlodipi ne (Lotrel) 2.5 mg/10 mg, 1 tab qd Enalapril/felodipine (Lexxel) 5 mg/5 mg, 1 tab qd Enalapril/diltiazem (Teczem) 5 mg/180 mg, 1 tab qd Trandolapril/verapa mil (Tarka) 2 mg/180 mg, 1 tab qd Angiotensin II receptor blocker/Diuretic Losartan/HCTZ (Hyzaar) 50 mg/12.5 mg, 1 tab qd Valsartan/HCTZ (Diovan HCT) 80 mg/12.5 mg, 1 tab qd Drug Initial dose Comments Alpha-1-Blocker/Diuretic Prazosin/polythiazid e (Minizide) 1 mg/0.5 mg, 1 cap bid Synergistic vasodilation K + -sparing diuretic/Thiazide Amiloride/HCTZ (Moduretic) 5 mg/50 mg, 1 tab qd Electrolyte-spar- ing effect Triamterene/HCTZ (Dyazide, Maxzide) 37.5 mg/25 mg, 1/2 tab qd References, see page 360. Hypertensive Crisis Severe hypertension is defined as an elevation in diastolic blood pressure (BP) higher than 130 mm Hg. I. Clinical evaluation of severe hypertension A. Hypertensive emergencies is defined by a diastolic blood pressure >120 mm Hg associated with ongoing vascular damage. Symptoms or signs of neurologic, cardiac, renal, or retinal dysfunction are present. Adequate blood pressure reduction is required within a few hours. Hypertensive emergencies include severe hypertension in the following settings: 1. Aortic dissection 2. Acute left ventricular failure and pulmonary edema 3. Acute renal failure or worsening of chronic renal failure 4. Hypertensive encephalopathy 5. Focal neurologic damage indicating thrombotic or hemorrhagic stroke 6. Pheochromocytoma, cocaine overdose, or other hyperadrenergic states 7. Unstable angina or myocardial infarction 8. Eclampsia B. Hypertensive urgency is defined as diastolic blood pressure >130 mm Hg without evidence of vascular damage; the disorder is asymptomatic and no retinal le- sions are present. C. Secondary hypertension includes renovascular hypertension, pheochromocytoma, cocaine use, withdrawal from alpha-2 stimulants, clonidine, beta-blo- ckers or alcohol, and noncompliance with antihypertensive medications. II. Initial assessment of severe hypertension A. When severe hypertension is noted, the measurement should be repeated in both arms to detect any signifi- cant differences. Peripheral pulses should be assessed for absence or delay, which suggests dissecting aortic dissection. Evidence of pulmonary edema should be sought. B. Target organ damage is suggested by chest pain, neurologic signs, altered mental status, profound headache, dyspnea, abdominal pain, hematuria, focal neurologic signs (paralysis or paresthesia), or hyper- tensive retinopathy. C. Prescription drug use should be assessed, including missed doses of antihypertensives. History of recent cocaine or amphetamine use should be sought. D. If focal neurologic signs are present, a CT scan may be required to differentiate hypertensive encephalopathy from a stroke syndrome. III. Laboratory evaluation A. Complete blood cell count, urinalysis for protein, glucose, and blood; urine sediment examination; chemistry panel (SMA-18). B. If chest pain is present, cardiac enzymes are obtained. C. If the history suggests a hyperadrenergic state, the possibility of a pheochromocytoma should be excluded with a 24-hour urine for catecholamines. A urine drug screen may be necessary to exclude illicit drug use. D. Electrocardiogram should be completed. E. Suspected primary aldosteronism can be excluded with a 24-hour urine potassium and an assessment of plasma renin activity. Renal artery stenosis can be excluded with captopril renography and intravenous pyelography. IV. Management of hypertensive emergencies A. The patient should be hospitalized for intravenous access, continuous intra-arterial blood pressure moni- toring, and electrocardiographic monitoring. Volume status and urinary output should be monitored. Rapid, uncontrolled reductions in blood pressure should be avoided because coma, stroke, myocardial infarction, acute renal failure, or death may result. B. The goal of initial therapy is to terminate ongoing target organ damage. The mean arterial pressure should be lowered not more than 20-25%, or to a diastolic blood pressure of 100 mm Hg over 15 to 30 minutes. Blood pressure should be controlled over a few hours. V. Management of hypertensive urgencies A. The initial goal in patients with severe asymptomatic hypertension should be a reduction in blood pressure to 160/110 over several hours with conventional oral therapy. B. If the patient is not volume depleted, furosemide (Lasix) is given in a dosage of 20 mg if renal function is nor- mal, and higher if renal insufficiency is present. A calcium channel blocker (isradipine ([DynaCirc], 5 mg or felodipine [Plendil], 5 mg) should be added. A dose of captopril (Capoten)(12.5 mg) can be added if the response is not adequate. This regimen should lower the blood pressure to a safe level over three to six hours and the patient can be discharged on a regimen of once-a-day medications. VI. Parenteral antihypertensive agents A. Nitroprusside (Nipride) 1. Nitroprusside is the drug of choice in almost all hypertensive emergencies (except myocardial ischemia or renal impairment). It dilates both arteries and veins, and it reduces afterload and preload. Onset of action is nearly instantaneous, and the effects disappear 1-2 minutes after discontinuation. 2. The starting dosage is 0.25-0.5 mcg/kg/min by continuous infusion with a range of 0.25-8.0 mcg/kg/min. Titrate dose to gradually reduce blood pressure over minutes to hours. 3. When treatment is prolonged or when renal insuffi- ciency is present, the risk of cyanide and thiocyanate toxicity is increased. Signs of thiocyanate toxicity include disorientation, fatigue, hallucinations, nau- sea, toxic psychosis, and seizures. B. Nitroglycerin 1. Nitroglycerin is the drug of choice for hypertensive emergencies with coronary ischemia. It should not be used with hypertensive encephalopathy because it increases intracranial pressure. 2. Nitroglycerin increases venous capacitance, de- creases venous return and left ventricular filling pressure. It has a rapid onset of action of 2-5 min- utes. Tolerance may occur within 24-48 hours. 3. The starting dose is 15 mcg IV bolus, then 5-10 mcg/min (50 mg in 250 mL D5W). Titrate by in- creasing the dose at 3- to 5-minute intervals. Gener- ally doses >1.0 mcg/kg/min are required for afterload reduction (max 2.0 mcg/kg/hr). Monitor for methemoglobinemia. C. Labetalol IV (Normodyne) 1. Labetalol is a good choice if BP elevation is associ- ated with hyperadrenergic activity, aortic dissection, an aneurysm, or postoperative hypertension. 2. Labetalol is administered as 20 mg slow IV over 2 min. Additional doses of 20-80 mg may be adminis- tered q5-10min, then q3-4h prn or 0.5-2.0 mg/min IV infusion. Labetalol is contraindicated in obstructive pulmonary disease, CHF, or heart block greater than first degree. D. Enalaprilat IV (Vasotec) 1. Enalaprilat is an ACE-inhibitor with a rapid onset of action (15 min) and long duration of action (11 hours). It is ideal for patients with heart failure or accelerated-malignant hypertension. 2. Initial dose, 1.25 mg IVP (over 2-5 min) q6h, then increase up to 5 mg q6h. Reduce dose in azotemic patients. Contraindicated in bilateral renal artery stenosis. E. Esmolol (Brevibloc) is a non-selective beta-blocker with a 1-2 min onset of action and short duration of 10 min. The dose is 500 mcg/kg/min x 1 min, then 50 mcg/kg/min; max 300 mcg/kg/min IV infusion. F. Hydralazine is a preload and afterload reducing agent. It is ideal in hypertension due to eclampsia. Reflex tachycardia is common. The dose is 20 mg IV/IM q4- 6h. G. Nicardipine (Cardene IV) is a calcium channel blocker. It is contraindicated in presence of CHF. Tachycardia and headache are common. The onset of action is 10 min, and the duration is 2-4 hours. The dose is 5 mg/hr continuous infusion, up to 15 mg/hr. H. Fenoldopam (Corlopam) is a vasodilator. It may cause reflex tachycardia and headaches. The onset of action is 2-3 min, and the duration is 30 min. The dose is 0.01 mcg/kg/min IV infusion titrated, up to 0.3 mcg/kg/min. I. Phentolamine (Regitine) is an intravenous alpha- adrenergic antagonist used in excess catecholamine states, such as pheochromocytomas, rebound hyper- tension due to withdrawal of clonidine, and drug inges- tions. The dose is 2-5 mg IV every 5 to 10 minutes. J. Trimethaphan (Arfonad) is a ganglionic-blocking agent. It is useful in dissecting aortic aneurysm when beta-blockers are contraindicated; however, it is rarely used because most physicians are more familiar with nitroprusside. The dosage of trimethoprim is 0.3-3 mg/min IV infusion. References, see page 360. Syncope Syncope is the abrupt and transient loss of consciousness associated with absence of postural tone, followed by a rapid and complete recovery. It is most often benign and self- limited. However, syncope can be a premonitory sign of sudden cardiac death, especially in patients with organic heart disease. The evaluation of the patient with syncope is the same as that for presyncope, which is the prodromal symptom of fainting. Such patients usually present with symptoms of dizziness. I. Differential diagnosis of syncope A. Cardiac cause, most often a bradyarrhythmia or tachyarrhythmia — 23 percent. B. Neurally mediated cause — 58 percent. C. Neurologic or psychiatric cause — 1 percent. D. Unexplained syncope — 18 percent. II. History A. Number of episodes. Benign causes of syncope are usually associated with a single syncopal episode or with multiple episodes over many years. The patient with multiple episodes occurring over a short period of time is more likely to suffer from a serious underlying disorder. B. Associated symptoms. Dyspnea may suggest an acute pulmonary embolism; angina frequently indi- cates an underlying cardiac cause; focal neurologic abnormalities favors a neurologic origin; nausea, vomiting, diaphoresis, and pallor after an episode suggest high vagal tone; and urination and defecation suggest a seizure. C. Prodrome. Neurocardiogenic syncope (also called vasovagal syncope) is usually, but not always, associ- ated with a prodrome of nausea, warmth, pallor, lightheadedness, and/or diaphoresis. “Auras” are associated with seizures. D. Position. Neurocardiogenic syncope commonly occurs when the patient is erect, not usually when supine. Syncope resulting from orthostatic hypotension is frequently associated with the change from a supine to erect posture. In comparison, syncope that occurs when the patient is supine suggests an arrhythmia. E. Warning. The sudden loss of consciousness without warning is most likely to result from an arrhythmia (bradycardia or tachycardia). F. Preceding events. Coughing, eating, drinking cold liquid, urinating, and defecating can all cause syncope; such etiologies are often referred to as situational syncope. G. Duration of symptoms. A prolonged loss of con- sciousness may indicate a seizure or aortic stenosis. By comparison, arrhythmias and neurocardiogenic syncope are often associated with a brief period of syncope, since the supine position reestablishes some blood flow to the brain. H. Recovery. Persistence of nausea, pallor, and diaphoresis in addition to a prolonged recovery from the episode suggest a vagal event. These findings are helpful in distinguishing neurocardiogenic syncope from syncope due to an arrhythmia. Significant neuro- logic changes or confusion during the recovery period may be due to a stroke or seizure. I. Witness. A witness to the syncopal event may verify the loss of consciousness, limb movements, and the presence of pallor or diaphoresis. The presence or absence of a pulse is important. J. Exertional syncope. Among the pathologic causes of exertional syncope are ventricular tachycardia and obstruction resulting from aortic stenosis, and hyper- trophic cardiomyopathy. Syncope associated with exercise also occurs in patients, usually young, who do not have underlying heart disease. The most common cause is neurocardiogenic syncope as detected by the upright tilt table test. K. Age. Neurocardiogenic syncope is more likely to occur among young, otherwise healthy patients; however, syncope resulting from the long QT syndrome or hypertrophic cardiomyopathy can also occur in young individuals. L. Pre-existing medical conditions. Patients with psychiatric illness may have syncope secondary to hyperventilation or panic attacks; syncope in a patient with diabetes mellitus may result from orthostatic hypotension secondary to autonomic neuropathy; antihypertensive medications can result in syncope; and the presence of heart disease strongly implies a cardiac cause for syncope. M. Injury. Syncope can result from the high vagal tone that can occur with extreme pain from any cause. N. Medications or recreational drugs. Antiarrhythmic (proarrhythmic effects) and antihypertensive agents (primarily due to orthostatic hypotension with sympa- thetic blockers) can cause syncope. The abuse of illicit drugs or alcohol is associated with syncope. O. Eating. A vagal “surge” upon swallowing can cause bradycardia and hypotension in predisposed patients. P. Distinction of syncope from seizures 1. Seizures are the probable cause of 5 to 15 percent of apparent syncopal episodes. Some patients with syncope present with abnormal movements that are suggestive of a seizure but are actually due to cerebral hypoxia. 2. Patients with seizures rarely have an abrupt and complete recovery. Instead, the postictal state is characterized by a slow and complete recovery. Another important clue is evidence of soft tissue injury at multiple sites due to tonic-clonic move- ments during the seizure. Medications Associated with Syncope Antihypertensives/anti- anginals Adrenergic antagonists Calcium channel blockers Diuretics Nitrates Vasodilators Antidepressants Tricyclic antidepressants Phenothiazines Antiarrhythmics Digoxin Quinidine Insulin Drugs of abuse Alcohol Cocaine Marijuana Differential Diagnosis of Syncope Non-cardiovascular Cardiovascular Metabolic Hyperventilation Hypoglycemia Hypoxia Neurologic Cerebrovascular insuffi- ciency Normal pressure hydro- cephalus Seizure Subclavian steal syn- drome Increased intracranial pressure Psychiatric Hysteria Major depression Reflex syncope (heart struc- turally normal) Vasovagal Situational Cough Defecation Micturition Postprandial Sneeze Swallow Carotid sinus syncope Orthostatic hypotension Drug-induced Cardiac Obstructive Aortic dissection Aortic stenosis Cardiac tamponade Hypertrophic cardiomyopathy Left ventricular dysfunc- tion Myocardial infarction Myxoma Pulmonary embolism Pulmonary hypertension Pulmonary stenosis Arrhythmias Bradyarrhythmias Sick sinus syn- drome Pacemaker failure Supraventricular and ventricular tachyarrhythmias Clues to the Etiology of Syncope Associated Feature Etiology Cough Micturition Defecation Swallowing Situational syncope Post-syncopal disori- entation Urinary or fecal incon- tinence Seizure Syncope with arm exercise Subclavian steal syndrome Syncope with shaving Carotid sinus syncope Prodromal symptoms (nausea, diaphoresis) Vasovagal syncope Abrupt onset Cardiac syncope Syncope with exertion Aortic stenosis, hypertrophic cardiomyopathy, arrhythmias Associated Feature Etiology Syncope with change of position Orthostatic hypotension Blood pressure/pulse differential Aortic dissection, subclavian steal syndrome Abnormal postural vital signs Orthostatic hypotension Cardiac mur- murs/rhythms Aortic stenosis, hypertrophic cardiomyopathy, arrhythmias, pul- monary hypertension Carotid bruit Cerebrovascular insufficiency III. Physical examination A. Abnormal vital signs. Blood pressure obtained in the supine, sitting, and erect position may detect orthostatic hypotension. The latter is diagnosed when, within two to five minutes of quiet standing, one or more of the following is present: 1. At least a 20 mm Hg fall in systolic pressure. 2. At least a 10 mm Hg fall in diastolic pressure. 3. Symptoms of cerebral hypoperfusion. B. Disturbances in heart rhythm or breathing. The heart rate may be rapid or slow due to a number of possible rhythm disturbances, or irregular due to atrial fibrillation. The pulse and blood pressure should be obtained when supine, sitting, and erect. Hyperventila- tion can be seen with pulmonary embolism or psychiat- ric causes of syncope. C. Cardiac auscultatory findings. The cardiac examina- tion may reveal the murmur of aortic stenosis, pul- monic stenosis, or atrial myxoma. Pulmonary hyperten- sion may be suggested by a loud, palpable P2. D. Physiologic maneuvers. Changes in an outflow murmur with the Valsalva maneuver may help diag- nose hypertrophic cardiomyopathy. E. Abnormal neurologic findings. Unilateral abnormali- ties found upon neurologic examination may reflect a cerebral vascular accident. F. Gastrointestinal bleeding. A positive stool guaiac indicates gastrointestinal blood loss, which can result sequentially in anemia, hypovolemia, and syncope. G. Carotid sinus massage. Carotid sinus hypersensitiv- ity, which is responsible for the carotid sinus syndrome, can be demonstrated by careful carotid sinus mas- s a g e , p r e f e r a b l y wi t h s i mu l t a n e o u s electrocardiographic monitoring. The test is considered positive if there is a pause of three seconds or more. IV. Testing A. Electrocardiogram 1. The ECG can help facilitate the diagnosis of the underlying cause of syncope if one or more of the following features are present: a. Sinus bradycardia. b. Atrioventricular nodal disease (second or third degree heart block). c. His-Purkinje system disease (Mobitz type II AV block). d. Bundle branch and/or fascicular block. e. Prolonged QT interval. 2. A prolonged QT interval on electrocardiogram may favor torsade de pointes as a possible underlying cause for syncope. Other possible causes of syn- cope that can be diagnosed from or suggested by the electrocardiogram include the Wolff-Parkinson- White syndrome, a myocardial infarction, chronic obstructive pulmonary disease, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, and Brugada syndrome. B. Ambulatory monitoring for 24 to 48 hours or patient activated event recording is commonly obtained in the assessment of syncope. Ambulatory monitoring estab- lishes a diagnosis in only 2 to 3 percent of patients. C. Event recorders appear to be somewhat more helpful than pure ambulatory monitoring in diagnosing the etiology of syncope or presyncope. However, they often do not provide useful information since the patient must be conscious in order to activate the unit and “store” the rhythm at the time of the symptom. D. Implantable loop recorders can record the ECG for over one year, storing events when the device is activated automatically by a rapid rate or manually with magnet application. Transient bradycardia is frequently found. An implantable loop recorder may become a preferred initial strategy for evaluation of unexplained syncope. E. Echocardiography may diagnose underlying struc- tural heart disease, such as left ventricular dysfunction, hypertrophic cardiomyopathy, or significant aortic stenosis. F. Neurologic testing, including electroencephalogram, brain CT scan, brain magnetic resonance imaging, and carotid Doppler ultrasound, is rarely useful. An electro- encephalogram can, however, be helpful in ruling out epilepsy in patients with syncope who have seizure-like activity. G. Exercise testing has a role in patients with a history of exertion-related syncope or exercise-induced arrhythmias, such as prolonged QT syndrome. Exer- cise testing may also be useful in patients with hyper- trophic cardiomyopathy. H. Upright tilt table test. The tilt table test is most useful in young, otherwise healthy patients in whom the diagnosis of neurocardiogenic syncope is often enter- tained. It is also useful in older persons with suspected neurally mediated syncope. I. Brain natriuretic peptide. Elevated plasma BNP concentrations are typically seen in patients with heart failure and may be seen in a variety of other cardiovas- cular disorders. V. Advanced cardiologic testing A. Signal-averaged electrocardiogram (SAECG) has become a valuable tool for the detection of patients at risk for ventricular tachyarrhythmias (particularly sustained monomorphic ventricular tachycardia); it has no role in the evaluation of sinus or AV nodal dysfunc- tion. B. Electrophysiology study. Patients with syncope in whom ventricular or supraventricular arrhythmias, left ventricular dysfunction, significant epicardial coronary artery disease, or other structural heart disease have been document ed, ar e candi dat es f or electrophysiology (EP) testing. EP testing also has an important role in the establishment of a diagnosis of syncope of unknown etiology, particularly among patients with structural heart disease, up to 70 percent of whom will have a “positive” study. VI. Indications for hospitalization. Hospitalization is recommended for elderly patients or those in whom a significant underlying cardiovascular disease is suspected to be the cause for syncope. Hospital admission of patients with syncope is recommended for the following: A. The presence of serious injury, or frequent and recur- rent symptoms. B. Old age. C. The diagnosis or suspicion of a serious cardiovascular or neurologic etiology. VII. Management of the patient with syncope A. Syncope and sudden death are two different entities that must be distinguished from each other in order to assess prognosis. Patients in whom cardiopulmonary resuscitation, or electric or pharmacologic cardiover- sion have been required should be labeled as having sudden death and not as having syncope. B. Metabolic or iatrogenic syncope. Metabolic abnor- malities, anemia, and hypovolemia can be managed by specific therapy which corrects these basic abnormali- ties. In addition, iatrogenic syncope resulting from drug therapy is a preventable condition. C. Orthostatic hypotension (ie, at least a 20 mm Hg fall in systolic pressure, a 10 mm Hg fall in diastolic pressure, or symptoms) in the absence of volume depletion is most often due to an autonomic neuropa- thy or the administration of antidepressant drugs. An important component of therapy for orthostatic hypotension is avoidance of both volume depletion and the administration of medications (such as sympathetic blockers and antidepressants) that can contribute to this problem. A major benefit may also be achieved from tensing the legs by crossing them while actively standing on both legs to minimize postural symptoms. D. Other physical measures that may be helpful include: 1. Arising slowly in stages from supine to seated to standing. 2. Performing dorsiflexion of the feet or handgrip exercise before standing. 3. Wearing Jobst stockings, up to and including the thighs, to minimize venous pooling. E. Induction of volume expansion with a combination of fludrocortisone (an oral mineralocorticoid given in a dose of 0.1 to 1.0 mg/day) and a high-salt diet is also effective. Patients must be carefully monitored for the development of edema or worsening seated or supine hypertension. F. Other drugs that can be tried if fludrocortisone does not work or is not well tolerated include: 1. Alpha-1-adrenergic agonists, such as midodrine (2.5 to 10 mg TID) or phenylephrine (60 mg every 6 to 12 hours). 2. Nonsteroidal anti-inflammatory drugs. 3. Caffeine. 4. Fluoxetine. G. Cardiovascular disease with obstruction. Cardiac diseases that obstruct the outflow of blood require surgical correction, such as aortic valve replacement for aortic stenosis. Dynamic outflow obstruction result- ing from hypertrophic cardiomyopathy is treated with beta-blockers or calcium channel blockers. H. Ventricular arrhythmias. Patients with syncope due to ventricular tachycardia (VT) that is inducible during an electrophysiologic (EP) evaluation or those with unexplained syncope and inducible ventricular arrhythmias are usually candidates for antiarrhythmic drug therapy guided by this technique. Additional therapeutic options in patients with documented or inducible ventricular arrhythmias, primarily VT, include an implantable cardioverter-defibrillator. I. Cardiomyopathy and unexplained syncope. Patients with advanced heart failure due to nonischemic cardiomyopathy who also have syncope, regardless of the cause, have a high one-year risk of sudden death (45 percent). J. Supraventricular arrhythmias can be treated with antiarrhythmic drugs, radio-frequency ablation has become a preferred therapy for the majority of such arrhythmias, especially those that involve the AV node or an accessory pathway. K. Bradycardia due to conduction abnormalities. Permanent pacemaker implantation is indicated when sinus node dysfunction or a high-grade AV block is the documented cause for syncope. L. Neurocardiogenic syncope 1. Treatment is aimed in part at preventing conditions that contribute to syncope. In situational vasovagal syncope, for example, the most frequently effective action is the avoidance or modulation of the triggers responsible for syncope. Patients assume a supine position with legs raised at the onset of warning symptoms. Other general support features may include support stockings, volume expansion by liberalizing salt intake, and occasionally the mineralocorticoid fludrocortisone. 2. Beta-blockers are the most commonly used ther- apy. If this fails, other medical options include disopyramide and the selective serotonin reuptake inhibitors. 3. Pacing can be considered in patients with cardioinhibitory neurocardiogenic syncope in whom other medical therapy is ineffective or not indicated. An orthostatic training program can be tried in young patients who respond poorly to medical therapy. 4. Carotid sinus hypersensitivity is often considered to be a variant of neurocardiogenic syncope and is known as carotid sinus syndrome; many of the same therapies have been used. Pacemakers are of benefit for patients with only cardioinhibitory responses but not in those with a vasodepressor response. References, see page 360. Hypercholesterolemia The Third Report of the Expert Panel on Detection, Evalua- tion and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III or ATP III) summarizes the current management of high serum cholesterol. I. Identification of patients at risk A. The ATP III recommendations that treatment of hyper- cholesterolemia be based upon the LDL-cholesterol fraction and influenced by the coexistence of CHD and the number of cardiac risk factors. Step 1. The first step in determining patient risk is to obtain a fasting lipid profile. Step 2. CHD equivalents, risk factors that place the patient at similar risk for CHD events as a history of CHD itself, should be identified in step 2: 1. Diabetes mellitus 2. Symptomatic carotid artery disease 3. Peripheral arterial disease 4. Abdominal aortic aneurysm Classification of LDL, Total, and HDL Cholesterol (mg/dL) LDL Cholesterol <100 Optimal 100-129 Near optimal/above optimal 130-159 Borderline high 160-189 High >190 Very high Total Cholesterol <200 Desirable 200-239 Borderline high >240 High HDL Cholesterol <40 Low >60 High Step 3. Major CHD factors other than LDL are identified in step 3: 1. Cigarette smoking 2. Hypertension (BP 140/90 or antihypertensive medica- tion) 3. Low HDL cholesterol (<40 mg/dL) 4. Family history of premature CHD (in male first degree relatives <55 years, in female first degree relatives <65 years) 5. Age (men 45 years, women 55 years) 6. HDL cholesterol 60 mg/dL counts as a "negative" risk factor; its presence removes one risk factor from the total count. Step 4. If two or more risk factors other than LDL (as defined in step 3) are present in a patient without CHD or a CHD equivalent (as defined in step 2), the 10-year risk of CHD is assessed using Framingham risk tables. Step 5.The last step in risk assessment is to determine the risk category that establishes the LDL goal, when to initiate therapeutic lifestyle changes, and when to consider drug therapy. LDL Cholesterol Goals for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories. Risk Category LDL-C Goal LDL Level at Which to Initi- ate Therapeutic Lifestyle Changes LDL Level at Which to Con- sider Drug Therapy CHD <100 mg/dL >100 mg/dL >130 mg/dL (100-129 mg/dL: drug optional) 2+ Risk Fac- tors <130 mg/dL >130 mg/dL 10-year risk 10- 20%:>130 mg/dL 10-year risk <10%:>160 mg/dL 0-1 Risk Factor <160 mg/dL >160 mg/dL >190 mg/dL (160-189 mg/dL: LDL-lowering drug optional) II. Treatment A. Cardiovascular benefits of cholesterol lowering with statin drugs have been demonstrated in the following groups: 1. Patients with CHD, with or without hyperlipidemia 2. Men with hyperlipidemia but no known CHD 3. Men and women with average total and LDL choles- terol levels and no known CHD B. Secondary prevention. In patients who already have CHD, a goal LDL-cholesterol value of less than 100 mg/dL is recommended for secondary prevention. Dietary modification should be employed in any patient with CHD and an LDL-cholesterol exceeding 100 mg/dL, and drug therapy should be considered if the LDL-cholesterol remains above 130 mg/dL. C. Primary prevention. The serum LDL-cholesterol concentration and risk factor status determine the suggested approach: 1. Individuals with desirable serum LDL-cholesterol values may be reevaluated in five years, while those with borderline high-risk values and less than two cardiac risk factors should be reevaluated in one year (one risk factor is subtracted if the serum HDL is 60 mg/dL). 2. A cholesterol lowering diet is indicated in patients with a high-risk serum LDL-cholesterol concentra- tion and in those with borderline high-risk values plus two or more cardiac risk factors. 3. Drug therapy with a statin should be considered if, after a trial of dietary modification, serum LDL-cholesterol remains above 190 mg/dL in any patient or above 160 mg/dL in a patient with two or more CHD risk factors. 4. The goal serum LDL-cholesterol concentration should be below 160 mg/dL in patients with less than two CHD risk factors. A lower value of 130 mg/dL is recommended in patients with two or more CHD risk factors. D. Patients with low HDL. Therapy aimed at raising HDL levels into the normal range has been advocated in patients with overt CHD and those at high risk because of a strong family history. Low HDL cholesterol is defined as <40 mg/dL. E. Hypertriglyceridemia should be treated in patients who also have hypercholesterolemia. Possible indica- tions for treatment of isolated hypertriglyceridemia include overt CHD, a strong family history of CHD, multiple coexisting cardiac risk factors, and very high triglyceride levels (>1000 mg/dL). F. Lifestyle modifications include reductions in dietary fat, weight loss in overweight patients, and aerobic exercise. All patients with high LDL cholesterol should undergo lifestyle modifications. Many will not reach the goal level of cholesterol and will require drug therapy. G. Drug therapy 1. Statins are commonly used in the treatment of hypercholesterolemia. They are the most powerful drugs for lowering LDL cholesterol, with reductions of 20 to 60%. Fluvastatin (Lescol) is somewhat less potent, decreasing LDL by 20-25%. Atorvastatin is the most potent, reducing LDL by 29-61%. An additional benefit of atorvastatin is more effective triglyceride lowering (14 to 33%). Adverse reactions occur less frequently with the statins than with other lipid-lowering agents. 2. Cholesterol absorption inhibitors - Ezetimibe (Zetia) modestly lowers the LDL cholesterol when used alone, but may have its greatest use in combi- nation with statins. It does not have the gastrointesti- nal effects of the bile acid sequestrants. It is more effective in lowering LDL cholesterol than doubling the dose of the statin. Dose, Side Effects, and Drug Interactions of Lipid- Lowering Drugs Drug class Dose Dosing Major side ef- fects and drug interactions HMG CoA reductase inhibitors Atorvastatin (Lipitor) Lovastatin (ge- neric, Mevacor) Extended-re- lease lovastatin (Altocor) Pravastatin (Pravachol) Simvastatin (Zocor) Fluvastatin (Lescol, Lescol XL) Rosuvastatin (Crestor) 10-40 mg/day 20-80 mg/day 10-60 mg/day 10-40 mg/day 5-40 mg/day 10-40 mg/day 10-40 mg/day Take at bedtime. Take BID if dose >20 mg/day. Headache; nau- sea; sleep distur- bance; elevations in liver enzymes and alkaline phosphatase. Myositis and rhabdomyolysis. Lovastatin and simvastatin poten- tiate warfarin and increase digoxin levels Cholesterol absorption inhibitors Ezetimibe (Zetia) 10 mg/day 10 mg qd Increased transaminases in combination with statins Bile acid sequestrants Cholestyramine (Questran, Questran Lite) Colestipol (Colestid) Colesevelam (WelChol) 4-24 g/day 5-30 g/day 3.75 gm once or divided BID Take within 30 min of meal. A double dose with dinner pro- duces same ef- fect as BID dosing Nausea, bloating, cramping, consti- pation; elevations in hepatic trans- aminases and al- kaline phosphatase. Im- paired absorption of fat soluble vita- mins, digoxin, war- farin, thiazides, beta-blockers, thy- roxine, phenobar- bital. Drug class Dose Dosing Major side ef- fects and drug interactions Nicotinic acid 1-12 g/day Given with meals. Start with 100 mg BID and titrate to 500 mg TID. After 6 weeks, check lipids, glu- cose, liver function, and uric acid. Prostaglandin-me- diated cutaneous flushing, head- ache, pruritus; hyper- pigmentation; acanthosis nigricans; dry skin; nausea; diarrhea; myositis. Fibrates Gemfibrozil (Lopid) 600 mg BID 50 to 60 min before meals. Potentiates warfa- rin. Absorption of gemfibrozil dimin- ished by bile acid sequestrants. Fenofibrate (Lofibra, micronized) 200 mg qd Take with breakfast. Use lower dosage with renal insuffi- ciency. Skin rash, nausea, bloating, cramp- ing, myalgia; low- ers cyclosporin levels; nephrotoxic in cyclosporin- treated patients. Fenofibrate (TriCor) 160 mg qd Probucol 500 mg BID Loose stools; eosinophilia; QT prolongation; angioneurotic edema. Extended-re- lease niacin plus (immediate-re- lease) lovastatin (Advicor) 1000 mg/40 mg/day 1000 mg + 40 mg h.s.3 markedly lowers LDL and triglycer- ides and raises HDL Average Reduction in LDL Levels with Statin Drugs Statin 1 0 - m g dosage 2 0 - m g dosage 4 0 - m g dosage 8 0 - m g dosage Atorvastatin (Lipitor) 38% 46% 51% 54% Simvastatin (Zocor) 28% 35% 40% 48% Lovastatin (Mevacor, generic) -- 29% 31% 48% Cerivastatin (Baycol) 0.2-mg dosage: 25% 0.3-mg dosage: 30% 0.4-mg dosage: 36% 0.8-mg dosage: 44% Pravastatin (Pravachol) 19% 24% 34% 40% Fluvastatin (Lescol) -- 17% 23% 33% 3. Fibrates (gemfibrozil, clofibrate, fenofibrate) primarily lower plasma triglyceride and raise HDL levels. They are effective for the treatment of hypertriglyceridemia and combined hyperlipidemia. 4. Bile acid sequestrants are effective in patients with mild to moderate elevations of LDL choles- terol. Bile acid sequestrants are also effective when used with a statin or nicotinic acid. Use is often limited by side effects. 5. Nicotinic acid is effective in patients with hyper- cholesterolemia and in combined hyperlipidemia associated with normal and low levels of HDL cholesterol. Use is often limited by poor tolerability. 6. Probucol modestly lowers LDL cholesterol, but more prominently reduces HDL cholesterol. Probucol should be limited to refractory hyper- cholesterolemia or familial hypercholesterolemia and xanthomas. References, see page 360. Hypertriglyceridemia Lipid disorders can occur as either a primary event or secondary to some underlying disease. The primary dyslipidemias are associated with overproduction and/or impaired removal of lipoproteins. Dyslipidemia is defined as total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, apolipoprotein (apo)-B, or Lp(a) levels above the 90th percentile or high-density lipoprotein (HDL)-cholesterol or apo A-1 levels below the 10th percentile for the general population. I. Normal serum triglyceride concentration. The serum triglyceride concentration can be stratified in terms of coronary risk: Normal <150 mg/dL Borderline high - 150 to 199 mg/dL High - 200 to 499 mg/dL Very high - >500 mg/dL II. Triglycerides and atherosclerosis A. CHD events. Population-based studies and analyses of patients with CHD suggest that serum triglycerides are a risk factor for CHD. Hypertriglyceridemia is associated with increased mortality in patients with known CHD and both increased mortality and reduced event-free survival after coronary artery bypass graft surgery (CABG). B. Coronary atherosclerosis. The total triglyceride concentration is a risk factor for progression of low- grade but not high-grade coronary artery lesions. C. Acquired disorders. A number of acquired disorders raise serum triglycerides. These include: 1. Obesity, often in association with an elevation in serum cholesterol. 2. Diabetes mellitus, where there is a relationship to poor glycemic control and, in type 2 diabetes, obesity. 3. Nephrotic syndrome, often is association with hypercholesterolemia, and renal failure. 4. Hypothyroidism, often in association with hypercho- lesterolemia. 5. Estrogen replacement, which is often associated with a fall in LDL cholesterol. The elevation in serum triglycerides may not be seen with transdermal estrogen delivery and is minimal with most oral contraceptives because of the lower estrogen dose. 6. Tamoxifen can cause marked hypertriglyceridemia in a minority of women. D. Mi xed hyper t r i gl ycer i demi a ( t ype V hyperlipoproteinemia) is characterized by triglyceride levels above the 99th percentile in association with a creamy plasma supernatant and increases in chylomicrons and VLDL. Clinical manifestations include hepatosplenomegaly and occasional eruptive xanthomas. However, patients with marked hypertriglyceridemia (>1000 mg/dL) may develop the chylomicronemia syndrome. Manifestations of this disorder include recent memory loss, abdominal pain and/or pancreatitis, dyspnea, eruptive xanthoma, flushing with alcohol, and lipemia retinalis. Mixed hypertriglyceridemia can be diagnosed by confirming the presence of chylomicrons and excess VLDL on agarose gel electrophoresis or ultracentrifugal analy- sis. E. Familial hypertriglyceridemia (type IV hyperlipoproteinemia phenotype) is an autosomal dominant disorder associated with moderate eleva- tions in the serum triglyceride concentration (200 to 500 mg/dL). It is often accompanied by insulin resis- tance, obesity, hyperglycemia, hypertension, and hyperuricemia. F. Familial combined hyperlipidemia (FCHL) is an autosomal disorder caused by overproduction of hepatically derived apolipoprotein B-100 associated with VLDL. It is associated with a clear increase in coronary risk and accounts for one-third to one-half of familial causes of CHD. G. Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is a multifactorial disorder that is inherited as an autosomal recessive trait. It is characterized by the presence of two apo E2 alleles. Premature CHD and peripheral vascular disease are common. Physical findings include tuberoeruptive xanthomas and xanthomas of the palmar creases (xanthomata palmare striatum). H. Hypertriglyceridemia and serum cholesterol. Hypertriglyceridemia reflects the accumulation of triglyceride-rich lipoproteins (chylomicrons, VLDL and remnant particles, beta-VLDL, and IDL) in plasma. Since triglyceride-rich lipoproteins also transport cholesterol, hypercholesterolemia of varying severity often accompanies hypertriglyceridemia. III. General treatment guidelines A. The epidemiologic data on the relationship between triglycerides and CHD provide strong evidence that hypertriglyceridemia promotes atherosclerosis. B. Recommendati ons of expert groups. Nonpharmacologic therapy is recommended for serum triglyceride values above 200 mg/dL. Although the risk is enhanced at these levels, some studies suggest that CHD risk begins to increase at a fasting triglyceride concentration of 160 to 190 mg/dL and, among pa- tients with CHD, may begin to increase at values above 100 mg/dL. 1. The National Cholesterol Education Program (Adult Treatment Panel [ATP] III) recommends that in all patients with borderline high or high triglycerides, the primary goal of therapy is to achieve the targets for LDL cholesterol. In addition, the following recom- mendations were made for various levels of ele- vated triglycerides: a. When triglycerides are borderline high (150 to 199 mg/dL), emphasis should be upon weight reduction and increased physical activity. b. When triglycerides are high (200 to 499 mg/dL), non-HDL cholesterol becomes a secondary target of therapy after LDL cholesterol. In addi- tion to nonpharmacologic therapy, drug therapy can be considered in high-risk patients, including those who have had an acute myocardial infarc- tion, to reach the non-HDL cholesterol goals. These goals may be achieved by intensifying therapy with an LDL-cholesterol-lowering drug, or by adding nicotinic acid or a fibrate. c. When triglycerides are very high (>500 mg/dL), the initial goal is to prevent pancreatitis by lower- ing triglycerides with the combination of nonpharmacologic therapy and a triglyceride- lowering drug, such as a fibrate or nicotinic acid. Once triglycerides are below 500 mg/dL, LDL cholesterol goals should be addressed. C. Nonpharmacologic therapy, such as weight loss in obese patients, aerobic exercise, avoidance of con- centrated sugars and medications that raise serum triglyceride levels, and strict glycemic control in diabet- ics should be the first-line of therapy. Other risk factors for CHD, such as hypertension and smoking, should also be addressed. Alcohol abuse must be avoided as it can cause large increases in triglyceride levels in patients with mixed or familial hypertriglyceridemia and can precipitate pancreatitis in such patients. D. Pharmacologic therapy Treatment of hypertriglyceridemia* Review medi- cations Laboratory studies Diet Change to lipid neutral or fa- vorable agents when possible (eg, alpha- blockers, biguanides, thiazolidinedion e) Exclude sec- ondary disor- ders of lipid metabolism Weight loss Fasting blood glucose Avoid concen- trated sugars Serum creatine Increase omega-3 fatty acid intake through fish consumption Lower doses of drugs that in- crease triglyc- erides, such as beta-blockers (particularly nonselective agents), glucocorticoids, diuretics (thiazide and loop), ticlopidine, estrogens. Thyroid func- tion studies Exercise Aerobic exer- cise minimum of 3 hours weekly * Hypertriglyceridemia is defined as a serum triglyceride concentration above 200 mg/dL 1. High-serum triglycerides with elevated LDL-C a. The more potent statins (eg, atorvastatin [Lipitor] or rosuvastatin [Crestor]) will control the LDL-C and, if the LDL-C is proportionately more ele- vated than serum tri gl yceri des, the hypertriglyceridemia as well. If additional triglyceride lowering is required, either a fibrate or nicotinic acid can be added. Nicotinic acid may worsen glucose tolerance in diabetic pa- tients. Glycemic control should be monitored carefully in diabetic patients treated with nicotinic acid. Gemfibrozil increases the risk of muscle toxicity induced by statin therapy. The latter risk can be minimized by using pravastatin or fluvastatin, which are not metabolized by CYP3A4. Although rosuvastatin is also not metabolized by CYP3A4, it is recommended that the dosage be limited to 10 mg/day in patients b e i n g t r e a t e d wi t h g e mf i b r o z i l . Fenofibrate(TriCor) does not increase statin levels, and it is considered a safer agent for combined therapy with a statin. b. Bile acid sequestrants should be avoided until triglyceride levels have been normalized since they can increase VLDL synthesis and exacer- bate the hypertriglyceridemia. 2. High-serum triglycerides and LDL-C <130 mg/dL or low HDL a. Possible indications for treatment of isolated hypertriglyceridemia include overt CHD, a strong family history of CHD, and multiple coexisting cardiac risk factors. The most effective triglyceride-lowering drugs are fibric acid deriva- tives and nicotinic acid. These drugs have the added benefit of also being most effective in raising HDL-C, which is commonly reduced in these patients and may be associated with adverse cardiac outcomes. b. A fibrate is generally preferred in such patients, and combination therapy can be given in pa- tients with marked hypertriglyceridemia or acute pancreatitis. c. Refractory cases may benefit from fish oil sup- plements (>3 g/day) which, by reducing VLDL production, can lower the serum triglyceride concentration by as much as 50 percent or more. 3. Very-high-serum triglycerides. Gemfibrozil ther- apy can lower the serum triglyceride concentration by 70 percent in patients with very-high-serum triglycerides, and reduce plasma viscosity, which may contribute to the clinical benefit. However, combination therapy with nicotinic acid is often given. References, see page 360. Pulmonary Disorders Asthma Asthma is the most common chronic disease among chil- dren. Asthma triggers include viral infections; environmental pollutants, such as tobacco smoke; aspirin, nonsteroidal anti- inflammatory drugs, and sustained exercise, particularly in cold environments. I. Diagnosis A. Symptoms of asthma may include episodic complaints of breathing difficulties, seasonal or nighttime cough, prolonged shortness of breath after a respiratory infection, or difficulty sustaining exercise. B. Wheezing does not always represent asthma. Wheez- ing may persist for weeks after an acute bronchitis episode. Patients with chronic obstructive pulmonary disease may have a reversible component superim- posed on their fixed obstruction. Etiologic clues include a personal history of allergic disease, such as rhinitis or atopic dermatitis, and a family history of allergic dis- ease. C. The frequency of daytime and nighttime symptoms, duration of exacerbations and asthma triggers should be assessed. D. Physical examination. Hyperventilation, use of acces- sory muscles of respiration, audible wheezing, and a prolonged expiratory phase are common. Increased nasal secretions or congestion, polyps, and eczema may be present. E. Measurement of lung function. An increase in the forced expiratory volume in one second (FEV 1 ) of 12% after treatment with an inhaled beta 2 agonist is suffi- cient to make the diagnosis of asthma. A 12% change in peak expiratory flow rate (PEFR) measured on a peak-flow meter is also diagnostic. II. Treatment of asthma A. Beta 2 agonists 1. Inhaled short-acting beta 2 -adrenergic agonists are the most effective drugs available for treatment of acute bronchospasm and for prevention of exercise- induced asthma. Levalbuterol (Xopenex), the R- isomer of racemic albuterol, offers no significant advantage over racemic albuterol. 2. Salmeterol (Serevent), a long-acting beta 2 agonist, has a relatively slow onset of action and a prolonged effect. a. Salmeterol should not be used in the treatment of acute bronchospasm. Patients taking salmeterol should use a short-acting beta 2 agonist as needed to control acute symptoms. Twice-daily inhalation of salmeterol has been effective for maintenance treatment in combination with inhaled corticosteroids. b. Fluticasone/Salmeterol (Advair Diskus) is a long- acting beta agonist and corticosteroid combina- tion; dry-powder inhaler [100, 250 or 500 g/puff],1 puff q12h. 3. Formoterol (Foradil) is a long-acting beta2 agonist like salmeterol. It should only be used in patients who already take an inhaled corticosteroid. Patients taking formoterol should use a short-acting beta 2 agonist as needed to control acute symptoms. For maintenance treatment of asthma in adults and children at least 5 years old, the recommended dosage is 1 puff bid. 4. Adverse effects of beta 2 agonists. Tachycardia, palpitations, tremor and paradoxical bronchospasm can occur. High doses can cause hypokalemia. Drugs for Asthma Drug Formulation Dosage Inhaled beta 2 -adrenergic agonists, short-acting Albuterol Proventil Proventil-HFA Ventolin Ventolin Rotacaps metered-dose in- haler (90 μg/puff) dry-powder inhaler (200 μg/inhalation) 2 puffs q4-6h PRN 1-2 capsules q4- 6h PRN Albuterol Proventil multi-dose vials Ventolin Nebules Ventolin nebulized 2.5 mg q4-6h PRN Levalbuterol - Xopenex nebulized 0.63-1.25 mg q6- 8h PRN Drug Formulation Dosage Inhaled beta2-adrenergic agonist, long-acting Formoterol - Foradil oral inhaler (12 μg/capsule) 1 cap q12h via inhaler Salmeterol Serevent Serevent Diskus metered-dose in- haler (21 μg/puff) dry-powder inhaler (50 μg/inhalation) 2 puffs q12h 1 inhalation q12h Fluticasone/Salm eterol Advair Diskus dry-powder inhaler (100, 250 or 500 μg/puff) 1 puff q12h Inhaled Corticosteroids Beclomethasone dipropionate Beclovent Vanceril Vanceril Double- Strength metered-dose in- haler (42 μg/puff) (84 μg/puff) 4-8 puffs bid 2-4 puffs bid Budesonide Pulmicort Turbuhaler dry-powder inhaler (200 μg/inhalation) 1-2 inhalations bid Flunisolide - AeroBid metered-dose in- haler (250 μg/puff) 2-4 puffs bid Fluticasone Flovent Flovent Rotadisk metered-dose in- haler (44, 110 or 220 μg/puff) dry-powder inhaler (50, 100 or 250 μg/inhalation) 2-4 puffs bid (44 μg/puff) 1 inhalation bid (100 μg/inhalation) Triamcinolone acetonide Azmacort metered-dose in- haler (100 μg/puff) 2 puffs tid-qid or 4 puffs bid Leukotriene Modifiers Montelukast - Singulair tablets 10 mg qhs Zafirlukast - Accolate tablets 20 mg bid Zileuton - Zyflo tablets 600 mg qid Mast Cell Stabilizers Cromolyn Intal metered-dose in- haler (800 μg/puff) 2-4 puffs tid-qid Nedocromil Tilade metered-dose in- haler (1.75 mg/puff) 2-4 puffs bid-qid Phosphodiesterase Inhibitor Theophylline Slo-Bid Gyrocaps, Theo-Dur, Unidur extended-release capsules or tablets 100-300 mg bid B. Inhaled corticosteroids 1. Regular use of an inhaled corticosteroid can suppress inflammation, decrease bronchial hyperresponsiveness and decrease symptoms. Inhaled corticosteroids are recommended for most patients. 2. Adverse effects. Inhaled corticosteroids are usually free of toxicity. Dose-dependent slowing of linear growth may occur within 6-12 weeks in some children. Decreased bone density, glaucoma and cataract formation have been reported. Churg- Strauss vasculitis has been reported rarely. Dysphonia and oral candidiasis can occur. The use of a spacer device and rinsing the mouth after inhalation decreases the incidence of candidiasis. C. Leukotriene modifiers 1. Leukotrienes increase production of mucus and edema of the airway wall, and may cause bronchoconstriction. Montelukast and zafirlukast are leukotriene receptor antagonists. Zileuton inhibits synthesis of leukotrienes. 2. Montelukast (Singulair) is modestly effective for maintenance treatment of intermittent or persistent asthma. It is taken once daily in the evening. It is less effective than inhaled corticosteroids, but addition of montelukast may permit a reduction in corticosteroid dosage. Montelukast added to oral or inhaled corticosteroids can improve symptoms. 3. Zafirlukast (Accolate) is modestly effective for maintenance treatment of mild-to-moderate asthma It is less effective than inhaled corticosteroids. Taking zafirlukast with food mark- edly decreases its bioavailability. Theophylline can decrease its effect. Zafirlukast increases serum concentrations of oral anticoagulants and may cause bleeding. Infrequent adverse effects include mild headache, gastrointestinal disturbances and increased serum aminotransferase activity. Drug- induced lupus and Churg-Strauss vasculitis have been reported. 4. Zileuton (Zyflo) is modestly effective for mainte- nance treatment, but it is taken four times a day and patients must be monitored for hepatic toxicity. D. Cromolyn (Intal) and nedocromil (Tilade) 1. Cromolyn sodium, an inhibitor of mast cell degr anul at i on, can decr ease ai r way hyperresponsiveness in some patients with asthma. The drug has no bronchodilating activity and is useful only for prophylaxis. Cromolyn has virtually no systemic toxicity. 2. Nedocromil has similar effects as cromolyn. Both cromolyn and nedocromil are much less effective than inhaled corticosteroids. E. Theophylline 1. Oral theophylline has a slower onset of action than inhaled beta 2 agonists and has limited usefulness for treatment of acute symptoms. It can, however, reduce the frequency and severity of symptoms, especially in nocturnal asthma, and can decrease inhaled corticosteroid requirements. 2. When theophylline is used alone, serum concen- trations between 8-12 mcg/mL provide a modest improvement is FEV 1 . Serum levels of 15-20 mcg/mL are only minimally more effective and are associated with a higher incidence of cardiovascu- lar adverse events. F. Oral corticosteroids are the most effective drugs available for acute exacerbations of asthma unre- sponsive to bronchodilators. 1. Oral corticosteroids decrease symptoms and may prevent an early relapse. Chronic use of oral corticosteroids can cause glucose intolerance, weight gain, increased blood pressure, osteoporo- sis, cataracts, immunosuppression and decreased growth in children. Alternate-day use of corticosteroids can decrease the incidence of adverse effects, but not of osteoporosis. 2. P r e d n i s o n e , p r e d n i s o l o n e o r methylprednisolone (Solu-Medrol), 40-60 mg qd; for children, 1-2 mg/kg/day to a maximum of 60 mg/day. Therapy is continued for 3-10 days. The oral steroid dosage does not need to be tapered after short-course “burst” therapy if the patient is receiving inhaled steroid therapy. Pharmacotherapy for Asthma Based on Disease Classification Classifi- cation Long-term control medications Quick-relief medica- tions Mild inter- mittent Short-acting beta 2 ag- onist as needed Mild per- sistent Low-dose inhaled corticosteroid or cromolyn sodium (Intal) or nedocromil (Tilade) Short-acting beta 2 ag- onist as needed Moderate persistent Medium-dose inhaled corticosteroid plus a long-acting bronchodilator (long-act- ing beta 2 agonist) Short-acting beta 2 ag- onist as needed Severe persistent High-dose inhaled corticosteroid plus a long-acting bronchodilator and sys- temic corticosteroid Short-acting beta 2 ag- onist as needed III. Management of acute exacerbations A. High-dose, short-acting beta 2 agonists delivered by a metered-dose inhaler with a volume spacer or via a nebulizer remains the mainstay of urgent treatment. B. Most patients require therapy with systemic corticosteroids to resolve symptoms and prevent relapse. Hospitalization should be considered if the PEFR remains less than 70% of predicted. Patients with a PEFR less than 50% of predicted who exhibit an increasing pCO 2 level and declining mental status are candidates for intubation. C. Non-invasive ventilation with bilevel positive airway pressure (BIPAP) may be used to relieve the work-of- breathing while awaiting the effects of acute treatment, provided that consciousness and the ability to protect the airway have not been compromised. References, see page 360. Chronic Obstructive Pulmonary Dis- ease Chronic obstructive pulmonary disease (COPD) is the most common cause of death in the United States and currently kills more than 100,000 Americans each year. COPD is characterized by airflow limitation that is not fully reversible. Airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. I. Pathophysiology A. Airflow obstruction is the result of both small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema). Airflow obstruction can be accompanied by partially reversible airways hyperreactivity. B. Alpha-1 antitrypsin (AAT) deficiency is the only genetic abnormality that predisposes to lung disease similar to COPD. Severe AAT deficiency has a fre- quency of about 1 in 3,000 live births. These individuals may have liver disease in infancy or in old age, or they may develop AAT-COPD in their thirties or forties, especially if they smoke. About 2 percent of patients with COPD or sustained asthma may have severe AAT deficiency. Persons with known COPD, or asthma with non-remittent airflow obstruction should be screened for AAT deficiency. II.Clinical features A. Patients with COPD have usually been smoking at least 20 cigarettes per day for 20 or more years before symptoms develop. Chronic productive cough, some- times with wheezing, often begins when patients are in their forties. B. Dyspnea on effort does not usually begin until the mid sixties or early seventies. Sputum production initially occurs only in the morning. Sputum is usually mucoid but becomes purulent with an exacerbation. Acute chest illnesses may occur intermittently, and are character- ized by increased cough, purulent sputum, wheezing, dyspnea, and occasionally fever. C. Late in the course of the illness, an exacerbation may cause hypoxemia with cyanosis. Associated findings also include: 1. Weight loss. 2. Hypercapnia with more severe hypoxemia in the setting of end-stage disease. Morning headache, which suggests hypercapnia. 3. Cor pulmonale with right heart failure and edema. These abnormalities can develop in patients with hypoxemia and hypercapnia. D. Physical examination of the chest early in the disease may show only prolonged expiration and wheezes on forced exhalation. As obstruction progresses, hyperin- flation becomes evident, and the anteroposterior diameter of the chest increases. The diaphragm is depressed. Breath sounds are decreased and heart sounds become distant. Coarse crackles may be heard at the lung bases. Wheezes are frequently heard. 1. Patients with end-stage COPD may lean forward with arms outstretched and weight supported on the palms. Other signs in a patient with end-stage disease may include: a. The full use of the accessory respiratory muscles of the neck and shoulder girdle. b. Expiration through pursed lips. c. Paradoxical retraction of the lower interspaces during inspiration (Hoover’s sign). d. Cyanosis. e. An enlarged, tender liver secondary to right heart failure. f. Asterixis due to severe hypercapnia. E. Plain chest radiography. Emphysema is characterized by over distention of the lungs as indicated on frontal chest radiographs by a low, flat diaphragm and a long, narrow heart shadow. Flattening of the diaphragmatic contour and an increased retrosternal airspace are present on the lateral projection. Rapid tapering of the vascular shadows accompanied by hypertransradiancy of the lungs is a sign of emphysema. Bullae, presenting as radiolucent areas larger than one centimeter in diameter and surrounded by arcuate hairline shadows, are proof of emphysema. F. Pulmonary function tests are necessary for diagnos- ing and assessing the severity of airflow obstruction, and are helpful in following its progress. The FEV 1 has less variability than other measurements of airways dynamics. In the mildest degree of airflow obstruction, the FEV 1 /FVC ratio falls below 0.70 and the FEV 1 percent predicted is normal. Up to 30 percent of pa- tients have an increase of 15 percent or more in their FEV 1 following inhalation of a beta-agonist. G. Arterial blood gases reveal mild or moderate hypoxemia without hypercapnia in the early stages. As the disease progresses, hypoxemia becomes more severe and hypercapnia supervenes. The frequency of erythrocytosis increases as arterial PO 2 falls below 55 mm Hg. H. Sputum examination. In stable chronic bronchitis, sputum is mucoid. During an exacerbation, sputum usually becomes purulent with an influx of neutrophils. The Gram stain usually shows a mixture of organisms. The most frequent pathogens cultured from the sputum are Streptococcus pneumoniae and Haemophilus influenzae. Diagnosis of chronic obstructive pulmonary dis- ease (COPD) History Smoking history Age at initiation Average amount smoked per day Date when stopped smoking or a current smoker Environmental history Cough Chronic productive cough for at least one quarter of the year for two successive years is the defining characteristic of chronic bronchitis. Sputum, blood or blood streaking in the sputum. Wheezing Acute chest illnesses Frequency of episodes of increased cough and sputum with wheezing. Dyspnea Amount of effort required to induce uncomfortable breathing. Physical examination Chest The presence of severe emphysema is indicated by: overdistention of the lungs in the stable position; decreased intensity of breath and heart sounds and prolonged expiratory phase. Wheezes during auscultation on slow or forced breathing and prolongation of forced expiratory time. Severe disease is indicated by pursed-lip breathing, use of accessory respiratory muscles, retraction of lower interspaces. Other Unusual positions to relieve dyspnea at rest. Digital clubbing suggests the possibility of lung cancer or bronchiectasis. Mild dependent edema may be seen in the absence of right heart failure. Differential diagnosis of COPD Diagnosis Features COPD Onset in mid-life Symptoms slowly progressive Long smoking history Dyspnea during exercise Largely irreversible airflow limitation Asthma Onset in childhood Symptoms vary from day to day Symptoms at night/early morning Allergy, rhinitis, and/or eczema also present Family history of asthma Largely reversible airflow limitation Heart failure Fine basilar crackles Chest X-ray shows dilated heart, pul- monary edema Pulmonary function tests indicate vol- ume restriction, not airflow limitation Bronchiectas is Large volumes of purulent sputum Commonly associated with bacterial infection Coarse crackles/clubbing on auscultation Chest X-ray/CT shows bronchial dila- tion, bronchial wall thickening Diagnosis Features Tuberculosis Onset all ages Chest X-ray shows lung infiltrate Microbiological confirmation High local prevalence of tuberculosis Obliterative bronchiolitis Onset in younger age, nonsmokers May have history of rheumatoid arthri- tis or fume exposure CT on expiration shows hypodense areas Diffuse panbronchiol itis Most patients are male and non- smokers. Almost all have chronic si- nusitis Chest X-ray and HRCT show diffuse small centrilobular nodular opacities and hyperinflation Classification of Severity of Chronic Obstructive Pulmonary Disease Stage Characteristics 0: At risk Normal spirometry Chronic symptoms (cough, sputum pro- duction) I: Mild COPD FEV 1 /FVC <70 percent FEV 1 >80 percent predicted With or without chronic symptoms (cough, sputum production) II: Moder- ate COPD FEV 1 /FVC <70 percent 30 percent 80 percent predicted with or without symptoms Short-acting bronchodilator when needed II: Moderate COPD IIA FEV 1 /FVC <70 percent 50 percent 55 mm Hg (7.3 kPa), OR c. Cor pulmonale is present. d. Candidates must be under 65 years of age, not have dysfunction of major organs other than the lung, and not have active or recent malignancy or infection with HIV, hepatitis B, or hepatitis C viruses. References, see page 360. Acute Bronchitis Acute bronchitis is one of the most common diagnoses in ambulatory care medicine, accounting for 2.5 million physi- cian visits per year. This condition is one of the top 10 diagnoses for which patients seek medical care. Acute bronchitis is one of the most common diagnoses made by primary care physicians. Viruses are the most common cause of acute bronchitis in otherwise healthy adults. Only a small portion of acute bronchitis infections are caused by nonviral agents, with the most common organisms being Mycoplasma pneumoniae and Chlamydia pneumoniae. I. Diagnosis A. The cough in acute bronchitis may produce either clear or purulent sputum. This cough generally lasts seven to 10 days. Approximately 50 percent of patients with acute bronchitis have a cough that lasts up to three weeks, and 25 percent of patients have a cough that persists for over a month. B. Physical examination. Wheezing, rhonchi, or a prolonged expiratory phase may be present. C. Diagnostic studies 1. The appearance of sputum is not predictive of whether a bacterial infection is present. Purulent sputum is most often caused by viral infections. Microscopic examination or culture of sputum generally is not helpful. Since most cases of acute bronchitis are caused by viruses, cultures are usually negative or exhibit normal respiratory flora. M. pneumoniae or C. pneumoniae infection are not detectable on routine sputum culture. 2. Acute bronchitis can cause transient pulmonary function abnormalities which resemble asthma. Therefore, to diagnose asthma, changes that persist after the acute phase of the illness must be docu- mented. When pneumonia is suspected, chest radiographs and pulse oximetry may be helpful. II. Pathophysiology Selected Triggers of Acute Bronchitis Viruses: adenovirus, coronavirus, coxsackievirus, enterovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, rhinovirus Bacteria: Bordetella pertussis, Bordetella parapertussis, Branhamella catarrhalis, Haemophilus influenzae, Streptococ- cus pneumoniae, atypical bacteria (eg, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species) Yeast and fungi: Blastomyces dermatitidis, Candida albicans, Candida tropicalis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum Noninfectious triggers: asthma, air pollutants, ammonia, canna- bis, tobacco, trace metals, others A. Acute bronchitis is usually caused by a viral infection. In patients younger than one year, respiratory syncytial virus, parainfluenza virus, and coronavirus are the most common isolates. In patients one to 10 years of age, parainfluenza virus, enterovirus, respiratory syncytial virus, and rhinovirus predominate. In patients older than 10 years, influenza virus, respiratory syncytial virus, and adenovirus are most frequent. B. Parainfluenza virus, enterovirus, and rhinovirus infec- tions most commonly occur in the fall. Influenza virus, respiratory syncytial virus, and coronavirus infections are most frequent in the winter and spring. III. Signs and symptoms A. Cough is the most commonly observed symptom of acute bronchitis. The cough begins within two days of infection in. Most patients have a cough for less than two weeks; however, 26 percent are still coughing after two weeks, and a few cough for six to eight weeks. B. Other signs and symptoms may include sputum pro- duction, dyspnea, wheezing, chest pain, fever, hoarse- ness, malaise, rhonchi, and rales. Sputum may be clear, white, yellow, green, or tinged with blood. Color alone should not be considered indicative of bacterial infection. IV. Physical examination and diagnostic studies A. The physical examination should focus on fever, tachypnea, wheezing, rhonchi, and prolonged expira- tion. Evidence of consolidation is absent. Fever may be present in some patients with acute bronchitis. How- ever, high fever should prompt consideration of pneu- monia or influenza. B. Chest radiography should be reserved for patients with possible pneumonia, heart failure, advanced age, chronic obstructive pulmonary disease, malignancy, tuberculosis, or immunocompromised or debilitated status. V. Differential diagnosis A. Acute bronchitis or pneumonia can present with fever, constitutional symptoms and a productive cough. Patients with pneumonia often have rales. When pneumonia is suspected on the basis of the presence of a high fever, constitutional symptoms or severe dyspnea, a chest radiograph should be obtained. Differential Diagnosis of Acute Bronchitis Disease process Signs and symptoms Asthma Evidence of reversible airway obstruction even when not infected Allergic aspergillosis Transient pulmonary infiltrates Eosinophilia in sputum and peripheral blood smear Occupational exposures Symptoms worse during the work week but tend to improve during weekends, holidays and vacations Chronic bron- chitis Chronic cough with sputum production on a daily basis for a minimum of three months Typically occurs in smokers Disease process Signs and symptoms Sinusitis Tenderness over the sinuses, postnasal drain- age Common cold Upper airway inflammation and no evidence of bronchial wheezing Pneumonia Evidence of infiltrate on the chest radiograph Congestive heart failure Basilar rales, orthopnea Cardiomegaly Evidence of increased interstitial or alveolar fluid on the chest radiograph S 3 gallop, tachycardia Reflux esophagitis Intermittent symptoms worse when lying down Heartburn Bronchogenic tumor Constitutional signs often present Cough chronic, sometimes with hemoptysis Aspiration syndromes Usually related to a precipitating event, such as smoke inhalation Vomiting Decreased level of consciousness B. Asthma should be considered in patients with repeti- tive episodes of acute bronchitis. Patients who repeat- edly present with cough and wheezing can be given spirometric testing with bronchodilation to help differen- tiate asthma from recurrent bronchitis. C. Congestive heart failure may cause cough, shortness of breath and wheezing in older patients. Reflux esophagitis with chronic aspiration can cause bronchial inflammation with cough and wheezing. Bronchogenic tumors may produce a cough and obstructive symp- toms. VI. Treatment A. Protussives and antitussives 1. Because acute bronchitis is most often caused by a viral infection, usually only symptomatic treatment is required. Treatment can focus on preventing or controlling the cough (antitussive therapy). 2. Antitussive therapy is indicated if cough is creating significant discomfort. Studies have reported suc- cess rates ranging from 68 to 98 percent. Nonspe- cific antitussives, such as hydrocodone (Hycodan), dextromethorphan (Delsym), codeine (Robitussin A-C), carbetapentane (Rynatuss), and benzonatate (Tessalon), simply suppress cough. Selected Nonspecific Antitussive Agents Preparation Dosage Side effects Hydromorphone-g uaifenesin (Hycotuss) 5 mg per 100 mg per 5 mL (one teaspoon) Sedation, nausea, vomiting, respira- tory depression Dextromethorpha n (Delsym) 30 mg every 12 hours Rarely, gastroin- testinal upset or sedation Hydrocodone (Hycodan syrup or tablets) 5 mg every 4 to 6 hours Gastrointestinal upset, nausea, drowsiness, con- stipation Codeine (Robitussin A-C) 10 to 20 mg every 4 to 6 hours Gastrointestinal upset, nausea, drowsiness, con- stipation Carbetapentane (Rynatuss) 60 to 120 mg ev- ery 12 hours Drowsiness, gas- trointestinal upset Benzonatate (Tessalon) 100 to 200 mg three times daily Hypersensitivity, gastrointestinal upset, sedation B. Bronchodilators. Patients with acute bronchitis who used an albuterol metered-dose inhaler are less likely to be coughing at one week, compared with those who received placebo. C. Antibiotics. Physicians often treat acute bronchitis with antibiotics, even though scant evidence exists that antibiotics offer any significant advantage over placebo. Antibiotic therapy is beneficial in patients with exacer- bations of chronic bronchitis. Oral Antibiotic Regimens for Bronchitis Drug Recommended regimen Azithromycin (Zithromax) 500 mg; then 250 mg qd Erythromycin 250-500 mg q6h Clarithromycin (Biaxin) 500 mg bid Levofloxacin (Levaquin) 500 mg qd Trovafloxacin (Trovan) 200 mg qd Trimethoprim/sulfamethoxaz ole (Bactrim, Septra) 1 DS tablet bid Doxycycline 100 mg bid D. Bronchodilators. Significant relief of symptoms occurs with inhaled albuterol (two puffs four times daily). When productive cough and wheezing are present, bronchodilator therapy may be useful. References, see page 360. Infectious Disorders Community-Acquired Pneumonia Four million cases of Community-acquired pneumonia (CAP) occur annually. Bacteria are the most common cause of pneumonia and have been divided into two groups: “typical” and “atypical”: “Typical” organisms include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and other Gram negative bacteria. Atypical” refers to pneumonia caused by Legionella sp, Mycoplasma pneumoniae, and Chlamydia pneumoniae. I. Pathophysiology A. Pneumococcal pneumonia 1. S. pneumoniae is the most common cause of CAP. The organism is isolated in only 5 to 18 percent. Risk factors for pneumococcal pneumonia include: advanced age, cigarette smoking, dementia, malnu- trition, the presence of chronic illnesses, and human immunodeficiency virus (HIV) infection. 2. Pneumonia caused by pneumococcus is usually associated with cough, sputum production, and fever. Bacteremia accompanies the pneumonia in 20 to 30 percent of cases. A parapneumonic pleural effusion is present in the majority of patients, but empyema occurs in only two percent of cases. 3. Penicillin resistance is an increasing problem. B. Other bacteria. H. influenzae (generally other than type B), S. aureus, Legionella, and Gram negative bacteria each account for 3 to 10 percent of cases of CAP. 1. The patient population and clinical presentation of H. influenzae pneumonia is similar to that with pneumococcal disease. 2. S. aureus pneumonia that is community-acquired is usually seen in the elderly and in younger patients who are recovering from influenza (post-influenza pneumonia). 3. Legionella accounts for 2 to 8 percent of cases of CAP. Among patients with pneumonia who can be treated as outpatients, the frequency of Legion- naires’ disease is less than 1 percent. Legionella is much more frequent in hospitalized patients, espe- cially those admitted to intensive care units. 4. Gram-negative bacilli, especially P. aeruginosa, are an uncommon cause of CAP except in patients with neutropenia, cystic fibrosis, late stage HIV infection and bronchiectasis. 5. Other bacteria that can cause CAP include Neisseria meningitidis, Moraxella catarrhalis, and Streptococcus pyogenes. 6. Anaerobic organisms may be the cause of aspira- tion pneumonia and lung abscess. II.Diagnostic approach A. Clinical evaluation. CAP caused by pyogenic organ- isms presents with the sudden onset of rigors, fever, pleuritic chest pain, and cough productive of purulent sputum. Chest pain occurs in 30 percent of cases, chills in 40 to 50 percent, and rigors in 15 percent. B. On physical examination, 80 percent are febrile, although this finding is frequently absent in older patients. A respiratory rate above 24 breaths/minute is noted in 45 to 70 percent of patients; tachycardia is also common. Chest examination reveals audible rales in most patients, while one-third have consolidation. C. The major blood test abnormality is leukocytosis (15,000 and 30,000 per mm 3 ) with a leftward shift. Leukopenia can occur. D. Chest radiographs. The presence of an infiltrate on plain chest radiograph is the “gold standard” for diagnosing pneumonia. The radiographic appearances include lobar consolidation, interstitial infiltrates, and cavitation. E. Sputum examination. An etiologic agent is found in 51 percent of patients. A specimen that has greater than 25 PMN and less than 10 epithelial cells per low power field represents a purulent specimen. Gram stain and culture may identify the cause of the pneu- monia. F. Blood cultures should be obtained in patients who require hospitalization. G. Urinary antigen testing for pneumococcal cell wall components has a sensitivity of 70 to 90 percent; specificity is 80 to 100 percent. Urinary antigen testing is also available for Legionella species and is highly sensitive and specific and inexpensive. Urinary antigen testing is recommended for both S. pneumoniae and Legionella, particularly in patients with risk factors for Legionella infection (eg, smoking, chronic lung dis- ease, immunosuppression, and CAP requiring hospi- talization). Causes of Community-acquired Pneumonia Etiology Prevalence (percent) Streptococcus pneumoniae Hemophilus influenzae Staphylococcus aureus Gram-negative bacilli Aspiration Miscellaneous Legionella sp. Mycoplasma pneumoniae Chlamydia pneumoniae Viruses 20-60 3-10 3-5 3-10 6-10 3-5 2-8 1-6 4-6 2-15 III. Treatment of Community-Acquired Pneumonia A. Empiric regimens. For uncomplicated pneumonia in patients who do not require hospitalization, macrolide therapy is recommended. Erythromycin is the least expensive macrolide but is associated with gastroin- testinal upset in many patients. Azithromycin (Zithromax [500 mg PO QD]) is recommended because it causes less gastrointestinal upset; if macrolide resistance in the community is high, doxycycline (100 mg PO twice a day) should be considered. Telithromycin (Ketek) or a quinolone is also reasonable if macrolide resistance is prevalent. Quinolones are not recommended for patients with CAP because achievable tissue concentrations of these agents will be close to the minimum inhibitory concentration for pneumococcus and resistance may emerge with overuse. B. Duration of therapy. The usual recommended duration of therapy is 7 to 14 days. Three days of azithromycin may be as effective as longer course of antibiotics. For a hospitalized patient, ceftriaxone (Rocephin [2 g IV QD]) with or without azithromycin (depending upon the likelihood of an atypical organ- ism) is recommended. For more severely ill patients who might have an atypical pneumonia or patients admitted to an ICU, therapy consists of a quinolone, such as levofloxacin (Levaquin [500 mg IV QD]) or azithromycin to treat legionella infection as well as mycoplasma and chlamydia. Consideration should be given to adding a second agent for pneumococcus to levofloxacin. Ceftriaxone should be given with azithromycin in these sicker patients. Recommended Empiric Drug Therapy for Patients with Community-Acquired Pneumonia Clinical Situa- tion Primary Treat- ment Alternative(s) Younger (<60 yr) outpatients without underly- ing disease Macrolide anti- biotics (azithromycin, clarithromycin, dirithromycin, or erythromycin) Levofloxacin or doxycycline Older (>60 yr) outpatients with underlying dis- ease Levofloxacin or cefuroxime or Trimethoprim- sulfa- methoxazole Add vancomycin in severe, life- threatening pneumonias Beta-lactamase inhib- itor (with macrolide if legionella infection suspected) Gross aspira- tion suspected Clindamycin IV Cefotetan, ampicillin/sulbactam Common Antimicrobial Agents for Community- Acquired Pneumonia in Adults Type Agent Dosage Oral therapy Macrolides Erythromycin Clarithromycin (Biaxin) Azithromycin (Zithromax) 500 mg PO qid 500 mg PO bid 500 mg PO on day 1, then 250 mg qd x 4 days Type Agent Dosage Beta- lactam/beta- lactamase in- hibitor Amoxicillin- clavulanate (Augmentin) Augmentin XR 500 mg tid or 875 mg PO bid 2 tabs q12h Quinolones Ciprofloxacin (Cipro) Levofloxacin (Levaquin) Ofloxacin (Floxin) 500 mg PO bid 500 mg PO qd 400 mg PO bid Tetracycline Doxycycline 100 m g PO bid Sulfonamide Trimethoprim- sulfamethoxazole 160 mg/800 mg (DS) PO bid Intravenous Therapy Cephalosporins Second- generation Third-gener- ation (anti- Pseudomo- nas aeruginosa) Cefuroxime (Kefurox, Zinacef) Ceftizoxime (Cefizox) Ceftazidime (Fortaz) Cefoperazone (Cefobid) 0.75-1.5 g IV q8h 1-2 g IV q8h 1-2 g IV q8h 1-2 g IV q8h Beta- lactam/beta- lactamase in- hibitors Ampicillin- sulbactam (Unasyn) Piperacillin/tazoba ctam (Zosyn) Ticarcillin- clavulanate (Timentin) 1.5 g IV q6h 3.375 g IV q6h 3.1 g IV q6h Quinolones Ciprofloxacin (Cipro) Levofloxacin (Levaquin) Ofloxacin (Floxin) 400 mg IV q12h 500 mg IV q24h 400 mg IV q12h Aminoglycosid es Gentamicin Amikacin Load 2.0 mg/kg IV, then 1.5 mg/kg q8h Vancomycin Vancomycin 1 gm IV q12h A. Patients initially treated with intravenous antibiotics can be switched to oral agents when the patient is afebrile. The regimens for the hospitalized patient are also appropriate for patients admitted from long-term care facilities. Discharged from the hospital may be com- pleted once oral therapy. B. Most patients respond to a course of 10 to 14 days of antibiotics, although 3 to 5 days of azithromycin is an alternative in ambulatory patients. C. Response to therapy. Some improvement in the patient’s clinical course should be seen within 48 to 72 hours. Fever in patients with lobar pneumonia often takes 72 hours or longer to improve. The chest x-ray usually clears within four weeks in patients younger than 50 years of age without underlying pulmonary disease. D. The nonresponding patient 1. If the patient does not improve within 72 hours, an organism which is not covered by the initial antibi- otic regimen should be considered. This could be the result of drug resistance, nonbacterial infection, unusual pathogens (eg, Pneumocystis carinii or Mycobacterium tuberculosis), drug fever, or a complication such as postobstructive pneumonia, empyema, or abscess. The differential diagnosis also includes noninfectious etiologies, such as malignancy, inflammatory conditions, or heart failure. 2. When evaluating a patient who is not responding to therapy, it is important to repeat the history to include travel and pet exposures to look for unusual pathogens. Bronchoscopy can be performed to evaluate the airway for obstruction due to a foreign body or malignancy. Previously unsuspected patho- gens may include P. carinii or M. tuberculosis. References, see page 360. Tuberculosis Beginning in 1986, an unexpected resurgence of tuberculo- sis occurred in the United States, with the incidence of the disease rising to 10.5 cases per 100,000 population. I. Screening for Tuberculosis A. Tuberculin testing generally should be performed in persons who belong to at least one of the high-risk groups. Screening should be performed using the Mantoux test (intracutaneous tuberculin test). B. Purified protein derivative (PPD) tuberculin 0.1 mL (5 units) injected intracutaneously, raising a wheal 6 to 10 mm in diameter. After 48 to 72 hours, the test should be “read.” II. Treatment of Latent Tuberculosis Infection A. Before initiating treatment of latent tuberculosis infec- tion, physicians must ensure that active disease is not present. B. The usual dosage of isoniazid is 5 mg per kg per day to a maximum of 300 mg per day. A nine-month regimen is recommended. A twice-weekly dosing regimen is acceptable when compliance is in question, but isoniazid should be administered only as directly observed therapy. C. A nine-month course of isoniazid is recommended in children. To reduce the risk of drug-related peripheral neuropathy with isoniazid therapy, pyridoxine (Hexa-Betalin), in a dosage of 10 to 50 mg per day, is coadministered in all children six years of age and older. Pyridoxine should also be strongly considered in patients who have conditions in which neuropathy is common (eg, diabetes, alcoholism and malnutrition), pregnant women and patients who are also taking anticonvulsant drugs. Groups at High Risk for Tuberculosis Persons with recent Mycobacterium tuberculosis infection (within the past 2 years) or a history of inadequately treated tuberculosis Close contacts of persons known or suspected to have tubercu- losis Persons infected with the human immunodeficiency virus Persons who inject illicit drugs or use other locally identified high-risk substances (eg crack cocaine) Residents and employees of high-risk congregate settings (eg correctional institutions, nursing homes, mental institutions or shelters for the homeless) Health-care workers who serve high-risk clients Foreign-born persons including children who have recently arrived (within 5 years) from countries that have a high incidence or prevalence of tuberculosis (Africa Asia and Latin America) Some medically underserved low-income populations High-risk racial or ethnic minority populations as defined locally Elderly persons Children less than 4 years of age or infants children and ado- lescents who have been exposed to adults in high-risk categories Persons with medical conditions known to increase the risk of tuberculosis: Chest radiograph findings suggestive of previous tubercu- losis in a person who received inadequate treatment or no treatment Diabetes mellitus Silicosis Organ transplantation Prolonged corticosteroid therapy (eg prednisone in a 15 mg or more per day for 1 month Other immunosuppressive therapy Cancer of the head and neck Hematologic and reticuloendothelial diseases (eg leukemia and lymphoma) End-stage renal disease Intestinal bypass or gastrectomy Chronic malabsorption syndromes Weight that is 10 percent or more below ideal body weight Interpretation of the Purified Protein Derivative Tuberculin Skin Test I. An induration of 5 mm or more is classified as positive in persons with any of the following: A. Human immunodeficiency virus infection B. Recent close contact with persons who have active tuberculosis C. Chest radiographs showing fibrosis (consistent with healed tuberculosis) II. An induration of 10 mm or more is classified as positive in all persons who do not meet any of the criteria in section I but have other risk factors for tuberculosis III. An induration of 15 mm or more is positive in persons who do not meet any of the criteria from sections I or II. IV. Recent tuberculin skin test conversion is defined as an increase in induration of 10 mm or more within a two-year period, regardless of age. V. In health-care workers, the recommendations in sections I, II and III generally should be followed. In facilities where tuberculosis patients frequently receive care, the optimal cut-off point for health-care workers with no other risk fac- tors may be an induration of 10 mm or greater. D. Monthly clinical assessments are mandatory in pa- tients taking isoniazid for latent tuberculosis. At each monthly visit, patients should be evaluated for hepati- tis, anemia and neurotoxicity. E. Measuring baseline liver enzyme levels before the initiation of isoniazid therapy is recommended only in patients with pregnancy, postpartum status, human immunodeficiency virus infection, alcoholism or chronic hepatitis. F. Isoniazid should be discontinued if transaminase levels are more than three times higher than the upper limit of normal in symptomatic patients or five times higher than the upper limit of normal in asymptomatic patients. G. Regimens for patients exposed to multidrug-resistant tuberculosis generally consist of two drugs to which the infecting organism is likely to be susceptible. III. Diagnosis of Active Tuberculosis A. Symptoms of pulmonary tuberculosis, particularly reactivation disease, include cough, fever, sweats, chills, anorexia, weight loss and malaise. Signs of active disease included upper-zone disease on the chest radiograph, fever, night sweats and weight loss, along with a CD4 count of less than 200 cells per mm 3 in HIV-infected patients. B. Extrapulmonary tuberculosis may be associated with altered mental status (central nervous system involve- ment), back pain (spinal disease) and abdominal pain (peritoneal disease). The most common types of extrapulmonary tuberculosis are pleural, lymphatic, bone and joint disease, genitourinary tract and miliary disease, meningitis and peritonitis. C. Although a PPD test should always be performed, it may be negative in 10 to 25 percent of patients with active disease. D. When pulmonary tuberculosis is suspected, chest radiographs should be obtained. In primary pulmonary tuberculosis, numerous abnormalities can be ob- served, including atelectasis, parenchymal consolida- tion, lymphadenopathy, pleural effusion and a miliary pattern. Any lung lobe may be affected, although lower-lobe involvement may be somewhat more common. In contrast, reactivation tuberculosis has a predilection for upper-lobe involvement, and cavitation occurs in approximately 50 percent of patients. E. In all patients with suspected active disease, three sputum samples for mycobacterial acid-fast stain examination and Mycobacterium tuberculosis cultures should be collected on each of three consecutive days. Acid-fast smears are usually complete within 24 hours. IV. Treatment of Active Tuberculosis A. A four-drug regimen should be initiated in all adults with confirmed or suspected active tuberculosis, and pyridoxine in a dosage of 50 mg per day should be administered with regimens containing isoniazid to help prevent neurotoxicity. B. After two months of a four-drug regimen to which the initial isolates were sensitive, patients continue treat- ment with isoniazid and rifampin alone if repeat sputum cultures are negative and the patient has improved clinically. Patients continue this dual regi- men for another four months, at which time treatment may be discontinued if sputum cultures remain nega- tive. Monthly evaluations, including sputum acid-fast smears and cultures, should be performed throughout treatment. Treatment of Active Tuberculosis: First-Line Medi- cations Drug Daily dosing Twice-we ekly dos- ing Thrice-w eekly dosing Adverse reactions Isoniazid (INH) Children: 10 mg per kg PO or IM Adults: 300 mg PO or IM Max: 300 mg Chil- dren: 20- 40 mg/kg PO/IM Adults: 15 mg per kg PO or IM Maximum: 300 mg Children: 20 to 40 mg per kg PO or IM Adults: 15 mg per kg PO or IM Maximum: 300 mg Elevation of hepatic enzyme levels, hepatitis, neuropa- thy, cen- tral ner- vous sys- tem ef- fects Rifampin (Rifadin) Children: 10 to 20 mg per kg PO or IV Adults: 10 mg per kg PO or IV Maximum: 600 mg Children: 10 to 20 mg per kg PO or IV Adults: 10 mg per kg PO or IV Maximum: 600 mg Children: 10 to 20 mg per kg PO or IV Adults: 10 mg per kg PO or IV Maximum: 600 mg Orange discolor- ation of secretions and urine, gastroin- testinal tract up- set, hepa- titis, bleeding problems, flu-like symp- toms, drug inter- actions, rash Drug Daily dosing Twice-we ekly dos- ing Thrice-w eekly dosing Adverse reactions Pyrazina mide Children: 20 to 30 mg per kg PO Adults: 25 mg per kg PO Maximum: 2 g Chil- dren: 50 to 70 mg per kg PO Adults: 50 to 70 mg per kg PO Maximum: 4 g Chil- dren: 50 to 70 mg per kg PO Adults: 50 to 70 mg per kg PO Maximum: 3 g Gastroin- testinal tract up- set, hepa- titis, hyperurice mia, arthralgias Ethambu tol (Myambu tol) Children and adults: 15 to 25 mg per kg PO Children and adults: 50 mg per kg PO Children and adults: 25 to 30 mg per kg PO Optic neu- ritis Preferred Initial Treatment of Children and Adults Option 1 (daily treat- ment) Administer isoniazid (INH), rifampin (Rifadin), pyrazinamide and ethambutol (Myambutol) daily for 2 months; then administer isoniazid and rifampin daily or two to three times a week (only by directly observed therapy) for susceptible isolates. Option 2 (twice-we ekly treat- ment) Administer isoniazid, rifampin, pyrazinamide and ethambutol daily for 2 weeks; then administer the same drugs two times a week for 6 weeks (only by directly observed therapy); subsequently administer isoniazid and rifampin two times a week for 4 months (only by directly observed therapy) for susceptible isolates. Option 3 (thrice-w eekly treat- ment) Administer isoniazid, rifampin, pyrazinamide and ethambutol three times a week for 6 months (only by directly observed therapy). Selected Regimens for Single-Drug Resistance Drug to which infection is resis- tant Treatment regi- men Duration of ther- apy Isoniazid (INH) Rifampin Ethambutol Pyrazinamide 6 to 9 months Rifampin (Rifadin) Isoniazid Ethambutol 18 months Ethambutol (Myambutol), pyrazinamide or streptomycin Isoniazid Rifampin 6 to 9 months References, see page 360. Tonsillopharyngitis In about a quarter of patients with a sore throat, the disorder is caused by group A beta-hemolytic streptococcus. Treat- ment of streptococcal tonsillopharyngitis reduces the occurrence of subsequent rheumatic fever, an inflammatory disease that affects the joints and heart, skin, central nervous system, and subcutaneous tissues. I. Prevalence of pharyngitis A. Group A beta-hemolytic streptococcus (GABHS) typically occurs in patients 5-11 years of age, and it is uncommon in children under 3 years old. Most cases of GABHS occur in late winter and early spring. B. Etiologic causes of sore throat 1. Viral. Rhinoviruses, influenza, Epstein-Barr virus 2. Bacterial. GABHS (Streptococcus pyogenes), Streptococcus pneumoniae, Haemophi l us influenzae, Moraxella catarrhalis, Staphylococcus aureus, anaerobes, Mycoplasma pneumoniae, Candida albicans. C. In patients who present with pharyngitis, the major goal is to detect GABHS infection because rheumatic fever may result. Severe GABHS infections may also cause a toxic-shock-like illness (toxic strep syndrome), bacteremia, streptococcal deep tissue infections (necrotizing fascitis), and streptococcal cellulitis. II. Clinical evaluation of sore throat A. GABHS infection is characterized by sudden onset of sore throat, fever and tender swollen anterior cervical lymph nodes, typically in a child 5-11 years of age. Headache, nausea and vomiting may occur. B. Cough, rhinorrhea and hoarseness are generally absent. III.Physical examination A. Streptococcal infection is suggested by erythema and swelling of the pharynx, enlarged and erythematous tonsils, tonsillar exudate, or palatal petechiae. The clinical diagnosis of GABHS infection is correct in only 50-75% of cases when based on clinical criteria alone. B. Unilateral inflammation and swelling of the pharynx suggests peritonsillar abscess. Distortion of the poste- rior pharyngeal wall suggests a retropharyngeal abscess. Corynebacterium diphtheriae is indicated by a dull membrane which bleeds on manipulation. Viral infections may cause oral vesicular eruptions. C. The tympanic membranes should be examined for erythema or a middle ear effusion. D. The lungs should be auscultated because viral infec- tion occasionally causes pneumonia. IV. Diagnostic testing A. Rapid streptococcal testing has a specificity of 90% and a sensitivity of 80%. A dry swab should be used to sample both the posterior wall and the tonsillar fossae, especially erythematous or exudative areas. B. Throat culture is the most accurate test available for the diagnosis of GABHS pharyngitis. C. Clinical predictors. Physicians are not able to reliably predict which patients will have a positive throat culture for GAS; sensitivity and specificity estimates range from 55 to 74 and 58 to 76 percent, respectively. The Centor criteria include: 1. Tonsillar exudates. 2. Tender anterior cervical adenopathy. 3. Fever by history. 4. Absence of cough. 5. If three or four of these criteria are met, the positive predictive value are 40 to 60 percent. However, the absence of three or four of the criteria has a fairly high negative predictive value of 80 percent. D. Diagnostic tests 1. Throat cultures are the "gold standard" for diagnos- ing GAS pharyngitis. However, cultures take 24 to 48 hours to grow and thus cannot be used to decide which patients merit antibiotic therapy. Throat culture has a 90 percent and specificity of 95 to 99 percent. 2. Rapid Antigen Test (RAT) uses enzyme or acid extraction of antigen from throat swabs. The diag- nostic accuracy shows a sensitivity of 80 to 90 percent and specificity of 90 to 100 percent. E. There are four reasons to treat a streptococcal pharyn- gitis with antibiotics: 1. To prevent rheumatic fever — treatment works, but this complication has nearly disappeared in North America. 2. To prevent peritonsillar abscess — again a vanish- ing complication. 3. To reduce symptoms, there is a modest (approxi- mately one day) reduction in symptoms with early treatment. 4. To prevent transmission — this is important in pediatrics due to extensive exposures. V. Recommendations: Using the Centor criteria and the rapid antigen test (RAT): A. Empirically treat patients who have all four clinical criteria (fever, tonsillar exudate, tender anterior cervical adenopathy, and absence of cough). B. Do not treat with antibiotics or perform diagnostic tests on patients with zero or one criterion. C. Perform RAT on those with two or three criteria and use antibiotic treatment only for patients with positive RAT results. D. Another approach is to treat empirically those adults with three or four of the clinical criteria. VI. Antibiotic therapy A. Starting antibiotic therapy within the first 24-48 hours of illness decreases the duration of sore throat, fever and adenopathy by 12-24 hours. Treatment also minimizes risk of transmission and of rheumatic fever. B. Penicillin VK is the antibiotic of choice for GABHS; 250 mg PO qid or 500 mg PO bid x 10 days [250, 500 mg]. A 10-day regimen is recommended. Penicillin G benzathine (Bicillin LA) may be used as one-time therapy when compliance is a concern; 1.2 million units IM x 1 dose. C. Azithromycin (Zithromax) offers the advantage of once-a-day dosing for just 5 days; 500 mg x 1, then 250 mg qd x 4 days [6 pack]. D. Clarithromycin (Biaxin), 500 mg PO bid; bacteriologic efficacy is similar to that of penicillin VK, and it may be taken twice a day. E. Erythromycin is also effective; 250 mg PO qid; or enteric coated delayed release tablet (PCE) 333 mg PO tid or 500 mg PO bid [250, 333, 500 mg]. Erythromycin ethyl succinate (EES) 400 PO qid or 800 mg PO bid [400 mg]. Gastrointestinal upset is common. VII. Treatment of recurrent GABHS pharyngitis A. When patient compliance is an issue, an injection of penicillin G benzathine may be appropriate. When pa- tient compliance is not an issue, therapy should be changed to a broader spectrum agent. 1. Cephalexin (Keflex) 250-500 mg tid x 5 days [250, 500 mg] 2. Cefadroxil (Duricef) 500 mg bid x 5 days [500 mg] 3. Loracarbef (Lorabid) 200-400 mg bid x 5 days [200, 400 mg] 4. Cefixime (Suprax) 400 mg qd x 5 days [200, 400 mg] 5. Ceftibuten (Cedax) 400 mg qd x 5 days [400 mg] 6. Cefuroxime axetil (Ceftin) 250-500 mg bid x 5 days [125, 250, 500 mg] B. Amoxicillin/clavulanate (Augmentin) has demon- strated superior results in comparison with penicillin; 250-500 mg tid or 875 mg bid [250, 500, 875 mg]. C. Sulfonamides, trimethoprim, and the tetracyclines are not effective for the treatment of GABHS pharyngitis. References, see page 360. Sinusitis Acute sinusitis is caused by infection of the paranasal sinuses. A viral infection associated with the common cold is the most frequent etiology of acute sinusitis. Only a small percentage (two percent) of viral rhinosinusitis is complicated by acute bacterial sinusitis. Uncomplicated viral rhinosinusitis usually resolves in seven to ten days. Acute bacterial sinusitis is also usually a self-limited disease, with 75 percent of cases resolving without treatment in one month. I. Pathophysiology A. Epidemiology. The average adult has from two to three colds and influenza-like illnesses per year. The average child has six to 10 colds per year. Approximately 0.5 to two percent of colds and influenza-like illnesses are complicated by acute bacterial sinusitis in adults. B. Microbial etiology. As noted above, viruses are the most frequent cause of rhinosinusitis. Acute bacterial sinusitis occurs in two percent of cases. 1. Viral. Rhinovirus, parainfluenza, and influenza viruses have all been recovered from sinus aspirates of patients with colds and influenza-like illnesses. 2. Bacterial. Bacterial sinusitis can be divided into community-acquired and nosocomial infections. a. Community-acquired bacterial sinusitis is usually a complication of viral rhinosinusitis, occurring in 0.5 to 2 percent of cases. Other risk factors include nasal allergy, swimming, intranasal cocaine, problems with mucociliary clearance (eg, cystic fibrosis, cilial dysfunction), and immunodefi- ciency (eg, HIV). Patients with polyps, foreign bodies or tumors are also at risk. (1) The most common organisms are Streptococ- cus pneumoniae and Haemophilus influenzae. Another form of community-acquired sinusitis results from extension of dental root infection. b. Nosocomial. Nasogastric tubes, sedation, and coma increase the risk of bacterial sinus infection. Nosocomial sinusitis can be due to Staphylococ- cus aureus, streptococcal spp., Pseudomonas spp., and other Gram negative bacteria. II.Diagnosis A. Clinical diagnosis. Symptoms of acute sinusitis include nasal congestion, purulent nasal discharge, maxillary tooth discomfort, hyposmia, and facial pain or pressure that is worse when bending forward. A patient with a cold or influenza-like illness that has persisted for seven to ten days may have developed bacterial sinusitis. Nasal discharge, particularly if purulent, and/or maxillary pain or tenderness in the face or teeth, particularly if unilateral, is suggestive of acute bacterial sinusitis. B. Patients with high fever, acute facial pain, swelling, and erythema should be treated for acute sinusitis. C. Sinus aspirate culture is the gold standard for diagno- sis in sinus infection and should be considered if there is a suspicion of extension of the infection or other serious complications. D. Radiologic tests are not indicated in the usual case of acute community-acquired sinusitis, unless intracranial or orbital complications are suspected. CT scanning is the imaging procedure of choice. CT scan should be obtained if a patient has failed one or two courses of antibiotic therapy. III. Therapy A. Viral rhinosinusitis 1. Treatment of viral rhinosinusitis should be directed at symptoms, especially the nasal fluid production. First-generation antihistamines reduce sneezing, rhinorrhea, nasal mucus weights and, cough. NSAIDs reduce cough, malaise and headache. 2. Used in combination, chlorpheniramine (12 mg sustained release) and ibuprofen (400 mg) are effective in reducing nasal mucus and sneezing, rhinorrhea, sore throat, cough, malaise, and head- ache. 3. An oral decongestant or a cough suppressant may be added. If symptoms persist despite treatment for seven to 10 days, a secondary bacterial sinusitis may have developed which may require antimicrobial treatment. Antiviral treatment is recommended for influenza. B. Community-acquired bacterial sinusitis 1. Narrow spectrum antibiotics, such as amoxicillin, doxycycline, and trimethoprim-sulfamethoxazole are recommended for first-line therapy of acute bacterial sinusitis. 2. Antibiotic treatment is recommended for patients with moderate to severe symptoms, including maxillary pain or tenderness in the face or teeth and persistent purulent nasal discharge. 3. Amoxicillin is commonly recommended at a dose of 1.5 to 3.5 g/day, although the higher end of the dose range (eg, 1 g three times per day) is recommended. 4. Antibiotics that cover resistant S. pneumoniae, H. influenzae, and M. catarrhalis include: amoxicillin- clavulanate (Augmentin [875-125 mg every 12 hours]) for 7 to 10 days, cefpodoxime (Vantin [200 mg every 12 hours]), cefdinir (Omnicef [600 mg once daily]), levofloxacin (Levaquin [500 mg once daily]) or moxifloxacin (Avelox [400 mg once daily]). A seven- to ten-day course of antimicrobial treatment is the accepted standard. Antimicrobials for acute community-acquired bac- terial sinusitis in adults Drug Dose Amoxicillin-clavulanate (Augmentin) Cefpodoxime proxetil (Vantin) Cefdinir (Omnicef) Levofloxacin (Levaquin) Moxifloxacin (Avelox) 875/125 mg q12h 200 mg q12h 600 mg qd 500 mg qd 400 mg qd C. Treatment failure 1. A second, more prolonged course of treatment with another antibiotic should be administered. Another approach is to obtain a sinus CT scan and refer the patient to an otolaryngologist for sinus aspirate culture and sinus washing, followed by another course of antibiotics. D. Complications of acute bacterial sinusitis, which now rarely occur, are related to local extension into the central nervous system (meningitis), orbit of the eye (orbital cellulitis), and periorbital tissues (osteitis of the sinus bones). References, see page 360. Conjunctivitis Conjunctivitis is the most likely diagnosis in a patient with a red eye and discharge. Most infectious conjunctivitis is viral in adults and children. I. Etiology and clinical manifestations A. Acute conjunctivitis can be classified as infectious or noninfectious and further divided into four main types: 1. Infectious: Bacterial or viral 2. Noninfectious: Allergic nonallergic Differential Diagnosis of Red Eye Conjunctivitis Infectious Viral Bacterial (eg, staphylo- coccus, Chlamydia) Noninfectious Allergic conjunctivitis Dry eye Toxic or chemical reaction Contact lens use Foreign body Factitious conjunctivitis Keratitis Infectious. Bacterial, viral, fungal Noninfectious. Recurrent epithelial erosion, foreign body Uveitis Episcleritis/scleritis Acute glaucoma Eyelid abnormalities Orbital disorders Preseptal and orbital cellulitis Idiopathic orbital inflamma- tion (pseudotumor) B. Bacterial conjunctivitis is commonly caused by Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. 1. Bacterial conjunctivitis is highly contagious; it is spread by direct contact with the patient and his secretions or with contaminated objects. 2. Bacterial conjunctivitis usually causes unilateral redness and discharge. Similar to viral and allergic conjunctivitis, the affected eye often is “stuck shut” in the morning. The purulent discharge continues throughout the day. The discharge is thick and globular; it may be yellow, white, or green. The appearance differs from that of viral or allergic conjunctivitis, which presents with a mostly watery discharge during the day, with a scanty, stringy component that is mucus rather than pus. C. Hyperacute bacterial conjunctivitis 1. N. gonorrhoeae can cause a hyperacute bacterial conjunctivitis that is severe and sight-threatening, requiring immediate ophthalmologic referral. Concur- rent urethritis is typically present. 2. The eye infection is characterized by a profuse purulent discharge. Other symptoms include red- ness, irritation, and tenderness to palpation. There is typically marked chemosis, lid swelling, and tender preauricular adenopathy. Gram negative diplococci can be identified on Gram stain of the discharge. These patients require hospitalization for systemic and topical therapy. D. Viral conjunctivitis is typically caused by adenovirus. The conjunctivitis may be followed by adenopathy, fever, pharyngitis, and upper respiratory tract infection. Viral conjunctivitis is highly contagious; it is spread by direct contact with the patient and his or her secretions or with contaminated objects and surfaces. 1. Viral conjunctivitis presents as injection, watery or mucoserous discharge, and a burning, sandy, or gritty feeling in one eye. Patients may have morning crusting followed by watery discharge with some scanty mucus throughout the day. The second eye usually becomes involved within 24 to 48 hours. 2. On examination there typically is only mucoid dis- charge on the lower lid in the corner of the eye. Usually there is profuse tearing rather than dis- charge. The tarsal conjunctiva may have a follicular or “bumpy” appearance. An enlarged and tender preauricular node may be present. 3. Viral conjunctivitis is a self-limited process. The symptoms frequently get worse for the first three to five days, with very gradual resolution over the following one to two weeks. E. Allergic conjunctivitis is caused by airborne allergens, which cause local mast cell degranulation and the release of histamine. 1. It typically presents as bilateral redness, watery discharge, and itching. Itching is the cardinal symp- tom of allergy, distinguishing it from a viral etiology, which is more typically described as grittiness, burning, or irritation. Eye rubbing can worsen symp- toms. Patients with allergic conjunctivitis often have a history of atopy, seasonal allergy, or specific allergy (eg, to cats). 2. Similar to viral conjunctivitis, allergic conjunctivitis causes diffuse injection with a follicular appearance to the tarsal conjunctiva and profuse watery or mucoserous discharge. There may be morning crusting. It is the complaint of itching and the history of allergy or hay fever and a recent exposure allows the distinction between allergic and viral conjunctivi- tis; the clinical findings are the same. II.Diagnosis A. Conjunctivitis is a diagnosis of exclusion. Conjunctivitis causes red eye and discharge; however, the vision is normal and there is no evidence of keratitis, iritis, or glaucoma. B. Patients with all types of conjunctivitis complain of morning crusting and daytime redness and discharge. On examination, there should be no focal pathology in the lids such as hordeolum (stye), cancerous mound or ulceration, or blepharitis (diffuse eyelid margin thicken- ing and hyperemia with lash crusts). The redness or injection should be diffuse. Foreign body, pterygium, or episcleritis should be considered if the conjunctival injection is localized rather than diffuse. C. Cultures are not necessary for the initial diagnosis and therapy of conjunctivitis. D. Red flags for more serious problems that should prompt evaluation by an ophthalmologist: 1. Reduction of visual acuity 2. Ciliary flush: A pattern of injection in which the redness is most pronounced in a ring at the limbus (the limbus is the transition zone between the cornea and the sclera). 3. Photophobia. 4. Severe foreign body sensation that prevents the patient from keeping the eye open. 5. Corneal opacity. 6. Fixed pupil. 7. Severe headache with nausea. III. Therapy. Bacterial conjunctivitis is likely to be self- limited, although treatment shortens the clinical course and reduces person-to-person spread. A. Bacterial conjunctivitis is treated with erythromycin ophthalmic ointment (Ilotycin and generic), or sulfa ophthalmic drops (Sulf-10, Bleph-10, Sulamyd, or as a 10% generic solution). The dose is 1/2" (1.25 cm) of ointment deposited inside the lower lid or 1 to 2 drops instilled four times daily for five to seven days. The dose may be reduced from four times daily to twice daily, if there is improvement in symptoms after three days. 1. Ointment is preferred over drops for children, drops are preferable for adults because ointments blur vision for 20 minutes after the dose is administered. 2. Alternative therapies include bacitracin ointment, sulfacetamide ointment, polymyxin-bacitracin oint- ment (Polysporin), or fluoroquinolone drops (Ciloxan, Ocuflox, Quixin, Zymar, Vigamox). Aminoglycosides are poor choices since they are toxic to the corneal epi thel i um and can cause a reacti ve keratoconjunctivitis. 3. The fluoroquinolones are effective and well tolerated; they are the treatment of choice for corneal ulcers and are extremely effective against pseudomonas. Conjunctivitis in a contact lens wearer should be treated with a fluoroquinolone because of the high incidence of pseudomonas infection. 4. Contact lens wearers with a red eye should discon- tinue contact lens wear. Contact lens wear can resume when the eye is white and has no discharge for 24 hours after the completion of antibiotic ther- apy. The lens case should be discarded and the lenses subjected to overnight disinfection or replaced if disposable. B. Viral conjunctivitis. Some patients derive symptomatic relief from topical antihistamine/decongestants. These are available over the counter (Naphcon-A, OcuHist, generics). Warm or cool compresses may provide additional symptomatic relief. C. Allergic conjunctivitis. There are numerous therapies available for allergic conjunctivitis (see below). References, see page 360. Allergic Conjunctivitis Allergic conjunctivitis is estimated to affect 20 percent of the population on an annual basis. Allergic conjunctivitis is associated with itching, tearing, redness, burning, photophobia, and mucus discharge. I. Pathophysiology A. Allergic conjunctivitis has an average age of onset of 20 years of age, and is principally a disease of young adults. Symptoms tend to decrease with age. B. Acute allergic conjunctivitis is an acute, hypersensi- tivity reaction caused by environmental exposure to allergens. It is characterized by intense episodes of itching, hyperemia, tearing, chemosis, and eyelid edema. It resolves in less than 24 hours. C. Seasonal allergic conjunctivitis (SAC) is also known as allergic conjunctivitis. It is frequently associated with rhinitis. It occurs in the spring and late summer, and it is caused by exposure to pollen, grasses, and rag- weed. D. Perennial allergic conjunctivitis (PAC) is a mild, chronic, allergic conjunctivitis related to environmental exposure to year-round allergens such as dust mites and mold. E. Acute allergic conjunctivitis, seasonal allergic conjunc- tivitis (SAC), and perennial allergic conjunctivitis (PAC) are referred to as "allergic conjunctivitis," and result from allergens. II. Clinical evaluation A. Allergic conjunctivitis is frequently associated with atopy, allergic rhinitis, skin allergies, and asthma. B. Signs and symptoms of allergic conjunctivitis include itching, tearing, conjunctival edema, hyper- emia, eyelid edema, watery discharge, burning, and photophobia. Symptoms are usually bilateral. The differential diagnosis includes infectious conjunctivitis, blepharitis, and dry eye. C. Acute allergic conjunctivitis occurs rapidly upon expo- sure to an allergen, such as cat dander. Symptoms can be severe and debilitating but resolve quickly, usually within 24 hours of removal of the allergen. Seasonal allergic conjunctivitis typically has a less dramatic onset; it will have a more predictable and chronic course that corresponds to the ragweed (late summer and early fall), grass (summer), and pollen (spring) seasons. D. Laboratory findings. The diagnosis of allergic con- junctivitis is usually made clinically; therefore, labora- tory testing is not typically performed. III.Treatment of allergic conjunctivitis A. Avoidance of the allergen is recommended. Preventive steps to reduce symptoms of SAC include limiting outdoor exposure during high "counts" of pollen and ragweed, use of air conditioning, and keeping windows closed. For those with PAC, prevention includes replacement of old pillows and mattresses, covers for pillows and mattresses, frequent washing of beddings, reducing humidity, and frequent vacuuming and dusting. Old curtains or drapes should be removed. When the allergen is animal dander, the animal may need to be removed from the home. B. In all types of allergic conjunctivitis, patients should not rub their eyes because that can cause mast cell degranulation. Patients should use topical antihista- mines, frequent artificial tears, and cool compresses. C. Mast cell stabilizers 1. Mast cell stabilizers include Crolom (cromolyn 4.0 percent), Opticrom (cromolyn), and Alomide (lodoxamide). These drugs are particularly useful for allergic conjunctivitis. Dosing is four times per day. Since the onset of action is 5 to 14 days after therapy has been initiated, these medicines are not useful for acute conjunctivitis. These drops cause burning and stinging. 2. These drugs are well tolerated, non-toxic, and can be used in contact lens wearers. However disadvan- tages include delayed onset of action, maintenance therapy, and multiple daily dosing. D. Antihistamines 1. Oral antihistamines and combinations of antihista- mines plus decongestants include Allegra (fexofenadine, 60 mg bid or tab ER: 180 mg qd), Allegra D (fexofenadine plus pseudoephedrine, 1 tab bid), Claritin (loratadine, 10 mg qd), Claritin-D (loratadine plus pseudoephedrine, 1 tab qd), and Zyrtec (cetirizine, 5-10 mg qd) or Zyrtec-D (cetirizine plus pseudoephedrine, 1 tab bid). 2. The full effect of oral administration of antihista- mines occurs hours after initiating therapy. Since oral antihistamine use is associated with drying of mucosal membranes, the use of oral antihistamines may worsen allergic symptoms. This effect is not observed with topical antihistamines. 3. Topical antihistamines include Emadine (emedastine) and Livostin (levocabastine), which are used as one drop up to 4 times daily. The advantages of topical antihistamine usage include a more rapid onset of action and reduced drowsi- ness and dry eyes. Emadine and Livostin are topical, highly specific, H1-receptor antagonists, and their onset of action is within minutes. 4. Topical, antihistamine/vasoconstrictor combina- tions have been shown to be effective. Examples of such combination drugs include Naphcon-A ( naphazol i ne/ pheni r ami ne) , Vasocon- A ( n a p h a z o l i n e / p h e n i r a mi n e ) , Oc u Hi s t (naphazol i ne/pheniramine), and Opcon-A (naphazoline/pheniramine). Dosing is up to four times daily. However, chronic use can lead to rebound hyperemia. 5. Olopatadine (Patanol) is a combination antihista- mine and mast cell stabilizer. It is the most com- monly prescribed drug for allergic conjunctivitis. The H1-receptor selectivity is superior to that of other antihistamines. Patanol is very safe and effective. Side effects include stinging and headache. Dosing is two to four times daily. E. Corticosteroids 1. Topical corticosteroid use should only be used for short "pulse therapy" when antihistamines and mast cell stabilizers provide inadequate therapy. Side effects from corticosteroids include cataract forma- tion, elevated intraocular pressure (IOP), glaucoma, and secondary infections. Ocular steroids should only be administered by ophthalmologists. 2. Prednisolone and dexamethasone have the greatest risk of raising IOP. "Soft" steroids are a group of topical corticosteroids that have a greatly reduced risk of causing increased IOP, since they undergo rapid inactivation upon penetration of the cornea. These drugs include Pred Mild (prednisolone), FML (fluorometholone), HMS (medrysone), Lotemax (loteprednol), and Vexol (rimexolone). They are administered two to four times per day for two weeks. F. Treatment recommendations 1. Acute allergic conjunctivitis a. Topical antihistamine/vasoconstrictors are usually sufficient in treating short exacerbations of symptoms. Combination drugs include Naphcon-A (naphazol i ne/pheni rami ne), Vasocon-A (naphazoline/pheniramine), OcuHist (naphazoline/pheniramine), and Opcon-A (naphazoline/pheniramine). Dosing is up to four times daily. Chronic use (greater than two weeks) can lead to rebound hyperemia. b. For frequent attacks of acute allergic conjunctivi- tis (occurring more than two days per month), mast cell stabilizers can be added. Olopatadine (Patanol), a combination drug consisting of an antihistamine and mast cell stabilizer, is a good agent for treating more frequent attacks. It can be used up to four times per day. c. If these are ineffective, oral antihistamines may be helpful. Oral antihistamines and combinations of antihistamines plus decongestants include Allegra (fexofenadine, 60 mg bid or tab ER: 180 mg qd), Allegra D (fexofenadine plus pseudoephedrine, 1 tab bid), Claritin (loratadine, 10 mg qd), Claritin-D (loratadine plus pseudoephedrine, 1 tab qd), and Zyrtec (cetirizine, 5-10 mg qd) or Zyrtec-D (cetirizine plus pseudoephedrine, 1 tab bid). Frequent use of artificial tears is recommended while using oral antihistamines. 2. Seasonal allergic conjunctivitis and perennial allergic conjunctivitis a. Olopatadine (Patanol) should be initiated two weeks before the onset of symptoms is antici- pated. Patanol, a combination mast cell stabi- lizer and antihistamine, has become the first-line drug of choice in treating SAC and PAC. It is approved for children older than five years of age and adults. Dosing is two to four times daily. b. Oral antihistamines may be helpful; however, these agents cause decreased tear production. These patients are frequently using oral antihis- tamines for systemic symptoms; therefore, artificial tears should be used. c. A short two-week course of topical steroids can be helpful in resistant cases. Pred Mild (prednisolone), FML (fluorometholone), HMS (medrysone), Lotemax (loteprednol), or Vexol (rimexolone) are administered two to four times per day for two to three weeks. References, see page 360. Bacterial Meningitis Meningitis is an infection of the meninges and the cerebrospinal fluid (CSF) of the subarachnoid space and the cerebral ventricles. Meningitis is one of the ten most com- mon infectious causes of death. Neurologic sequelae are common among survivors. I. Epidemiology A. Causative organisms in adults 1. Up to age 60, S. pneumoniae is responsible for 60 percent of cases, followed by N. meningitidis (20 percent), H. influenzae (10 percent), L. monocytogenes (6 percent), and group B strepto- coccus (4 percent). 2. Age 60 and above, almost 70 percent of cases are caused by S. pneumoniae, 20 percent to L. monocytogenes, and 3 to 4 percent each to N. meningitidis, group B streptococcus, and H. influenzae. An increased prevalence of L. monocytogenes occurs in the elderly. B. Predisposing factors. Major mechanisms for devel- oping meningitis: 1. Colonization of the nasopharynx with subsequent bloodstream invasion and subsequent central nervous system (CNS) invasion 2. Invasion of the CNS following bacteremia due to a localized source, such as infective endocarditis or a urinary tract infection 3. Direct entry of organisms into the CNS from a contiguous infection (eg, sinuses, mastoid), trauma, neurosurgery, or medical devices (eg, shunts or intracerebral pressure monitors). C. Host factors that can predispose to meningitis include asplenia, complement deficiency, corticosteroid excess, and HIV infection. Other predisposing factors for meningitis include: 1. Recent exposure to someone with meningitis 2. A recent infection (especially respiratory or otic infection) 3. Recent travel, particularly to areas with endemic meningococcal disease such as sub-Saharan Africa 4. Injection drug use 5. Recent head trauma 6. Otorrhea or rhinorrhea II.Clinical features. Patients with bacterial meningitis appear ill and often present soon after symptom onset. A. Presenting manifestations. The classic triad of acute bacterial meningitis consists of fever, nuchal rigidity, and a change in mental status, although many patients do not have all three features. Most patients have high fevers, often greater than 38ºC, but a small percentage have hypothermia. B. Headache is also common. The headache is severe and generalized. It is not easily confused with normal headaches. C. Fever is present in 95 percent at presentation and developed in another 4 percent within the first 24 hours. D. Nuchal rigidity is present in 88 percent. E. Mental status is altered in 78 percent. Most were confused or lethargic, but 22 percent are responsive only to pain and 6 percent are unresponsive to all stimuli. F. Significant photophobia is common. G. Neurologic complications such as seizures, focal neurologic deficits (including cranial nerve palsies), and papilledema, may be present early or occur later in the course. Seizures occur in 15 to 30 percent and focal neurologic deficits in 20 to 30 percent. Hearing loss is a late complication. Dexamethasone therapy may reduce the rate of neurologic sequelae. H. N. meningitidis can cause petechiae and palpable purpura. I. Examination for nuchal rigidity. Passive or active flexion of the neck will usually result in an inability to touch the chin to the chest. 1. Brudzinski sign refers to spontaneous flexion of the hips during flexion of the neck. 2. The Kernig sign refers to the inability or reluctance to allow full extension of the knee when the hip is flexed 90º. 3. The sensitivity of meningeal signs is extremely low (5 percent for each sign and 30 percent for nuchal rigidity); the specificity was 95 percent for each sign and 68 percent for nuchal rigidity. J. Initial blood tests should include a complete blood count with differential and platelet count, and two sets of blood cultures. A specimen of cerebrospinal fluid (CSF) should be obtained for cell count and differential, glucose and protein concentration, Gram stain, and culture. Characteristic findings in bacterial meningitis include a CSF glucose concentration below 45 mg/dL, a protein concentration above 500 mg/dL, and a white blood cell count above 1000/microL, usually composed primarily of neutrophils. Most often the white blood cell count is elevated with a shift toward immature forms. Severe infection can be associated with leukopenia. The platelet count may be reduced if disseminated intravascular coagulation or meningococcal bacteremia is present. 1. Blood cultures are often positive. Approximately 50 to 75 percent of patients with bacterial meningitis have positive blood cultures. Cultures obtained after antimicrobial therapy are much less likely to be positive, particularly for meningococcus. Tests of serum and urine for bacterial antigens are unhelpful. K. Lumbar puncture. Every patient with suspected meningitis should have CSF obtained unless the procedure is contraindicated. Risk factors for an occult mass lesion on CT scan include the presence of im- paired cellular immunity, history of previous central nervous system disease, a seizure within the previous week, reduced level of consciousness, and focal motor or cranial abnormalities. A CT scan is recommended before an LP only in patients with suspected bacterial meningitis who have one or more risk factors for a mass lesion. 1. Opening pressure is typically elevated in patients with bacterial meningitis. The mean opening pres- sure is 350 mm H 2 O (normal up to 200 mm H 2 O). 2. CSF analysis. When the clinical diagnosis strongly suggests meningitis, CSF Gram stain, culture, and analysis can distinguish between bacterial and viral infection. A Gram stain should be obtained whenever there is suspicion of bacterial meningitis. The follow- ing findings may be seen: 3. Gram positive diplococci suggest pneumococcal infection. 4. Gram negative diplococci suggest meningococcal infection. 5. Small pleomorphic Gram negative coccobacilli suggest Haemophilus influenzae. 6. Gram positive rods and coccobacilli suggest listerial infection. Utility of CSF Analysis in Infectious Causes of CNS Infection Glucose Protein Total WBC <10 mg/ dL 10- 45 mg/ dL >50 0 mg/ dL 50- 500 mg/ dL >10 00 10 0- 100 0 5- 100 Mor e co mm on Bac teri al me nin gitis Bac teri al me nin gitis Bac teri al me nin gitis Vi- ral me nin gitis Bac teri al me nin gitis Bac teri al or vi- ral me nin gitis Earl y bac teri al me nin gitis Ly me dis eas e Vi- ral me nin gitis Me nin gea l syp hilis Me nin gea l syp hilis TB me nin gitis Les s co mm on TB me nin gitis Me nin gea l syp hilis TB me nin gitis So me cas es of mu mp s Enc eph aliti s (inc ludi ng We st Nile vi- rus) Enc eph aliti s (incl udi ng Her pes sim plex vi- rus) Common self-limited forms of viral meningitis usually have a CSF protein concentration below 100 mg/dL (1 g/L) and a total WBC less than 100/μL. In addition to the total WBC, the percent neutrophils also may be helpful: more than 50 percent suggests bacterial meningitis while a value below 10 percent is compatible with viral infection III. Treatment of bacterial meningitis in adults A. Antibiotic therapy should be initiated immediately after the results of lumbar puncture (LP) or immediately after LP alone if the clinical suspicion is high. A screening CT scan is not necessary in the majority of patients. Risk factors for cerebral herniation include presence of impaired cellular immunity, history of previous central nervous system disease, or a seizure within the previ- ous week reduced level of consciousness, focal motor or cranial abnormalities, and papilledema. Should LP be delayed by the need for cranial imaging, blood cultures should be obtained and antibiotics should be adminis- tered empirically before the imaging study, followed as soon as possible by the LP. In addition, dexamethasone (0.15 mg/kg IV every six hours) should be given shortly before or at the same time as the antibiotics clinical and laboratory evidence suggests bacterial meningitis. B. Empiric drug regimen. Selected third-generation cephalosporins, such as cefotaxime and ceftriaxone, are the beta-lactams of choice in the empiric treatment of meningitis. 1. Cefotaxime and ceftriaxone are equivalent or supe- rior to penicillin and ampicillin because of their consistent CSF penetration and their activity against the major pathogens of meningitis with one notable exception, some penicillin-resistant S. pneumoniae. Ceftazidime, another third-generation cephalosporin, is much less active against penicillin-resistant pneumococci than cefotaxime and ceftriaxone. Empiric antibiotic therapy in adults with suspected bacterial meningitis and a nondiagnostic CSF gram stain Suggested antibiotics Most likely pathogens Immunocompetent adults Age 18 to 60 years Ceftriaxone (2 g twice daily) OR, less prefera- bly, cefotaxime (2 g every four to six or six to eight hours) AND vancomycin (2 g/day in two to four divided doses) if cephalosporin-resistant pneumococci in com- munity S. Pneumoniae, N. Men- ingitis H. influenzae, and, much less often, L. monocytogenes and group B streptococci Age >60 years As above plus ampicillin (200 mg/kg per day in six divided doses S. Pneumoniae, L. monocytogenes, and, less often, group B strep- tococci, N. Meningitis, H. influenzae Impaired cellular immu- nity Ceftazidime (2 g every eight hours) PLUS Ampicillin (2 g every four hours) AND vancomycin (2 g/day in two to four divided doses) if cephalosporin-resistant pneumococci in com- munity L. Monocytogenes, gram negative bacilli 2. Intravenous antibiotics should be directed at the presumed pathogen if the Gram stain is diagnostic. Antibiotic therapy should then be modified once the CSF culture results are available. a. If Gram positive cocci are seen in community- acquired meningitis, S. pneumoniae should be the suspected pathogen. However, in the setting of neurosurgery or head trauma within the past month, a neurosurgical device, or a CSF leak, Staphylococcus aureus and coagulase negative staphylococci are more common and vancomycin is required. b. If Gram negative cocci are seen, N. meningitidis is the probable pathogen. c. Gram positive bacilli suggest Listeria. d. Gram negative bacilli usually represent Enterobacteriaceae (eg, Klebsiella, Escherichia coli) in cases of community-acquired meningitis. e. If there is a history of neurosurgery or head trauma within the past month, a neurosurgical device, or a CSF leak in patients with Gram negative rods, ceftriaxone should be replaced with ceftazidime since such patients are at greater risk for Pseudomonas and Acinetobacter infection. C. Adjuvant dexamethasone. Permanent neurologic sequelae, such as hearing loss and focal neurologic deficits, are not uncommon in survivors of bacterial meningitis, particularly with pneumococcal meningitis. Intravenous dexamethasone (0.15 mg/kg every six hours) should be given shortly before or at the time of initiation of antibiotic therapy in adults with suspected bacterial meningitis who have a Glasgow coma score of 8 to 11. Dexamethasone should be continued for four days if the Gram stain or the CSF culture reveals S. pneumoniae. Dexamethasone should be discontinued if the Gram stain and/or culture reveal another patho- gen or no meningitis. D. Choice of agent when pathogen is unknown. Antibi- otic selection must be empiric when lumbar puncture is delayed or Gram stain of the CSF does not reveal a pathogen. 1. In adults up to age 60, S. pneumoniae was responsi- ble for 60 percent of cases, followed by N. meningitidis (20 percent), H. influenzae (10 percent), L. monocytogenes (6 percent), and group B strepto- coccus (4 percent). 2. In adults >60 years of age, almost 70 percent of cases are caused by S. pneumoniae, 20 percent to L. monocytogenes, and 3 to 4 percent each to N. meningitidis, group B streptococcus, and H. influenzae. An increased prevalence of L. monocytogenes in the elderly has been noted. 3. No known immune deficiency. Meningococcus, pneumococcus, and, less often, H. influenzae and group B streptococcus are the most likely causes of community-acquired bacterial meningitis in adoles- cents and adults up to the age of 60. Such patients should be treated with intravenous ceftriaxone (2 g BID) or cefotaxime (2 g every six to eight hours). If cephalosporin resistance occurs in more than 3 percent S. pneumoniae isolates, vancomycin should be added (2 g/day intravenously in two to four di- vided doses if renal function is normal). Beta-lactams should be continued even if in vitro tests suggest possible intermediate or resistant organisms, since they will provide synergy with vancomycin. Adults >60 years of age, in whom 20 percent of cases are due to listeria, should receive ampicillin (200 mg/kg per day IV in six divided doses). Antibiotic recommendations for adults with sus- pected meningitis with a positive cerebrospinal fluid gram stain or culture Bacterial type Recommended antibiotic regimen Morphology on CSF Gram stain Gram positive cocci Vancomycin (500 mg Q6h) ‡ PLUS either ceftriaxone (2 g Q12h) or, less preferably, cefotaxime (2 g Q4- 6h or Q6-8h) Gram negative cocci Penicillin G (4 million U Q4h) or, if H. Influenzae (which typi- cally appears as small, pleomorphic rods) is sus- pected, ceftriaxone (2 g Q12h) or cefotaxime (2 g Q6-8h) Gram positive bacilli Ampicillin (2 g Q4h) PLUS gentamicin (1-2 mg/kg Q8h) Gram negative ba- cilli Ceftriaxone (2 g Q12h) or cefotaxime (2 g Q6-8h) PLUS gentamicin (1-2 mg/kg Q8h) Growth in CSF culture S. pneumoniae Vancomycin (500 mg Q6h) ‡ PLUS either ceftriaxone (2 g Q12h) or, less preferably, cefotaxime (2 g Q4-6h or Q6- 8h) for 14 days; vancomycin can be discontinued if the iso- late is not cephalosporin-resis- tant N. meningitis Penicillin G (4 million units Q4h) for seven days H. influenzae Ceftriaxone (2 g Q12h) or cefotaxime (2 g Q6h) for seven days L. Monocytogenes Ampicillin (2 g Q4h) or penicil- lin G (3-4 million U Q4h) PLUS gentamicin (1-2 mg/kg Q8h); ampicillin is given for two to f o u r w e e k s i n immunocompetent patients and for at lease six to eight weeks in immunocompromised patients; gentamicin is gen until the patient improves (usu- ally 10 to 14 days) or, in poor responders, for up to three weeks if there are no signs of nephrotoxicity and ototoxicity Group B strepto- cocci Penicillin G (4 million U Q4h) for two to three weeks Enterobacteriaceae Ceftriaxone (2 g Q12h) or cefotaxime (2 g Q6h-8h) PLUS gentamicin (1-2 mg/kg Q8h) for three weeks Pseudomonas or acinetobacter ceftazidime (2 g Q8h) PLUS gentamicin (1-2 mg/kg Q8h) for 21 days 4. Impaired cellular immunity due to lymphoma, cytotoxic chemotherapy, or high-dose glucocorticoids requires coverage against L. monocytogenes and Gram negative bacilli as well as S. pneumoniae. Patients should receive ceftazidime (2 g every eight hours) and ampicillin (200 mg/kg per day IV in six divided doses). Vancomycin should be added (2 g/day intravenously in two to four divided doses if renal function is normal) if there is possible cephalosporin-resistant pneumococci. 5. Nosocomial infection. Empiric therapy must cover both Gram negative (such as Klebsiella pneumoniae and Pseudomonas aeruginosa) and Gram positive nosocomial pathogens. Ceftazidime (2 g every eight hours) plus vancomycin (2 g/day intravenously in two to four divided doses if renal function is normal) is recommended. E. Prevention 1. Vaccines are available for S. pneumoniae, N. meningitidis, and H. influenzae. a. Pneumococcal vaccine is administered to chron- ically ill and older adults (over age 65). b. Meningococcal vaccine is not warranted as postexposure prophylaxis unless the strain is documented to have a capsular serotype repre- sented in the vaccine (type A, C, Y or W-135). Meningococcal vaccination is indicated for pa- tients with asplenia and complement deficiencies. c. H. influenzae vaccine. A marked reduction in H. influenzae meningitis has been associated with the near universal use of a H. influenzae vaccine. 2. Chemoprophylaxis a. Neisseria meningitidis. Chemoprophylaxis of close contacts consists of rifampin (600 mg PO every 12 h for a total of four doses in adults), ciprofloxacin (500 mg PO once), and ceftriaxone (250 mg IM once). Antimicrobial chemoprophylaxis regimens for meningococcal infection Drug Age group Dose Duration Rifampin (oral) Children <1 month Children >1 month Adults 5 mg/kg every 12 hours 20 mg/kg every 12 hours 600 mg every 12 hours Two days Two days Two days Ciprofloxa cin (IM) Adults 500 mg Single dose Ceftriaxon e (IM) Children <12 years Older chil- dren and adults 125 mg 250 mg Single dose Single dose b. H. influenzae. Unvaccinated, young children (less than four years of age) who have close contact with patients with H. influenzae type b meningitis require rifampin (20 mg/kg with a max of 600 mg/day PO for four days). References, see page 360. Shock Shock is characterized by a reduction in tissue perfusion, resulting in decreased tissue oxygen delivery. These abnor- malities may cause end-organ damage, failure of multiple organ systems, and death. The mortality from shock is 35 to 40 percent I. Stages of shock. The shock syndrome is characterized by physiologic stages beginning with an initial event which causes a systemic circulatory disturbance; shock may subsequently progress through three stages, culminating in irreversible end-organ damage and death. A. Preshock. During this stage, the homeostatic mecha- nisms of the body compensate for diminished perfusion. Tachycardia, peripheral vasoconstriction, and a modest decrease in systemic blood pressure may be the only clinical signs of hypovolemic or low preload shock. By comparison, distributive or low afterload shock is frequently characterized by peripheral vasodilation and a hyperdynamic state. B. Shock. During this stage, the regulatory mechanisms are overwhelmed and signs and symptoms of organ dysfunction appear, including tachycardia, tachypnea, metabolic acidosis, oliguria, and cool and clammy skin. The emergence of these signs and symptoms corre- sponds to one or more of the following: 1. A 20 to 25 percent reduction in effective blood volume in low preload shock. 2. A fall in the cardiac index to less than 2.5 L/min/M 2 . 3. Activation of mediators of the sepsis syndrome. C. End-organ dysfunction. During this stage, progressive end-organ dysfunction leads to irreversible organ damage and death: 1. Urine output declines, culminating in anuria. 2. Restlessness evolves into agitation, obtundation, and coma. 3. Acidosis further decreases cardiac output and alters cellular metabolic processes. 4. Multiple organ system failure proceeds to cause the demise of the patient. II.Classification of shock. Three broad types of shock states are recognized: hypovolemic, cardiogenic, and distributive. Each type is characterized by one primary physiologic derangement. A. Hypovolemic shock results from decreased preload. Since preload is one of the determinants of stroke volume, cardiac output falls when preload drops. Hypovolemic shock can be further divided into hemor- rhagic and fluid loss. The causes of hemorrhage include trauma, upper and lower gastrointestinal bleeding, ruptured aortic or ventricular aneurysm, ruptured hematoma, hemorrhagic pancreatitis, and fractures. Fluid loss can be a result of diarrhea, vomiting, heat stroke, inadequate repletion of insensible losses, burns, and “third spacing” (in intestinal obstruction, pancreati- tis, and cirrhosis). B. Cardiogenic shock results from pump failure, mani- fested as decreased systolic function and cardiac output. The causes can be divided into four broad categories: myopathic, arrhythmic, mechanical, and extracardiac (obstructive). C. Distributive (vasodilatory) shock results from a severe decrease in SVR, often associated with an increased cardiac output. Causes include: 1. Septic shock. 2. Activation of the systemic inflammatory response (eg, by pancreatitis, burns, or multiple traumatic injuries). 3. Toxic shock syndrome. 4. Anaphylaxis and anaphylactoid reactions. 5. Drug or toxin reactions, including insect bites, trans- fusion reactions, and heavy metal poisoning. 6. Addisonian crisis (which should be considered if clinical signs of sepsis exist without evidence of infection). 7. Myxedema coma. 8. Neurogenic shock after a central nervous system or spinal cord injury. 9. Some patients after acute myocardial infarction who develop cardiogenic shock accompanied by a sys- temic inflammatory state. 10. Post-cardiopulmonary bypass. III. Common features of shock A. Hypotension (systolic BP <90 mm Hg) occurs in most shock patients. However, early in the development of shock (preshock), the hypotension may only be relative to the patient’s baseline blood pressure. As a result, a drop in systolic blood pressure of greater than 40 mm Hg suggests impending shock. As shock advances toward later, irreversible stages, profound hypotension may occur, and vasopressors are often necessary to maintain adequate perfusion pressure. B. Cool, clammy skin, regulatory processes may com- pensate for decreased effective tissue perfusion. Potent vasoconstrictive mechanisms redirect blood from the periphery to the vital organs, thus maintaining coronary, cerebral, and splanchnic perfusion but causing cool, clammy skin of shock. Notable exceptions are the flushed, hyperemic skin of early distributive shock, and the peripheral vasodilation of terminal shock states associated with failure of the mechanisms maintaining increased peripheral vascular resistance. C. Oliguria reflects shunting of renal blood flow to other vital organs and is an objective measure of intravascular volume depletion. Other signs of hypovolemia in patients with shock include tachycardia, orthostatic hypotension, poor skin turgor, absent axillary sweat, and dry mucous membranes. D. Change in mental status. Mental status changes in shock begin with agitation, progressing to confusion or delirium, and ending in obtundation or frank coma. E. Metabolic acidosis. Initially, shock patients may have a respiratory alkalosis. However, as shock progresses, a metabolic acidosis develops, reflecting decreased clearance of lactate. If shock progresses to produce circulatory failure and tissue hypoxia, lactate production is increased due to anaerobic metabolism. IV. Initial examination in shock A. History. The patient’s general condition, recent com- plaints, and activities prior to presentation may suggest a cause of shock. Additional clues include: 1. Food and medicine allergies. 2. Recent changes in medications. 3. Potential acute or chronic drug intoxication. 4. Pre-existing diseases. 5. Immunosuppressed states. 6. Hypercoagulable conditions. B. Physical examination 1. HEENT. Scleral icterus; dry conjunctivae; dry mu- cous membranes; pinpoint pupils; dilated and fixed pupils; nystagmus. 2. Neck. Jugular venous distention; delayed carotid upstroke (pulsus parvus et tardus); carotid bruits; meningeal signs. 3. Chest. Tachypnea; shallow breaths; crackles (rales); consolidation; egophony; absent breath sounds; rub. 4. Cardiovascular system. Irregular rhythm; tachycar- dia; bradycardia; S3 gallop; diffuse PMI; right or left ventricular heave; murmurs; distant heart sounds; rub; pulsus paradoxus. 5. Abdomen. Tenseness; distention; tenderness; rebound; guarding; absence of or high-pitched bowel sounds; pulsatile masses; hepatosplenomegaly; ascites. 6. Rectal exam. Decreased tone; bright red blood; melena; Hemoccult positive stool. 7. Extremities. Swollen calf; palpable cord; unequal intensity of pulses or disparity of blood pressure between upper extremities. 8. Neurologic exam. Agitation; confusion; delirium; obtundation; coma. 9. Skin. Cold, clammy or warm, hyperemic skin; rashes; petechiae; urticaria; cellulitis. C. Laboratory evaluation. Complete blood count with differential; basic chemistry tests; liver function test; amylase and lipase; fibrinogen and fibrin split products; lactate; cardiac enzymes; arterial blood gases; toxicol- ogy screen; chest x-ray; abdominal x-ray for intestinal obstruction; electrocardiogram; urinalysis. D. Pulmonary artery catheterization is frequently used to provide hemodynamic measurements in shock patients, including CO, pulmonary artery wedge (pulmonary capillary wedge) pressure, and SVR. Right heart catheterization with a Swan-Ganz catheter is potentially useful in monitoring fluid resuscitation, titrating vasoconstrictive agents, and measuring the effects of changes in mechanical ventilatory settings (including PEEP) on hemodynamics. References, see page 360. Sepsis About 400,000 cases of sepsis, 200,000 cases of septic shock, and 100,000 deaths from both occur each year. I. Pathophysiology A. Sepsis is defined as the systemic response to infection. In the absence of infection, it is called systemic inflam- matory response syndrome and is characterized by at least two of the following: temperature greater than 38°C or less than 36°C; heart rate greater than 90 beats per minute; respiratory rate more than 20/minute or PaCO 2 less than 32 mm Hg; and an alteration in white blood cell count (>12,000/mm 3 or <4,000/mm 3 ). B. Septic shock is defined as sepsis-induced hypotension that persists despite fluid resuscitation and is associ- ated with tissue hypoperfusion. C. The initial cardiovascular response to sepsis includes decreased systemic vascular resistance and de- pressed ventricular function. Low systemic vascular resistance occurs. If this initial cardiovascular response is uncompensated, generalized tissue hypoperfusion results. Aggressive fluid resuscitation may improve cardiac output and systemic blood pressure, resulting in the typical hemodynamic pattern of septic shock (ie, high cardiac index and low systemic vascular resis- tance). D. Although gram-negative bacteremia is commonly found in patients with sepsis, gram-positive infection may affect 30-40% of patients. Fungal, viral and parasitic i nf ect i ons ar e usual l y encount er ed i n immunocompromised patients. Defining sepsis and related disorders Term Definition Systemic inflammatory response syn- drome (SIRS) The systemic inflammatory response to a severe clinical insult manifested by >2 of the following conditions: Temperature >38EC or <36EC, heart rate >90 beats/min, respiratory rate >20 breaths/min or PaCO 2 <32 mm Hg, white blood cell count >12,000 cells/mm 3 , <4000 cells/mm 3 , or >10% band cells Sepsis The presence of SIRS caused by an infec- tious process; sepsis is considered severe if hypotension or systemic manifestations of hypoperfusion (lactic acidosis, oliguria, change in mental status) is present. Septic shock Sepsis-induced hypotension despite ade- quate fluid resuscitation, along with the presence of perfusion abnormalities that may induce lactic acidosis, oliguria, or an alteration in mental status. Multiple organ dysfunction syndrome (MODS) The presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention E. Sources of bacteremia leading to sepsis include the urinary, respiratory and GI tracts, and skin and soft tissues (including catheter sites). The source of bacteremia is unknown in 30% of patients. F. Escherichia coli is the most frequently encountered gram-negative organism, followed by Klebsiella pneumoniae, Enterobacter aerogenes or cloacae, Serratia marcescens, Pseudomonas aeruginosa, Proteus mirabilis, Providencia, and Bacteroides species. Up to 16% of sepsis cases are polymicrobic. G. Gram-positive organisms, including methicillin-sensi- tive and methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, are associated with catheter or line-related infections. II. Diagnosis A. A patient who is hypotensive and in shock should be evaluated to identify the site of infection, and monitor for end-organ dysfunction. History should be obtained and a physical examination performed. B. The early phases of septic shock may produce evidence of volume depletion, such as dry mucous membranes, and cool, clammy skin. After resuscitation with fluids, however, the clinical picture resembles hyperdynamic shock, including tachycardia, bounding pulses with a widened pulse pressure, a hyperdynamic precordium on palpation, and warm extremities. C. Signs of infection include fever, localized erythema or tenderness, consolidation on chest examination, abdominal tenderness, and meningismus. Signs of end-organ hypoperfusion include tachypnea, oliguria, cyanosis, mottling of the skin, digital ischemia, abdomi- nal tenderness, and altered mental status. D. Laboratory studies should include arterial blood gases, lactic acid level, electrolytes, renal function, liver function tests, and chest radiograph. Cultures of blood, urine, and sputum should be obtained before antibiotics are administered. Cultures of pleural, peritoneal, and cerebrospinal fluid may be appropriate. If thrombocytopenia or bleeding is present, tests for disseminated intravascular coagulation should include fibrinogen, d-dimer assay, platelet count, peripheral smear for schistocytes, prothrombin time, and partial thromboplastin time. Manifestations of Sepsis Clinical features Temperature instability Tachypnea Hyperventilation Altered mental status Oliguria Tachycardia Peripheral vasodilation Laboratory findings Respiratory alkaloses Hypoxemia Increased serum lactate lev- els Leukocytosis and increased neutrophil concentration Eosinopenia Thrombocytopenia Anemia Proteinuria Mildly elevated serum biliru- bin levels III. Treatment of septic shock A. Early management of septic shock is aimed at restor- ing mean arterial pressure to 65 to 75 mm Hg to improve organ perfusion. Continuous SVO 2 monitor- ing is recommended to insure optimal organ perfusion at the cellular level. Clinical clues to adequate tissue perfusion include skin temperature, mental status, and urine output. Urine output should be maintained at >20 to 30 mL/hr. Lactic acid levels should decrease within 24 hours if therapy is effective. B. Intravenous access and monitoring 1. Intravenous access is most rapidly obtained through peripheral sites with two 16- to 18-gauge catheters. More stable access can be achieved later with central intravenous access. Placement of a large-bore introducer catheter in the right internal jugular or left subclavian vein allows the most rapid rate of infusion. 2. Arterial lines should be placed to allow for more reliable monitoring of blood pressure. Pulmonary artery catheters measure cardiac output, systemic vascular resistance, pulmonary artery wedge pressure, and mixed venous oxygen saturation. These data are useful in providing rapid assess- ment of response to various therapies. C. Fluids 1. Aggressive volume resuscitation is essential in treatment of septic shock. Most patients require 4 to 8 L of crystalloid. Fluid should be administered as a bolus. The mean arterial pressure should be increased to 65 to 75 mm Hg and organ perfusion should be improved within 1 hour of the onset of hypotension. 2. Repeated boluses of crystalloid (isotonic sodium chloride solution or lactated Ringer's injection), 500 to 1,000 mL, should be given intravenously over 5 to 10 minutes, until mean arterial pressure and tissue perfusion are adequate (about 4 to 8 L total over 24 hours for the typical patient). Boluses of 250 mL are appropriate for patients who are elderly or who have heart disease or suspected pulmonary edema. Red blood cells should be reserved for patients with a hemoglobin value of less than 10 g/dL and either evidence of decreased oxygen delivery or significant risk from anemia (eg, coro- nary artery disease). D. Vasoactive agents 1. Patients who do not respond to fluid therapy should receive vasoactive agents. The primary goal is to increase mean arterial pressure to 65 to 75 mm Hg. 2. Dopamine (Intropin) traditionally has been used as the initial therapy in hypotension, primarily because it is thought to increase systemic blood pressure. However, dopamine is a relatively weak vasoconstrictor in septic shock. Hemodynamic effects of vasoactive agents Agent Dose Effect CO MAP SVR Dopamine (Intropin) 5-20 mcg/kg/min 2+ 1+ 3+ Norepin- ephrine (Levophed) 0.05-0.5 mcg/kg/min -/0/+ 2+ 4+ Dobutamin e (Dobutrex) 10 mcg/kg/min 2+ -/0/+ -/0 Epineph- rine 0.05-2 mcg/kg/min 3+ 2+ 4+ Phenylephr ine (Neo-Syne phrine) 2-10 mcg/kg/min 0 2+ 4+ 3. Norepinephrine (Levophed) is superior to dopa- mine in the treatment of hypotension associated with septic shock. Norepinephrine is the agent of choice for treatment of hypotension related to septic shock. 4. Dobutamine (Dobutrex) should be reserved for patients with a persistently low cardiac index or underlying left ventricular dysfunction. E. Antibiotics should be administered within 2 hours of the recognition of sepsis. Use of vancomycin should be restricted to settings in which the causative agent i s most l i kel y resi st ant Ent erococcus, methicillin-resistant Staphylococcus aureus, or high-level penicillin-resistant Streptococcus pneumoniae. Recommended Antibiotics in Septic Shock Suspected source Recommended antibiotics Pneumonia Third or 4th-generation cephalosporin (cefepime, ceftazidime, cefotaxime, ceftizoxime) plus macrolide (antipseudomonal beta lactam plus aminoglycoside if hospi- tal-acquired) + anaerobic coverage with metronidazole or clindamycin. Urinary tract Ampicillin plus gentamicin (Garamycin) or third-generation cephalosporin (ceftazidime, cefotaxime, ceftizoxime) or a quinolone (ciprofloxacin, levofloxacin). Skin or soft tissue Nafcillin (add metronidazole [Flagyl] or clindamycin if anaerobic infection suspected) Meningitis Third-generation cephalosporin (ceftazidime, cefotaxime, ceftizoxime) Intra-abdomin al Third-generation cephalosporin (ceftazidime, cefotaxime, ceftizoxime) plus metronidazole or clindamycin Primary bacteremia Ticarcillin/clavulanate (Timentin) or piperacillin/tazobactam(Zosyn) Dosages of Antibiotics Used in Sepsis Agent Dosage Cefepime (Maxipime) 2 gm IV q12h; if neutropenic, use 2 gm q8h Ceftizoxime (Cefizox) 2 gm IV q8h Ceftazidime (Fortaz) 2 g IV q8h Cefotaxime (Claforan) 2 gm q4-6h Cefuroxime (Kefurox, Zinacef) 1.5 g IV q8h Cefoxitin (Mefoxin) 2 gm q6h Cefotetan (Cefotan) 2 gm IV q12h Piperacillin/tazobactam (Zosyn) 3.375-4.5 gm IV q6h Ticarcillin/clavulanate (Timentin) 3.1 gm IV q4-6h (200-300 mg/kg/d) Ampicillin 1-3.0 gm IV q6h Ampicillin/sulbactam (Unasyn) 3.0 gm IV q6h Nafcillin (Nafcil) 2 gm IV q4-6h Piperacillin, ticarcillin, mezlocillin 3 gm IV q4-6h Meropenem (Merrem) 1 gm IV q8h Imipenem/cilastatin (Primaxin) 1.0 gm IV q6h Gentamicin or tobramycin 2 mg/kg IV loading dose, then 1.7 mg/kg IV q8h Amikacin (Amikin) 7.5 mg/kg IV loading dose, then 5 mg/kg IV q8h Vancomycin 1 gm IV q12h Metronidazole (Flagyl) 500 mg IV q6-8h Clindamycin (Cleocin) 600-900 mg IV q8h Linezolid (Zyvox) 600 mg IV/PO q12h Quinupristin/dalfopristin (Synercid) 7.5 mg/kg IV q8h 1. Initial treatment of life-threatening sepsis usually consists of a third or 4th-generation cephalosporin (cefepime, ceftazidime, cefotaxime, ceftizoxime) or piperacillin/tazobactam (Zosyn). An aminoglycoside (gentamicin, tobramycin, or amikacin) should also be included. Antipseudomonal coverage is impor- tant for hospital- or institutional-acquired infections. Appropriate choices include an antipseudomonal penicillin, cephalosporin, or an aminoglycoside. 2. Methicillin-resistant staphylococci. If line sepsis or an infected implanted device is a possibility, vancomycin should be added to the regimen to cover for methicillin-resistant Staph aureus and methicillin-resistant Staph epidermidis. 3. Vancomycin-resistant enterococcus (VRE): An increasing number of enterococcal strains are resistant to ampicillin and gentamicin. The inci- dence of vancomycin-resistant enterococcus (VRE) is rapidly increasing. a. Linezolid (Zyvox) is an oral or parenteral agent act i ve agai nst vancomyci n-resi st ant enterococci, including E. faecium and E. faecalis. Linezolid is also active against methicillin-resistant staphylococcus aureus. b. Quinupristin/dalfopristin (Synercid) is a parenteral agent active against strains of vancomycin-resistant enterococcus faecium, but not enterococcus faecalis. Most strains of VRE are enterococcus faecium. F. Other therapies 1. Hydrocortisone (100 mg every 8 hours) in pa- tients with refractory shock significantly improves hemodynamics and survival rates. Corticosteroids may be beneficial in patients with refractory shock caused by an Addison’s crisis. 2. Activated protein C (drotrecogin alfa [Xigris]) has antithromboti c, profibrinolytic, and anti-inflammatory properties. Activated protein C reduces the risk of death by 20%. Activated protein C is approved for treatment of patients with severe sepsis who are at high risk of death. Drotrecogin alfa is administered as 24 mcg/kg/hr for 96 hours. There is a small risk of bleeding. Contraindications are thrombocytopenia, coagulopathy, recent surgery or recent hemorrhage. References, see page 360. Diverticulitis By age 50, one-third of adults have diverticulosis coli; two- thirds have diverticulosis by age 80. Diverticulitis or diverticular hemorrhage occurs in 10-20% of patients with diverticulosis. Causes of diverticulosis include aging, elevation of colonic intraluminal pressure, and decreased dietary fiber. Eighty-five percent are found in the sigmoid colon. I. Clinical presentation of diverticulitis A. Diverticulitis is characterized by the abrupt onset of unremitting left-lower quadrant abdominal pain, fever, and an alteration in bowel pattern. Diverticulitis of the transverse colon may simulate ulcer pain; diverticulitis of the cecum and redundant sigmoid may resemble appendicitis. B. Physical exam. Left-lower quadrant tenderness is characteristic. Abdominal examination is often decep- tively unremarkable in the elderly and in persons taking corticosteroids. Differential Diagnosis of Diverticulitis Elderly Middle Aged and Young Ischemic colitis Carcinoma Volvulus Colonic Obstruction Penetrating ulcer Nephrolithiasis/urosepsis Appendicitis Salpingitis Inflammatory bowel disease Penetrating ulcer Urosepsis II. Diagnostic evaluation A. Plain X-rays may show ileus, obstruction, mass effect, ischemia, or perforation. B. CT scan with contrast is the test of choice to evalu- ate acute diverticulitis. The CT scan can be used for detecting complications and ruling out other diseases. C. Contrast enema. Water soluble contrast is safe and useful in mild-to-moderate cases of diverticulitis when the diagnosis is in doubt. D. Endoscopy. Acute diverticulitis is a relative contraindi- cation to endoscopy; perforation should be excluded first. Endoscopy is indicated when the diagnosis is in doubt to exclude the possibility of ischemic bowel, Crohn's disease, or carcinoma. E. Complete blood count may show leukocytosis. III. Diagnosis. Computer tomographic scanning has become the optimal method of diagnosis of acute diverticulitis. IV. Treatment of acute diverticulitis A. Complicated diverticulitis refers to the presence of a perforation, obstruction, an abscess, or a fistula. Ap- proximately 25 percent of patients diagnosed with diverticulitis for the first time present with complicated diverticulitis. Nearly all of these patients require surgery. B. Uncomplicated diverticulitis, accounting for 75 percent of cases, refers to diverticulitis without the complications noted above. The majority of these patients respond to medical therapy, although up to 30 percent require surgery. C. Uncomplicated diverticulitis 1. Conservative treatment (with bowel rest and antibiot- ics) is successful in 70 to 100 percent of patients with acute uncomplicated diverticulitis. A CT scan can be helpful for identifying patients who are likely to respond to conservative therapy. 2. The elderly, immunosuppressed, those with signifi- cant comorbidities, and those with high fever or significant leukocytosis should be hospitalized. 3. Choice of antibiotics should be effective against gram negative rods and anaerobes (particularly E. coli and B. fragilis). Reasonable choices include a quinolone with metronidazole, amoxicillin- clavulanate, or sulfamethoxazole-trimethoprim with metronidazole. 4. An outpatient regimen includes ciprofloxacin (Cipro), 500 mg PO twice daily plus metronidazole, 500 mg PO three times daily, although amoxicillin- clavulanate (Augmentin [875/125 mg twice daily]) is an acceptable alternative. Treatment should be continued for 7 to 10 days. 5. Oral ciprofloxacin achieves levels similar to those with intravenous administration, has broad coverage of enteric Gram negative pathogens, and requires only twice-daily dosing. a. Clindamycin or metronidazole are reasonable choices for anaerobic coverage, while Gram negative coverage can be achieved with a third- generation cephalosporin or quinolone. b. Single-agent coverage with a beta-lactamase inhibitor combination such as ampicillin- sulbactam, piperacillin-tazobactam, or ticarcillin- clavulanate is a reasonable alternative. The second-generation cephalosporin cefoxitin and the cephamycin, cefotetan, cover anaerobes but are not sufficiently active for Gram negative aerobic bacteria to use empirically for serious infection. D. Dietary recommendations. Outpatients should con- sume clear liquids only. Clinical improvement should be evident after two to three days, after which the diet can be advanced slowly. Patients requiring hospitalization can be treated with clear liquids or NPO with intrave- nous hydration. E. Recommendations following resolution. Two to six weeks after recovery, patients should undergo an evaluation of the colon to exclude colonic neoplasia and to evaluate the extent of the diverticulosis. This is usually accomplished with a colonoscopy. Patients should be advised to consume a diet high in fiber. F. Surgery. Up to 30 percent of patients with uncompli- cated diverticulitis require surgical intervention during the initial attack. Surgery is advised after a first attack of complicated diverticulitis or after two or more episodes of uncomplicated diverticulitis. Indications for Surgery in Acute Diverticulitis Absolute Complications of diverticulitis: peritonitis, abscess (failed percutaneous drainage), fistula, obstruction Clinical deterioration or failure to improve with medi- cal therapy Recurrent episodes Intractable symptoms Inability to exclude carcinoma Relative Indications Symptomatic stricture Immunosuppression Right-sided diverticulitis ?Young patient 1. Preoperative preparation. A second- or third generation cephalosporin is administered or more broad-spectrum antibiotics, depending upon the degree of contamination. Regimens include cefazolin (Ancef [1 g IV every eight hours]) plus metronidazole (Flagyl [500 mg IV every 8 hours]); ampicillin- sulbactam (Unasyn [1.5 g IV every six hours]); or ticarcillin-clavulanate (Timentin 3.1 g IV every six hours]). Bowel preparation is often possible in nonemergent situations. V. Treatment A. Outpatient treatment 1. Clear liquid diet 2. Oral antibiotics a. Ciprofloxacin (Cipro) 500 mg PO bid AND b. Metronidazole (Flagyl) 500 mg PO qid. B. Inpatient treatment 1. Severe cases require hospitalization for gastrointesti- nal tract rest (NPO), intravenous fluid hydration, and antibiotics. Nasogastric suction is initiated if the patient is vomiting or if there is abdominal distention. 2. Antibiotic coverage should include enteric gram- negative and anaerobic organisms a. Ampicillin 1-2 gm IV q4-6h AND b. Gentamicin or tobramycin 100-120 mg IV (1.5-2 mg/kg), then 80 mg IV q8h (5 mg/kg/d) AND c. Metronidazole (Flagyl) 500 mg IV q6-8h (15-30 mg/kg/d) OR d. Cefoxitin (Mefoxin) 2 gm IV q6h OR e. Piperacillin-tazobactam (Zosyn) 3.375-4.5 gm IV q6h. C. Failure to improve or deterioration are indications for reevaluation and consideration of surgery. Analgesics should be avoided because they may mask acute deterioration, and they may obscure the need for urgent operation. D. Oral antibiotics should be continued for 1-2 weeks after resolution of the acute attack. Ciprofloxacin, 500 mg PO bid. E. After the acute attack has resolved, clear liquids should be initiated, followed by a low residue diet for 1-2 weeks, followed by a high-fiber diet with psyllium. VI. Surgical therapy A. An emergency sigmoid colectomy with proximal colos- tomy is indicated for attacks of diverticulitis associated with sepsis, peritonitis, obstruction, or perforation. B. Elective sigmoid resection is indicated for second or subsequent attacks of diverticulitis, or for attacks with complications managed nonoperatively (eg, percutaneous CT-guided drainage of an abscess), or carcinoma. C. Operative procedures 1. Single-stage procedure. This procedure is usually performed as an elective procedure after resolution of the acute attack of diverticulitis. The segment containing inflamed diverticulum (usually sigmoid colon) is resected with primary anastomosis. A bowel prep is required. 2. Two-stage procedure. This procedure is indicated for acute diverticulitis with obstruction or perforation with an unprepared bowel. The first stage consists of resection of the involved segment of colon with end colostomy and either a mucous fistula or a Hartmann rectal pouch. The second stage consists of a colos- tomy take-down and reanastomosis after 2-3 months. References, see page 360. Acute Cystitis Cystitis is an infection of the bladder. Acute cystitis in the healthy nonpregnant adult woman is considered to be uncomplicated. A complicated infection is associated with a condition that increases the risk of failing therapy. About 7.8 percent of girls and 1.6 percent of boys have had a symp- tomatic UTI. Approximately 50 to 60 percent of adult women have had a UTI at some time during their life. Young sexually active women have 0.5 episodes of acute cystitis per year. I. Microbiology Clinical features A. Escherichia coli is the causative pathogen in 80 to 85 percent of episodes of acute uncomplicated cystitis. Staphylococcus saprophyticus is responsible for most other episodes, while Proteus mirabilis, Klebsiella species, enterococci or other uropathogens are isolated from a small proportion of patients. B. Acute uncomplicated cystitis is characterized by dysuria, usually in combination with frequency, urgency, suprapubic pain, and/or hematuria. Fever (>38ºC), flank pain, costovertebral angle tenderness, and nausea or vomiting suggest pyelonephritis C. Vaginitis should be considered if there is vaginal discharge or odor, pruritus, dyspareunia, external dysuria, and the absence of frequency or urgency. II.Diagnosis A. Physical examination should include temperature, abdominal examination, and assessment for costovertebral angle tenderness. A pelvic examination is indicated if symptoms of urethritis or vaginitis are present. B. Urinalysis. Pyuria is usually present with acute cystitis; its absence strongly suggests a noninfectious cause for the symptoms. An unspun voided midstream urine specimen should be examined with a hemocytometer; 10 or more leukocytes per mm 3 is considered abnormal. White blood cell casts in the urine are diagnostic of upper tract infection. Hematuria is common with UTI but not in urethritis or vaginitis. Microscopic evaluation of the urine for bacteriuria is generally not recommended for acute uncomplicated cystitis because pathogens in low quantities <10 4 CFU/mL) are difficult to find on the wet mount or Gram stain. C. Indications for voided midstream urine cultures 1. Suspected complicated infection. 2. The symptoms are not characteristic of UTI. 3. The patient has persistent symptoms of UTI following treatment. 4. UTI symptoms recur less than one month after treatment of a previous UTI. D. Acute urethral syndrome. A CFU count >10 2 /mL should be considered positive on a midstream urine specimen in women with acute symptoms and pyuria. Some women with acute dysuria have neither bacteriuria nor pyuria. The symptoms usually resolve after antimicrobial therapy. E. Urine dipsticks 1. Dipsticks detect the presence of leukocyte esterase and nitrite; the former detect pyuria and the latter Enterobacteriaceae which convert urinary nitrate to nitrite. The leukocyte esterase test is a practical screening test with a sensitivity of 75 to 96 percent and specificity of 94 to 98 percent. A microscopic evaluation for pyuria or a culture is indicated with a negative leukocyte esterase test with urinary symp- toms. 2. The nitrite test is fairly sensitive and specific for detecting >10 5 Enterobacteriaceae CFU per mL of urine. However, it lacks adequate sensitivity for detection of "low count" UTIs, or, in some cases, infections caused by common uropathogenic spe- cies. III. Treatment A. Resistance 1. E. coli strains a. One-third or more of isolates demonstrate resis- tance to ampicillin and sulfonamides; these agents should not be used for empiric therapy. b. An increasing proportion of uropathogens demon- strate resistance to trimethoprim and/or TMP- SMX. c. The prevalence of resistance to nitrofurantoin among E. coli is less than 5 percent, although non-E. coli uropathogens are often resistant. d. Resistance to the fluoroquinolones remains well below 5 percent in most studies. e. The prevalence of resistance to trimethoprim and TMP-SMX has increased to more than 18 percent among E. coli isolates, and from 8 to 16 percent among all isolates combined. 2. S. saprophyticus. Three percent are resistant to TMP-SMX, 1 percent to cephalothin, 0 percent to nitrofurantoin, and 0.4 percent to ciprofloxacin. B. Recommendation 1. Because of increasing fluoroquinolone resistance, TMP-SMX should be the first-line treatment for acute cystitis if the woman: a. Has no history of allergy to the drug. b. Has not been on antibiotics, especially TMP-SMX, in the past three months. c. Has not been hospitalized recently. d. If the prevalence of E. coli resistance to TMP-SMX in the area is not known to be more than 20 percent among women with acute uncomplicated cystitis. 2. A fluoroquinolone is an appropriate choice for women who have an allergy to TMP-SMX or risk factors for TMP-SMX resistance and who have moderate to severe symptoms. Oral Antibiotics for Acute Uncomplicated Cystitis Drug, dose Dose and in- terval Duration Levofloxacin (Levaquin) 250 mg q24h 3 days Ciprofloxacin (Cipro) 100 to 250 mg q12h OR 500 mg q24h 3 days 3 days Gatifloxacin (Tequin) 400 mg single dose OR 200 mg q24h 3 days Drug, dose Dose and in- terval Duration Trimethoprim- sulfamethoxaz ole (Bactrim) 160/800 mg q12h 3 days Trimethoprim 100 mg q12h 3 days Cefpodoxime proxetil (Vantin) 100 mg q12h 3-7days Nitrofurantoin macrocrystals (Macrobid) 50 mg q6h 7 days Nitrofurantoin monohydrate macrocrystals (Macrobid) 100 mg q12h 7 days Amoxicillin/clav ulanate (Augmentin) 500 mg q12h 7 days 3. Nitrofurantoin (Macrodantin [for seven days]) should be used for women with mild-to-moderate symptoms who have allergy to TMP-SMX or risk factors for TMP-SMX resistance. 4. Urinary analgesia (phenazopyridine [Pyrimidine] 200 mg orally TID) is offered to those with severe dysuria (10 percent). Phenazopyridine is usually given for only one to two days. 5. Routine post-treatment cultures in non-pregnant women who have become asymptomatic after an episode of cystitis are not indicated. In patients whose symptoms do not resolve, urine culture and antimicrobial susceptibility testing should be per- formed. Empiric therapy in these situations should include a fluoroquinolone unless such an agent was used initially. IV. Acute complicated cystitis A. Urinary tract infection may lead to serious complications in the person who is pregnant, very young or old, diabetic, immunocompromised, or who has an abnor- mal genitourinary tract. B. Clinical presentation. Acute complicated cystitis generally presents with dysuria, frequency, urgency, suprapubic pain, and/or hematuria. Fever (>38ºC), flank pain, costovertebral angle tenderness, and nausea or vomiting suggest the infection has extended beyond the bladder. C. Bacteriology. The spectrum of uropathogens causing complicated cystitis is much broader than that causing uncomplicated cystitis. Infection with Proteus, Klebsiella, Pseudomonas, Serratia, and Providencia species, and enterococci, staphylococci and fungi is more common in complicated cystitis. These uropathogens, including E. coli, are much more likely to be resistant to common antimicrobials. D. Diagnosis. Pyuria is present in almost all patients with complicated cystitis. Urine cultures with susceptibility testing should be obtained in complicated cystitis. A Gram stain may be helpful since the presence of Gram positive cocci, suggestive of enterococci, may influence the choice of empiric antibiotics. E. Treatment 1. Complicated cystitis should be treated with an oral fluoroquinolone such as ciprofloxacin, levofloxacin, or gatifloxacin. The fluoroquinolones are well toler- ated, provide a broad spectrum of activity covering most expected pathogens (including P. aeruginosa), and achieve high levels in the urine and urinary tract tissue. The recommended dose for ciprofloxacin (Cipro) is 500 mg PO twice daily, for levofloxacin (Levaquin) is 500 mg PO once daily, and for gatifloxacin (Tequin) is 400 mg PO once daily, each for 7 to 14 days. 2. Amoxicillin, nitrofurantoin and sulfa drugs are poor choices for empiric therapy in complicated cystitis because of the high prevalence of resistance. 3. Parenteral therapy is occasionally indicated for the treatment of complicated cystitis caused by multiply- resistant uropathogens, or for those patients who are allergic or intolerant to fluoroquinolones. Parenteral levofloxacin (500 mg) or gatifloxacin (400 mg), ceftriaxone (1 g), or an aminoglycoside (3 to 5 mg/kg of gentamicin or tobramycin) can be administered once daily. Patients initially given parenteral therapy can be switched to oral agents, usually a fluoroquinolone, after clinical improvement. 4. Gram positive cocci, suggestive of enterococci, may require the addition of ampicillin (1 g every six hours) or amoxicillin (500 mg PO every eight hours) to a treatment regimen. 5. If the patient does not show improvement within 24 to 48 hours, a repeat urine culture and ultrasound or computerized tomography should be considered to rule out urinary tract pathology. 6. The recommended duration of treatment for acute complicated cystitis is 7 to 14 days. A follow-up urine culture is not indicated in the asymptomatic patient. V. Cystitis in young men. A small number of 15- to 50- year-old men suffer acute uncomplicated UTIs. Risk factors include homosexuality, intercourse with an infected female partner, and lack of circumcision. A. Dysuria, frequency, urgency, suprapubic pain, or hematuria are typical of cystitis in men. The absence of pyuria suggests a non-infectious diagnosis. A mid- stream urine culture is recommended. B. Other causes of infection. Urethritis must be consid- ered in sexually active men; examination for penile ulcerations and urethral discharge, evaluation of a urethral swab specimen Gram stain, and diagnostic tests for N. gonorrheae and C. trachomatis are war- ranted. A urethral Gram stain demonstrating leukocytes and predominant Gram negative rods suggests E. coli urethritis. C. Chronic prostatitis should also be considered, particu- larly in men who have had recurrent UTIs. D. Treatment of cystitis. The etiologic agents causing uncomplicated urinary tract infections in men are similar to those in women. Thus, the TMP-SMX (Bactrim) is appropriate for empiric use in men, although 7-day regimens are recommended. Nitrofurantoin and beta- lactams should not be used in men with cystitis since they do not achieve reliable tissue concentrations and would be ineffective for occult prostatitis. Fluoroquinolones provide the best antimicrobial spec- trum and prostatic penetration. References, see page 360. Acute Pyelonephritis Urinary tract infections (UTIs) are common, especially in young children and sexually active women. UTI is defined either as a lower tract (acute cystitis) or upper tract (acute pyelonephritis) infection. I. Clinical features A. Acute uncomplicated pyelonephritis is suggested by flank pain, nausea/vomiting, fever (>38ºC) and/or costovertebral angle tenderness. Frequency, dysuria, and suprapubic pain are found in the majority of patients whether infection is localized to the upper or lower tract. B. Fever >37.8ºC is strongly correlated with acute pyelonephritis. The examination should focus on temper- ature, abdomen, and costovertebral angle tenderness. C. Pelvic examination may be indicated since pelvic inflammatory disease is a condition often mistaken for acute uncomplicated pyelonephritis. Pelvic examination does not need to be performed, however, in a woman with unilateral CVA pain and tenderness, fever, pyuria, and no vaginal symptoms. Risk Factors for Occult Renal Infection or a Compli- cated Urinary Tract Infection Male sex Elderly Presentation in emer- gency department Hospital-acquired infec- tion Pregnancy Indwelling urinary cathe- ter Recent urinary tract in- strumentation Childhood urinary tract infection Functional or anatomic abnormality of the urinary tract Recent antimicrobial use Symptoms for more than seven days at presenta- tion Diabetes mellitus Immunosuppression II.Laboratory features A. Pyuria is present in virtually all women with acute pyelonephritis; its absence strongly suggests an alterna- tive diagnosis. Hematuria is common with urinary tract infection but not in urethritis or vaginitis. Most patients with acute pyelonephritis have leukocytosis and an elevated erythrocyte sedimentation rate and serum C- reactive protein. B. Some patients with pyelonephritis may have colony counts of 10 3 to 10 4 CFU per mL. Blood cultures are positive in 10 to 20 percent of women with acute uncom- plicated pyelonephritis. C. A urinalysis should be performed to look for pyuria. White cell casts indicate a renal origin for the pyuria. Gram stain, usually performed on spun urine, may distinguish Gram negative from Gram positive infections. A pregnancy test should be performed if there is missed menses or lack of contraception. D. Urine culture and antimicrobial susceptibility testing should be performed routinely in acute pyelonephritis. E. Rapid methods for detection of bacteriuria, such as the nitrite test, should not be relied upon in the evaluation of patients with suspected pyelonephritis because tests lack adequate sensitivity for detection of “low count” urinary tract infection and common uropathogenic species. The nitrite test has a sensitivity of 35 to 80 percent and does not detect organisms unable to reduce nitrate to nitrite, such as enterococci and staphylococci. F. Blood cultures are limited to those patients who warrant hospitalization. III. Treatment. Microbiology of acute uncomplicated upper and lower urinary tract infection is rather limited with Escherichia coli accounting for 70 to 95 percent of infections and Staphylococcus saprophyticus 5 to 20 percent. A. Indications for admission to the hospital include: 1. Inability to maintain oral hydration or take medica- tions. 2. Patient noncompliance. 3. Uncertainty about the diagnosis. 4. Severe illness with high fevers, pain, and marked debility. 5. Outpatient therapy should generally be reserved for nonpregnant women with mild-to-moderate uncompli- cated pyelonephritis who are compliant. B. Empiric antibiotic therapy 1. Ampicillin and sulfonamides should not be used for empiric therapy because of the high rate of resis- tance. An increasing proportion of uropathogens demonstrate resi stance to tri methopri m- sulfamethoxazole. In comparison, resistance to the fluoroquinolones and aminoglycosides is very low in uncomplicated UTIs. 2. Oral agents. In patients with acute uncomplicated pyelonephritis, an oral fluoroquinolone, such as ciprofloxacin (500 mg PO BID), levofloxacin (Levaquin [250 to 500 mg PO QD]), or gatifloxacin (Tequin [400 mg PO QD]), is recommended for outpatients as initial empiric treatment of infection caused by Gram negative bacilli. The newer fluoroquinolones, sparfloxacin, trovafloxacin and moxifloxacin, should be avoided because they may not achieve adequate concentrations in urine. a. Trimethoprim, trimethoprim-sulfamethoxazole or other agents can be used if the infecting strain is known to be susceptible. If enterococcus is sus- pected by the presence of small Gram positive cocci on Gram stain, amoxicillin (500 mg PO TID) should be added to the treatment regimen until the causative organism is identified. b. Cefixime (Suprax) and cefpodoxime proxetil (Vantin) also appear to be effective for the treat- ment of acute uncomplicated pyelonephritis. Cefixime is less effective against S. saprophyticus. Nitrofurantoin should not be used for the treatment of pyelonephritis since it does not achieve reliable tissue levels. Parenteral Regimens for Empiric Treatment of Acute Uncomplicated Pyelonephritis Antibiotic, dose Interval Ceftriaxone (Rocephin), 1 g q24h Ciprofloxacin (Cipro), 200-400 mg q12h Levofloxacin (Levaquin), 250-500 mg q24h Ofloxacin (Floxin), 200-400 mg q12 h Gatifloxacin (Tequin), 400 mg q24h Gentamicin, 3-5 mg/kg (+ampicillin) q24h Gentamicin, 1 mg per kg (+ampicillin) q8h Ampicillin, 1-2 g (plus gentamicin) * q6h Aztreonam (Azactam), 1 g q8-12h * Recommended regimen if enterococcus suspected. 3. Parenteral therapy. For hospitalized patients, ceftriaxone (Rocephin [1 gram IV QD]) is recom- mended if enterococcus is not suspected. Aminoglycosides (3 to 5 mg/kg) given once daily provide a therapeutic advantage compared with beta lactams because of their marked and sustained concentration in renal tissue. a. Ciprofloxacin, ofloxacin, levofloxacin and gatifloxacin are also effective for the parenteral treatment of uncomplicated pyelonephritis but should be used orally if the patient is able to tolerate oral medications since the costs are lower and serum levels are equivalent. b. If enterococcus is suspected based upon the Gram stain, ampicillin (1 to 2 g IV Q6h) plus gentamicin (1.0 mg/kg IV Q8h) or piperacillin- tazobactam (3.375 g IV Q8h) are reasonable broad spectrum empiric choices. Once-daily dosing of aminoglycosides is not recommended for serious probable enterococcal infection since this regimen may not provide adequate synergy against the organism. C. Duration. Patients with acute uncomplicated pyelonephritis can often be switched to oral therapy at 24 to 48 hours. Patients should be evaluated for compli- cated pyelonephritis if they fail to defervesce or if bacteremia persists. A 14-day regimen is recommended. In sicker patients, a longer duration of treatment may be required (14 to 21 days). D. Posttreatment follow-up cultures in an asymptomatic patient are not indicated. In women whose pyelonephritis symptoms resolve but recur within two weeks, a repeat urine culture and antimicrobial suscepti- bility testing should be performed. If the initially infecting species is isolated again with the same susceptibility profile, a renal ultrasound or computed tomographic (CT) scan should be performed. Retreatment with a two- week regimen using another agent should be consid- ered. E. Urologic evaluation 1. Routine urologic investigation of young healthy women with acute uncomplicated pyelonephritis is generally not recommended. Ultrasound or CT scan should be considered if the patient remains febrile or has not shown clinical improvement after 72 hours of treatment. CT scan or renal ultrasound should be performed after two recurrences of pyelonephritis. IV. Acute complicated pyelonephritis A. Clinical features. In addition to flank pain, dysuria and fever, complicated urinary tract infections may also be associated with malaise, fatigue, nausea, or abdominal pain. B. A urine Gram stain and culture should always be per- formed in patients with suspected complicated UTI. A colony count threshold of >10 3 CFU per mL should be used to diagnose symptomatic complicated infection except when urine cultures are obtained through a newly-inserted catheter in which case a level of >10 (2) CFU per mL is evidence of infection. C. Microbiology. E. coli is still the predominant uropathogen, but other uropathogens, including Citrobacter sp, Enterobacter sp, Pseudomonas aeruginosa, enterococci, Staphylococcus aureus, and fungi account for a higher proportion of cases compared with uncomplicated urinary tract infections. D. Treatment. Patients with complicated pyelonephritis, including pregnant women, should be managed as inpatients. Underlying anatomic (eg, stones, obstruc- tion), functional (eg, neurogenic bladder), or metabolic (eg, poorly controlled diabetes) defects must be cor- rected. 1. In contrast to uncomplicated UTI, S. aureus is rela- tively more likely to be found. For those patients with mild to moderate illness who can be treated with oral medication, a fluoroquinolone is the best choice for empiric therapy. Fluoroquinolones are comparable or superior to other broad spectrum regimens, including parenteral therapy. Sparfloxacin, trovafloxacin and moxifloxacin are not effective. 2. Antimicrobial regimen can be modified when the infecting strain susceptibilities are known. Patients on parenteral regimens can be switched to oral treat- ment, generally a fluoroquinolone, after clinical improvement. Patients undergoing effective treatment with an antimicrobial to which the infecting pathogen is susceptible should have definite improvement within 24 to 48 hours and, if not, a repeat urine culture and imaging studies should be performed. 3. At least 10 to 14 days of therapy is recommended. Urine culture should be repeated one to two weeks after the completion of therapy. Suppressive antibiot- ics may be considered with complicated pyelonephritis and a positive follow-up urine culture. Parenteral Regimens for Empiric Treatment of Acute Complicated Pyelonephritis Antibiotic, dose Interval Cefepime (Maxipime) , 1 g Ciprofloxacin (Cipro), 400 mg Levofloxacin (Levaquin), 500 mg Ofloxacin (Floxin), 400 mg Gatifloxacin (Tequin), 400 mg Gentamicin, 3-5 mg/kg (+ ampicillin)* Gentamicin, 1 mg per kg (+ ampicillin)* Ampicillin, 1-2 g (+ gentamicin)* Ticarcillin-clavulante (Timentin), 3.2 g Piperacilin-tazobactam (Zosyn), 3.375 g* Imipenem-cilastatin, 250-500 mg q12 hours q12 hours q24 hours q12 hours q24 hours q24 hours q8 hours q6 hours q8 hours q6-8 hours q6-8 hours *Recommended regimen if enterococcus suspected References, see page 360. Early Syphilis Syphilis is a chronic infection caused by the bacterium Treponema pallidum (Tp). Early syphilis is defined as the stages of syphilis that typically occur within the first year after acquisition of the infection. Early latent syphilis is defined as asymptomatic infection, with positive serology and a negative physical examination, when the date of infection can be established as having occurred within one year’s time. Early syphilis is a reportable infection. The proportion of early syphilis in men is 3.5 times higher than in women. I. Clinical manifestations A. Early syphilis begins when an uninfected person ac- quires Tp, usually via direct contact with an infectious lesion during sex. The spirochete gains access at sites of minor trauma. Transmission occurs in one-third of patients exposed to early syphilis. B. Primary syphilis. After an average incubation period of two to three weeks, a painless papule appears at the site of inoculation. This soon ulcerates to produce the classic chancre of primary syphilis, a one to two centi- meter ulcer with a raised, indurated margin. The ulcer has a non-exudative base and is associated with regional lymphadenopathy. Most lesions are seen on the genitalia. Chancres heal spontaneously within three to six weeks. C. Secondary syphilis. Weeks to a few months later, 25% of individuals with untreated infection will develop a systemic illness that represents secondary syphilis. Secondary syphilis can produce a wide variety of symptoms. 1. Rash is the most characteristic finding of secondary syphilis. The rash is classically a symmetric papular eruption involving the entire trunk and extremities including the palms and soles. Individual lesions are discrete red or reddish-brown and measure 0.5 to 2 cm in diameter. They are often scaly but may be smooth and rarely pustular. The involvement of the palms and soles is an important clue to the diagnosis of secondary syphilis. Large, raised, gray to white lesions, involving warm, moist areas such as mucous membranes in the mouth or perineum, may develop in some patients during secondary syphilis. These are referred to as condyloma lata. 2. Systemic symptoms include fever, headache, malaise, anorexia, sore throat, myalgias, and weight loss. 3. Diffuse lymphadenopathy. Most patients with secondary syphilis have lymph node enlargement with palpable nodes present in the inguinal, axillary, posterior cervical, femoral, and/or epitrochlear regions. These nodes are generally minimally tender, firm, and rubbery in consistency. 4. Alopecia. “Moth-eaten” alopecia is occasionally seen among patients presenting with secondary syphilis. This condition is usually reversible with treatment. 5. Neurologic abnormalities. Central nervous system (CNS) syphilis may occur within the first few weeks after initial infection or up to 25 years later. a. Asymptomatic CNS syphilis has both an early and late form. b. The acute manifestations of secondary syphilis (including the neurologic abnormalities) typically resolve spontaneously, even in the absence of therapy. c. The primary indications for lumbar puncture are symptoms of meningitis or focal neurologic find- ings. d. Early syphilis in HIV-infected patients. There is a strong association between syphilis and the human immunodeficiency virus (HIV) infection, both of which are sexually transmitted disease (STDs). e. Latent syphilis refers to the period during which patients infected with Tp have no symptoms but have infection demonstrable by serologic testing. Early latent syphilis is defined as infection of one year’s duration or less. All other cases are re- ferred to as late latent syphilis or latent syphilis of unknown duration. A longer duration of therapy is recommended for patients with late latent syphilis. II.Diagnosis. The chancre of primary syphilis is best diag- nosed by darkfield microscopy, while secondary syphilis is reliably diagnosed by serologic testing. A. Serologic testing for syphilis 1. Darkfield microscopy. The most rapid method for diagnosing primary and secondary syphilis is direct visualization of the spirochete from moist lesions by darkfield microscopy. Darkfield microscopy is gener- ally only available in clinics that specialize in the diagnosis and treatment of sexually transmitted diseases (STDs). 2. Serologic tests. Most patients suspected of having syphilis must be diagnosed by serologic testing. There are two types of serologic tests for syphilis: nontreponemal tests such as the Venereal Disease Research Laboratory (VDRL) test and the Rapid Plasma Reagin (RPR) test, and treponemal tests such as the fluorescent treponemal antibody absorp- tion (FTA-ABS) test, the microhemagglutination test for antibodies to Treponema pallidum (MHA-TP), and the Treponema pallidum particle agglutination assay (TPPA). a. Nontreponemal tests are based upon the reac- tivity of serum from patients with syphilis to a cardiolipin-cholesterol-lecithin antigen. These tests measure IgG and IgM antibodies and are used as the screening test for syphilis. Positive tests are usually reported as a titer of antibody, and they can be used to follow the response to treatment in many patients. b. Treponemal tests are used as confirmatory tests when the nontreponemal tests are reactive. These tests all use T. pallidum antigens and are based upon the detection of antibodies directed against treponemal cellular components. Causes of False-positive Tests for Syphilis Nontreponem al tests (VDRL, RPR) - acute Nontreponem al tests (VDRL, RPR) - chronic Treponemal tests (FTA- ABS, MHA-TP) Pneumococcal pneumonia Scarlet fever Leprosy Lymphogranulo ma venereum Relapsing fever infective endocarditis Malaria Rickettsial in- fections Psittacosis Leptospirosis Chancroid Tuberculosis Mycoplasma infections Trypanosomias is Varicella infec- tions HIV Measles Infectious mononucleosis Mumps Viral hepatitis Pregnancy Chronic liver disease Malignancy (advanced) Injection drug use Myeloma Advanced age Connective tissue disease Multiple trans- fusions Lyme borreliosis Leprosy Malaria Infectious mononucleosis Relapsing fever Leptospirosis Systemic lupus erythematosus 3. Algorithm for screening and testing. Serologic testing to diagnose syphilis is performed in two settings: screening of patients at increased risk and evaluation of patients with suspected disease. a. Screening is recommended for all pregnant women and people at higher risk of acquiring syphilis (MSM who engage in high risk behaviors, commercial sex workers, persons who exchange sex for drugs, and those in adult correctional facilities). b. Screening begins with a nontreponemal test such as the VDRL; a reactive specimen is then con- firmed with a treponemal test such as the FTA- ABS. c. The most common cause of a false negative syphilis serologic test is performance prior to the development of antibodies. Twenty to 30 percent of patients presenting with a chancre will not yet have developed a reactive serologic test for syphilis. Indications for cerebrospinal fluid examination in patients with reactive syphilis serologic tests Signs of neurosyphilis Weakness, pain, paresthesias, sensory changes in the legs Hyperactive deep tendon reflexes (later, absent DTRs) Loss of vibratory and position sense in the legs Broad-based, stamping gait Fecal or urinary incontinence Confusion, psychotic behavior, dementia Signs of ophthalmic syphilis Chorioretinitis Acute optic neuritis Optic atrophy Pupillary abnormalities (small, fixed pupils that do not react to light) Evidence of active tertiary syphilis Cardiovascular syphilis (aortic aneurysm, aortic regurgitation) Late benign syphilis (gummatous syphilis): most frequently involving bones, skin Treatment failure In primary and secondary syphilis: Failure of non-treponemal test titer to decline fourfold after six months Failure of non-treponemal test titer to decline eightfold after twelve months In early latent syphilis Failure of non-treponemal test titer to decline fourfold after twelve months HIV-infected patients with late latent syphilis or latent syphilis of unknown duration 4. Monitoring the response to therapy. The following reductions in reagin antibody titers are noted after recommended antibiotic therapy: a. Among patients with primary and secondary syphilis, a fourfold decline by six months and an eightfold decline by 12 months. b. Compared to those with primary and secondary syphilis, the rate of decline is slower among patients with early latent syphilis — fourfold de- cline by 12 months. III. Treatment of early syphilis A. Antibiotic treatment of syphilis must be prolonged. A single dose of benzathine penicillin G (2.4 million units IM) is standard therapy for all forms of early syphilis. B. The single dose of benzathine penicillin as therapy is only appropriate when it is possible to document that there was a non-reactive syphilis serologic within the past year or if there is good documentation of the chancre of primary syphilis serology within the past year. Otherwise it should be referred to as latent syphilis of unknown duration for which three doses of benzathine penicillin at weekly intervals are recom- mended. C. Some patients do not respond, based upon failure of serum VDRL titers to decrease at least fourfold over 6 to 12 months of follow-up. Some of these cases may be due to reinfection. Such treatment failures are managed by giving another course of benzathine penicillin, and making sure all sexual contacts are also treated. D. Patients with early syphilis who are allergic to penicillin may be treated with 14 days of either doxycycline (100 mg PO BID) or tetracycline (500 mg PO QID). E. Azithromycin has also been considered an option for penicillin-allergic patients. However, there are increas- ing reports of azithromycin resistance. Azithromycin should be avoided in regions where azithromycin resistance is relatively common and in patients with frequent macrolide use (eg, MAC prophylaxis in HIV- infected patients). F. There is no alternative to penicillin for the treatment of syphilis during pregnancy; penicillin allergic pregnant patients should be desensitized to penicillin. Stages of Syphilitic Infection Stag e Clinical mani- festatio ns Diagnosis (sensitiv- ity) Treatment Pri- mary syphi- lis Chancre Dark-field microscopy of skin le- sion (80%) Nontrepon emal tests (78% to 86%) Treponema l-specific tests (76% to 84%) Penicillin G benzathine, 2.4 million units IM (sin- gle dose) Alternatives in non- pregnant patients with penicillin al- lergy: doxycycline (Vibramycin), 100 mg orally twice daily for 2 weeks; tetracycline, 500 mg orally four times daily for 2 weeks; ceftriaxone (Roce- phin), 1 g once daily IM or IV for 8 to 10 days; or azithromycin (Zithromax), 2 g orally (single dose) Sec- ondar y syphi- lis Skin and mu- cous mem- branes: diffuse rash, condylo ma latum, other lesions Renal system: glomerul onephriti s, nephroti c syn- drome Liver: hepatitis Central nervous system: head- ache, meningi smus, cranial neurop- athy, iritis and uveitis Consti- tutional symp- toms: fever, malaise, general- ized lymphad enopath y, arthralgi as, weight loss, others Dark-field microscopy of skin le- sion (80%) Nontrepon emal tests (100%) Treponema l-specific tests (100%) Same treatments as for primary syph- ilis Stag e Clinical mani- festatio ns Diagnosis (sensitiv- ity) Treatment La- tent syphi- lis None Nontrepon emal tests (95% to 100%) Treponema l-specific tests (97% to 100%) Early latent syphilis: same treatments as for primary and secondary syphilis Late latent syphilis: penicillin G benzathine, 2.4 million units IM once weekly for 3 weeks Alternatives in nonpregnant pa- tients with penicillin allergy: doxycycline, 100 mg orally twice daily for 4 weeks; or tetracycline, 500 mg orally four times daily for 4 weeks Ter- tiary (late) syphi- lis Gummat ous dis- ease, cardio- vascular disease Nontrepon emal tests (71% to 73%) Treponema l-specific tests (94% to 96%) Same treatment as for late latent syphi- lis Neur o- syphi- lis Sei- zures, ataxia, aphasia, paresis, hyperref lexia, person- ality changes , cogni- tive dis- turbanc e, visual changes , hear- ing loss, neurop- athy, loss of bowel or bladder function, others Cerebrospi nal fluid examina- tion Aqueous crystalline penicillin G, 3 to 4 million units IV ev- ery 4 hours for 10 to 14 days; or peni- cillin G procaine, 2.4 million units IM once daily, plus probenecid, 500 mg orally four times daily, with both drugs given for 10 to 14 days References, see page 360. Gastrointestinal Disorders Helicobacter Pylori Infection and Peptic Ulcer Disease The spiral-shaped, gram-negative bacterium Helicobacter pylori is found in gastric mucosa or adherent to the lining of the stomach. Acute infection is most commonly asymptom- atic but may be associated with epigastric burning, abdomi- nal distention or bloating, belching, nausea, flatulence, and halitosis. H. pylori infection can lead to ulceration of the gastric mucosa and duodenum and is associated with malignancies of the stomach. The prevalence of H. pylori infection is as high as 52 percent. I. Pathophysiology A. Helicobacter pylori (HP), a spiral-shaped, flagellated organism, is the most frequent cause of peptic ulcer disease (PUD). Nonsteroidal anti-inflammatory drugs (NSAIDs) and pathologically high acid-secreting states (Zollinger-Ellison syndrome) are less common causes. More than 90% of ulcers are associated with H. pylori. Eradication of the organism cures and prevents relapses of gastroduodenal ulcers. B. Complications of peptic ulcer disease include bleeding, duodenal or gastric perforation, and gastric outlet obstruction (due to inflammation or strictures). II. Clinical evaluation A. Symptoms of PUD include recurrent upper abdominal pain and discomfort. The pain of duodenal ulceration is often relieved by food and antacids and worsened when the stomach is empty (eg, at nighttime). In gastric ulceration, the pain may be exacerbated by eating. B. Nausea and vomiting are common in PUD. Hematemesis (“coffee ground” emesis) or melena (black tarry stools) are indicative of bleeding. C. Physical examination. Tenderness to deep palpation is often present in the epigastrium, and the stool is often guaiac-positive. Presentation of Uncomplicated Peptic Ulcer Dis- ease Epigastric pain (burning, vague abdominal discomfort, nausea) Often nocturnal Occurs with hunger or hours after meals Usually temporarily relieved by meals or antacids Persistence or recurrence over months to years History of self-medication and intermittent relief D. NSAID-related gastrointestinal complications. NSAID use and H pylori infection are independent risk factors for peptic ulcer disease. The risk is 5 to 20 times higher in persons who use NSAIDs than in the general population. Misoprostol (Cytotec) has been shown to prevent both NSAID ulcers and related complications. The minimum effective dosage is 200 micrograms twice daily; total daily doses of 600 micro- grams or 800 micrograms are significantly more effective. III. When to test and treat A. In the absence of alarm symptoms for cancer or complicated ulcer disease, the approach to testing in patients with dyspepsia can be divided into four clinical scenarios: (1) known peptic ulcer disease, currently or previously documented; (2) known nonulcer dyspep- sia; (3) undifferentiated dyspepsia, and (4) gastroesophageal reflux disease (GERD). B. Peptic ulcer disease. Treatment of H. pylori infection in patients with ulcers almost always cures the dis- ease and reduces the risk for perforation or bleeding. C. Nonulcer disease. There is no convincing evidence that empiric eradication of H. pylori in patients with nonulcer dyspepsia improves symptoms. D. Undifferentiated dyspepsia. A test-and-treat strategy is recommended in which patients with dyspepsia are tested for the presence of H. pylori with serology and treated with eradication therapy if the results are positive. Endoscopy is reserved for use in patients with alarm signs or those with persistent symptoms despite empiric therapy. Alarm Signs for Risk of Gastric Cancer of Compli- cated Ulcer Disease Older Than 45 years Rectal bleeding or melena Weight los of >10 percent of body weight Anemia Abdominal mass Jaundice Family history of gastric can- cer Previous history of peptic Dysphagia ulcer Anorexia/early satiety Evaluation for Helicobacter pylori-Related Disease Clinical scenario Recommended test Dyspepsia in patient with alarm symptoms for cancer or complicated ulcer (eg, bleeding, perforation) Promptly refer to a gastroenterologist for endos- copy. Known PUD, uncomplicated Serology antibody test; treat if result is positive. Dyspepsia in patient with pre- vious history of PUD not pre- viously treated with eradica- tion therapy Serology antibody test; treat if result is positive. Dyspepsia in patient with PUD previously treated for H. pylori Stool antigen or urea breath test; if positive, treat with reg- imen different from the one previously used; retest to confirm eradication. Consider endoscopy. Undifferentiated dyspepsia (without endoscopy) Serology antibody test; treat if result is positive. Documented nonulcer dys- pepsia (after endoscopy) Unnecessary GERD Unnecessary Asymptomatic with history of documented PUD not previ- ously treated with eradication therapy Serology antibody test; treat if result is positive. Asymptomatic Screening unnecessary E. Gastroesophageal Reflux Disease. H. pylori infection does not increase the risk of GERD. Eradication therapy does not eliminate GERD symptoms (sensa- tion of burning and regurgitation. IV.Helicobacter pylori Tests A. Once testing and eradication are chosen, several diagnostic tests are available. Unless endoscopy is planned, a practical approach is to use serology to identify initial infection, and use the stool antigen test or urea breath test to determine cure, if indicated. Noninvasive Testing Options for Detecting Helicobacter pylori Test What does it mea- sure? Sensit ivity Test of cure ? Comments Serol- ogy: lab- ora- tory-bas ed ELISA IgG 90 to 93 No Accurate; con- venient for initial infec- tion; titers may remain positive after one year Whole blood: of- fice-bas ed ELISA IgG 50 to 85 No Less accurate but fast, con- venient Stool: HpSA H. pylori antigens 95 to 98 Yes Relatively convenient and available Urea breath test Urease activity 95 to 100 Yes Sensitivity reduced by acid suppres- sion B. Endoscopy and Biopsy. Alarm symptoms for cancer or ulcer complication warrant prompt endoscopic evaluation. A gastric antral biopsy specimens is considered the gold standard for detecting the pres- ence of H. pylori. Cultures of biopsy specimens ob- tained during endoscopy can be tested for antimicrobial resistance in cases of treatment failure. C. Serology/ELISA. When endoscopy is not performed, the most commonly used diagnostic approach is the laboratory-based serologic antibody test. This en- zyme-linked immunosorbent assay (ELISA) detects IgG antibodies to H. pylori, indicating current or past infection. A positive serologic test suggests active infection in patients who have not undergone eradica- tion therapy. The serologic test results may not revert to negative once the organism is eradicated; therefore, the test is not used to identify persistent infection. D. Stool testing with enzyme-linked immunoassay for H. pylori antigen in stool specimens is highly sensitive and specific, the stool antigen test reverts to negative from five days to a few months after eradication of the organism, with 90 percent specificity. This test is useful in confirming eradication, and, because it is of- fice-based, is less costly and more convenient than the urea breath test. False-positive results may occur even four weeks following eradication therapy. E. Urea Breath Test. The urea breath test is a reliable test for cure and can detect the presence or absence of active H. pylori infection with greater accuracy than the serologic test. It is usually administered in the hospital outpatient setting because it requires time and special equipment. V. Treatment Regimens for Helicobacter Pylori A. Initial treatment 1. The regimen of choice is triple therapy with a proton pump inhibitor (eg, lansoprazole 30 mg twice daily, omeprazole (Prilosec) 20 mg twice daily, pantoprazole (Protonix) 40 mg twice daily, rabeprazole (AcipHex) 20 mg twice daily, or esomeprazole (Nexium) 40 mg once daily), amoxicillin (1 g twice daily), and clarithromycin (500 mg twice daily) for two weeks (10 days may be adequate). The combination of lansoprazole, amoxicillin and clarithromycin is available in a daily-dose package, Prevpac. 2. Metronidazole (Flagyl [500 mg twice daily]) can be substituted for amoxicillin but only in penicillin- allergic individuals since metronidazole resistance is common. 3. A proton pump inhibitor (PPI) may be combined with bismuth (525 mg four times daily) and two antibiotics (eg, metronidazole 500 mg four times daily and tetracycline 500 mg four times daily) for two weeks. One week of bismuth based treatment may be sufficient as long as it is given with a PPI. Triple Therapy Regimens for Helicobacter pylori Infection Treatment (10 to 14 days of ther- apy recommended) Conve- nience factor Tolerab ility 1. Omeprazole (Prilosec), 20 mg two times daily or Lansoprazole (Prevacid), 30 mg two times daily plus Metronidazole (Flagyl), 500 mg two times daily or Amoxicillin, 1 g two times daily plus Clarithromycin (Biaxin), 500 mg two times daily Prepackaged triple-ther- apy(Prevpac): taken bid for 14 days; consists of 30 mg lansoprazole, 1 g amoxicillin, and 500 mg clarithromycin. Twice-d aily dos- ing Fewer signifi- cant side effects, but more abnor- mal taste versus other regi- mens 2. Ranitidine bismuth citrate (Tritec), 400 mg twice daily plus Clarithromycin, 500 mg twice daily or Metronidazole, 500 mg twice daily plus Tetracycline, 500 mg twice daily or Amoxicillin, 1 g twice daily 92 (RMA) Twice-d aily dos- ing In- creased diarrhea versus other regi- mens 4. Dual therapy regimens using a PPI plus one antibi- otic have eradication rates significantly lower (60 to 85 percent) than the standard regimens. 5. One-week treatment protocols have ulcer healing rates of 90 percent and H. pylori eradication rates of 77 to >85 percent. B. Treatment failures. Initial eradication of H. pylori fails in 5 to 12 percent of patients. For patients failing one course of H. pylori treatment, quadruple therapy consisting of a PPI twice daily and bismuth-based triple therapy (Pepto Bismol 2 tablets, tetracycline 500 mg, and high dose metronidazole 500 mg all four times daily) preferably given with meals for 14 days is recommended. Two weeks should be the duration of subsequent courses of treatment. C. Side effects are reported in up to 50 percent of patients taking one of the triple agent regimens: 1. The most common side effect is a metallic taste due to metronidazole or clarithromycin. 2. Metronidazole can cause peripheral neuropathy, seizures, and a disulfiram-like reaction when taken with alcohol. 3. Tetracycline can induce a photosensitivity reaction. It should not be administered to pregnant women. 4. Amoxicillin can cause diarrhea or an allergic reac- tion. 5. Bismuth side effects are rare. Proton pump inhibi- tors have no significant documented adverse effects. D. Treatment of NSAID-related ulcers 1. When the ulcer is caused by NSAID use, healing of the ulcer is greatly facilitated by discontinuing the NSAID. Acid antisecretory therapy with an H2- blocker or proton pump inhibitor speeds ulcer healing. Proton pump inhibitors are more effective in inhibiting gastric acid production and are often used to heal ulcers in patients who require continu- ing NSAID treatment. 2. If serologic or endoscopic testing for H pylori is positive, antibiotic treatment is necessary. 3. Acute H 2 -blocker therapy a. Ranitidine (Zantac), 150 mg bid or 300 mg qhs. b. Famotidine (Pepcid), 20 mg bid or 40 mg qhs. c. Nizatidine (Axid Pulvules), 150 mg bid or 300 mg qhs. d. Cimetidine (Tagamet), 400 mg bid or 800 mg qhs. 4. Proton pump inhibitors a. Omeprazole (Prilosec), 20 mg qd. b. Lansoprazole (Prevacid), 15 mg before break- fast qd. c. Esomeprazole (Nexium) 20-40 mg qd. d. Pantoprazole (Protonix) 40 mg PO, 20 minuted before the first meal of the day or IV once daily. e. Rabeprazole (AcipHex) 20 mg/day, 20 to 30 minutes before the first meal of the day. VI.Surgical treatment of peptic ulcer disease A. Indications for surgery include exsanguinating hemorrhage, >5 units transfusion in 24 hours, rebleeding during same hospitalization, intractability, perforation, gastric outlet obstruction, and endoscopic signs of rebleeding. B. Unstable patients should receive a truncal vagotomy, oversewing of bleeding ulcer bed, and pyloroplasty. References, see page 360. Gastroesophageal Reflux Disease Gastroesophageal reflux disease is caused by the combina- tion of excess reflux of gastric juice and impaired clearance of this refluxate from the esophagus. GERD is defined as symptoms or tissue damage caused by reflux of gastric contents with or without esophageal inflammation. I. Clinical manifestations A. Typical symptoms of GERD are heartburn and regurgi- tation; atypical symptoms include odynophagia, dysphagia, chest pain, cough, and reactive airway disease. Up to half of the general population has monthly heartburn or regurgitation. B. Heartburn, the most common symptom of GERD, is a substernal burning sensation that rises from the upper abdomen into the chest and neck. Dysphagia, the sensation that swallowed material is lodged in the chest, may be caused by esophageal inflammation or impaired motility. Esophageal cancer also is an impor- tant differential diagnostic consideration when dysphagia is the presenting complaint. Symptoms of GERD Heartburn (pyrosis) Regurgitation Dysphagia Water brash Globus Odynophagia Hoarseness Chronic cough Nocturnal cough Asthma Dyspepsia Hiccups Chest pain Nausea C. Chest pain due to GERD can mimic angina. Extraesophageal manifestations of GERD include asthma, chronic cough, sinusitis, pneumonitis, laryngi- tis, hoarseness, hiccups, and dental disease. Compli- cations of long-standing GERD include esophageal stricture and Barrett's esophagus. Differential diagnostic considerations in GERD Esophageal neoplasm Infectious esophagitis Caustic esophagitis Pill esophagitis Gastritis Peptic ulcer disease Nonulcer dyspepsia Coronary artery disease Hepatobiliary disease Esophageal motility disorders Cholelithiasis II. Diagnosis A. Diagnosis of GERD is often based on clinical findings and confirmed by the response to therapy. Diagnostic evaluation should be pursued if symptoms are chronic or refractory to therapy or if esophageal or ex- tra-esophageal complications are suspected. Indications for esophageal endoscopy in patients with GERD Dysphagia or odynophagia Persistent or progressive symptoms despite therapy Esophageal symptoms in an immunocompromised patient Mass, stricture, or ulcer on upper gastrointestinal barium study Gastrointestinal bleeding or iron deficiency anemia At least 10 years of GERD symptoms (screen for Barrett's esophagus) B. Ambulatory esophageal pH monitoring is performed by placing a pH electrode just above the lower esopha- geal sphincter. This test has a sensitivity of 60-100%. C. Short PPI trials are useful for diagnosis of GERD and have a sensitivity of 70 to 90% and specificity of 55 to 85%. III. Treatment options A. Lifestyle modification. Strategies include elevation of the head of the bed 6 to 8 in; reduced consumption of fatty foods, chocolate, alcohol, colas, red wine, citrus juices, and tomato products; avoidance of the supine position after meals; not eating within 3 hours of bedtime; avoidance of tight-fitting clothing; weight loss if obese; and smoking cessation. B. Although H 2 -blockers are less expensive than PPIs, PPIs provide superior acid suppression, healing rates and symptom relief. Therefore, PPIs may be more cost-effective than H 2 -blockers, especially in patients with more severe acid-peptic disorders, because of their lower and less frequent dosing requirements and their comparatively shorter duration of required ther- apy. C. Histamine 2 -blockers are used extensively. The four available agents, cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac), are equivalent. Dosage must be reduced in patients with renal failure. In general, doses of H 2 blockers required to control GERD symptoms and heal esophagitis are two to three times higher than those needed for treat- ment of peptic ulcer disease. Rates of symptom control and healing are about 50%. 1. Cimetidine (Tagamet), 800 mg twice daily; ranitidine (Zantac), 150 mg four times daily; famotidine (Pepcid), 40 mg twice daily; and nizatidine (Axid), 150 mg twice daily. D. Proton pump inhibitors (PPIs) irreversibly bind and inhibit the proton pump. 1. The five available PPIs, esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (AcipHex), have similar pharmacologic activities. PPIs should be taken 20 to 30 minutes before the first meal of the day. PPIs are more effective than are H2 blockers. 2. In contrast to the other Proton Pump Inhibitors (PPIs), rabeprazole (AcipHex) forms a partially reversible bond with the proton pump. Therefore, it may have a more sustained acid-suppressing effect than the other PPIs. Rabeprazole and pantoprazole, seem to have fewer drug interactions. Pantoprazole is the least expensive. Proton Pump Inhibitors Drug Dosage Esomeprazole - Nexium 20 mg or 40 mg, 20 to 30 minutes before the first meal of the day Lansoprazole - Prevacid 30 mg, 20 to 30 minutes before the first meal of the day Omeprazole - Prilosec, generic 20 mg/day, 20 to 30 minutes be- fore the first meal of the day Pantoprazole - Protonix 40 mg PO, 20 minuted before the first meal of the day or IV once daily Drug Dosage Rabeprazole - AcipHex 20 mg/day, 20 to 30 minutes be- fore the first meal of the day E. Surgical treatment. The most common of the antireflux procedures used to treat GERD is the Nissen fundoplication, which is a laparoscopic procedure. A portion of the stomach is wrapped around the distal esophagus. Indications include patient preference for surgical treatment over prolonged medical therapy, incomplete control despite medical therapy, and refractory manifestations of reflux (eg, pneumonia, laryngitis, asthma). IV. Management considerations A. Patients with frequent or unrelenting symptoms or esophagitis, or both, should be treated from the outset with a PPI once or twice daily as appropriate. B. Refractory GERD. Increasing the dosage of PPIs often can control GERD in patients receiving a single daily dose. Sometimes switching to a different PPI can improve symptoms. Antireflux surgical treatment is an alternative. Alternative diagnoses in patients with refractory GERD Esophageal hypersensitivity (visceral hyperalgesia) Achalasia Distal esophageal cancer Stricture NSAID-induced symptoms Infection (eg, Candida, her- pes, cytomegalovirus esophagitis) Caustic exposure Impaired gastric emptying Eosinophilic gastroenteritis Bile acid reflux Nonulcer dyspepsia Pill esophagitis References, see page 360. Abnormal Liver Function Tests The most common liver function tests include the enzyme tests (serum aminotransferases, alkaline phosphatase, gamma glutamyl transpeptidase), tests of synthetic function (serum albumin concentration, prothrombin time), and serum bilirubin, which reflects hepatic transport capability. I. Epidemiology A. Abnormal liver function tests (LFTs) are frequently detected in asymptomatic patients. Serious underlying liver disease is uncommon. Abnormal serum aminotransferase levels are detected in 0.5 percent. A cause is found in only 12 percent (including chronic hepatitis B and C, autoimmune hepatitis, and cholelithiasis). No specific diagnosis can be established in 87 percent. B. A diagnosis can be established noninvasively in most patients with abnormal LFTs. The majority of patients in whom the diagnosis remains unclear after obtaining a history and laboratory testing will have alcoholic liver disease, steatosis, or steatohepatitis. C. History. Important considerations include exposure to any chemical or medication (including over-the-counter medications) which may be temporally related to the onset of LFT abnormalities. 1. The duration of LFT abnormalities. 2. The presence jaundice, arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool. 3. A history of arthralgias and myalgias predating jaundice suggests viral or drug-related hepatitis, while jaundice associated with the sudden onset of severe right upper quadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis. 4. Transfusions, intravenous and intranasal drug use, tattoos, and sexual activity should be assessed. Recent travel history, exposure to people with jaun- dice, exposure to possibly contaminated foods, occupational exposure to hepatotoxins, and alcohol consumption should be assessed. II.Physical examination A. Temporal and proximal muscle wasting suggest long- standing diseases. B. Stigmata of chronic liver disease include spider nevi, palmar erythema, gynecomastia, caput medusae. C. Dupuytren’s contractures, parotid gland enlargement, and testicular atrophy are commonly seen in advanced Laennec’s cirrhosis and occasionally in other types of cirrhosis. D. An enlarged left supraclavicular node (Virchow’s node) or periumbilical nodule (Sister Mary Joseph’s nodule) suggest an abdominal malignancy. E. Jugular venous distension, a sign of right sided heart failure, suggests hepatic congestion F. A right pleural effusion may be seen in advanced cirrhosis. G. The abdominal examination should focus upon the size and consistency of the liver, the size of the spleen (a palpable spleen is enlarged), and should include an assessment for ascites (fluid wave or shifting dullness). H. Patients with cirrhosis may have an enlarged left lobe of the liver (which can be felt below the xiphoid) and an enlarged spleen. A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy. An enlarged tender liver could be viral or alcoholic hepatitis or, less often, an acutely congested liver secondary to right-sided heart failure. I. Severe right upper quadrant tenderness with respiratory arrest on inspiration (Murphy’s sign) suggests cholecystitis or, occasionally, ascending cholangitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread. III. Laboratory testing A. A critical step in guiding the evaluation is determining the overall pattern of the abnormal LFTs, which can be broadly divided into two categories: 1. Patterns predominantly reflecting hepatocellular injury. 2. Patterns predominantly reflecting cholestasis. B. aminotransferases compared with the alkaline phosphatase, while those with a cholestatic process have the opposite findings. The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not helpful in differentiating between the two. C. The serum albumin and a prothrombin time should be obtained to assess liver function. A low albumin sug- gests a chronic process such as cirrhosis or cancer, while a normal albumin suggests a more acute process such as viral hepatitis or choledocholithiasis. An ele- vated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury. D. The presence of bilirubin in the urine reflects direct hyperbilirubinemia and underlying hepatobiliary disease. IV. Mild chronic elevation in serum aminotransferases. The laboratory evaluation of patients with chronic (>six months), mild elevation (<250 U/L) of one or both of the aminotransferases is as follows: A. Step one. Medication that can cause elevation of the serum aminotransferases, alcohol use, and testing viral hepatitis B and C, hemochromatosis, and fatty liver should be performed. 1. Medications. Almost any medication can cause an elevation of liver enzymes. Common ones include nonsteroidal anti-inflammatory drugs, antibiotics, HMG-CoA reductase inhibitors, antiepileptic drugs, and antituberculous drugs. Herbal preparations and illicit drug use may also be the cause. 2. Alcohol abuse should be assessed by history. The diagnosis is supported by an AST to ALT ratio of 2:1 or greater. A twofold elevation of the gamma glutamyltransferase (GGT) in patients whose AST to ALT ratio is greater than 2:1 strongly suggests alcohol abuse. It is rare for the AST to be greater than eightfold elevated and even less common for the ALT to be greater than fivefold elevated. 3. Hepatitis B. Risk for hepatitis B is increased in patients with a history of parenteral exposures and in patients from southeast Asia, China, and sub-Saha- ran Africa. a. Initial testing for patients suspected of having chronic hepatitis B includes: (1)Hepatitis B surface antigen. (2)Hepatitis B surface antibody. (3)Hepatitis B core antibody. b. Patients who are surface antigen and core anti- body positive are chronically infected and addi- tional testing (hepatitis B “e” antigen and “e” antibody and a hepatitis B DNA) is indicated. A positive HBsAb and HBcAb indicates immunity to hepatitis B and another cause of aminotransferase elevation should be sought. c. The presence of a positive HBV DNA in the pres- ence or absence of the “e” antigen indicates viral replication. A positive HBV DNA and a negative “e” antigen indicates that the patient has a precore mutant of hepatitis B. Both of these situations warrant further evaluation with a liver biopsy and possible treatment. d. A positive hepatitis B surface antigen with a nega- tive HBV DNA and a negative “e” antigen suggests that the patient is a carrier of hepatitis B and in a non-replicative state. The presence of a carrier state does not explain elevated aminotransferases and another cause should be sought. 4. Hepatitis C. Chronic hepatitis C is very common in the United States. Approximately 3.9 million Ameri- cans are positive for the antibody to hepatitis C and an estimated 2.7 million people are chronically infected. The risk is highest in individuals with a history of parenteral exposure (blood transfusions, intravenous drug use, occupational), cocaine use, tattoos, body piercing, and high risk sexual behavior. a. The initial test for hepatitis C is the hepatitis C antibody. It has a sensitivity of 92 to 97 percent. A positive hepatitis C antibody in a patient with risk factors for the infection is sufficient to make the diagnosis and a quantitative hepatitis C RNA, hepatitis C genotype, and liver biopsy should next be done to assess the patient’s need for treatment. A positive hepatitis C antibody in a low-risk patient should be verified with either a RIBA or a qualita- tive PCR test. A negative hepatitis C antibody in a patient with risk factors for hepatitis C should be verified with a qualitative PCR test. 5. Hereditary hemochromatosis (HHC) is a common genetic disorder. The frequency of heterozygotes is about 10 percent in Caucasians, with a frequency of about 0.5 percent for the homozygous state. Screen- ing should begin with a serum iron and total iron binding capacity (TIBC), which permits the calculation of the iron or transferrin saturation (serum iron/TIBC). An iron saturation of greater than 45 percent warrants obtaining a serum ferritin. A serum ferritin concentra- tion of greater than 400 ng/mL in men and 300 ng/mL in women further supports the diagnosis of HHC. 6. Hepatic steatosis and non-steatohepatitis (NASH) may present with mild elevations of the serum aminotransferases, which are usually less than fourfold elevated. NASH is more common in women and associated with obesity and type 2 diabetes. In contrast to alcohol related liver disease, the ratio of AST to ALT is usually less than one. The initial evaluation to identify the presence of fatty infiltration of the liver is ultrasound, computed tomographic imaging, or magnetic resonance imaging. B. Step two. The next set of tests should look for non- hepatic causes of elevated aminotransferases, which include principally muscle disorders and thyroid disease. Much less common causes are occult celiac disease and adrenal insufficiency. 1. Muscl e di sor der s. El evat ed ser um aminotransferases, especially AST, may be caused by disorders that affect striated muscle, such as inborn errors of muscle metabolism, polymyositis, and heavy exercise. If striated muscle is the source of increased aminotransferases, serum levels of creatine kinase and aldolase will be elevated. 2. Thyroid disorders can produce elevated aminotransferases. TSH is a reasonable screening test for hypothyroidism while a set of thyroid function tests should be checked if hyperthyroidism is sus- pected. 3. Celiac disease. The serum AST ranges from 29 to 80, and the serum ALT ranges from 60 to 130 with the ALT usually slightly greater than AST. Serum aminotransferases return to normal following a gluten-free diet. The diagnosis is suggested by antibody screening. 4. Adrenal insufficiency. Aminotransferase elevation (1.5 to 3 times normal) has been described in pa- tients with adrenal insufficiency (due to Addison’s disease or secondary causes). Aminotransferases normalize within one week following treatment. C. Step three. The next set of tests is aimed at identifying rarer liver conditions. 1. Autoimmune hepatitis (AIH) is a condition found primarily in young to middle-aged women. The diagnosis is based upon elevated serum aminotransferases, the absence of other causes of chronic hepatitis, and serological evidence of AIH. a. A useful screening test for AIH is the serum pro- tein electrophoresis (SPEP). Additional tests include antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), and liver-kidney microsomal antibodies (LKMA). 2. Wilson’s disease, a genetic disorder of biliary copper excret i on, may cause el evated aminotransferases in asymptomatic patients. The prevalence of Wilson’s disease is very low. a. Patients usually present between ages 5 to 25, but the diagnosis should be considered in patients up to the age of 40. The initial screening test for Wilson’s disease is a serum ceruloplasmin. If the ceruloplasmin is normal and Kayser-Fleischer rings are absent, but there is still a suspicion of Wilson’s disease, the next test is a 24-hour urine collection for quantitative copper excretion. 3. Alpha-1-antitrypsin deficiency is an uncommon cause of chronic liver disease in adults. Obtaining an alpha-1-antitrypsin phenotype is the most cost- effective test. In adults, alpha-1-antitrypsin deficiency should be suspected in patients who have a history of emphysema. D. Step four. A liver biopsy is often considered in patients in whom all of the above testing has been unyielding. However, in some settings, the best course may be observation. 1. Who to observe. Observation is recommended only in patients in whom the ALT and AST are less than twofold elevated and no chronic liver condition has been identified by the above noninvasive testing. 2. Who to biopsy. A liver biopsy is recommended in patients in whom the ALT and AST are persistently greater than twofold elevated. V. Isolated hyperbilirubinemia occurs principally in two settings: A. Overproduction of bilirubin. B. Impaired uptake, conjugation, or excretion of bilirubin. C. The initial step in evaluating an isolated elevated hyperbilirubinemia is to fractionate the bilirubin to determine whether the hyperbilirubinemia is predomi- nantly conjugated or unconjugated. 1. Unconjugated hyperbilirubinemia results from either overproduction, impairment of uptake, or impaired conjugation of bilirubin. 2. Conjugated hyperbilirubinemia is caused by de- creased excretion into the bile ductules or backward leakage of the pigment. It is characterized by mild hyperbilirubinemia (with a direct-reacting fraction of 50 percent) in the absence of other abnormalities of liver function tests. Normal levels of serum alkaline phosphatase and gamma-glutamyltranspepetidase help to distinguish these conditions from disorders associated with biliary obstruction. Hepatocellular Conditions That Can Produce Jaun- dice Viral hepatitis Hepatitis A, B, C, and E Epstein-Barr virus Cytomegalovirus Alcohol Drugs Predictable, dose-dependent (eg, acetaminophen) Unpredictable, idiosyncratic (many drugs) Environment toxins Vinyl chloride Jamaica bush tea - Pyrrolizidine alkaloids Autoimmune hepatitis Wilson’s disease Classification of jaundice according to type of bile pigment and mechanism Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia Increased bilirubin pro- duction Extravascular hemolysis Extravasation of blood into tissues Dyserythropoiesis Impaired hepatic bilirubin uptake Congestive hear failure Portosystemic shunts Some patients with Gilbert’s syndrome Certain Drugs - rifampin, probenecid, flavaspadic acid, bunamiodyl Impaired bilirubin conju- gation Crigler-Najjar syn- drome type I and II Gilbert’s syndrome Neonates Hyperthyroidism Ethinyl estradiol Liver diseases - chronic persistent hepatitis, advanced cirrhosis, Wilson’s disease Extrahepatic cholestasis (biliary obstruction) Choledocholithiasis Intrinsic and extrinsic tumors (eg, cholangiocarcinoma) Primary sclerosing cholangitis AIDS cholangiopathy Strictures after invasive procedures Certain parasitic infec- tions (eg, Ascaris lumbricoides, liver flukes Intrahepatic cholestasis Viral hepatitis Nonalcoholic hepatitis Primary biliary cirrhosis Drugs and toxins (eg, alkylated steroids, chlorpromazine, herbal medications [eg, Jamaican bush tea], arsenic) Sepsis and hypoperfusion states Infiltrative diseases (eg, amyloidosis, lymphoma, sarcoidosis, tuberculosis Total parenteral nutri- tion Postoperative patient Following organ trans- plantation Hepatic crisis in sickle cell disease Pregnancy End-stage liver disease Hepatocellular injury D. Isolated elevation of the alkaline phosphatase and/or gamma glutamyl transpeptidase. Serum alkaline phosphatase is derived predominantly from the liver and bones. Individuals with blood types O and B can have elevated serum alkaline phosphatase after eating a fatty meal due to an influx of intestinal alkaline phosphatase. E. Determining the source of the alkaline phosphatase. The first step in the evaluation of an elevated alkaline phosphatase is to identify its source. Electrophoretic separation is the most sensitive and specific method. F. Initial testing for alkaline phosphatase of hepatic origin. Chronic cholestatic or infiltrative liver diseases should be considered in patients in whom the alkaline phosphatase is determined to be of liver origin and persists over time. The most common causes include partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, adult bile ductopenia, and androgenic steroids and phenytoin. Infiltrative diseases include sarcoidosis, other granulomatous diseases, and cancer metastatic to the liver. 1. Initial testing should include a right upper quadrant ultrasound (which can assess the hepatic paren- chyma and bile ducts) and an antimitochondrial antibody (AMA), which is highly suggestive of PBC. The presence of biliary dilatation suggests obstruc- tion of the biliary tree. G. Patients in whom initial testing is unrevealing. A liver biopsy and either an ERCP or magnetic resonance cholangiopancreatogram (MRCP) are recommended if the AMA and ultrasound are both negative and the alkaline phosphatase is persistently more than 50 percent above normal for more than six months. If the alkaline phosphatase is less than 50 percent above normal, all of the other liver tests are normal, and the patient is asymptomatic, observation alone is suggested. H. Gamma glutamyl transpeptidase. Gamma glutamyl transpeptidase (GGT) is found in hepatocytes and biliary epithelial cells. GGT is very sensitive for detecting hepatobiliary disease. Elevated levels of serum GGT have been reported in pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes, and alcoholism. High serum GGT values are also found in patients taking phenytoin and barbiturates. 1. GGT is best used to evaluate elevations of other serum enzyme tests (eg, to confirm the liver origin of an elevated alkaline phosphatase or to support a suspicion of alcohol abuse in a patient with an ele- vated AST and an AST:ALT ratio of greater than 2:1). An elevated GGT with otherwise normal liver tests should not lead to an exhaustive work-up for liver disease. VI. Evaluation of patients with simultaneous elevation of several LFTs. Patients should be divided into those with a predominantly hepatocellular process and those with a predominantly cholestatic process. Patients with a predominantly cholestatic pattern may be further divided into those with intra- or extrahepatic cholestasis. A. While ALT and AST values less than eight times normal may be seen in either hepatocellular or cholestatic liver disease, values 25 times normal or higher are seen primarily in hepatocellular diseases. B. Predominantly hepatocellular pattern with jaundice. Common hepatocellular diseases that can cause jaundice include viral and toxic hepatitis (including drugs, herbal therapies, alcohol) and end-stage cirrhosis from any cause. Wilson’s disease should be considered in young adults. 1. Autoimmune hepatitis predominantly occurs in young to middle-aged women (although it may affect men and women of any age) and should particularly be considered in patients who have other autoim- mune diseases. 2. Alcoholic hepatitis can be differentiated from viral and toxin related hepatitis by the pattern of the serum aminotransferases. Patients with alcoholic hepatitis typically have an AST:ALT ratio of at least 2:1. The AST rarely exceeds 300 U/L. In contrast, patients with acute viral hepatitis and toxin related injury severe enough to produce jaundice typically have aminotransferases greater than 500 U/L with the ALT greater than or equal to the AST. 3. Viral hepatitis. Patients with acute viral hepatitis can develop jaundice. Testing for acute viral hepatitis includes a: 4. Hepatitis A IgM antibody. 5. Hepatitis B surface antigen. 6. Hepatitis B core IgM antibody. 7. Hepatitis C viral RNA. 8. Patients with acute hepatitis C are usually asymptom- atic. Testing for acute HCV should be performed by requesting an assay for serum hepatitis C viral RNA since hepatitis C antibody may take weeks to months to become detectable. C. Toxic hepatitis. Drug-induced hepatocellular injury can be classified either as predictable or unpredictable. Predictable drug reactions are dose-dependent and affect all patients who ingest a toxic dose of the drug in question (eg, acetaminophen hepatotoxicity). Unpredict- able, or idiosyncratic, drug reactions are not dose dependent and occur in a minority of patients. Virtually any drug can cause an idiosyncratic reaction. Environ- mental toxins are also an important cause of hepatocellular injury. Examples include industrial chemicals such as vinyl chloride, herbal preparations (Jamaica bush tea), and the mushrooms Amanita phalloides or verna containing highly hepatotoxic amatoxins. D. Shock liver (ischemic hepatitis). Patients who have a prolonged period of systemic hypotension (such as following a cardiac arrest or patients with severe heart failure) may develop ischemic injury to the liver. Striking increases in serum aminotransferases (exceeding 1000 IU/L or 50 times the upper limit of normal) and lactic dehydrogenase may be seen. Patients may also develop jaundice, hypoglycemia, and hepatic synthetic dysfunc- tion. The majority of patients have deterioration of renal function. Hepatic function usually returns to normal within several days of the acute episode. E. Wilson’s disease can occasionally present with acute and even fulminant hepatitis. The diagnosis should be considered in patients younger than 40, particularly those who have concomitant hemolytic anemia. VII. Predominantly cholestatic pattern. The first step in evaluating patients whose LFT pattern predominantly reflects cholestasis is to determine whether the cholestasis is due to intra- or extrahepatic causes. The first step is to obtain a right upper quadrant ultrasound, which can detect dilation of the intra- and extrahepatic biliary tree with a high degree of sensitivity and specific- ity. The absence of biliary dilatation suggests intrahepatic cholestasis, while the presence of biliary dilatation indicates extrahepatic cholestasis. References, see page 360. Acute Pancreatitis The incidence of acute pancreatitis ranges from 54 to 238 episodes per 1 million per year. Patients with mild pancreati- tis respond well to conservative therapy, but those with severe pancreatitis may have a progressively downhill course to respiratory failure, sepsis, and death (less than 10%). I. Etiology A. Alcohol-induced pancreatitis. Consumption of large quantities of alcohol may cause acute pancreatitis. B. Cholelithiasis. Common bile duct or pancreatic duct obstruction by a stone may cause acute pancreatitis. (90% of all cases of pancreatitis occur secondary to alcohol consumption or cholelithiasis). C. Idiopathic pancreatitis. The cause of pancreatitis cannot be determined in 10 percent of patients. D. Hypertriglyceridemia. Elevation of serum triglycerides (>l,000mg/dL) has been linked with acute pancreatitis. E. Pancreatic duct disruption. In younger patients, a malformation of the pancreatic ducts (eg, pancreatic divisum) with subsequent obstruction is often the cause of pancreatitis. In older patients without an apparent underlying etiology, cancerous lesions of the ampulla of Vater, pancreas or duodenum must be ruled out as possible causes of obstructive pancreatitis. F. Iatrogenic pancreatitis. Radiocontrast studies of the hepatobiliary system (eg, cholangiogram, ERCP) can cause acute pancreatitis in 2-3% of patients undergo- ing studies. G. Trauma. Blunt or penetrating trauma of any kind to the peri-pancreatic or peri-hepatic regions may induce acute pancreatitis. Extensive surgical manipulation can also induce pancreatitis during laparotomy. Causes of Acute Pancreatitis Alcoholism Cholelithiasis Drugs Hypertriglyceridemia Idiopathic causes Infections Microlithiasis Pancreas divisum Trauma Medications Associated with Acute Pancreatitis Definitive Association: Azathioprine (Imuran) Sulfonamides Thiazide diuretics Furosemide (Lasix) Estrogens Tetracyclines Valproic acid (Depakote) Pentamidine Didanosine (Videx) Probable Association: Acetaminophen Nitrofurantoin Methyldopa Erythromycin Salicylates Metronidazole NSAIDS ACE-inhibitors II. Pathophysiology. Acute pancreatitis results when an initiating event causes the extrusion of zymogen gran- ules, from pancreatic acinar cells, into the interstitium of the pancreas. Zymogen particles cause the activation of trypsinogen into trypsin. Trypsin causes auto-digestion of pancreatic tissues. III. Clinical presentation A. Signs and symptoms. Pancreatitis usually presents with mid-epigastric pain that radiates to the back, associated with nausea and vomiting. The pain is sudden in onset, progressively increases in intensity, and becomes constant. The severity of pain often causes the patient to move continuously in search of a more comfortable position. B. Physical examination 1. Patients with acute pancreatitis often appear very ill. Findings that suggest severe pancreatitis include hypotension and tachypnea with decreased basilar breath sounds. Flank ecchymoses (Grey Tuner's Sign) or periumbilical ecchymoses (Cullen's sign) may be indicative of hemorrhagic pancreatitis. 2. Abdominal distension and tenderness in the epigastrium are common. Fever and tachycardia are often present. Guarding, rebound tenderness, and hypoactive or absent bowel sounds indicate peritoneal irritation. Deep palpation of abdominal organs should be avoided in the setting of sus- pected pancreatitis. IV. Laboratory testing A. Leukocytosis. An elevated WBC with a left shift and elevated hematocrit (indicating hemoconcentration) and hyperglycemia are common. Pre-renal azotemia may result from dehydration. Hypoalbuminemia, hyper- triglyceridemia, hypocalcemia, hyperbilirubinemia, and mild elevations of transaminases and alkaline phosphatase are common. B. Elevated amylase. An elevated amylase level often confirms the clinical diagnosis of pancreatitis. C. Elevated lipase. Lipase measurements are more specific for pancreatitis than amylase levels, but less sensitive. Hyperlipasemia may also occur in patients with renal failure, perforated ulcer disease, bowel infarction and bowel obstruction. D. Abdominal Radiographs may reveal non-specific findings of pancreatitis, such as "sentinel loops" (dilated loops of small bowel in the vicinity of the pancreas), ileus and, pancreatic calcifications. E. Ultrasonography demonstrates the entire pancreas in only 20 percent of patients with acute pancreatitis. Its greatest utility is in evaluation of patients with possible gallstone disease. F. Helical high resolution computed tomography is the imaging modality of choice in acute pancreatitis. CT findings will be normal in 14-29% of patients with mild pancreatitis. Pancreatic necrosis, pseudocysts and abscesses are readily detected by CT. Selected Conditions Other Than Pancreatitis Asso- ciated with Amylase Elevation Carcinoma of the pancreas Common bile duct obstruc- tion Post-ERCP Mesenteric infarction Pancreatic trauma Perforated viscus Renal failure Acute alcoholism Diabetic ketoacidosis Lung cancer Ovarian neoplasm Renal failure Ruptured ectopic pregnancy Salivary gland infection Macroamylasemia V. Prognosis. Ranson's criteria is used to determine prognosis in acute pancreatitis. Patients with two or fewer risk factors have a mortality rate of less than 1 percent, those with three or four risk-factors a mortality rate of 16 percent, five or six risk factors, a mortality rate of 40 percent, and seven or eight risk factors, a mortality rate approaching 100 percent. Ranson's Criteria for Acute Pancreatitis At admission During initial 48 hours 1. Age >55 years 2. WBC >16,000/mm 3 3. Blood glucose >200 mg/dL 4. Serum LDH >350 IU/L 5. AST >250 U/L 1. Hematocrit drop >10% 2. BUN rise >5 mg/dL 3. Arterial pO 2 <60 mm Hg 4. Base deficit >4 mEq/L 5. Serum calcium <8.0 mg/dL 6. Estimated fluid sequestration >6 L VI. Treatment of pancreatitis A. Expectant management. Most cases of acute pancreatitis will improve within three to seven days. Management consists of prevention of complications of severe pancreatitis. B. NPO and bowel rest. Patients should take nothing by mouth. Total parenteral nutrition should be instituted for those patients fasting for more than five days. A nasogastric tube is warranted if vomiting or ileus. C. IV fluid resuscitation. Vigorous intravenous hydration is necessary. A decrease in urine output to less than 30 mL per hour is an indication of inade- quate fluid replacement. D. Pain control. Morphine is discouraged because it may cause Oddi's sphincter spasm, which may exacerbate the pancreatitis. Meperidine (Demerol), 25-100 mg IV/IM q4-6h, is favored. Ketorolac (Toradol), 60 mg IM/IV, then 15-30 mg IM/IV q6h, is also used. E. Antibiotics. Routine use of antibiotics is not recom- mended in most cases of acute pancreatitis. In cases of infectious pancreatitis, treatment with cefoxitin (1-2 g IV q6h), cefotetan (1-2 g IV q12h), imipenem (1.0 gm IV q6h), or ampicillin/sulbactam (1.5-3.0 g IV q6h) may be appropriate. F. Alcohol withdrawal prophylaxis. Alcoholics may require alcohol withdrawal prophylaxis with lorazepam (Ativan) 1-2mg IM/IV q4-6h as needed x 3 days, thiamine 100mg IM/IV qd x 3 days, folic acid 1 mg IM/IV qd x 3 days, multivitamin qd. G. Octreotide. Somatostatin is also a potent inhibitor of pancreatic exocrine secretion. Octreotide is a somatostatin analogue, which has been effective in reducing mortality from bile-induced pancreatitis. Clinical trials, however, have failed to document a significant reduction in mortality H. Blood sugar monitoring and insulin administra- tion. Serum glucose levels should be monitored. VII. Complications A. Chronic pancreatitis B. Severe hemorrhagic pancreatitis C. Pancreatic pseudocysts D. Infectious pancreatitis with development of sepsis (occurs in up to 5% of all patients with pancreatitis) E. Portal vein thrombosis References, see page 360. Lower Gastrointestinal Bleeding The spontaneous remission rates for lower gastrointestinal bleeding is 80 percent. No source of bleeding can be identified in 12 percent of patients, and bleeding is recurrent in 25 percent. Bleeding has usually ceased by the time the patient presents to the emergency room. I. Clinical evaluation A. The severity of blood loss and hemodynamic status should be assessed immediately. Initial management consists of resuscitation with crystalloid solutions (lactated Ringers) and blood products if necessary. B. The duration and quantity of bleeding should be as- sessed; however, the duration of bleeding is often underestimated. C. Risk factors that may have contributed to the bleeding include nonsteroidal anti-inflammatory drugs, anticoag- ulants, colonic diverticulitis, renal failure, coagulopathy, colonic polyps, and hemorrhoids. Patients may have a prior history of hemorrhoids, diverticulosis, inflamma- tory bowel disease, peptic ulcer, gastritis, cirrhosis, or esophageal varices. D. Hematochezia. Bright red or maroon output per rectum suggests a lower GI source; however, 12 to 20% of patients with an upper GI bleed may have hematochezia as a result of rapid blood loss. E. Melena. Sticky, black, foul-smelling stools suggest a source proximal to the ligament of Treitz, but Melena can also result from bleeding in the small intestine or proximal colon. F. Clinical findings 1. Abdominal pain may result from ischemic bowel, inflammatory bowel disease, or a ruptured aneurysm. 2. Painless massive bleeding suggests vascular bleeding from diverticula, angiodysplasia, or hemor- rhoids. 3. Bloody diarrhea suggests inflammatory bowel disease or an infectious origin. 4. Bleeding with rectal pain is seen with anal fissures, hemorrhoids, and rectal ulcers. 5. Chronic constipation suggests hemorrhoidal bleeding. New onset of constipation or thin stools suggests a left sided colonic malignancy. 6. Blood on the toilet paper or dripping into the toilet water suggests a perianal source of bleeding, such as hemorrhoids or an anal fissure. 7. Blood coating the outside of stools suggests a lesion in the anal canal. 8. Blood streaking or mixed in with the stool may results from polyps or a malignancy in the descend- ing colon. 9. Maroon colored stools often indicate small bowel and proximal colon bleeding. II. Physical examination A. Postural hypotension indicates a 20% blood volume loss, whereas, overt signs of shock (pallor, hypotension, tachycardia) indicates a 30 to 40 percent blood loss. B. The skin may be cool and pale with delayed refill if bleeding has been significant. C. Stigmata of liver disease, including jaundice, caput medusae, gynecomastia and palmar erythema, should be sought because patients with these findings fre- quently have GI bleeding. III. Differential diagnosis of lower GI bleeding A. Angiodysplasia and diverticular disease of the right colon accounts for the vast majority of episodes of acute lower GI bleeding. Most acute lower GI bleeding originates from the colon however 15 to 20 percent of episodes arise from the small intestine and the upper GI tract. B. Elderly patients. Diverticulosis and angiodysplasia are the most common causes of lower GI bleeding. C. Younger patients. Hemorrhoids, anal fissures and inflammatory bowel disease are most common causes of lower GI bleeding. Clinical Indicators of Gastrointestinal Bleeding and Probable Source Clinical Indicator Probability of Up- per Gastrointesti- nal source Probability of Lower Gastroin- testinal Source Hematemesis Almost certain Rare Melena Probable Possible Hematochezia Possible Probable Blood-streaked stool Rare Almost certain Occult blood in stool Possible Possible IV. Diagnosis and management of lower gastrointesti- nal bleeding A. Rapid clinical evaluation and resuscitation should precede diagnostic studies. Intravenous fluids (1 to 2 liters) should be infused over 10- 20 minutes to restore intravascular volume, and blood should be transfused if there is rapid ongoing blood loss or if hypotension or tachycardia are present. Coagulopathy is corrected with fresh frozen plasma, platelets, and cryoprecipitate. B. When small amounts of bright red blood are passed per rectum, then lower GI tract can be assumed to be the source. In patients with large volume maroon stools, nasogastric tube aspiration should be performed to exclude massive upper gastrointestinal hemorrhage. C. If the nasogastric aspirate contains no blood then anoscopy and sigmoidoscopy should be performed to determine weather a colonic mucosal abnormality (ischemic or infectious colitis) or hemorrhoids might be the cause of bleeding. D. Colonoscopy in a patient with massive lower GI bleeding is often nondiagnostic, but it can detect ulcerative colitis, antibiotic-associated colitis, or ischemic colon. E. Polyethylene glycol-electrolyte solution (CoLyte or GoLytely) should be administered by means of a nasogastric tube (Four liters of solution is given over a 2-3 hour period), allowing for diagnostic and therapeu- tic colonoscopy. V. Definitive management of lower gastrointestinal bleeding A. Colonoscopy 1. Colonoscopy is the procedure of choice for diagnos- ing colonic causes of GI bleeding. It should be performed after adequate preparation of the bowel. If the bowel cannot be adequately prepared because of persistent, acute bleeding, a bleeding scan or angiography is preferable. 2. If colonoscopy fails to reveal the source of the bleeding, the patient should be observed because, in 80% of cases, bleeding ceases spontaneously. B. Radionuclide scan or bleeding scan. Technetium- labeled (tagged) red blood cell bleeding scans can detect bleeding sites when bleeding is intermittent. Localization may not he a precise enough to allow segmental colon resection. C. Angiography. Selective mesenteric angiography detects arterial bleeding that occurs at rates of 0.5 mL/per minute or faster. Diverticular bleeding causes pooling of contrast medium within a diverticulum. Bleeding angiodysplastic lesions appear as abnormal vasculature. When active bleeding is seen with diverticular disease or angiodysplasia, selective arterial infusion of vasopressin may be effective. D. Surgery 1. If bleeding continues and no source can be found, surgical intervention is usually warranted. Surgical resection may be indicated for patients with recurrent diverticular bleeding, or for patients who have had persistent bleeding from colonic angiodysplasia and have required blood transfusions. 2. Surgical management of lower gastrointestinal bleeding is ideally undertaken with a secure knowl- edge of the location and cause of the bleeding lesion. A segmental bowel resection to include the lesion and followed by a primary anastomosis is usually safe and appropriate in all but the most unstable patients. VI. Diverticulosis A. Diverticulosis of the colon is present in more than 50% of the population by age 60 years. Bleeding from diverticula is relatively rare, affecting only 4% to 17% of patients at risk. B. In most cases, bleeding ceases spontaneously, but in 10% to 20% of cases, the bleeding continues. The risk of rebleeding after an episode of bleeding is 25%. Right-sided colonic diverticula occur less frequently than left-sided or sigmoid diverticula but are responsi- ble for a disproportionate incidence of diverticular bleeding. C. Operative management of diverticular bleeding is indicated when bleeding continues and is not amenable to angiographic or endoscopic therapy. It also should be considered in patients with recurrent bleeding in the same colonic segment. The operation usually consists of a segmental bowel resection (usually a right colectomy or sigmoid colectomy) followed by a primary anastomosis. VII. Arteriovenous malformations A. AVMs or angiodysplasias are vascular lesions that occur primarily in the distal ileum, cecum, and ascend- ing colon of elderly patients. The arteriographic criteria for identification of an AVM include a cluster of small arteries, visualization of a vascular tuft, and early and prolonged filling of the draining vein. B. The typical pattern of bleeding of an AVM is recurrent and episodic, with most individual bleeding episodes being self-limited. Anemia is frequent, and continued massive bleeding is distinctly uncommon. After nondiagnostic colonoscopy, enteroscopy should be considered. C. Endoscopic therapy for AVMs may include heater probe, laser, bipolar electrocoagulation, or argon beam coagulation. Operative management is usually re- served for patients with continued bleeding, anemia, repetitive transfusion requirements, and failure of endoscopic management. Surgical management consists of segmental bowel resection with primary anastomosis. VIII. Inflammatory bowel disease A. Ulcerative colitis and, less frequently, Crohn's colitis or enteritis may present with major or massive lower gastrointestinal bleeding. Infectious colitis can also manifest with bleeding, although it is rarely massive. B. When the bleeding is minor to moderate, therapy directed at the inflammatory condition is appropriate. When the bleeding is major and causes hemodynamic instability, surgical intervention is usually required. When operative intervention is indicated, the patient is explored through a midline laparotomy, and a total abdominal colectomy with end ileostomy and oversewing of the distal rectal stump is the preferred procedure. IX. Tumors of the colon and rectum A. Colon and rectal tumors account for 5% to 10% of all hospitalizations for lower gastrointestinal bleeding. Visible bleeding from a benign colonic or rectal polyp is distinctly unusual. Major or massive hemorrhage rarely is caused by a colorectal neoplasm; however, chronic bleeding is common. When the neoplasm is in the right colon, bleeding is often occult and manifests as weak- ness or anemia. B. More distal neoplasms are often initially confused with hemorrhoidal bleeding. For this reason, the treatment of hemorrhoids should always be preceded by flexible sigmoidoscopy in patients older than age 40 or 50 years. In younger patients, treatment of hemorrhoids without further investigation may be appropriate if there are no risk factors for neoplasm, there is a consistent clinical history, and there is anoscopic evidence of recent bleeding from enlarged internal hemorrhoids. X. Anorectal disease A. When bleeding occurs only with bowel movements and is visible on the toilet tissue or the surface of the stool, it is designated outlet bleeding. Outlet bleeding is most often associated with internal hemorrhoids or anal fissures. B. Anal fissures are most commonly seen in young patients and are associated with severe pain during and after defecation. Other benign anorectal bleeding sources are proctitis secondary to inflammatory bowel disease, infection, or radiation injury. Additionally, stercoral ulcers can develop in patients with chronic constipation. C. Surgery for anorectal problems is typically undertaken only after failure of conservative medical therapy with hi gh-f i ber di et s, st ool sof t eners, and/or hemorrhoidectomy. XI. Ischemic colitis A. Ischemic colitis is seen in elderly patients with known vascular disease. The abdomen pain may be postpran- dial and associated with bloody diarrhea or rectal bleeding. Severe blood loss is unusual but can occur. B. Abdominal films may reveal "thumb-printing" caused by submucosal edema. Colonoscopy reveals a well- demarcated area of hyperemia, edema and mucosal ulcerations. The splenic flexure and descending colon are the most common sites. Most episodes resolve spontaneously, however, vascular bypass or resection may be required. References, see page 360. Acute Diarrhea Acute diarrhea is defined as diarrheal disease of rapid onset, often with nausea, vomiting, fever, and abdominal pain. Most episodes of acute gastroenteritis will resolve within 3 to 7 days. I. Clinical evaluation of acute diarrhea A. The nature of onset, duration, frequency, and timing of the diarrheal episodes should be assessed. The appearance of the stool, buoyancy, presence of blood or mucus, vomiting, or pain should be determined. B. Contact with a potential source of infectious diarrhea should be sought. C. Drugs that may cause diarrhea include laxatives, magnesium-containing compounds, sulfa-drugs, and antibiotics. II. Physical examination A. Assessment of volume status. Dehydration is sug- gested by dry mucous membranes, orthostatic hypotension, tachycardia, mental status changes, and acute weight loss. B. Abdominal tenderness, mild distention and hyperac- tive bowel sounds are common in acute infectious diarrhea. The presence of rebound tenderness or rigidity suggests toxic megacolon or perforation. C. Evidence of systemic atherosclerosis suggests ischemia. Lower extremity edema suggests malabsorption or protein loss. III. Acute infectious diarrhea A. Infectious diarrhea is classified as noninflammatory or inflammatory, depending on whether the infectious organism has invaded the intestinal mucosa. B. Noninflammatory infectious diarrhea is caused by organisms that produce a toxin (enterotoxigenic E coli strains, Vibrio cholerae). Noninflammatory, infectious diarrhea is usually self-limiting and lasts less than 3 days. C. Blood or mucus in the stool suggests inflammatory disease, usually caused by bacterial invasion of the mucosa (enteroinvasive E coli, Shigella, Salmonella, Campylobacter). Patients usually have a septic appear- ance and fever; some have abdominal rigidity and severe abdominal pain. D. Vomiting out of proportion to diarrhea is usually related to a neuroenterotoxin-mediated food poisoning from Staphylococcus aureus or Bacillus cereus, or rotavirus (in an infant), or Norwalk virus (in older children or adults). The incubation period for neuroenterotoxin food poisoning is less than 4 hours, while that of a viral agent is more than 8 hours. E. Traveler's diarrhea is a common acute diarrhea. Three or four unformed stools are passed/per 24 hours, usually starting on the third day of travel and lasting 2-3 days. Anorexia, nausea, vomiting, abdomi- nal cramps, abdominal bloating, and flatulence may also be present. F. Antibiotic-related diarrhea 1. Antibiotic-related diarrhea ranges from mild illness to life-threatening pseudomembranous colitis. Overgrowth of Clostridium difficile causes pseudomembranous col i t i s. Amoxi ci l l i n, cephalosporins and clindamycin have been impli- cated most often, but any antibiotic can be the cause. 2. Patients with pseudomembranous colitis have high fever, cramping, leukocytosis, and severe, watery diarrhea. Latex agglutination testing for C difficile toxin can provide results in 30 minutes. 3. Enterotoxigenic E coli a. The enterotoxigenic E coli include the E coli serotype 0157:H7. Grossly bloody diarrhea is most often caused by E. coli 0157:H7, causing 8% of grossly bloody stools. b. Enterotoxigenic E coli can cause hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, intestinal perforation, sepsis, and rectal prolapse. IV. Diagnostic approach to acute infectious diarrhea A. An attempt should be made to obtain a pathologic diagnosis in patients who give a history of recent ingestion of seafood (Vibrio parahaemolyticus), travel or camping, antibiotic use, homosexual activity, or who complain of fever and abdominal pain. B. Blood or mucus in the stools indicates the presence of Shigella, Salmonella, Campylobacter jejuni, enteroinvasive E. coli, C. difficile, or Yersinia entero- colitica. C. Most cases of mild diarrheal disease do not require laboratory studies to determine the etiology. In moder- ate to severe diarrhea with fever or pus, a stool culture for bacterial pathogens (Salmonella, Shigella, Campylobacter) is submitted. If antibiotics were used recently, stool should be sent for Clostridium difficile toxin. V. Laboratory evaluation of acute diarrhea A. Fecal leukocytes is a screening test which should be obtained if moderate to severe diarrhea is present. Numerous leukocytes indicate Shigella, Salmonella, or Campylobacter jejuni. B. Stool cultures for bacterial pathogens should be obtained if high fever, severe or persistent (>14 d) diarrhea, bloody stools, or leukocytes is present. C. Examination for ova and parasites is indicated for persistent diarrhea (>14 d), travel to a high-risk region, gay males, infants in day care, or dysentery. D. Blood cultures should be obtained prior to starting antibiotics if severe diarrhea and high fever is present. E. E coli 0157:H7 cultures. Enterotoxigenic E coli should be suspected if there are bloody stools with minimal fever, when diarrhea follows hamburger consumption, or when hemolytic uremic syndrome is diagnosed. F. Clostridium difficile cytotoxin should be obtained if diarrhea follows use of an antimicrobial agent. G. Rotavirus antigen test (Rotazyme) is indicated for hospitalized children <2 years old with gastroenteritis. The finding of rotavirus eliminates the need for antibiot- ics. VI. Treatment of acute diarrhea A. Fluid and electrolyte resuscitation 1. Oral rehydration. For cases of mild to moderate diarrhea in children, Pedialyte or Ricelyte should be administered. For adults with diarrhea, flavored soft drinks with saltine crackers are usually adequate. 2. Intravenous hydration should be used if oral rehydration is not possible. B. Diet. Fatty foods should be avoided. Well-tolerated foods include complex carbohydrates (rice, wheat, potatoes, bread, and cereals), lean meats, yogurt, fruits, and vegetables. Diarrhea often is associated with a reduction in intestinal lactase. A lactose-free milk preparation may be substituted if lactose intolerance becomes apparent. VII. Empiric antimicrobial treatment of acute diarrhea A. Febrile dysenteric syndrome 1. If diarrhea is associated with high fever and stools containing mucus and blood, empiric antibacterial therapy should be given for Shigella or Campylobacter jejuni. 2. Norfloxacin (Noroxin) 400 mg bid OR 3. Ciprofloxacin (Cipro) 500 mg bid. B. Travelers' diarrhea. Adults are treated with norfloxacin 400 mg bid, ciprofloxacin (Cipro) 500 mg bid, or ofloxacin (Floxin) 300 mg bid for 3 days. References, see page 360. Chronic Diarrhea Diarrhea is considered chronic if it lasts longer than 2 weeks. I. Clinical evaluation of chronic diarrhea A. Initial evaluation should determine the characteristics of the diarrhea, including volume, mucus, blood, flatus, cramps, tenesmus, duration, frequency, effect of fasting, stress, and the effect of specific foods (eg, dairy products, wheat, laxatives, fruits). B. Secretory diarrhea 1. Secretory diarrhea is characterized by large stool volumes (>1 L/day), no decrease with fasting, and a fecal osmotic gap <40. 2. Evaluation of secretory diarrhea consists of a giardia antigen, Entamoeba histolytica antibody, Yersinia culture, fasting serum glucose, thyroid function tests, and a cholestyramine (Cholybar, Questran) trial. C. Osmotic diarrhea 1. Osmotic diarrhea is characterized by small stool vol- umes, a decrease with fasting, and a fecal osmotic gap >40. Postprandial diarrhea with bloating or flatus also suggests osmotic diarrhea. Ingestion of an osmotically active laxative may be inadvertent (sugarless gum containing sorbitol) or covert (with eating disorders). 2. Evaluation of osmotic diarrhea a. Trial of lactose withdrawal. b. Trial of an antibiotic (metronidazole) for small- bowel bacterial overgrowth. c. Screening for celiac disease (anti-endomysial antibody, antigliadin antibody). d. Fecal fat measurement (72 hr) for pancreatic insufficiency. e. Trial of fructose avoidance. f. Stool test for phenolphthalein and magnesium if laxative abuse is suspected. g. Hydrogen breath analysis to identify disaccharidase deficiency or bacterial over- growth. D. Exudative diarrhea 1. Exudative diarrhea is characterized by bloody stools, tenesmus, urgency, cramping pain, and nocturnal occurrence. It is most often caused by inflammatory bowel disease, which may be sug- gested by anemia, hypoalbuminemia, and an in- creased sedimentation rate. 2. Evaluation of exudative diarrhea consists of a complete blood cell count, serum albumin, total protein, erythrocyte sedimentation rate, electrolyte measurement, Entamoeba histolytica antibody titers, stool culture, Clostridium difficile antigen test, ova and parasite testing, and flexible sigmoidoscopy and biopsies. References, see page 360. Inflammatory Bowel Disease Ulcerative colitis is limited to the rectum and colon. Crohn's disease may involve both the small and the large bowel, but 15% to 25% of cases are isolated to the colon. Both Crohn's disease and ulcerative colitis can follow an active and remitting course and have a highly variable response to therapy. I. Clinical presentation A. Crohn’s disease is a chronic, transmural, granulomatous disorder that can involve any segment of gastrointestinal tract from the mouth to the anus. In the bowel it may affect multiple distinct segments, with normal intervening bowel. Crohn’s disease also may be complicated by intestinal strictures, fistulas, and perianal fistulas. The clinical presentation of Crohn’s disease ranges from intestinal obstruction, to bloody or nonbloody diarrhea, to malabsorption. B. Ulcerative colitis is a nongranulomatous inflammatory condition that always starts in the rectum and extends proximally throughout the colon in a continuous and confluent fashion, never involving the small bowel. The clinical presentation of ulcerative colitis is more uni- form than that of Crohn’s disease and includes rectal bleeding or bloody diarrhea. In addition to gastrointes- tinal symptoms, extraintestinal manifestations can occur and may involve the skin (eg, erythema nodosum, pyoderma gangrenosum), joints (sacroiliitis, ankylosing spondylitis, and peripheral arthritis), eyes (iritis and uveitis), and liver (sclerosing cholangitis). Extraintestinal manifestations are due to the release of bacterial antigens from the colonic lumen. C. Differential diagnosis. In patients with new-onset bloody diarrhea and abdominal cramps, an infectious cause must first be ruled out. In addition to routine cultures, cultures for Clostridium difficile, ova and parasites, and hemorrhagic Escherichia coli should be done. Colonic ischemia presents with symptoms similar to those of IBD--abdominal cramps, rectal bleeding, and diarrhea--and should be a consideration in older patients. Nonsteroidal anti-inflammatory drugs can also cause colonic ulcerations that mimic colonic Crohn’s disease. II. Induction therapy A. Mild-to-moderate Crohn’s disease 1. Patients with mild to moderate colonic Crohn’s disease may be managed successfully with 5-ASA products, such as sulfasalazine (Azulfidine), 1 g two to four times daily, which produces remission in about 50%. 2. Sulfasalazine is composed of a sulfapyridine moiety attached to 5-ASA. It is activated in the colon by colonic bacteria that releases sulfapyridine, which is then absorbed. The 5-ASA remains in the colon. Side effects include nausea, gastrointestinal upset, rash, headache, and reversible male infertility. Rare hypersensitivity reactions include hemolytic anemia, neutropenia, and hepatitis. 3. For patients with colonic Crohn’s disease who are unable to tolerate sulfasalazine or who are allergic to sulfa drugs, sulfa-free 5-ASA products have been developed. Olsalazine (Dipentum), 500 mg two or three times daily, and balsalazide (Colazal), 2.25 g three times daily, work exclusively in the colon, whereas the mesalamine preparations--Asacol, 800 to 1,600 mg three or four times daily, and Pentasa, 1 g four times daily--are released in the small bowel and the colon. 4. Antibiotics also have been used in the treatment of colonic Crohn’s disease. Metronidazole (Flagyl), 250 to 500 mg three times daily, has been shown to be beneficial in colonic Crohn’s disease as well as in Crohn’s in patients with perianal abscesses and fistulas. Ciprofloxacin (Cipro) has been used as an alternative to metronidazole for both colonic and perianal Crohn’s disease. B. Mild-to-moderate ulcerative colitis 1. Ulcerative colitis with fewer than six loose bowel movements per day, with or without blood, and without significant weight loss or anemia is consid- ered to be mild-to-moderate disease. In this setting, 5-ASA drugs such as sulfasalazine or Asacol are often used as primary therapy. Onset of action is usually within 1 week, but peak effect is not reached for 3 to 6 weeks. 2. For patients with isolated proctitis, corticosteroid (Anusol) or mesalamine (Canasa) suppository given once or twice a day is usually sufficient therapy. When ulcerative colitis extends beyond the rectum, corticosteroid foam (Cortifoam, ProctoFoam) or enema (Cortenema) or mesalamine enema (Rowasa) may be used nightly. C. Moderate-to-severe Crohn’s disease 1. Patients with moderate to severe Crohn’s disease often present with severe abdominal pain, diarrhea, weight loss, fever, and symptoms of obstruction. 2. Budesonide (Entocort), 9 mg once daily, is ap- proved for the treatment of ileal and ileocecal Crohn’s disease. Although prednisone and budesonide are equally efficacious, budesonide’s extensive first-pass metabolism through the liver and high affinity for the glucocorticoid receptor in the small bowel. 3. Another novel therapy for Crohn’s disease is infliximab (Remicade), which is approved for induc- tion of remission. Infliximab is a monoclonal anti- body to tumor necrosis factor alpha and is given intravenously. A single outpatient infusion of infliximab yielded a clinical response in up to 80%. 4. Methotrexate, 25 mg intramuscularly, has been shown to be efficacious in a subgroup of ste- roid-dependent patients. D. Moderate-to-severe ulcerative colitis 1. Patients presenting with moderate to severe ulcer- ative colitis usually have more than six loose to watery bowel movements per day, often containing blood, along with abdominal cramps, weight loss, and anemia. Patients with ulcerative colitis may be treated with oral prednisone or intravenous therapy. If a severely ill patient fails to respond within 7 to 10 days, intravenous cyclosporine or colectomy should be considered. 2. Cyclosporine. In a trial of patients with ulcerative colitis refractory to corticosteroids, 83% responded to cyclosporine. Cyclosporine should be used as a transitional agent or bridge to longer-term therapy with an immunomodulating drug or to elective colectomy. III. Maintenance therapy A. Most of the drugs used for induction of remission also may be used for maintenance therapy. Treatments include 5-ASA products, immunomodulators (6-mercaptopurine [Purinethol] and azathioprine [Imuran]), and infliximab. Corticosteroids, however, should almost never be used for long-term therapy. B. For patients with Crohn’s disease or ulcerative colitis refractory to prednisone therapy or who become prednisone-dependent, use of immunomodulating agents such as 6-mercaptopurine, 1.5 to 2 mg/kg per day, and its prodrug azathioprine, 2 to 2.5 mg/kg per day, has proved beneficial. Infliximab has recently been shown to be efficacious in the maintenance of remission for Crohn’s disease. References, see page 360. Neurologic Disorders Acute Ischemic Stroke I. Initial general assessment. Sudden loss of focal brain function is the core feature of the onset of ischemic stroke. The goals in this initial phase include: A. Medically stabilize the patient. B. Reverse any conditions that are contributing to the patient’s problem. C. Assess the pathophysiologic basis of the neurologic symptoms. D. Screen for potential contraindications to thrombolysis in acute ischemic stroke patients. E. Diagnosing an intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) as soon as possible can be lifesaving. The presence of onset headache and vomiting favor the diagnosis of ICH or SAH compared with a thromboembolic stroke, while the abrupt onset of impaired cerebral function without focal symptoms favors the diagnosis of SAH. F. History and physical examination should distinguish between seizures, syncope, migraine, and hypoglycemia, which can mimic acute ischemia. In patients with focal signs and altered level of conscious- ness, it is important to determine whether the patient takes insulin or oral hypoglycemic agents, has a history of a seizure disorder or drug overdose or abuse, medications on admission, or recent trauma. Acute stroke differential diagnosis Migraine Intracerebral hemorrhage Head trauma Brain tumor Todd’s palsy (paresis, aphasia, neglect, etc., after a seizure episode) Functional deficit (conversion reaction) Systemic infection Toxic-metabolic disturbances (hypoglycemia, acute renal failure, hepatic insufficiency, exogenous drug intoxication) G. Physical examination should evaluate the neck and retroorbital regions for vascular bruits, and palpate of pulses in the neck, arms, and legs to assess for their absence, asymmetry, or irregular rate. 1. The heart should be auscultated for murmurs. Fluctuations in blood pressure occasionally precede fluctuations in clinical signs. 2. The skin should be examined for signs of endocarditis, cholesterol emboli, purpura, or ecchymoses. The funduscopic examination may reveal cholesterol emboli or papilledema. The head should be examined for signs of trauma. A tongue laceration may occur during a seizure. 3. The neck should be immobilized until evaluated radiographically for evidence of serious trauma if there is a suspicion of a fall. The chest x-ray is helpful if it shows cardiomegaly, metastases, or a widened mediastinum suggesting aortic dissection. Examination of the extremities is important to detect deep vein thrombosis. 4. Breathing. Patients with increased ICP due to hemorrhage, vertebrobasilar ischemia, or bihemispheric ischemia can present with a de- creased respiratory drive or muscular airway obstruc- tion. Intubation may be necessary to restore ade- quate ventilation. Patients with adequate ventilation should have the oxygen saturation monitored. Patients who are hypoxic should receive supplemen- tal oxygen. H. Immediate laboratory studies 1. All patients with acute neurologic deterioration or acute stroke should have an electrocardiogram. Chest radiography is indicated if lung or heart dis- ease is suspected. Oxygen saturation or arterial blood gas tests are indicated if hypoxia is suspected. 2. Blood studies include: a. Complete blood count including platelets, and erythrocyte sedimentation rate. b. Electrolytes, urea nitrogen, creatinine. c. Serum glucose. Finger stick for faster glucose measurement if diabetic, taking insulin or oral hypoglycemic agents, or if there is clinical suspi- cion for hypoglycemia. d. Liver function tests. e. Prothrombin time and partial thromboplastin time. f. Toxicology screen and blood alcohol level in selected patients. g. Blood for type and cross match in case fresh frozen is needed to reverse a coagulopathy if ICH is present. h. Urine human chorionic gonadotropin in women of child-bearing potential. i. Consider evaluation for hypercoagulable state in young patients without apparent stroke risk fac- tors. Laboratory studies Complete blood count and erythrocyte sedimentation rate Electrolytes, urea nitrogen, creatinine, glucose Liver function tests Prothrombin time and partial thromboplastin time Toxicology screen Blood for type and cross match Urine human chorionic gonadotropin in women of child-bearing potential Consider evaluation for hypercoagulable state in young patients without apparent stroke risk factors 3. Anticoagulant use is a common cause of intracerebral hemorrhage. Thus, the prothrombin and partial thromboplastin time and the platelet count should be checked. The effects of warfarin are corrected with intravenous vitamin K and fresh- frozen plasma (typically 4 units) in patients with intracerebral hemorrhage. 4. A drug overdose can mimic an acute stroke. In addition, cocaine, intravenous drug abuse, and amphetamines can cause an ischemic stroke or intracranial hemorrhage. Hyponatremia and throm- botic thrombocytopenic purpura (TTP) can present with focal neurologic deficits, suggesting the need for measurement of serum electrolytes and a complete blood count with platelet count. 5. Hyperglycemia, defined as a blood glucose level >108 mg/dL, is associated with poor functional outcome from acute stroke at presentation. Stress hyperglycemia is common in stroke patients, al- though newly diagnosed diabetes may be detected. Treatment with fluids and insulin to reduce serum glucose to less than 300 mg/dL is recommended. 6. Hypoglycemia can cause focal neurologic deficits mimicking stroke. The blood sugar should be checked and rapidly corrected if low. Glucose should be administered immediately after drawing a blood sample in "stroke" patients known to take insulin or oral hypoglycemic agents. 7. Fever. Primary central nervous system infection, such as meningitis, subdural empyema, brain ab- scess, and infective endocarditis, need to be ex- cluded as the etiology of fever. Common etiologies of fever include aspiration pneumonia and urinary tract infection. Fever may contribute to brain injury in patients with an acute stroke. Maintaining normothermia is recommended after an acute stroke. Prophylactic administration of acetaminophen (1 g four times daily) is more effective in preventing fever than placebo (5 versus 36 percent). 8. Blood pressure management. Acute management of blood pressure (BP) may vary according to the type of stroke. a. Ischemic stroke. Blood pressure should not be treated acutely in the patient with ischemic stroke unless the hypertension is extreme (diastolic BP above 120 mm Hg and/or systolic BP above 220 mm Hg), or the patient has active ischemic coro- nary disease, heart failure, or aortic dissection. If pharmacologic therapy is given, intravenous labetalol is the drug of choice. b. Intracranial hemorrhage. With ICH, intravenous labetalol, nitroprusside, or nicardipine, should be given if the systolic pressure is above 170 mm Hg. The goal is to maintain the systolic pressure between 140 and 160 mm Hg. Intravenous labetalol is the first drug of choice in the acute phase since it allows rapid titration. I. Neurologic evaluation. The history should focus upon the time of symptom onset, the course of symptoms over time, possible embolic sources, items in the differential diagnosis, and concomitant diseases. The neurologic examination should attempt to confirm the findings from the history and provide a quantifiable examination for further assessment over time. J. Neuroimaging studies are used to exclude hemorrhage as a cause of the deficit, to assess the degree of brain injury, and to identify the vascular lesion responsible for the ischemic deficit. 1. Computed tomography. In the hyperacute phase, a non-contrast CT (NCCT) scan is usually ordered to exclude or confirm hemorrhage. A NCCT scan should be obtained as soon as the patient is medi- cally stable. a. Noncontrast CT. Early signs of infarction include: Subtle parenchymal hypodensity, which can be detected in 45 to 85 percent of cases. Early focal brain swelling is present in up to 40 percent of patients with early infarction and also has been adversely related to outcome. A hyperdense middle cerebral artery (MCA) can be visualized in 30 to 40 percent of patients with an MCA distribu- tion stroke, indicating the presence of thrombus inside the artery lumen (bright artery sign). 2. Transcranial Doppler ultrasound (TCD) visualizes intracranial vessels of the circle of Willis. It is a noninvasive means of assessing the patency of intracranial vessels. 3. Carotid duplex ultrasound is as a noninvasive examination to evaluate extracranial atherosclerotic disease. It may help to establish the source of an embolic stroke, but is not used acutely. Initial management of acute stroke Determine whether stroke is ischemic or hemorrhagic by com- puted tomography Consider administration of t-PA if less than three hours from stroke onset General management: • Blood pressure (avoid hypotension) • Assure adequate oxygenation • Administer intravenous glucose • Take dysphagia/aspiration precautions • Consider prophylaxis for venous thrombosis if the patient is unable to walk • Suppress fever, if present • Assess stroke mechanism (eg, atrial fibrillation, hyperten- sion) • Consider aspirin or clopidogrel (Plavix) therapy if ischemic stroke and no contraindications (begin 24 hours after t-PA). Antiplatelet Agents for Prevention of Ischemic Stoke • Enteric-coated aspirin (Ecotrin) 325 mg PO qd • Clopidogrel (Plavix) 75 mg PO qd • Extended-release aspirin 25 mg with dipyridamole 200 mg (Aggrenox) one tab PO qd Eligibility criteria for the treatment of acute ischemic stroke with recombinant tissue plasminogen activator (rt-PA) Inclusion criteria Clinical diagnosis of ischemic stroke, with the onset of symptoms within three hours of the initiation of treatment (if the exact time of stroke onset is not know, it is defined as the last time the patient was known to be normal), and with a measurable neuro- logic deficit. Exclusion criteria Historical Stroke or head trauma within the prior 3 months Any prior history of intracranial hemorrhage Major surgery within 14 days Gastrointestinal or genitourinary bleeding within the previous 21 days Clinical Rapid improving stroke symptoms Only minor and isolated neurologic signs Seizure at the onset of stroke with postictal residual neurologic impairments Symptoms suggestive of subarachnoid hemorrhage, even if the CT is normal Clinical presentation consistent with acute MI or post-MI pericarditis Persistent systolic BP >185 diastolic >110 mm Hg, or requiring aggressive therapy to control BP Pregnancy or lactation Active bleeding or acute trauma (fracture) Laboratory Platelets <100,000/mm 3 Serum glucose <50 mg/dL or >400 mg/dL INR >1.5 if on warfarin Elevated partial thromboplastin time if on heparin Head CT scan Evidence of hemorrhage Evidence major early infarct signs, such as diffuse swelling of the affected hemisphere, parenchymal hypodensity, and /or effacement of >35 percent of the middle cerebral artery territory K. Thrombolytic therapy. Patients presenting within three hours of symptom onset may be given IV alteplase (Activase) (0.9 mg/kg up to 90 mg; 10 percent as a bolus, then a 60 minute infusion). References, see page 360. Transient Cerebral Ischemia Transient ischemic attack (transient cerebral ischemia, TIA) is a temporary focal neurologic deficit caused by the brief interruption of local cerebral blood flow. The prevalence of TIAs 1.6-4.1 percent. Stroke occurs in one-third of patients who have a TIA. The duration of a focal neurologic deficit that leads to cerebral infarction is 24 hours or greater. Transient ischemic attacks (TIA) are divided into three subtypes: Large artery low flow TIA (true TIA), embolic TIA, and lacunar or small penetrating vessel TIA. I. Pathophysiology. The most frequent mechanism of TIA is embolization by a thrombus from an atherosclerotic plaque in a large vessel (stenotic carotid artery). TIAs may also occur as manifestations of intracranial atherosclerotic disease (lacunar TIAs) or large-vessel occlusion. In addition, they can be associated with atrial fibrillation or mitral valve prolapse, carotid or vertebral dissection, and hypercoagulable states (antiphospholipid antibody syndrome). II. Evaluation of TIA symptoms A. The primary objective when evaluating a patient with a transient ischemic attack (TIA) is to determine whether the ischemic insult has occurred in the anterior or posterior circulation. B. Anterior circulation ischemia causes motor or sensory deficits of the extremities or face, amaurosis fugax, aphasia, and/or homonymous hemianopia. C. Posterior circulation ischemia causes motor or sensory dysfunction in association with diplopia, dysphasia, dysarthria, ataxia, and/or vertigo. D. Assessment should determine the activity in which the patient was engaged and the patient's physical posi- tion at the onset of the attack. A description of the specific symptoms of the attack should be obtained, including the speed with which they developed, whether they were bilateral or unilateral, and their duration. E. History of hypertension, diabetes, cardiac disease, previous TIA or stroke, cigarette smoking, or use of street drugs should be sought. F. Differentiating TIAs from other entities 1. Seizures almost always involve a change in the level of consciousness or awareness, excessive motor activity and confusion, none of which charac- terizes a TIA. 2. Syncope. Changes in cardiac output produce generalized, rather than focal, cerebral ischemia, characterized by loss of consciousness and a rapid heartbeat (often due to an arrhythmia). 3. Benign positional vertigo. Recurrent waves of dizziness, which last 2-10 seconds and are related to movement (standing up or sitting down), are characteristic. G. Physical examination 1. Heart rate and rhythm and the blood pressure in both arms, peripheral pulses, skin lesions (petechiae of embolic origin), and skin manifesta- tions of connective tissue disease should be as- sessed. 2. Carotid bruits may suggest carotid stenosis. Ophthalmoscopic examination can detect arterial or venous occlusion and emboli. 3. Neurologic examination a. The neurologic examination should be normal in TIA patients unless the patient has had a previ- ous stroke or is currently experiencing a TIA or stroke. b. Evaluation should include the level of conscious- ness, orientation, ability to speak and under- stand language; cranial nerve function, espe- cially eye movements and pupil reflexes and facial paresis. Neglect, gaze preference, arm and leg strength, sensation, and walking ability should be assessed. Common Clinical Findings Associated with Ischemia in Various Arterial Distributions Anterior cerebral artery Weakness in contralateral leg Sensory loss in contralateral leg, with or without weakness or numb- ness in proximal contralateral arm Middle cerebral artery Contralateral hemiparesis Deviation of head and eyes toward side of lesion Contralateral hemianesthesia Contralateral hemianopia Aphasia (if dominant hemi- sphere is affected) Unawareness of stroke (if nondominant hemisphere is affected) Lenticulostriate arteries Pure motor hemiparesis (lacunar syndrome) Posterior cerebral artery Visual field disturbance Contralateral sensory loss Amnesia Vertebrobasilar arteries Vertigo Nausea and vomiting Ataxia Nystagmus H. Laboratory testing is helpful in ruling out metabolic and hematologic causes of neurologic symptoms, including hypoglycemia, hyponatremia, and thrombocytosis. 1. Electrocardiogram may reveal unsuspected cases of atrial fibrillation or a recent myocardial infarction. Initial Evaluation of a Patient with Transient Ischemic Attack Complete blood cell count with platelet count Chemistry profile (including cholesterol and glucose levels) Prothrombin time and activated partial thromboplastin time Erythrocyte sedimentation rate Syphilis serology Electrocardiography Cranial computed tomography (particularly with hemispheric transient ischemic attack) Noninvasive arterial imaging (ultrasonography, magnetic resonance angiography) I. Imaging studies. Brain imaging with CT or MRI is indicated in all patients with suspected TIA to search for an obstructive lesion in a larger artery supplying the affected territory. The presence of a brain infarct on CT or MRI scan, particularly in an area suggested by the anatomy of the TIA or stroke. Infarction is more likely to be identified acutely on MRI than on CT. However, CT scanners are more widely available emergently than MRI. J. Cardiac evaluation. All patients with TIA should have the following tests: 1. Standard 12 lead electrocardiogram (ECG) 2. Chest radiography 3. Echocardiography is indicated for patients who are candidates for anticoagulation or for patients who have suspected endocarditis. a. Transesophageal echocardiography (TEE) is the test of choice for evaluation of aortic atheroscle- rosis. b. Transthoracic echocardiography (TTE) with agitated saline contrast is usually a first test because it is noninvasive and better tolerated. It i s al so l ess sensi t i ve t han TEE. Transesophageal echocardiography (TEE) should be performed if the TTE is negative and treatment decisions hinge on identifying one of the possible TEE findings. 4. Cardiac monitoring is an essential part of this evaluation to exclude atrial fibrillation. Holter moni- toring or continuous telemetry may be most useful in patients with a history of palpitations, paroxysmal atrial fibrillation, evidence of spontaneous echo contrast on TEE, and cryptogenic TIA. K. Other tests. Blood cultures, an erythrocyte sedimen- tation rate, or antinuclear antibody testing are indi- cated if bacterial or nonbacterial endocarditis is suspected. L. Neurovascular evaluation. Noninvasive options for evaluation of large vessel occlusive disease include magnetic resonance angiography (MRA), computed tomography angiography (CTA), carotid duplex ultrasonography (CDUS), and transcranial Doppler ultrasonography (TCD). 1. Anterior circulation. Patients with symptoms referable to the anterior circulation require extracranial carotid artery evaluation. 2. Posterior circulation. Patients with symptoms referable to the posterior circulation should have MRA or CTA of the neck to detect dissection and vertebral origin atherosclerosis. 3. Intracranial large vessels. In most cases, cardiac and extracranial evaluations should be performed prior to intracranial evaluation. Evaluation of intracranial vessels with CTA, MRA, or TCD should be performed routinely, especially for the following higher prevalence situations: a. Age less than 50 without clear cardiac or extracranial source b. Patients with recurrent stereotyped TIAs c. Patients with posterior circulation event and no clear cardiac source d. Patients with preoperative evaluation of collat- eral circulation before carotid endarterectomy 4. Small vessels are not directly visible with any of the currently available imaging techniques. How- ever, evaluation of the extracranial carotid artery is recommended for patients with lacunar infarction or suspected small vessel TIA referable to the anterior circulation. M. Blood tests 1. In patients with TIA, the following tests should be considered: a. Complete blood count (CBC) b. Partial thromboplastin time (aPTT) c. Erythrocyte sedimentation rate (ESR) 2. Suspicion for blood disorders as potential sources of cerebral ischemia should be raised in the follow- ing settings: a. Cryptogenic stroke b. Age 45 or younger c. History of clotting dysfunction d. Multiple venous and arterial occlusions e. Suspected or confirmed cancer f. Family history of thrombotic events III. Treatment of transient cerebral ischemia and minor stroke A. Large vessel disease 1. Antiplatelet therapy. Patients with large vessel atherothrombotic disease in anterior and posterior cerebral circulation sites other than the internal carotid artery and patients with the latter lesions who cannot undergo carotid endarterectomy benefit from antiplatelet therapy. 2. Anticoagulation (eg, with warfarin). Virtually all patients with atrial fibrillation who have a history of stroke or TIA should be treated with warfarin in the absence of contraindications since long-term anticoagulation reduces the risk of recurrent stroke. In contrast, warfarin has not been found to be superior to antiplatelet agents as secondary prevention in patients without atrial fibrillation. 3. Car ot i d r evascul ar i zat i on. Car ot i d endarterectomy (CEA) should be considered for patients with large vessel atherothrombotic disease in the internal carotid artery that causes low flow or embolic TIAs. 4. Amaurosis fugax refers to transient monocular blindness caused by a small embolus to the oph- thalmic artery. It accounts for one-quarter of TIAs involving the anterior cerebral circulation. Amaurosis fugax frequently occurs as a result of carotid stenosis. Amaurosis fugax is more typical of carotid stenosis than atrial fibrillation. Carotid endarterectomy may improve outcomes in those with additional risk factors for stroke. 5. Risk factor management is appropriate for all patients with less than 50 percent carotid stenosis or for those who are at high risk of developing complications from surgery. Risk factor manage- ment includes treatment of hypertension, diabetes mel l i t us, smoki ng, dysl i pi demi a, and hyperhomocysteinemia. 6. Carotid occlusion. Surgical revascularization is a viable option only when residual flow can be dem- onstrated in the carotid artery. Carotid artery occlusion can be associated with TIA and stroke. Short-term (three to six months) anticoagulation may be administered for acute symptomatic occlu- sion. 7. Vertebral revascularization. Large artery lesions at the origin of the vertebral artery have been treated with angioplasty, stenting, and vertebral artery transposition to the common carotid artery. These procedures are considered when maximal medical therapy has failed to prevent embolism or low-flow ischemic events. 8. Intracranial large vessel disease a. There is no clear difference in effectiveness for either aspirin or anticoagulation for large vessel intracranial disease. Therefore, aspirin or other antiplatelet therapy is recommended, since warfarin is potentially more hazardous. b. Antiplatelet therapy (eg, aspirin 75 to 325 mg/day) and risk factor management should be initiated for patients with large vessel intracranial disease. However, warfarin may still benefit selected patients with large artery le- sions who have recurrent embolic or low-flow TIAs despite maximal antiplatelet therapy. Use of warfarin (goal INR 2 to 3) may be considered for such patients if there is thrombus in the basilar artery, middle cerebral artery stem, or the siphon portion of the internal carotid artery. 9. Dissection. Patients who experience acute ischemic symptoms due to carotid or vertebral dissection should be treated with intravenous heparin followed by warfarin therapy until the carotid or vertebral artery is occluded and healed, or is resolved back to a clonic state of circulation. This usually involves treatment for six months to one year. B. Small vessel disease. Small vessel disease that causes transient ischemia is a diagnosis of exclusion. The efficacy of aspirin versus warfarin in preventing further TIAs or stroke in the setting of a small vessel TIA is uncertain. Attention to serum lipids, homocysteine metabolism, hypertension, and other modifiable risk factors are additional means of pre- venting lacunar strokes in patients with small vessel disease. C. Cardiogenic embolism. Approximately 60 percent of all strokes are caused by embolism (eg, heart, aorta, or an unknown source). 1. The distinction between artery-to-artery and non- artery-to-artery sources of embolism can be diffi- cult. Suspicion of the former typically arises once vascular pathology in a large vessel has been identified (eg, with noninvasive testing). Repetitive spells within a single vascular territory are also suggestive of an artery-to-artery source, as is a normal echocardiogram. Transesophageal echocardiography (TEE) is better for identifying these lesions. TTE with agitated saline contrast should be performed as a first test, and proceeding to TEE if there is a strong suspicion of a cardioembolic source. Cardiac monitoring is also an essential part of this evaluation to exclude atrial fibrillation. 2. Definite cardiac sources of embolism for which antithrombotic therapy has proven effective in- clude: a. Atrial fibrillation. b. Left ventricular thrombus. c. Left atrial thrombus. d. Rheumatic valve disease. e. Mechanical prosthetic heart valve. f. Bioprosthetic heart valve. g. Cardiomyopathy with an ejection fraction less than 30 percent. h. Recent myocardial infarction in high-risk pa- tients, with risk factors including anterior wall MI, coexisting left ventricular dysfunction, hyperten- sion before MI, and history of systemic or pul- monary embolism. 3. Atrial fibrillation is a major risk factor for ischemic stroke. Anticoagulation is the most effective treat- ment to reduce stroke risk. a. Acute heparin therapy. It is reasonable to follow the guidelines for acute heparin therapy after stroke. b. Warfarin. Virtually all patients with atrial fibrilla- tion who have a history of embolic stroke or TIA should be treated with warfarin in the absence of contraindications. Warfarin treatment can reduce the risk of stroke by 70 percent. An INR between 2.0 and 3.0 is recommended for most patients with AF who receive warfarin anticoagulation. 4. Infective endocarditis. An important cause of embolic TIA for which anticoagulation is hazardous is infective endocarditis. Emboli from vegetations can cause focal neurologic signs which are fleet- ing. Thus, endocarditis must be excluded in any patient with a TIA and other suggestive findings such as fever and a heart murmur. Treatment consists of antibiotic therapy for the infection. 5. Minor causes of cardiogenic embolism. Minor potential sources of cardiogenic embolism include left ventricular regional wall motion abnormalities, severe mitral annular calcification, mitral valve prolapse, and mitral valve strands. The risk of stroke associated with these sources is uncertain, as is the efficacy of and need for treatment. D. Antiplatelet agents for stroke prevention 1. The Sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy recommended that every patient with an atherothrombotic stroke or TIA and no contraindi- cation should receive an antiplatelet agent to reduce the risk of recurrent stroke and other vascu- lar events. Fewer gastrointestinal side effects and bleeding occur with lower doses (75 to 150 mg/day). Aspirin, clopidogrel (75 mg/day), and the combination of aspirin and dipyridamole are all acceptable options. However, initial therapy with aspirin (50 to 325 mg/day) is recommended; doses less than 150 mg/day are associated with less gastrointestinal toxicity. 2. Clopidogrel is an alternative for patients who cannot tolerate aspirin. Combination therapy with aspirin and dipyridamole can be considered in patients who have an event while on aspirin alone. Ticlopidine should be reserved for patients intoler- ant of both aspirin and clopidogrel. References, see page 360. Dementia Dementia is characterized by a general decrease in the level of cognition (especially memory), behavioral disturbances, and interference with daily function and independence. Alzheimer's disease (AD) is the most common form of dementia, accounting for 60 to 80 percent of cases. I. Identification of dementia A. The normal cognitive decline associated with aging consists of mild changes in memory and the rate of information processing, which are not progressive and do not affect daily function. B. Patients with dementia may have difficulty with one or more of the following: 1. Learning and retaining new information (eg, trouble remembering events). 2. Handling complex tasks (eg, balancing a check- book). 3. Reasoning (eg, unable to cope with unexpected events). 4. Spatial ability and orientation (eg, getting lost in familiar places). 5. Language (eg, word finding). 6. Behavior. C. The date of onset of dementia can often be identified when the patient stopped driving or managing finances. Useful questions are, “When did you first notice the memory loss?” and “How has the memory loss pro- gressed since then?” D. The diagnosis of dementia must be distinguished from delirium and depression. Delirium is usually acute in onset with a clouding of the sensorium. Patients with delirium may have fluctuations in their level of con- sciousness and have difficulty with attention and con- centration. E. Patients with depression are more likely to complain about memory loss than those with dementia. Patients with depression may have psychomotor slowing and poor effort on testing. F. Mild cognitive impairment (MCI) is defined by the following features: 1. Memory complaint, corroborated by an informant. 2. Objective memory impairment. 3. Normal general cognitive function. 4. Intact activities of daily living. 5. Not demented. G. Patients with MCI are at increased risk of dementia. The prevalence of MCI was estimated at 3 to 4 percent. H. Dementia syndromes. The major dementia syndromes include: 1. Alzheimer's disease. 2. Vascular (“multi-infarct”) dementia. 3. Parkinson's disease and related dementias (includ- ing Lewy body dementia and progressive supranuclear palsy). 4. Frontal lobe dementia. 5. Reversible dementias. 6. Most elderly patients with chronic dementia have Alzheimer's disease (60 to 80 percent). The vascular dementias account for 10 to 20 percent, and Parkin- son's disease 5 percent. Alcohol-related dementia, medication side effects, depression, normal pressure hydrocephalus, and other central nervous system illnesses are responsible for the remainder of the chronic dementias. DSM-IV Criteria for Dementia 1.Memory impairment 2.At least one of the following: Aphasia Apraxia Agnosia Disturbance in executive functioning 3.The disturbance in 1 and 2 significantly interferes with work, social activities, or relationships 4.Disturbance does not occur exclusively during delir- ium Additional criteria for dementia type Dementia of the Alzheimer’s type: Gradual onset and continuing cognitive decline Not caused by identifiable medical, psychiatric, or neurologic condition Vascular dementia Focal from history, physical exam, or laboratory findings of a specific medical condition Dementia due to other medical conditions Evidence from history, physical exam, or laboratory findings of a specific medical condition causing cog- nitive deficits (HIV disease, head trauma, Parkin- son’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt-Jacob) I. Alzheimer's disease is a progressive neurologic disorder that results in memory loss, personality changes, global cognitive dysfunction, and functional impairments. Loss of short-term memory is most prominent early. In the late stages of disease, patients are totally dependent upon others for basic activities of daily living, such as feeding and toileting. 1. Alzheimer's disease is characterized by cerebral extracellular deposition of amyloid-beta protein, intracellular neurofibrillary tangles, and loss of neurons. The DSM-IV criteria for the diagnosis of Alzheimer's dementia include the following: a. The gradual onset and continuing decline of cognitive function from a previously higher level, resulting in impairment in social or occupational function. b. Impairment of recent memory (inability to learn new information) and at least one of the following: disturbance of language; inability to execute skilled motor activities in the absence of weak- ness; disturbances of visual processing; or distur- bances of executive function (including abstract reasoning and concentration). c. The cognitive deficits are not due to other psychi- atric, neurologic, or systemic diseases. d. The deficits do not occur exclusively in the setting of delirium. 2. Behavioral problems are common in Alzheimer's disease; personality changes (progressive passivity to open hostility) may precede the cognitive impair- ments. Delusions (particularly paranoid) and halluci- nations contribute to the behavioral difficulties. J. Vascular dementia. Features that suggest the diagno- sis include: 1. The onset of cognitive deficits associated with a stroke. 2. Abrupt onset of symptoms followed by stepwise deterioration. 3. Findings on neurologic examination consistent with prior stroke(s). 4. Infarcts on cerebral imaging. K. Poststroke dementia develops in 19.3 percent of subjects with stroke. Subjects with stroke have a twofold higher risk of dementia at 10 years. L. Mixed dementia. Many individuals have mixed features of vascular and Alzheimer's dementia. M. Reversible dementia. The potentially reversible dementias include the following: 1. Medi cat i on- i nduced ( eg, anal gesi cs, anticholinergics, psychotropic medications, and sedative-hypnotics). 2. Alcohol-related (eg, intoxication, withdrawal). 3. Metabolic disorders (eg, thyroid disease, vitamin B12 deficiency, hyponatremia, hypercalcemia, hepatic and renal dysfunction). 4. Depression. 5. Central nervous system neoplasms, chronic subdural hematomas, chronic meningitis. 6. Normal pressure hydrocephalus. 7. Bismuth exposure can cause a myoclonic encephalopathy that can be confused with CJD. 8. Hashimoto’s thyroiditis can cause encephalopathy with myoclonus or choreoathetosis and seizures. 9. Whipple’s disease is characterized by dementia, supranuclear gaze palsy, oculomasticatory myorhythmia, and myoclonus. N. Normal pressure hydrocephalus is often considered in patients who present with the triad of gait distur- bance, urinary incontinence, and cognitive dysfunction. 1. The Miller Fisher test, consisting of objective gait assessment before and after the removal of 30 mL of spinal fluid, is useful to confirm the diagnosis of normal pressure hydrocephalus. Radioisotope diffusion studies in the cerebrospinal fluid also confirm the diagnosis. O. Other disorders 1. Creutzfel dt -Jakob di sease i s a rare neurodegenerative disease caused by prions. It presents with a rapidly progressive dementia that is usually fatal within one year. The diagnosis may be suspected on the basis of the rapid onset of cognitive impairment, motor deficits, and seizures. The dis- ease is not treatable, but the disease is potentially transmissible. 2. Other more common infectious disorders that may be associated with dementia include tertiary syphilis and HIV infection. II.Diagnostic approach A. History of cognitive and behavioral changes should be assessed. Drugs that impair cognition (eg, analgesics, anticholinergics, psychotropic medications, and sedative-hypnotics) should be sought. B. Physical examination, including neurologic examina- tion. The work-up may include laboratory and imaging studies should be completed. C. Mini-Mental State Examination (MMSE) is the most widely used cognitive test for dementia. It tests a broad range of cognitive functions, including orientation, recall, attention, calculation, language manipulation, and constructional praxis. The MMSE includes the following tasks: 1. Orientation a. What is the date: (year, season, date, day, month) - 5 points b. W h e r e a r e w e : (state)(county)(town)(hospital)(floor) - 5 points 2. Registration a. Name three objects. Ask the patient all three after you have said them. Give one point for each correct answer. Then repeat them until he learns all three. Maximum score - 3 points. 3. Attention and calculation a. Serial 7s, beginning with 100 and counting back- ward. One point for each correct, stop after 5 answers. Alternatively, spell WORLD backwards (one point for each letter that is in correct order). Maximum score - 5 points. b. Ask for the three objects repeated above. One point for each correct. Maximum score - 3 points. c. Show and ask patient to name a pencil and wrist watch - 2 points. d. Repeat the following, “No ifs ands or buts.” Allow only one trial - 1 point. e. Follow a three stage command, “Take a paper in your right hand, fold it in half, and put it on the floor.” Score one point for each task executed. Maximum score - 3 points. f. On a blank piece of paper write “close your eyes” and ask the patient to read and do what it says - 1 point. g. Give the patient a blank piece of paper and ask him to write a sentence. The sentence must contain a noun and verb and be sensible - 1 point. h. Ask the patient to copy intersecting pentagons. All ten angles must be present and two must intersect - 1 point. 4. A total maximal score on the MMSE is 30 points. A score of less than 24 points is suggestive of demen- tia or delirium. The MMSE has a sensitivity of 87 percent and a specificity of 82 percent. However, the test is not sensitive in cases of mild dementia, and scores are spuriously low in individuals with a low education level, poor motor function, black or Latino ethnicity, poor language skills, or impaired vision. D. Physical examination and a neurologic examination should seek for focal neurologic deficits that may be consistent with prior strokes, signs of Parkinson’s disease (eg, cogwheel rigidity and tremors), gait, and eye movements. E. Laboratory testing 1. Screening for B12 deficiency and hypothyroidism is recommended. Routine laboratory studies may include a complete blood count, electrolytes, cal- cium, glucose, blood urea nitrogen, creatinine, and liver function tests. Screening for neurosyphilis (RPR) is not recommended unless there is a high clinical suspicion of neurosyphilis. 2. Red blood cell folate should be obtained in ethanol dependence. Ionized serum calcium should be measured in multiple myeloma, prostate cancer, or breast cancer. F. Neuroimaging. A noncontrast head CT or MRI is recommended for all patients with dementia. III. Treatment of dementia A. Cholinesterase inhibitors 1. Patients with AD have reduced cerebral production of choline acetyl transferase, which leads to a de- crease in acetylcholine synthesis and impaired cortical cholinergic function. Cholinesterase inhibitors increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft. 2. Four cholinesterase inhibitors, tacrine, donepezil, rivastigmine, and galantamine are currently ap- proved. Tacrine was can cause hepatotoxicity and is rarely used. The choice between the other three agents is based upon cost and patient tolerability because efficacy is similar. 3. Donepezil (Aricept) has relatively little peripheral anticholinesterase activity and is generally well- tolerated. This combined with its once-daily dosing has made it a popular drug in patients with AD. The recommended dose for donepezil is 5 mg per day for 4 weeks, then increasing to 10 mg per day. a. Cognition, as measured by the Alzheimer's Dis- ease Assessment Scale (ADAS-cog), and the Clinician's global ratings significantly improved. b. There was a small but significant beneficial effect of donepezil for cognition compared with placebo, with a 0.8 point difference in the Mini Mental Status Exam (MMSE) score (95% CI 0.5-1.2). c. Donepezil may have some symptomatic benefit in patients with mild cognitive impairment (MCI) who are likely to convert to AD, delaying the clinical diagnosis but not changing the underlying course of the disease. d. Prolonged treatment with donepezil appears to be safe and effective. Cholinergic side effects (pri- marily diarrhea, nausea, and vomiting) are tran- sient and generally mild, occurring in about 20 percent of patients. 4. Rivastigmine (Exelon) appears to be beneficial for patients with mild-to-moderate AD. Its side-effect profile is related to cholinergic effects, with significant nausea, vomiting, anorexia, and headaches. It should be given with food to minimize nausea. One case of esophageal rupture do to severe vomiting has been reported. Therapy is initiated at 1.5 mg BID with titration every two weeks up to 6 mg BID and, if treatment is interrupted for longer than several days, it should be restarted at the lowest daily dose and then titrated again. Its efficacy appears similar although it may have more gastrointestinal side- effects. 5. Galantamine (Reminyl) and appears to be effective in patients with mild-to-moderate AD. Treatment with galantamine (maintenance dose 24 or 32 mg/day) slows the decline in both cognition and activities of daily living compared with placebo in patients with early Alzheimer's disease. a. Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, weight loss) are the most common adverse effects of galantamine. Like rivastigmine, galantamine appears to have similar efficacy to donepezil in patients with AD, but may have more gastrointestinal side-effects. 6. Degree of benefit. Cholinesterase inhibitors can improve cognitive function in patients with AD, vascular dementia, and diffuse Lewy body disease. However, the average benefit is a small improvement in cognition and activities of daily living. 7. Administration. Cholinesterase inhibitors are a symptomatic treatment and not disease-modifying; therefore, the drugs should be given for eight weeks and the patient's response should be reviewed. Treatment is continued if improvement is noted. The medication should be discontinued when a patient progresses to advanced dementia Cholinesterase Inhibitors for the Treatment of Mild- to-Moderate Alzheimer's Disease Drug Dosage Side effects Specific cautions Donepezil (Aricept) Initial dosage is 5 mg once daily; if necessary, dosage can be increased to 10 mg once daily after 4 to 6 weeks. Mild side ef- fects, including nausea, vomit- ing, and diar- rhea; effects can be reduced by taking with food. Initial increase of agitation in some; agitation subsides after a few weeks. Possible inter- actions with cimetidine (Tagamet), theophylline, warfarin (Coumadin), and digoxin (Lanoxin) Rivastigmi ne (Exelon) Initial dosage of 1.5 mg bid (3 mg per day) is well tolerated; dosage can be increased as tolerated to maximum of 6 mg twice daily (12 mg per day). Nausea, vomit- ing, diarrhea, headaches, diz- ziness, abdomi- nal pain, fa- tigue, malaise, anxiety, and agitation; these effects can be reduced by tak- ing rivastigmine with food. Weight loss Interacting drugs include amino- glycosides and procainamide (Procanbid). Drug Dosage Side effects Specific cautions Galantami ne (Reminyl) Initial dosage is 4 mg bid (8 mg per day) for 4 weeks; dosage is then in- creased to 8 mg twice daily (16 mg per day) for at least 4 weeks. An increase to 12 mg twice daily (24 mg per day) should be considered. Mild side ef- fects, including nausea, vomit- ing, and diar- rhea; these ef- fects can be reduced by tak- ing galantamine with food. No apparent association with sleep distur- bances (which can occur with other cholinergic treatments) Contraindi- cated for use in patients with hepatic or re- nal impairment Tacrine (Cognex) Initial dosage is 10 mg four times daily (40 mg per day) for 4 weeks. High incidence of side effects, including gas- trointestinal problems. Hepatotoxicity is a problem; hence, liver tests should be performed. IV. Disease-modifying agents A. Memantine (Namenda) is an N-methyl-D-aspartate (NMDA) receptor antagonist. Glutamate is the principle excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the NMDA receptor, which is involved in learning and memory. Excessive NMDA stimulation can be induced by ischemia and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia. 1. Memantine results in a small but statistically signifi- cant improvement in ADAS-cog scores compared with placebo (difference between the groups 2 points on a 70 point scale. 2. Memantine appears to be effective in patients with moderate to severe Alzheimer's disease. A 28-week randomized trial in 252 patients with MMSE scores of 3 to 14 (mean approximately 8) at study entry found that memantine significantly reduced deterioration on multiple scales of clinical efficacy. 3. The mechanism of action of memantine is distinct from that of the cholinergic agents; it appears to be neuroprotective. Memantine also appears to have fewer side effects than the cholinergic agents. 4. Memantine plus cholinesterase inhibitors. Treat- ment with memantine plus donepezil results in significantly better outcomes than placebo plus donepezil on measures of cognition, activities of daily living, global outcome, and behavior. Memantine is used in combination with a cholinesterase inhibitor in patients with advanced disease. Since it may be disease-modifying. Memantine should be continued even when there is no clinical improvement. B. Recommendations 1. Start patients with mild-to-moderate dementia on a cholinesterase inhibitor. Tacrine should not be used. The choice between donepezil, rivastigmine, and galantamine can be based upon cost, individual patient tolerance, and physician experience, as efficacy appears to be similar. 2. In patients with moderate to advanced dementia, add memantine to a cholinesterase inhibitor, or use memantine alone in patients who do not tolerate or benefit from a cholinesterase inhibitor. 3. In patients with severe dementia, cholinesterase inhibitors can be discontinued, but they should be restarted if the patient worsens without the medica- tion. Memantine should be continued even in severe dementia, given the possibility that memantine may be disease modifying. However, in some patients with advanced dementia medications should be discontinued to maximize quality of life and patient comfort. 4. For delusions and hallucinations, the atypical neuroleptics olanzapine (starting at a dose of 2.5 mg daily, titrating up to a maximum of 5 mg twice a day) or quetiapine (starting at a dose of 25 mg at bedtime, titrating up to a maximum of 75 mg twice a day) are recommended at the lowest effective doses. 5. For depression, avoid tricyclic antidepressants. SSRIs are preferred, but fluoxetine should be avoided because of its long half-life and drug interac- tions, and avoid paroxetine because it is more anticholinergic than other SSRIs. 6. For agitation and aggression, look for triggers and try to treat those first. Most behavioral symptoms have precipitants (constipation, urinary retention, fear of unrecognized caregivers, etc). Frightening delusions respond to atypical neuroleptics, and agitation may be due to unrecognized depression and responds to SSRIs. If a treatable etiology cannot be found, treat with trazodone starting with 25 mg at bedtime or twice daily and titrating the dose up to 50 to 100 mg twice daily. If this is unsuccessful, an atypical neuroleptic should be used. References, see page 360. Seizures A seizure is a sudden change in behavior that is the result brain dysfunction. Epileptic seizures result from electrical hypersynchronization of the cerebral cortex. Epilepsy is characterized by recurrent epileptic seizures caused by a brain disorder. Approximately 0.5 to 1 percent of the popula- tion has epilepsy. I. Etiology A. Epileptic seizures 1. An identifiable cause can be determined in less than one-half of epilepsy cases. Epilepsy in most of these other patients is genetically determined. In causes of epileptic seizures include congenital brain malforma- tions, inborn errors of metabolism, high fevers, head trauma, brain tumors, stroke, intracranial infection, cerebral degeneration, withdrawal states, and iatro- genic drug reactions. 2. In the elderly, vascular, degenerative, and neoplastic etiologies are more common than in younger adults and children. A higher proportion of epilepsy in children is due to congenital brain malformations. Head injury accounts for a relatively small proportion of epilepsy overall. B. Physiological nonepileptic seizures 1. Hyperthyroidism can cause seizures and can exacer- bate seizures in patients with epilepsy. 2. Hypoglycemic seizures are most common in diabetic patients who take excessive amounts of insulin or oral hypoglycemics. 3. Nonketotic hyperglycemia most commonly occurs in elderly diabetics and can cause focal motor seizures. 4. Precipitous falls in serum sodium concentrations can trigger generalized tonic-clonic seizures. 5. Hypocalcemia is a rare cause of seizures and most often occurs in neonates. In adults, hypocalcemia may occur after thyroid or parathyroid surgery or with renal failure, hypoparathyroidism, or pancreatitis. Magnesium levels below 0.8 mEq/L may result in irritability, agitation, confusion, myoclonus, tetany, and convulsions. Renal failure and uremia are often associated with seizures. 6. Cerebral anoxia as a complication of cardiac or respiratory arrest, carbon monoxide poisoning, drowning, or anesthetic complication can cause myoclonic and generalized tonic-clonic seizures. Cerebral anoxia due to syncope can result in very brief tonic and/or clonic movements without a pro- longed postictal state. Nonepileptic paroxysmal disorders that can mimic epilep- tic seizure Syncope ! Reflex (vasovagal, carotid sinus, glossopharyngeal, cough) ! Decreased cardiac output ! Decreased left ventricular filling (hypovolemia, orthostatic hypotension, pulmonary embolism) ! Cardiac arrhythmia Migraine with auras, basilar migraine, confusional migraine Transient ischemic attack Periodic paralysis Sleep disorders (parasomnias, daytime amnestic episodes) Gastrointestinal disorders (reflux, motility disorders) Movement disorders (tics, Tourette's syndrome, nonepileptic myoclonus, paroxysmal choreoathetosis, shuddering attacks) Psychiatric disorders (panic, somatization, dissociation, conver- sion [nonepileptic psychogenic seizures]) Drug toxicity and substance abuse Breath-holding spells Classification of epileptic seizures Generalized Partial Absence Myoclonic Tonic Atonic Clonic Tonic-clonic (grand mal sei- zure) Simple partial (conscious- ness not impaired) Complex partial (conscious- ness impaired) Partial with secondary gener- alization (can be tonic-clonic, tonic, or clonic) A. Differential diagnosis 1. REM behavior disorder is a parasomnia that consists of sudden arousals from REM sleep imme- diately followed by complicated, often aggressive, behaviors for which the patient is amnestic. Diagno- sis is clarified by sleep testing (polysomnography). 2. Transient ischemic attacks (TIAs) may last sec- onds to minutes. They are generally characterized by "negative" symptoms and signs (such as weak- ness or visual loss rather than jerking movements, stiffening, that accompany seizures. 3. Transient global amnesia is a condition of possibly vascular or migrainous etiology, that typically occurs after the age of 50. Affected patients have a deficit of short-term memory that begins abruptly and persists for minutes to hours. 4. Migraine auras such as visual illusions and altered consciousness can mimic complex partial seizures. II. Clinical evaluation A. Seizure precipitants or triggers. Environmental or physiological precipitants or triggers immediately preceding the seizure should be assessed. Triggers of seizures include strong emotions, intense exercise, flashing lights, and loud music. Fever, the menstrual period, lack of sleep, and stress can also cause sei- zures. However, the majority of patients with epilepsy have no identifiable or consistent trigger to their sei- zures. B. Seizure symptoms and signs 1. Auras. The symptoms that a patient experiences at the beginning of the seizure are referred to as the aura. Auras are seizures that cause symptoms, but not enough to interfere with consciousness. Auras are called simple partial seizures; “simple” means that consciousness is not impaired and “partial” means that only part of the cortex is disrupted by the seizure. A seizure that begins in the occipital cortex may result in flashing lights, while a seizure that affects the motor cortex will result in rhythmic jerking movements of the face, arm, or leg on the side of the body opposite to the involved cortex (Jacksonian seizure). 2. Complex partial seizures are characterized by an abrupt loss of consciousness. Complex partial seizures are the most common type of seizure in adults. Patients appear to be awake but are not in contact with others. They often seem to stare into space and either remain motionless or engage in repetitive behaviors, called automatisms, such as facial grimacing, gesturing, chewing, lip smacking, snapping fingers, repeating words or phrases, walking, running, or undressing. Complex partial seizures typically last less than three minutes and may be immediately preceded by a simple partial seizure. Afterward, the patient enters the postictal phase, characterized by somnolence, confusion, and headache. The patient has no memory of the seizure. 3. Generalized seizures originate in all the regions of the cortex. Absence seizures and generalized tonic- clonic seizures are types of generalized seizures. Other subtypes of generalized seizures are clonic, myoclonic, tonic, and atonic seizures. a. Absence seizures usually occur during childhood and typically last between 5 and 10 seconds. Absence seizures cause sudden staring with impaired consciousness. b. A generalized tonic-clonic seizure begins with an abrupt loss of consciousness. All of the muscles of the arms and legs as well as the chest and back then become stiff. The patient may begin to appear cyanotic. After approximately one minute, the muscles begin to jerk and twitch for one to two minutes. The tongue can be bitten. The postictal phase begins once the twitching move- ments end. The patient is initially in a deep sleep, breathing deeply, and then gradually wakes up, often complaining of a headache. c. Clonic seizures cause rhythmical jerking muscle contractions that usually involve the arms, neck, and face. d. Myoclonic seizures consist of sudden, brief muscle contractions that may occur singly or in clusters and that can affect any group of mus- cles, although typically the arms are affected. Consciousness is usually not impaired. e. Tonic seizures cause sudden muscle stiffening, often associated with impaired consciousness and falling to the ground. f. Atonic seizures produce a sudden loss of control of the muscles, particularly of the legs, that results in collapsing to the ground and possible injuries. Phases of Tonic-clonic Seizures Aura None Tonic Phase 10 to 20 seconds Sudden loss of consciousness Loss of posture with high risk of self injury depending on activity Brief flexion of arms, eyes deviated upward Extension of back, neck, arms, and legs Involuntary crying out from contraction of respiratory muscles Shallow respiration, cyanosis may occur Ends with tremors, which gradually slow and merge with clonic phase Clonic phase 30 to 90 seconds Brief, violent, generalized flexor contractions alternat- ing with progressively longer muscle relaxation Cyanosis Possible cheek or tongue biting Foamy salivation Possible loss of bowel or bladder control Ends with deep inspiration, sustained muscle relax- ation Postictal phase Minutes to several hours Headache, mild confusion Muscles sore Fatigue, patient may sleep and awake refreshed Other features Fast heart rate Elevated blood pressure Respiratory and metabolic acidosis Dilated pupils Risk of vertebral fracture, pneumonia C. Other aspects of the patient history 1. Medication history. Some medications have been associated with iatrogenic seizures. Partial-onset seizures are less likely to be drug-induced than generalized tonic-clonic seizures. 2. Past medical history. Risk factors for epileptic seizures include head injury, stroke, Alzheimer's disease, history of intracranial infection, and alcohol or drug abuse. 3. Family history of seizures is highly suggestive of epilepsy. Absence seizures and myoclonic seizures may be inherited. D. Physical and neurologic examination is generally unrevealing in patients with epileptic seizures, but is important when central nervous system infection or hemorrhage are diagnostic possibilities. Weakness, hyperreflexia, or a positive Babinski sign, that may point to a contralateral structural brain lesion, should be sought. History of a suspected seizure Before the event Unusual stress (eg, severe emotional trauma) Sleep deprivation Recent illness Unusual stimuli (eg, flickering lights)Use of medications and drugs Activity immediately before event (eg, change in posture, exer- cise) During the event Symptoms at onset (eg, aura) Temporal mode of onset: gradual versus sudden Duration: brief (ictal phase <5 min) versus prolonged Stereotypy: duration and features of episodes nearly identical versus frequently changing Time of day: related to sleep or occurring on awakening Ability to talk and respond appropriately Ability to comprehend Ability to recall events during the seizure Abnormal movements of the eyes, mouth, face, head, arms, and legs Bowel or bladder incontinence Bodily injury After the event Confusion Lethargy Abnormal speech Focal weakness or sensory loss (ie, Todd's paralysis) Headache, muscle soreness, or physical injury III. Diagnostic studies A. Laboratory screening includes glucose, calcium, magnesium, hematology studies, renal function tests, and toxicology screens. B. Lumbar puncture is essential if an acute infectious process involving the central nervous system is possi- ble or the patient has a history of cancer that is known to metastasize to the meninges. Lumbar puncture should only be performed after a space occupying brain lesion has been excluded by neuroimaging studies. C. Electroencephalography (EEG) is an essential study. If abnormal, the EEG may substantiate the diagnosis of epileptic seizures. Obtaining the EEG in the sleep- deprived state and using provocative measures, such as hyperventilation and intermittent photic stimulation, increase the yield. A normal EEG does not rule out epilepsy. D. Neuroimaging study should be done to exclude a structural brain abnormality. Brain magnetic resonance imaging (MRI) is preferred over computed tomography (CT) to identify cortical dysplasias, infarcts, or tumors. IV. Management of epilepsy A. Chronic drug therapy is not necessary if a first seizure is provoked by factors that resolve. Antiepileptic drug therapy should be started if a patient appears to be at increased risk for recurrent seizures. The overall risk of recurrence following a first seizure in adults is 14 percent at one year. The worst prognosis is in patients with a history of a neurologic insult and provoked seizures in the past; these individuals have an 80 percent recurrence rate at five years. B. Factors contributing to the risk of recurrent seizures include: 1. A history of brain insult (eg, head injury with loss of consciousness). 2. A lesion on brain CT or MRI studies. 3. Focal abnormalities detected during the neurologic examination. 4. Cognitive impairment. 5. A partial seizure as the first seizure. 6. An abnormal EEG (particularly epileptiform abnor- malities). C. AED therapy should be initiated after the first inci- dent if the patient is considered at high risk for recurrence. Antiepileptic drug treatment is generally started after the second seizure. The risk of another seizure after two unprovoked seizures is greater than 65 percent. Initial treatment for partial and generalized epilepsies Type of epilepsy First-line agents Second-line agents Partial Carbamazepine, oxcarbazepine (Trileptal), phenytoin (Dilantin) Divalproex (Depakote), felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), tiagabine (Gabitril Filmtabs), topiramate (Topamax), valproate (Depakene), zonisamide (Zonegran) Generalized Absence seizures Ethosuximide (Zarontin), valproate Lamotrigine, levetiracetam Idiopathic Lamotrigine, valproate Topiramate, zonisamide Symptom- atic Lamotrigine, topiramate, valproate, zonisamide Barbiturates, benzodiazepines Dosing of Antiepileptic Drugs Drug Intravenous dose Oral dose Barbiturates, Mysoline Phenobarbital: 90 to 120 mg every 10 to 15 min as needed to maxi- mum of 100 mg 1 to 5 mg/kg/day Drug Intravenous dose Oral dose Carbamazepine (Tegretol; Tegretol-XR; Carbatrol) Not applicable Start at 2 to 3mg/kg/day; in- crease dose ev- ery 5 days to 10 mg/kg/day; dose may need to be increased to 15 to 20 mg/kg/day af- ter 2 to 3 months because of hepatic autoinduction Ethosuximide (Zarontin) Not applicable 20 to 40 mg/day in 1 to 3 divided doses Felbamate (Felbatol) Not applicable 12 mg/day in 3 divided doses; increase by 600 to 1200 mg/day every 2 weeks to recommended maximum of 3600 mg/day Gabapentin (Neurontin) Not applicable 300 mg on the first day, 300 mg twice daily on the second day, 300 mg three times daily on the third day; increase as needed to 1800 mg/day in 3 di- vided doses; lower doses rec- ommended in patients with renal insufficiency Lamotrigine (Lamictal) Not applicable For patients tak- ing an enzyme- inducing antiepileptic drug: 25 mg BID, titrated upward by 5 mg incre- ments every 1 to 2 weeks as needed. For patients tak- ing valproate: 25 mg every other day, with in- creases of 25 to 50 mg ev- ery 2 weeks as needed to a maximum of 300 to 500 mg/day. Levetiracetam (Keppra) Not applicable Start at 500 mg twice daily; in- crease as needed by 100 mg/day every two weeks to a maximum total dose of 400 mg per day in two divided doses; lower doses rec- ommended in patients with renal insufficiency Oxcarbazepine (Trileptal) Not applicable Start at 300 to 600 mg/day in two or three di- vided doses; in- crease by 600 mg/day weekly to a total dose of 900 to 3000 mg per day in two or three divided doses D. Choosing an antiepileptic drug. Treatment should be started with a single drug (monotherapy) with gradual increase in dosage as needed to produce optimal seizure control. Combination therapy should be attempted only when at least two adequate sequential trials of single agents have failed. With the exception of felbamate, second-generation AEDs (eg, gabapentin, lamotrigine, topiramate, ti agabi ne, l eveti racetam, oxcarbazepi ne, zonisamide) have potentially significant advantages over older AEDs (eg, phenobarbital, phenytoin, carbamazepine, valproate) with generally lower side effect rates, little or no need for serum monitoring, and fewer drug interactions. Pharmacokinetics of Antiepileptic Drugs Drug Fre- quency of dosing Fre- quency of initial labora- tory mon- itoring Thera- peutic level (μg/mL) Carbamaze pine BID, TID, or QID 3, 6, or 9 weeks 4 to 12 Ethosuximid e QD, BID, or TID 2 to 3 weeks 40 to 100 Felbamate BID or TID Every 2 weeks for other antiepileptic drugs until felbamate dose stabi- lized. Blood count and liver function weekly to monthly Not estab- lished Gabapentin TID None Not estab- lished Lamotrigine BID None Not estab- lished Levetiraceta m BID None Not estab- lished Oxcarbazep ine BID or TID None Not estab- lished Phenobarbi- tal QD or BID 3 to 4 weeks 10 to 40 Phenytoin QD or BID 2 to 3 weeks 10 to 20 Tiagabine BID, TID, QID None Not estab- lished Topiramate BID None Not estab- lished Valproate BID or TID 1 to 2 weeks (ob- tain platelet count if level >100) 50 to 150 Zonisamide QD or BID None Not estab- lished Side Effects of Antiepileptic Drugs Drug Systemic side effects Neurotoxic side effects Carbamazepine Nausea, vomiting, diarrhea, hyponatremia, rash, pruritus Drowsiness, dizzi- ness, blurred or double vision, lethargy, head- ache Ethosuximide Nausea, vomiting Sleep distur- bance, drowsi- ness, hyperactiv- ity Felbamate Nausea, vomiting, anorexia, weight loss Insomnia, dizzi- ness, headache, ataxia Gabapentin None Somnolence, diz- ziness, ataxia Lamotrigine Rash, nausea Dizziness, som- nolence Levetiracetam Infection Fatigue, somno- lence, dizziness, agitation, anxiety Oxcarbazepine Nausea, rash, hyponatremia Sedation, head- ache, dizziness, vertigo, ataxia, diplopia Drug Systemic side effects Neurotoxic side effects Phenytoin Gingival hypertro- phy, body hair increase, rash, lymphadenopathy Confusion, slurred speech, double vision, ataxia, neuropa- thy Primidone, phe- nobarbital Nausea, rash Alteration of sleep cycles, sedation, lethargy, behav- ioral changes, hyperactivity, ataxia, tolerance, dependence Tiagabine None known Dizziness, lack of energy, somno- lence, nausea, nervousness, tremor, difficulty concentrating, abdominal pain Topiramate Weight loss, renal stones, paresthesias Fatigue, nervous- ness, difficulty concentrating, confusion, de- pression, an- orexia, language problems, anxi- ety, mood prob- lems, tremor Valproate Weight gain, nau- sea, vomiting, hair loss, easy bruising Tremor Zonisamide Nausea, anorexia Somnolence, diz- ziness, ataxia, confusion, diffi- culty concentrat- ing Rare side effects of antiepileptic drugs Drug Side effects Carbamazepine Agranulocytosis, Stevens-Johnson syn- drome, aplastic anemia, hepatic failure, dermatitis/rash, serum sickness, pancre- atitis Ethosuximide Agranulocytosis, Stevens-Johnson syn- drome, aplastic anemia, hepatic failure, dermatitis/rash, serum sickness Felbamate Aplastic anemia, liver failure Gabapentin Unknown Lamotrigine Stevens-Johnson syndrome, hypersensi- tivity Levetiracetam Unknown Oxcarbazepine Unknown Phenytoin Agranulocytosis, Stevens-Johnson syn- drome, aplastic anemia, hepatic failure, dermatitis/rash, serum sickness Primidone, phe- nobarbital Agranulocytosis, Stevens-Johnson syn- drome, hepatic failure, dermatitis/rash, serum sickness Tiagabine Unknown Topiramate Acute myopia and glaucoma; oligohidrosis and hyperthermia, which primarily occur in children Valproate Agranulocytosis, Stevens-Johnson syn- drome, aplastic anemia, hepatic failure, dermatitis/rash, serum sickness, pancre- atitis Zonisamide Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, agranulocytosis, nephrolithiasis; in chil- dren, fever and hyperhidrosis E. Oral contraceptive therapy. The expected contraceptive failure rate of 0.7 per 100 woman-years with oral contraceptive therapy is increased to 3.1 per 100 woman-years in patients who are receiving a first- generation antiepileptic drug (AED [carbamazepine, phenobarbital, or phenytoin]). Valproate and benzodiazepines are exceptions. F.Surgical procedures for refractory epilepsy include surgical resection of epileptogenic tissue, surgical removal of the cortex of a grossly diseased hemisphere, multiple subpial transection, callosotomy, and implanta- tion of the vagus nerve stimulator. Patients with poorly controlled epileptic seizures that are interfering with daily activities, education, employment, or family and social activities should be considered for surgical therapy. G. Vagal nerve stimulation. Many patients who fail AED therapy are not candidates for standard epilepsy surgery. Others may undergo resective surgery and still have excessive numbers of seizures. These patients may be candidates for vagal nerve stimulation (VNS). VNS reduces seizure frequency by about 50 percent in 50 percent of patients. References, see page 360. Migraine Headache Migraine affects 15% to 17% of women and 6% of men. Headaches can generally be grouped into three major cate- gories: migraine, tension-type, and organic. I. Clinical evaluation A. Migraine headaches are usually unilateral, and the acute attack typically lasts from 4 to 24 hours. Migraine headaches can occur with an aura or without an aura. The aura may consist of focal neurologic symptoms starting 5 to 30 minutes before onset of an acute headache attack. B. The most common aura symptoms associated with migraine include scotomata (blind spots), teichopsia (fortification spectra, or the sensation of a luminous appearance before the eyes), photopsia (flashing lights), and paresthesias, as well as visual and auditory hallucinations, diplopia, ataxia, vertigo, syncope, and hyperosmia. C. Tension-type headache is characterized by steady, aching pain of mild to moderate intensity, often as a band-like pain around the head. Gastrointestinal and neurologic signs and symptoms usually do not occur. D. Physical examination should assess the fundus of the eye, neck rigidity, and identify infectious processes of the nose and throat. The temporal artery may appear dilated and pulsating. Neurologic symptoms should be evaluated with computed tomographic scanning. Features of Migraine Headache and Headache Caused by Underlying Disease Migraine headache Headache caused by serious underlying disease History • Chronic headache pat- tern similar from attack to attack • Gastrointestinal symp- toms • Aura, especially visual • Prodrome • Onset before puberty or after age 50 (tumor) • "Worst headache ever" (subarachnoid hemorrhage) • Headache occurring after exertion, sex, or bowel movement (subarachnoid hemorrhage) • Headache on rising in the morning (increased intracranial pressure, tumor) • Personality changes, sei- zures, alteration of con- sciousness (tumor) • Pain localized to temporal arteries or sudden loss of vision (giant cell arteritis) • Very localized headache (tumor, subarachnoid hem- orrhage, giant cell arteritis) Physical examination • No signs of toxicity • Normal vital signs • Normal neurologic ex- amination • Signs of toxicity (infection, hemorrhage) • Fever (sinusitis, meningitis, or other infection) • Meningismus (meningitis) • Tenderness of temporal ar- teries (giant cell arteritis) • Focal neurologic deficits (tu- mor, meningitis, hemor- rhage) • Papilledema (tumor) Laboratory tests and neuroimaging Migraine headache Headache caused by serious underlying disease • Normal results • Erythrocyte sedimentation rate >50 mm/hr (giant cell arteritis) • Abnormalities on lumbar puncture (meningitis, hemor- rhage) • Abnormalities on CT or MRI (tumor, hemorrhage, aneu- rysm) II. Pathophysiology of migraine A. Migraine headache is probably generated by a nucleus in the brainstem. The central generator is the contralateral dorsal raphe nucleus of the midbrain. After the dorsal raphe central generator turns on, there is an activation of the trigeminovascular system. This system connects the generator to the meningeal blood vessels, which dilate and become inflamed, a process referred to as neurogenic inflammation. B. Two key serotonin (5-HT) receptors, 5-HT 1B and 5-HT 1D , reverse the migraine processes. The 5-HT 1D receptors are vasoconstrictive and are located in the lumen of the meningeal vessels. III. Treatment of migraine A. 5-HT 1D receptor agonists ("Triptans") 1. Rizatriptan (Maxalt) a. Rizatriptan (Maxalt) is a high-efficacy, quick- onset triptan, like sumatriptan and zolmitriptan. Oral bioavailability is more than 40%. b. Rizatriptan has two doses, 5 and 10 mg, and two forms, traditional tablet and mint-flavored, orally dissolvable tablet or melt. Two-hour head- ache response for the optimal dose (10 mg) is 67-77%. Recurrence rate is 30-47%. c. The melt is not absorbed through the buccal mucosa, but rather dissolves on the tongue, is swallowed, and then is absorbed in the gastroin- testinal tract. Its efficacy is the same as the traditional tablet, with a two-hour headache response of 66-74%. Adverse events for rizatriptan are similar to those seen with sumatriptan and zolmitriptan tablets. d. Propranolol raises the circulating rizatriptan level, so patients on propranolol should be given the 5-mg rizatriptan dose. Others should take the 10-mg dose. The maximum rizatriptan dose is 30 mg per 24 hours, but 15 mg per 24 hours for patients on propranolol. 2. Almotriptan (Axert) a. Almotriptan works as well as sumatriptan; how- ever, it is better tolerated. Almotriptan causes less chest pain than sumatriptan; however, it remains contraindicated in patients with ischemic heart disease or uncontrolled hyper- tension as are all triptans. It comes in 6.25 and 12.5 mg tablets. b. Most patients should take 12.5 mg at the onset of a migraine. Patients with hepatic or renal impairment should start with 6.25 mg. Patients should not take more than 2 doses in 24 hours. 3. Sumatriptan (Imitrex) a. Sumatriptan (Imitrex) is available in three forms: subcutaneous injection, nasal spray, and oral tablet. Injectable sumatriptan comes as a 6 mg dose for use with an autoinjector. Subcutaneous sumatriptan is the most effective triptan. It works extremely quickly with 50% headache response at 30 minutes, a one-hour headache response of 77%, and more than 80% at two hours. Re- currence of migraine within 24 hours after a headache response with injectable sumatriptan is 34-38%. Recurrence with the spray and tablet is 35-40%. b. Nasal spray sumatriptan. 20 mg is the optimal dose, with a two-hour headache response of 64%. Almost 40% have headache response at 30 minutes. The spray comes in a single-use device. When sniffed, it causes a terrible taste in the back of the throat; therefore, patients should spray it once in one nostril and not sniff in. c. The sumatriptan oral tablet has a bioavailability of 14%. The optimal starting dose is 50 mg, with a 61% headache response at two hours. d. Maximum sumatriptan dosages are two 6-mg subcutaneous doses, two 20-mg nasal sprays, or four 50-mg tablets per 24 hours. However, if a patient needs to switch, she can use one injection or one spray plus two tablets in the same day, or one injection plus one spray in 24 hours. e. All triptans can cause subjective "triptan sensa- tions," which include heat feelings and flushing, numbness, paresthesias, tiredness and tighten- ing, and heaviness of neck, jaw, and chest. Triptans can narrow coronary arteries. These drugs are contraindicated in coronary artery disease, vascular disease, uncontrolled hyper- tension, basilar or hemiplegic migraine or within 24 hours of another triptan or ergot. f. Sumatriptan is the most used triptan. The injec- tion has the fastest onset for a triptan, and the highest overall efficacy. 4. Zolmitriptan (Zomig) a. Zolmitriptan has an oral bioavailability of 40%. Zolmitriptan is contraindicated with MAO-A inhibitors. The optimal dose is 2.5 mg. The maximum dose is 10 mg per 24 hours. Two-hour headache response is 62-65%. Recurrence rate averages about 30%. Adverse events are triptan sensations, similar to sumatriptan tablets. b. Zolmitriptan is superior to oral sumatriptan (50 mg) for headache response at two hours, 67.1% vs. 63.8%, respectively. Zolmitriptan has a longer duration of action than sumatriptan. 5. Naratriptan (Amerge) has good oral bioavailability (63-74%) and a longer T 1/2 (6 hours) than sumatriptan. It works more slowly, and in a lower percentage of patients, than the other three triptans. Two-hour headache response for the optimal dose of 2.5 mg is 48%. The maximum dose is 5 mg per 24 hours. Naratriptan should not be used in patients with rapid onset migraine or who wake up with migraine. Naratriptan should only be selected for those patients who are sensi- tive to side effects. 6. Frovatriptan (Frova) has the longest half-life (26 hours compared to 6 hours or less for the others). It has a slow onset and is less effective than the other triptans. Frova comes in 2.5 mg tablets. Patients start with one tablet and can repeat after 2 hours if the headache recurs; maximum 3 tabs in 24 hours. 7. Eletriptan (Relpax) appears to be at least as effective as oral sumatriptan for acute treatment of migraine. Eletriptan interacts with CYP3A4 inhibi- tors, including verapamil, which is used for mi- graine prophylaxis. Initial dosage is 20 or 40 mg, which can be repeated after 2 hours if headache improves and then recurs. The maximum dosage is 80 mg in 24 hours. 8. Triptan selection a. Patients with migraine should receive a triptan as the first-line medication. If they have signifi- cant nausea, an oral drug is not recommended. Rather, a parenteral or nasal spray sumatriptan should be used. b. Most patients should initially be treated with rizatriptan (Maxalt) or almotriptan (Axert). Other agents may be used if the patient requires a faster onset, longer duration, or fewer side effects. c. Sumatriptan provides the greatest versatility in multiple forms to allow a patient various modes of treatment. The 6-mg subcutaneous injection offers the greatest speed and the highest effi- cacy of any triptan. d. Rizatriptan (Maxalt) tends to be faster and more effective than oral sumatriptan with a similar incidence of adverse effects. e. Almotriptan (Axert) seems to work about as well as sumatriptan, but it’s better tolerated. f. Zolmitriptan (Zomig) has similar efficacy and tolerability compared to sumatriptan. g. Naratriptan (Amerge) has a slower onset and is less effective, but this agent is better toler- ated. h. Frovatriptan (Frova) has the longest half-life (26 hours compared to 6 hours or less for the others). It has a slow onset and is less effective than the other triptans. Drugs for Treatment of Migraine and Tension Headache Drug Dosage 5-HT 1 Receptor Agonists ("Triptans") Rizatriptan (Maxalt) 5- or 10-mg tablet or wafer (MLT); can be repeated in 2 hours; max 30 mg/day, 15 mg/day in patients on propranolol Drug Dosage Almotriptan (Axert) 12.5 mg at the onset of a migraine. Patients with hepatic or renal im- pairment should start with 6.25 mg. Max 2 doses per day. Sumatriptan (Imitrex) 6 mg SC; can be repeated in 1 hour; max 2 injections/day 50 mg PO; can be repeated in 2 hours; max 100 mg 20 mg intranasally; can be repeated after 2 hours; max 40 mg/day Max in combination: two injections or sprays; or one of either plus two tablets Naratriptan (Amerge) 2.5-mg tablet, can be repeated 4 hours later; max 5 mg/day Zolmitriptan (Zomig, Zomig-ZMT, Zomig nasal spray) 2.5-5 mg PO; can be repeated in 2 hours. Tablets and orally disinte- grating tablets, 2.5, 5 mg. Intranasally 5 mg; can be repeated after 2 hours; max 10 mg/day Frovatriptan (Frova) 2.5 mg PO, repeat after 2 hours if the headache recurs; max 3 tabs in 24 hours. Longest half-life, slow onset, less effective Eletriptan (Relpax) 20 or 40 mg, repeated after 2 hours if headache recurs; max 80 mg in 24 hours. NSAIDs Ibuprofen (Motrin) 400-800 mg, repeat as needed in 4 hr Naproxen sodium (Anaprox DS) 550-825 mg, repeat as needed in 4 hr Ergot Alkaloids Dihydroergotamine DHE 45 Migranal Nasal Spray 1 mg IM; can be repeated twice at 1-hour intervals (max 3 mg/attack) 1 spray (0.5 mg)/nostril, repeated 15 minutes later (2 mg/dose; max 3 mg/24 hours) Ergotamine 1 mg/caffeine 100 mg (Ercaf, Gotamine, Wigraine) 2 tablets PO, then 1 q30min, x 4 PRN (max 6 tabs/attack) Butalbital combinations Aspirin 325 mg, caf- feine 40 mg, butalbital 50 mg (Fiorinal) 2 tablets, followed by 1 tablet q4-6h as needed Isometheptene combination Isometheptene 65 mg, acetaminophen 325 mg, dichloral- phenazone 100 mg (Midrin) 2 tablets, followed by 1 tablet as needed q4-6h prn Opioid Analgesics Butorphanol (Stadol NS) One spray in one nostril; can be repeated in the other nostril in 60-90 minutes; the same two-dose se- quence can be repeated in 3 to 5 hours B. Prophylaxis against migraine 1. Patients with frequent or severe migraine head- aches or those refractory to symptomatic treatment may benefit from prophylaxis. Menstrual or other predictable migraine attacks may sometimes be prevented by a brief course of an NSAID, taken for several days before and during menstruation. 2. Beta-adrenergic blocking agents are used most commonly for continuous prophylaxis. Propranolol, timolol, metoprolol (Lopressor), nadolol (Corgard) and atenolol (Tenormin) have been effective. 3. Tricyclic antidepressants can prevent migraine and may be given with other prophylactic agents. Amitriptyline (Elavil) in a dosage ranging from 10 to 50 mg qhs is commonly used. 4. Valproate (Depakote), an anticonvulsant, has been effective in decreasing migraine frequency. Its effectiveness is equal to that of propranolol. Adverse effects include nausea, weight gain and fatigue. Drugs for Prevention of Migraine Drug Dosage Propranolol (Inderal) 80 to 240 mg/day, divided bid, tid or qid Timolol (Blocadren) 10 to 15 mg bid Divalproex (Depakote) 250 mg bid Amitriptyline (Elavil) 25-50 mg qhs References, see page 360. Vertigo The clinical evaluation of vertigo begins with the patient's description of symptoms and the circumstances in which they occur. Many drugs can cause dizziness. Common nonvestibular causes (eg, hyperventilation, orthostatic hypotension, panic disorder) are often diagnosed. I. History and physical examination A. Patients may use the term "dizziness" to describe one or more different sensations. These sensations include vertigo (spinning), light-headedness, unsteadiness and motion intolerance. The onset of symptoms, whether the sensation is constant or episodic, how often episodes occur and the duration of episodes should be assessed. Activities or movements that provoke or worsen a patient's dizziness should be sought as well as activities that minimize symptoms. Rotational vertigo when rolling over in bed is highly suggestive of BPPV. B. Vertigo is a sensation of movement of the self or of one's surroundings. Patients may describe vertigo as a sensation of floating, giddiness or disorientation. The duration of vertiginous symptoms and whether head movement provokes symptoms (positional vertigo) or if attacks occur without provocation (spontaneous vertigo) should be assessed. C. Hearing loss, tinnitus and aural fullness should be sought. Vision, strength and sensation, coordination, speech and swallowing should be evaluated. Double vision or hemiplegia strongly suggest a central nervous system lesion rather than a peripheral vestibular disorder. History for cardiac disease, migraine, cerebrovascular disease, thyroid disease and diabetes should be sought. Drugs Associated with Dizziness Class of drug Type of dizziness Mechanism Alcohol Positional vertigo Specific-gravity difference in endolymph vs cupula Intoxication CNS depression Disequilibrium Cerebellar dysfunc- tion Tranquilizers Intoxication CNS depression Anticonvulsants Intoxication Disequilibrium CNS depression Cerebellar dysfunc- tion Antihypertensives Near faint Postural hypotension Aminoglycosides Vertigo Disequilibrium Oscillopsia Asymmetric hair-cell loss Vestibulospinal reflex loss Vestibulo-ocular reflex loss D. Physical examination should evaluate orthostatic blood pressure changes followed by a complete head and neck examination as well as otologic and neuro- logic examinations. A pneumatic otoscope should be used to confirm normal tympanic membrane mobility. Balance, gait, cerebellar and cranial nerve function, and nystagmus should be evaluated. E. Nystagmus consists of involuntary eye movements caused by asymmetry of signals from the right and left vestibular systems. Nystagmus of peripheral vestibular origin is usually horizontal with a slight or dramatic rotary component. Nystagmus of central origin is usually predominantly vertical. F. The Dix-Hallpike test is particularly helpful to elicit nystagmus associated with BPPV. This maneuver stimulates the posterior semicircular canal, which is the semicircular canal most commonly involved in BPPV. G. An audiogram should be performed if a specific cause of dizziness cannot be found after a thorough history and physical examination. Additional testing may include electronystagmography, auditory evoked brainstem response testing, radiologic imaging of the brain, brainstem and temporal bone and selected blood tests. Auditory evoked brainstem response testing measures the integrity of the auditory system and is useful to screen for acoustic tumors. Magnetic reso- nance imaging (MRI) should be reserved for patients with unilateral otologic symptoms or neurologic symp- toms or those in whom dizziness persists despite appropriate treatment. II. Benign paroxysmal positional vertigo A. The most common cause of peripheral vestibular vertigo is BPPV. This condition is characterized by sudden, brief and sometimes violent vertigo after a change in head position. The sensation of vertigo usually lasts for only a few seconds. This form of vertigo is often noticed when a patient lies down, arises or turns over in bed. BPPV does not cause hearing loss, ear fullness or tinnitus. BPPV can occur at any age but is most commonly seen in elderly persons. Although usually unilateral, bilateral BPPV occurs in up to 15 percent of patients. Nystagmus is characteristic of BPPV. B. BPPV is caused by displacement of otoconia from the utricle or saccule into the posterior semicircular canal. Therefore, when a patient moves the head into a provocative position, the otoconia provoke movement of the endolymphatic fluid inside the semicircular canal, creating a sensation of vertigo. C. Treatment of BPPV. In-office physical therapy, known as repositioning maneuvers, redirects displaced otoconia into the utricle. This form of treatment is effective in 85 to 90 percent of patients. Another type of exercise that is performed at home also attempts to redirect displaced otoconia and is effective in 60 to 70 percent of patients. D. During these exercises, the patient initially sits upright on the edge of a bed or couch. Then the patient rapidly lies down on his side with the affected ear down. Vertigo usually occurs. After the vertigo subsides (or after one minute if no vertigo occurs), the patient rapidly turns in a smooth arc to the opposite side. After vertigo associated with this movement subsides (or after one minute if no vertigo occurs), the patient slowly sits upright. The entire maneuver is repeated five times twice per day until the patient no longer experiences vertigo for two successive days. Surgical treatment is reserved for the 2 to 5 percent of cases that fail to respond to nonsurgical treatment. III. Vestibular neuronitis A. Vestibular neuronitis is characterized by acute onset of intense vertigo associated with nausea and vomiting that is unaccompanied by any neurologic or audiologic symptoms. The symptoms usually reach their peak within 24 hours and then gradually subside. During the first 24 to 48 hours of a vertiginous episode, severe truncal unsteadiness and imbalance are present. B. Vestibular neuronitis is presumed to have a viral etiology because it is often associated with a recent history of a flu-like illness. Management of the initial stage of vestibular neuronitis includes bed rest and the use of antiemetics (eg, promethazine [Phenergan]) and vestibular suppressants (eg, diazepam [Valium]). After the patient is able to stand, the brain begins compen- sating for the acute loss of unilateral vestibular func- tion. The compensation process may be enhanced by performance of vestibular exercises twice per day for eight to 10 weeks. IV. Ménière's disease A. Ménière's disease is characterized by fluctuating hearing loss, tinnitus, episodic vertigo and, occasion- ally, a sensation of fullness or pressure in the ear. Vertigo rapidly follows and is typically severe, with episodes occurring abruptly and without warning. The duration of vertigo is usually several minutes to hours. Unsteadiness and dizziness may persist for days after the episode of vertigo. B. Diseases with similar symptoms include syphilis, acoustic neuroma and migraine. Isolated episodes of hearing loss or vertigo may precede the characteristic combination of symptoms by months or years. C. Ménière's disease results from excessive accumulation of endolymphatic fluid (endolymphatic hydrops). As inner-ear fluid pressure increases, symptoms of Ménière's disease develop. D. Diuretics (eg, triamterene-hydrochlorothiazide [Dyazide, Maxzide]) and a low-salt diet are the main- stays of treatment. This combined regimen reduces endolymphatic fluid pressure. Other preventive mea- sures include use of vasodilators and avoidance of caffeine and nicotine. Acute vertiginous episodes may be treated with oral or intravenous diazepam. Promethazine or glycopyrrolate (Robinul) is effective in the treatment of nausea. E. Surgical treatments are an option when appropriate prophylactic measures fail to prevent recurrent epi- sodes of vertigo. Surgical procedures used in the treatment of Ménière's disease range from draining excess endolymphatic fluid from the inner ear (endolymphatic shunt) to severing the vestibular nerve (with hearing preservation). In selected cases, a chemical labyrinthectomy may be performed. Chemical labyrinthectomy involves the injection of a vestibulotoxic gentamicin (Garamycin) solution into the middle ear. Antivertiginous and Antiemetic Drugs Classes and agents Dosage Comments Antihistamines Dimenhydrinat e (Benadryl) 50 mg PO q4-6h or 100-mg supp. q8h Available without pre- scription, mild sedation, minimal side effects Meclizine (Antivert) 25-50 mg PO q4-6h Mild sedation, minimal side effects Promethazine (Phenergan) 25-50 mg PO, IM, or supposi- tory q4-6h Good for nausea, vertigo, more sedation, extrapyramidal effects Monoaminergic agents Amphetamine 5 or 10 mg PO q4-6h Stimulant, can counteract sedation of antihista- mines, anxiety Ephedrine 25 mg PO q4-6h Available without pre- scription Benzodiazepine Diazepam (Valium) 5 or 10 mg PO q6-8h Sedation, little effect on nausea Phenothiazine Prochlorperazi ne (Compazine) 5-25 mg PO, IM, or supposi- tory q4-6h Good antiemetic; extrapyramidal side ef- fects, particularly in young patients References, see page 360. Chronic Fatigue Syndrome Chronic fatigue syndrome is characterized by clinically evaluated, unexplained, persistent or relapsing fatigue plus four or more specifically defined associated symptoms. Many people can have unexplained chronic fatigue and not fit the case criteria for CFS. Such individuals are defined as having idiopathic chronic fatigue. Twenty-four percent of patients complain of fatigue for more than one month. CFS is primar- ily a disorder of young to middle aged adults, but cases in children have been recognized. I. Clinical presentation A. Relatively sudden onset of fatigue is common, often associated with a typical infection, such as an upper respiratory infection or mononucleosis. After resolution of the initial infection, the patient is left with overwhelm- ing fatigue and a number of additional symptoms, especially altered sleep and cognition. Excessive physical activity exacerbates the symptoms. There is often, however, a history of psychiatric disorders in the past. B. Physical examination is usually normal. 1. Patients commonly feel febrile; however, few ever demonstrate elevated temperatures (greater than 37.4ºC). 2. Joints ache, but there is no erythema, effusion, or limitation of motion. 3. Although the muscles are easily fatigued, strength is normal, as are biopsies and electromyograms. 4. Mild lymphadenitis is occasionally noted, and painful lymph nodes (lymphadynia) is a frequent complaint, but not true lymphadenopathy. 5. Many patients with chronic fatigue syndrome are partially or totally disabled by the fatigue. Symptoms in Patients with Chronic Fatigue Syn- drome Symptom Percent of patients Easy fatigability Difficulty concentrating Headache Sore throat Tender lymph nodes Muscle aches Joint aches Feverishness Difficulty sleeping Psychiatric problems Allergies Abdominal cramps Weight loss Rash Rapid pulse Weight gain Chest pain Night sweats 100 90 90 85 80 80 75 75 70 65 55 40 20 10 10 5 5 5 Diagnostic criteria for the chronic fatigue syn- drome Major criteria New onset of fatigue lasting six months, severe enough to reduce daily activity to less than 50 percent of the patient’s premorbid activity level The exclusion of other conditions that can produce fatigue Minor criteria Symptom criteria Low-grade fever: temperature 37.5 to 38.6EC orally or chills Sore throat Painful cervical or axillary lymph nodes Generalized muscle weakness Muscle pain Postexertional fatigue lasting more than 24 hours Generalized headaches Migratory arthralgia Neuropsychological complaints (photophobia, tran- sient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, or depression) Sleep disturbance Acute onset of symptoms over a few hours to a few days Physical criteria. Determined by the physician on two occasions at least two months apart Low-grade fever Nonexudative pharyngitis Palpable cervical or axillary lymph nodes up to 2 cm in diameter Common causes of fatigue Diagnosis Frequency in primary care Fatigued pa- tients (%) Depression Very common 18 Environment (life- style) Very common 17 Anxiety, anemia, asthma Very common 14 Diabetes Very common 11 Infections Common 10 Thyroid, tumors Common 7 Rheumatologic Common 5 Endocarditis, car- diovascular Common 8 Drugs Common 5 II.Diagnosis. The diagnosis of CFS is made by exclusion. Patients with CFS must have clinically evaluated, unex- plained, persistent or relapsing fatigue plus four or more associated symptoms. Under 10 percent of patients with chronic fatigue have CFS. A. Recommended testing in the patients suspected of CFS including complete blood count with differential, erythro- cyte sedimentation rate, standard chemistries including plasma calcium concentration, thyroid function tests, antinuclear antibody titer, urinalysis, tuberculin skin test, and screening questionnaires for psychiatric disorders. Other tests may include plasma cortisol, rheumatoid factor, immunoglobulin levels, Lyme serology in en- demic areas, and tests for HIV antibody. B. Serologies for EBV, CMV, or Lyme disease or antinuclear antibodies are recommended only in spe- cific cases. C. The diagnosis of CFS is generally made if the patient has a typical history and no abnormality can be de- tected on physical examination or in the screening tests. Laboratory evaluation of chronic fatigue For all patients Complete blood cell count with differential Erythrocyte sedimentation rate Urinalysis Other tests based on findings Thyroid stimulating hormone Blood Chemistry levels: Alanine aminotransferase Aspartate aminotransferase Blood urea nitrogen Electrolytes Glucose Heterophil antibody test (Monospot) Serologic studies for Lyme or HIV antibody titers III. Management of the fatigued patient A. Regular exercise will improve functional capacity, mood, and sleep. Regular sleep habits should be advised. In those complaining of depressive symp- toms or sleep disturbance, an antidepressant or sleep hypnotic is indicated. A sedating antidepressant, such as amitriptyline (Elavil) 25 mg qhs, may be helpful for complaints of insomnia or restlessness. If the primary complaints are hypersomnia and psychomotor retar- dation, a selective serotonin reuptake inhibitor is indicated. B. For physical symptoms such as headaches, myalgias, or arthralgias, nonsteroidal anti-inflammatory agents may be helpful. Therapies for which no effectiveness has been demonstrated in CFS include vitamins, acycl ovi r, gamma gl obul i n, f ol i c aci d, cyanocobalamin, and magnesium. C. Antidepressants 1. Selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice. Fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (LuVox) are effective in reducing fatigue, myalgia, sleep disturbance, and depres- sion. 2. For the patient who has significant difficulty with insomnia or with pain, paroxetine at bedtime is recommended because it is mildly sedating. Fluoxetine is useful in patients who complain of lack of energy because it has activating properties. Fluoxetine often improves cognitive functioning, especially concentrating ability. 3. Initial dosage should be low because many CFS patients are sensitive to side effects. a. Fluoxetine (Prozac) 20 mg PO qAM; 20-40 mg/d [20 mg]. b. Paroxetine (Paxil) 10 mg qAM; increase as needed to max of 40 mg/d. [10, 20, 30, 40 mg]. c. Fluvoxamine (LuVox) 50-100 mg qhs; max 300 mg/d [50, 100 mg] d. Sertraline (Zoloft) 50-100 mg PO qAM [50, 100 mg]. IV. Prognosis. CFS is a chronic illness, but 40-60% of patients improve within1-3 years after diagnosis. The mean duration of illness prior to diagnosis is 52.6 months. References, see page 360. Dermatologic and Allergic Disorders Herpes Simplex Virus Infections Herpes simplex virus (HSV) affects more than one-third of the world's population. Ninety percent of infections caused by HSV-2 are genital, and 90 percent of those caused by HSV-1 are oral. I. Diagnosis A. The diagnosis of genital HSV infection may be made clinically, but laboratory confirmation is recommended in patients presenting with primary or suspected recurrent infection. The gold standard of diagnosis is viral isolation by tissue culture, although this process can take as long as four to five days, and the sensitivity rate is 70 to 80 percent. B. Antigen detection tests have lower sensitivity rates (50 to 70 percent) than viral culture. II. Genital Herpes A. Genital HSV infection is usually transmitted through sexual contact. About 22 percent of adults have serologic evidence of HSV-2 infection. B. Clinical Presentation 1. Primary genital herpes has an incubation period of two to 12 days, followed by a prodrome of itching, burning or erythema. Multiple transient, painful vesicles then appear on the penis, perineum, vulva, vagina or cervix, and tender inguinal lymphadenopathy may follow. The initial ulceration crusts and heals by 14 to 21 days. Fever, head- ache, malaise, abdominal pain and myalgia are common in primary disease. Recurrences are usually less severe and shorter in duration. 2. Women with established genital HSV-2 infection have asymptomatic shedding 1 to 5 percent of days. C. Treatment of Primary Infection 1. Antiviral therapy is recommended for the initial genital herpes outbreak. Oral acyclovir is effective in reducing symptoms. Topical acyclovir reduces the length of time before all lesions become crusted but is much less effective than oral acyclovir. 2. The oral acyclovir dosage for treatment of primary or initial nonprimary genital herpes is 200 mg five times daily for 10 days. 3. Valacyclovir, given twice daily, is effective for the treatment of primary genital herpes but costs more than acyclovir. Famciclovir, given three times daily, is as effective as acyclovir, although it may be twice as expensive. Dosage Regimens for Primary Genital Herpes In- fection Drug Dosage Acyclovir (Zovirax) 200-400 mg three times daily for 10 days Famciclovir (Famvir) 250 mg three times daily for 10 days Valacyclovir (Valtrex) 1 g twice daily for 10 days D. Treatment of Recurrent Infection 1. Drug therapy to prevent recurrences is effective; it is prescribed for use in patients who have more than six outbreaks per year. 2. Acyclovir has been used to suppress recurrences of genital herpes, decreasing the frequency by 80 percent and preventing recurrence by 45 percent. 3. Famciclovir and valacyclovir are as effective as acyclovir in suppressing recurrent genital herpes. Valacyclovir has the advantage of once-daily dos- ing. Famciclovir must be given twice daily. Dosages and Characteristics of Chronic Suppres- sive Treatment Regimens for Recurrent Genital Herpes Infection Drug Dosage Decrease in recurrence rate (per- centage) Use in pa- tients with >6 recur- rences per year Acyclovir (Zovirax) 400 mg twice daily 78 to 79 Yes Drug Dosage Decrease in recurrence rate (per- centage) Use in pa- tients with >6 recur- rences per year Famciclovir (Famvir) 250 mg twice daily 79 Yes Valacyclovir (Valtrex) 1 g once daily 78 to 79 Yes 250 mg twice daily 78 to 79 Yes 500 mg once daily 71 No 250 mg once daily 54 No E. Episodic Therapy. Acyclovir, taken hours after the prodrome of recurrence begins, exerts a benefit in recurrent genital herpes. Famciclovir and valacyclovir are slightly more effective than acyclovir for the treat- ment of recurrent infections. Dosages of Antiviral Agents for Treatment of Epi- sodic Genital Herpes Drug Dosage Acyclovir (Zovirax) 200 mg 5 times daily for 5 days 800 mg twice daily for 5 days Famciclovir (Famvir) 125 mg twice daily for 5 days Valacyclovir (Valtrex) 500 mg twice daily for 5 days III.Orolabial Herpes A. Orolabial herpes (gingivostomatitis) is the most prevalent form of herpes infection; 35 to 60 percent of persons show serologic evidence of having been infected by HSV-1. B. Primary herpetic gingivostomatitis usually affects children under the age of five. It appears as painful vesicles and ulcerative erosions on the tongue, palate, gingiva, buccal mucosa and lips. C. Systemic symptoms are often present, including fever (38.4 to 40°C), malaise and myalgia. The duration of the illness is two to three weeks, and oral shedding of virus may continue for a 23 days. D. Recurrences typically occur two or three times a year. The duration is shorter and the discomfort less severe than in primary infections, and the vesicles heal completely by eight to 10 days. E. Treatment of Primary Infection 1. Topical medication for HSV infection is not highly effective. Topical penciclovir, applied every two hours for four days, reduces healing time by only about one day. 2. Oral acyclovir, in a dosage of 200 mg five times daily for five days, accelerates loss of crusts by one day (seven versus eight days) and can reduce the duration of pain by 36 percent F. Treatment of Recurrent Infection 1. Oral acyclovir, in dosages ranging from 400 to 1,000 mg daily, is effective in reducing by 50 to 78 percent the frequency of herpes labialis following UV light exposure. Oral acyclovir may lessen the severity of lesions. Short-term prophylactic therapy with acyclovir may be desirable in some patients who anticipate intense exposure to UV light (eg, skiers). 2. Early treatment of recurrent orolabial HSV infection with high dosages of antiviral medication markedly decreases the size and duration of lesions. Famciclovir, in a dosage of 250 mg three times daily for five days decreases lesion surface area by 50 percent and accelerates healing time. References, see page 360. Herpes Zoster and Postherpetic Neu- ralgia Herpes zoster (shingles) results from reactivation of the varicella-zoster virus. Herpes zoster has a lifetime incidence of 10 to 20 percent. The incidence of herpes zoster in- creases sharply with advancing age, doubling in each decade past the age of 50 years. I. Clinical evaluation A. Herpes zoster typically presents with a prodrome consisting of hyperesthesia, paresthesias, burning dysesthesias or pruritus along the affected dermatome(s). The prodrome generally lasts one to two days. B. The prodromal phase is followed by development of a maculopapular rash that follows a dermatomal distribu- tion. The maculopapular rash evolves into vesicles with an erythematous base. The vesicles are painful, and their development is often associated with flu-like symptoms. C. Although any vertebral dermatome may be involved, T5 and T6 are most commonly affected. The most fre- quently involved cranial nerve dermatome is the ophthalmic division of the trigeminal nerve. D. The most common chronic complication of herpes zoster is postherpetic neuralgia. Pain that persists for longer than one to three months after resolution of the rash is a sign of postherpetic neuralgia. Affected patients usually report constant burning, lancinating pain. Symptoms tend to abate over time. Less than one-quarter of patients still experience pain at six months after the herpes zoster eruption, and fewer than one in 20 has pain at one year. II. Treatment of herpes zoster A. Antiviral agents 1. Antiviral agents have been shown to decrease the duration of herpes zoster rash and the severity of pain in patients who receive antiviral agents within 72 hours after the onset of rash. 2. Acyclovir (Zovirax), valacyclovir (Valtrex) and famciclovir (Famvir) therapy appear to produce a moderate reduction in the development of postherpetic neuralgia. Major drawbacks of orally administered acyclovir include its lower bioavailability compared with other agents and its dosing frequency (five times daily). 3. Valacyclovir (Valtrex) is administered three times daily. Compared with acyclovir, valacyclovir may be slightly better at decreasing the severity of pain and the duration of postherpetic neuralgia. 4. Famciclovir (Famvir). The advantages of famciclovir are its dosing schedule (three times daily), its longer intracellular half-life compared with acyclovir and its better bioavailability compared with acyclovir and valacyclovir. Treatment Options for Herpes Zoster Medication Dosage Acyclovir (Zovirax) 800 mg orally five times daily for 7 to 10 days 10 mg per kg IV every 8 hours for 7 to 10 days Famciclovir (Famvir) 500 mg orally three times daily for 7 days Valacyclovir (Valtrex) 1,000 mg orally three times daily for 7 days Prednisone (Deltasone) 30 mg orally twice daily on days 1 through 7; then 15 mg twice daily on days 8 through 14; then 7.5 mg twice daily on days 15 through 21 2 (2 to 4) for days 1 through 7 2 (1 to 3) for days 8 through 14 1 (1 to 2) for days 15 to 21 B. Corticosteroids. Prednisone used in conjunction with acyclovir has been shown to reduce the pain associ- ated with herpes zoster. Prednisone may decrease the incidence of postherpetic neuralgia. It should be used only in patients more than 50 years of age because they are at greater risk of developing postherpetic neuralgia. C. Analgesics. Mild to moderate pain may respond to over-the-counter analgesics. More severe pain may require a narcotic. Lotions containing calamine (eg, Caladryl) may be used on open lesions to reduce pain and pruritus. Once the lesions have crusted over, capsaicin cream (Zostrix) may be applied. Topical lidocaine (Xylocaine) and nerve blocks have also been reported to be effective in reducing pain. D. Ocular involvement. Ocular herpes zoster is treated with oral antiviral agents and corticosteroids. Ophthalmologic consultation is recommended. III. Treatment of postherpetic neuralgia A. Although postherpetic neuralgia is generally a self-limited condition, it can last indefinitely. Treatment Options for Postherpetic Neuralgia Medication Dosage Topical agents Capsaicin cream (Zostrix) Apply to affected area three to five times daily. Lidocaine (Xylocaine) patch Apply to affected area every 4 to 12 hours as needed. Tricyclic antidepressants Amitriptyline (Elavil) 0 to 25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks until response is adequate, or to maximum dosage of 150 mg per day. Nortriptyline (Pamelor) 0 to 25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks until response is adequate, or to maximum dosage of 125 mg per day. Imipramine (Tofranil) 25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks until re- sponse is adequate, or to maximum dos- age of 150 mg per day. Desipramine (Norpramin) 25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks until re- sponse is adequate, or to maximum dos- age of 150 mg per day. Anticonvulsants Phenytoin (Dilan- tin) 100 to 300 mg orally at bedtime; increase dosage until response is adequate or blood drug level is 10 to 20 μg per mL (40 to 80 μmol per L). Carbamazepine (Tegretol) 100 mg orally at bedtime; increase dos- age by 100 mg every 3 days until dosage is 200 mg three times daily, response is adequate or blood drug level is 6 to12 μg per mL (25.4 to 50.8 μmol per L). Gabapentin (Neurontin) 100 to 300 mg orally at bedtime; increase dosage by 100 to 300 mg every 3 days until dosage is 300 to 900 mg three times daily or response is adequate. B. Analgesics 1. Capsaicin is more efficacious than placebo but must be applied to the affected area three to five times daily. Pain will likely increase during the first few days to a week after capsaicin therapy is initiated. 2. Lidocaine patches reduce pain intensity, with mini- mal systemic absorption. The effect lasts only four to 12 hours with each application. 3. Acetaminophen and nonsteroidal anti-inflammatory drugs are useful for potentiating the pain-relieving effects of narcotics. C. Tricyclic Antidepressants 1. Tricyclic antidepressants can be effective adjuncts in reducing pain. Tricyclic antidepressants com- monly used in the treatment of postherpetic neural- gia include amitriptyline (Elavil), nortriptyline (Pamelor), imipramine (Tofranil) and desipramine (Norpramin). 2. The tricyclic antidepressants may cause sedation, dry mouth, postural hypotension, blurred vision and urinary retention. Nortriptyline is better tolerated. D. Gabapentin is effective in treating the pain of postherpetic neuralgia. The dosages required for analgesia are often lower than those used in the treatment of epilepsy. E. Transcutaneous electric nerve stimulation (TENS), biofeedback and nerve blocks are also sometimes used. References, see page 360. Atopic Dermatitis and Eczema Atopic dermatitis is a chronic inflammation of the skin that occurs in persons of all ages but is more common in chil- dren. Atopic dermatitis affects 10 percent of children. The symptoms of atopic dermatitis resolve by adolescence in 50 percent of affected children. I. Diagnosis A. Exposure to aeroallergens, irritating chemicals, foods and emotional stress may worsen the rash. B. Acute lesions are papules and vesicles on a back- ground of erythema. Subacute lesions may develop scales and lichenification. Chronically involved areas become thick and fibrotic. Lesions can develop sec- ondary infections with crusting and weeping. Xerosis (dry skin) is characteristic. Diagnostic Features of Atopic Dermatitis Major features Pruritus Chronic or relapsing dermatitis Personal or family history of atopic disease Typical distribution and morphology of atopic dermatitis rash: Facial and extensor surfaces in infants and young children Flexure lichenification in older children and adults Minor features Eyes Cataracts (anterior subcapsular) Keratoconus Infraorbital folds affected Facial pallor Palmar hyperlinearity Xerosis Pityriasis alba White dermatographism Ichthyosis Keratosis pilaris Nonspecific dermatitis of the hands and feet Nipple eczema Positive type I hypersensitivity skin tests Propensity for cutaneous in- fections Elevated serum IgE level Food intolerance Impaired cell-mediated immu- nity Erythroderma Early age of onset C. In infants and young children, pruritus commonly is present on the scalp, face (cheeks and chin) and extensor surfaces of the extremities. Older children and adults typically have involvement of the flexor surfaces (antecubital and popliteal fossa), neck, wrists and ankles. D. Exposure to pollens, molds, mites and animal dander may be important in some patients. II.Treatment A. Bathing and moisturizers. Bathing should occur once daily with warm water for five to 10 minutes. Soap should not be used unless it is needed for the removal of dirt. A mild cleanser (eg, Dove, Basis, Kiss My Face or Cetaphil) may be used. After bathing, patients should apply a moisturizer liberally (eg, Vaseline, Aquaphor, Eucerin, Moisturel, mineral oil or baby oil). Ointments are superior to creams. Lotions are least effective because of their alcohol content. To avoid injury to the skin from scratching, fingernails should be cut short, and cotton gloves can be worn at night. B. Pruritus that is refractory to moisturizers and conserva- tive measures can be treated with sedating agents such as hydroxyzine (Atarax) and diphenhydramine (Benadryl). Tricyclic antidepressants such as doxepin (Sinequan) and amitriptyline (Elavil) also induce sleep and reduce pruritus. C. Systemic corticosteroids should be reserved for use in patients with severe treatment-resistant atopic dermati- tis. D. It is reasonable to use a mild topical steroid initially in infants and for intertriginous areas in patients of any age. If the dermatitis is severe, a more potent steroid is needed. Commonly Used Topical Corticosteroids Preparation Size Low-Potency Agents Hydrocortisone ointment, cream, 1, 2.5% (Hytone) 30 g Mild-Potency Agents Alclometasone dipropionate cream, ointment, 0.05% (Aclovate) 60 g Triamcinolone acetonide cream, 0.1% (Aristocort) 60 g Fluocinolone acetonide cream, 0.01% (Synalar) 60 g Medium-Potency Agents Triamcinolone acetonide ointment (Aristocort A), 0.1% 60 g Betamethasone dipropionate cream (Diprosone), 0.05% 45 g Mometasone cream 0.1% (Elocon) 45 g Fluocinolone acetonide ointment, 0.025% (Synalar) 60 g Betamethasone valerate cream, 0.1% (Valisone) 45 g Hydrocortisone valerate cream, ointment, 0.2% (Westcort) 60 g E. Immunosuppressants and antineoplastics 1. Pimecrolimus (Elidel) is a non-steroid cream for the treatment of mild to moderate eczema. Pimecrolimus has anti-inflammatory activity. It does not cause skin atrophy. Topical application is comparable to that of a potent topical steroid. 1% pimecrolimus cream is applied twice daily. It may be used in children >2 years old. The FDA has issued warnings about a possible link between the topical calcineurin inhibitors and cancer. 2. Tacrolimus (Protopic) is more potent than pimecrolimus in the treatment of severe or refrac- tory atopic dermatitis, with few adverse effects. Tacrolimus is available in 0.1% and 0.03%. The lower strength may be used in children >2 years old. The FDA has issued warnings about a possible link between the topical calcineurin inhibitors and cancer. 3. Cyclosporine (Sandimmune) has been effective in patients with refractory atopic dermatitis. The condition returns after the cessation of therapy, although not always at the original level of severity. References, see page 360. Acne Vulgaris Acne vulgaris is a polymorphous skin disorder of the seba- ceous follicles that begins around the time of puberty and peaks during the teenage years. Prevalence exceeds 85% in teenagers and then declines to about 8% in 25-to 34-year olds and to 3% in 35- to 44-year-olds. More adolescent boys than girls are afflicted. I. Pathophysiology of acne A. Acne is a disease of the pilosebaceous follicle, most commonly on the face, neck, and upper trunk. Acne vulgaris arises from increased sebum production. Androgenic hormones produced during the pubertal period enlarge sebaceous glands, causing increased sebum production. B. Proliferation of Propionibacterium acnes is felt to play a pivotal role in the pathogenesis of inflammatory acne lesions. II. Clinical evaluation. Acne vulgaris occurs primarily on the face and (to a varying degree) the neck, upper back, chest, and shoulders. Classification is based on the number and predominant type of lesions and on the affected sites. The three distinct types are obstructive acne, inflammatory ache, and acne scars. III. Treatment of acne A. Topical agents are generally preferred for comedonal lesions and for superficial inflammatory acne without scarring. Cream is the vehicle of choice in patients with dry or sensitive skin. Topical gels and solutions contain alcohol and are preferred by those with excessively oily skin. B. Topical comedolytic agents reduce the formation of the microcomedo by reversing abnormal keratinization process duct. These agents are the cornerstone of obstructive acne treatment and an important adjunct in all patients with inflammatory acne. 1. Topical tretinoin (Retin-A), a vitamin A derivative, promotes the drainage of preexisting comedones and reduces the formation of new ones. The full cosmetic benefit may not be apparent for 6-12 weeks. Tretinoin should be applied lightly every night at bedtime. Skin irritation (dryness, erythema, and peeling) is common. Patients should avoid excessive sun exposure or should use a protective sunscreen. 2. Tretinoin (Retin-A) is available in creams (0.025%, 0.05%, 0.1%), gels (0.01%, 0.025%), liquid (0.05%), and a microsphere (Retin-A Micro 0.1%). The liquid is the most irritating. Patients with fair or sensitive skin should begin by using the 0.025% cream every other day and gradually increase to daily use at a higher concentration as tolerated. The microsphere reduces the potential for irritation. 3. Adapalene (Differin 0.1% gel), a naphthoic acid derivative with retinoid activity, is comparable to tretinoin, it appears to be less irritating, and it has anti-inflammatory activity. Adapalene is applied as a thin film daily at bedtime. A therapeutic effect is typically seen within 8-12 weeks. Skin irritation occurs in 10-40% of patients. Users should minimize exposure to sunlight. 4. Tazarotene (Tazorac, 0.05% and 0.1% gel), a synthetic acetylenic retinoid with comedolytic proper- ties, is FDA-approved for topical treatment of mild- to-moderate facial acne. It is applied every evening. Tazarotene is associated with skin irritation. Tazarotene does not offer any significant advan- tages over tretinoin or adapalene. C. Topical antibiotics inhibit the growth and activity of P acnes. Choices include clindamycin (Cleocin-T 1% solution, lotion, or gel), erythromycin (A/T/S 2% gel or solution, Erygel 2% gel, Akne-Mycin 2% ointment, T- Stat 2% solution and pads), sulfacetamide (Klaron 10% lotion), and a 3% erythromycin and 5% benzoyl peroxide gel (Benzamycin). Topical antibiotics are applied twice daily. Skin dryness and irritation are the most common side effects. Antibiotic resistance is possible. Resistance is less likely with the erythromycin and benzoyl peroxide combination, making it an option for patients who have developed resistance to other agents. D. Benzoyl peroxide is an antibacterial, agent that may also have mild comedolytic properties. It is available over-the-counter and in prescription formulations (2.5%, 5%, and 10% lotions, creams, and gels). Benzoyl peroxide is typically applied as a thin film, once or twice daily. Mild redness and scaling are common during the first few weeks. E. Azelaic acid (Azelex 20% cream), a dicarboxylic acid with combined antimicrobial and comedolytic proper- ties, is FDA-approved for mild-to-moderate inflamma- tory acne. It is massaged in twice daily. Mild skin irritation occurs in 5-10% of patients. Because azelaic acid does not cause photosensitivity, it is an alternative comedolytic agent for patients who are reluctant to refrain from activities that involve significant exposure to the sun. Hypopigmentation is a rare adverse reac- tion. F. Systemic agents 1. Oral antibiotics are the foundation of moderate-to- severe inflammatory acne treatment because they reduce ductal concentrations of P acnes. Improve- ment can generally be seen within 2-3 weeks. 2. Tetracycline is favored because of its better tolerability and lower incidence of P acnes resis- tance. It is initiated at a dose of 1-2 g/d in 2-4 divided doses. Tetracycline should be taken on an empty stomach. Many individuals whose acne is controlled can be weaned off oral antibiotics after 6 months of therapy, and then topical antimicrobial therapy can be continued for maintenance. 3. Long-term use is considered safe; the most com- mon side effects are gastrointestinal upset and vulvovaginal candidiasis. Gram-negative folliculitis may occur, typically manifested by the sudden appearance of superficial pustular or cystic acne lesions around the nares and flaring out over the cheeks. 4. M i n o c y c l i n e ( M i n o c i n ) a n d trimethoprim/sulfamethoxazole (TMP/SMX [Bactrim, Septra]) have a place in treating some refractory cases. Minocycline can be particularly valuable for patients with treatment-resistant inflammatory acne. Minocycline, like all tetracyclines, is contraindicated in pregnant women and in children younger than 9 years of age because of potential adverse effects on developing bones and teeth. 5. TMP/SMX is prescribed at a dose of 1 regular- strength tablet, qd or bid. Hematologic and dermatologic side effects have restricted its use to patients with severe acne refractory to other antibiot- ics and to those who develop gram-negative folliculitis secondary to long-term antibiotic therapy. G. Hormone therapy improves acne by suppressing sebum production. A triphasic oral contraceptive pill containing ethinyl estradiol, 35 μg, and norgestimate (Ortho Tri-Cyclen) has been shown to reduce inflam- matory acne lesions by 40%. H. Oral isotretinoin (13-cis-retinoic acid [Accutane]) is the only available agent with the potential to cure acne. Most patients are started at 0.5-1 mg/kg qd or bid, typically for 15-20 weeks. Adverse reactions include cheilitis, nose bleeds, dry skin and mucous mem- branes, and photosensitivity. Less common are arthralgias myalgias, headache, nyctalopia, and, in rare cases, pseudotumor cerebri. Isotretinoin can induce abnormalities in liver, hematologic, and lipid functions. Isotretinoin is a teratogen. Contraception must be ensured. I. Comedone extraction is an office procedure used to disimpact obstructive acne lesions. The obstructing plug can usually be expressed after enlarging the pore with a 25-gauge needle. J. Intralesional corticosteroid injection can rapidly (within 48-72 hours) resolve large or recalcitrant inflammatory acne lesions and reduce the risk for scarring. A 30- gauge needle is used to inject 0.05-0.3 mL of a solu- tion containing triamcinolone acetonide through the pore of the lesion. References, see page 360. Dermatophyte (Tinea) Infections Superficial fungal infections can be divided into dermatophytic infections, tinea versicolor, and cutaneous candidiasis. Up to 20% of the US population is infected with dermatophytes. Dermatophytes are the most common type of fungi that cause infection of the skin and nails. Three types of superficial fungi/dermatophytes account for the majority of infections: Epidermophyton, Trichophyton, and Microsporum. The fungi attack skin, nails, and hair. I. Tinea Capitis A. Tinea capitis, ringworm of the scalp, almost always occurs in small children. Tinea capitis can occur in two forms, “gray patch” and “black dot.” Black dot tinea capitis is the form predominantly seen in the United States. B. Gray patch tinea capitis (GPTC) is usually contracted from cats and dogs. Person-to-person spread is rare. 1. The infection begins with an erythematous, scaling, well-demarcated lesion on the scalp that spreads centrifugally for a few weeks or months and persists indefinitely. 2. The inflammation subsides, and the hairs within the patch break off a millimeter or two above the level of the scalp. The hair stubs take on a frosted appearance. In a few cases the lesions change abruptly to become boggy, elevated, tender nodules (kerion). C. Black dot tinea capitis. 1. Black dot tinea capitis (BDTC) is the most common form of scalp ringworm. It is largely a disease of childhood. All ethnic groups may be infected, but African-American children are particularly suscepti- ble. Spread is usually from child to child contact. Fomites (shared hats, combs, brushes, barrettes, rollers) may play an important role. Asymptomatic carriers in the household may also be involved. 2. BDTC usually begins as an asymptomatic, erythematous, scaling patch on the scalp, which slowly enlarges. Hairs within the patches break off. In some cases inflammation is prominent. Left untreated, scarring with permanent alopecia can occur. A sudden transition to kerion may occur. D. Diagnosis of tinea capitis is made by KOH examina- tion of spores on the hair shaft. Diagnosis can be confirmed by culture on Sabouraud’s medium. E. Treatment 1. Griseofulvin (microsize) remains the drug of choice. Griseofulvin treatment schedules are as follows: a. Adults: 250 mg ultramicrosize by mouth twice daily for 6 to 12 weeks. A few cases of the black dot type may require 250 mg three times daily for the same length of time. b. Children: 20 to 25 mg/kg of body weight for 6 to 12 weeks. 2. Terbinafine (Lamisil [250 mg PO QD]) or itraconazole (Sporanox [200 mg per day]) are effective alternatives for resistant cases or for patients who are allergic to griseofulvin. 3. Topical treatment of tinea capitis is ineffective. Treatment or removal of an animal is important only when the diagnosis is gray patch tinea capitis. 4. Identification of asymptomatic carriers and house- hold fomites is an important part of the manage- ment of black dot tinea capitis. Carriers should be treated with selenium sulfide shampoo. II. Tinea Pedis A. Tinea pedis, ringworm of the feet (athlete’s foot), is the most common dermatophyte infection. It is often accompanied by tinea manuum, onychomycosis, or tinea cruris. A sterile vesicular eruption often occurs on the palms and fingers, referred to as an “id” reac- tion. This improves as the primary infection is treated. B. The disease begins as a slowly progressive pruritic, erythematous lesions between the toes. Extension onto the sole follows and later onto the sides or even the top of the foot (“moccasin ringworm”). The normal creases and markings of the skin tend to accumulate scale. C. Treatment. Tinea pedis can usually be treated with a topical antifungal cream for four weeks; interdigital tinea pedis may only require one week of therapy. D. Diagnosis. The diagnosis should be confirmed by KOH examination of scrapings from the lesions. Culture on Sabouraud’s medium is also helpful in difficult cases. E. Topical antifungal creams are available over the counter; some prescription agents have a broader spectrum of action and may be administered once instead of twice daily, but all of the creams are equally effective. F. Patients with chronic disease or extensive disease may require oral griseofulvin (250 to 500 mg of microsize BID), terbinafine (Lamisil [250 mg QD]), or itraconazole (Sporanox [200 mg per day]) for four weeks. Terbinafine is more effective than griseofulvin, while the efficacy of terbinafine and itraconazole are similar. Nail involvement is another indication for oral therapy. Secondary infection should be treated with oral antibiotics. Topical Antifungal Agents Drug Dose How supplied Terbinafine (Lamisil) QD to BID Cream 1%: 15g, 30g Gel 1%: 5g, 15g, 30g Clotrimazole (Lotrimin)* BID Cream 1%: 15g, 30g, 45g, 90g Lotion 1%: 30mL Solution 1%: 10mL, 30mL Econazole (Spectazole) QD (BID for candidiasis) Cream 196: 15g, 30g, 85g Sulconazole (Exelderm) QD to BID Cream 1%: 15g, 30g, 60g Solution 1%: 30mL Oxiconazole (Oxistat) QD to BID Cream 1%: 15g, 30g, 60g Lotion 1%: 30mL Naftifine (Naftin) QD (cream), BID (gel) Cream 1%: 15g, 30g, 60g Gel 1%: 20g, 40g, 60g Ciclopirox (Loprox) BID Cream 1%: 15g, 30g, 90g Lotion 1%: 30mL, 60mL Ketoconazole (Nizoral) QD Cream 2%: 15g, 30g, 60g Miconazole (Monistat- Derm)* BID Cream 2%: 15g, 30g, 56.7g, 85g Tolnaftate (Tinactin)* BID Cream 1% : 15g, 30g Gel 1%: 15g Powder 1%: 45g, 90g Topical aero- sol: liquid (1%): 59.2mL, 90mL, 120mL powder (1%):56.7g, 100g, 105g, 150g Solution 1%: 10 mL * Also available in over the counter preparations III. Onychomycosis A. Onychomycosis refers to nail infections caused by dermatophyte molds (tinea unguium, ringworm of the nails). The great toe is usually the first to be affected. The disease begins with a whitish, yellowish, or brownish discoloration of a distal corner of the nail, which gradually spreads. The distal portion of the nail plate breaks away. Portions of the plate may be heaped up and irregular. The condition persists indefinitely if left untreated. B. Diagnosis 1. KOH examination of scrapings from the nail bed to demonstrate hyphae and arthrospores is the best means of diagnosis. 2. Cultures (on Sabouraud’s medium) are helpful if negative KOH examination is negative. However, results are not available for four to six weeks. The dermatophyte test medium (DTM) culture is an alternative to fungal culture. DTM costs less than culture on Sabouraud’s medium, can be performed in the office, and results are available within three to seven days. 3. Treatment. Traditional topical therapies are ineffec- tive, and even oral therapy is associated with a high rate of treatment failure and recurrence. Cure rates are better with terbinafine (Lamisil) than itraconazole. Oral Antifungal Agents Terbinafine (Lamisil): For fingernails — 250 mg daily by mouth for 6 weeks For toenails — 250 mg daily by mouth for 12 weeks Itraconazole (Sporanox): Fixed dosage For fingernails — 200 mg daily by mouth for 8 weeks For toenails — 200 mg daily by mouth for 12 weeks Pulse therapy For fingernails — 400 mg daily by mouth for one week per month for two months For toenails — 400 mg daily by mouth for one week per month for three months IV.Tinea Corporis A. Tinea corporis begins as a pruritic circular or oval erythematous scaling lesion that spreads centrifugally. Central clearing follows, while the active advancing border, a few millimeters wide, retains its red color and is slightly raised. The result is a lesion shaped like a ring. B. Treatment. Tinea corporis usually responds well to the daily application of topical antifungals such as 1 percent terbinafine cream. Extensive cases and those associated with immunologic compromise are best treated with oral griseofulvin, 250 mg three times daily for 14 days. V. Tinea Cruris A. Tinea cruris (jock itch) is a special form of tinea corporis involving the crural fold. Tinea cruris is far more common in men than women. The disease often begins after physical activity and copious sweating. B. Tinea cruris begins with a macular erythematous lesion high on the inner aspect of one or both thighs, opposite the scrotum. It spreads centrifugally, with partial central clearing and a slightly elevated, erythematous, sharply demarcated border. C. Diagnosis. KOH examination of scales scraped from the lesion will show the segmented hyphae and arthrospores characteristic of all dermatophyte infec- tions. Cultures on Sabouraud’s medium can also be used to confirm the diagnosis. D. Treatment. Topical antifungal treatment will usually suffice. One percent terbinafine cream (Lamisil) is a good choice. It should be applied once or twice daily and continued for at least two weeks. Failure to treat concomitant tinea pedis usually results in recurrence. Lesions resistant to topical medications can be treated with griseofulvin 250 mg three times daily by mouth for 14 days. Daily application of talcum, avoidance of hot baths and tight-fitting clothing, and wearing boxer shorts rather than briefs is recommended. VI.Tinea Manuum A. Tinea manuum is an unusual dermatophytic infection of the interdigital and palmar surfaces. It may coexist with other fungal infections, such as tinea pedis. The palmar surface often has diffuse areas of dry, hyperkeratotic skin. Differential diagnosis should include pompholyx, eczema, secondary syphilis, and callus formation. B. The condition often responds to topical therapy. VII. Tinea Versicolor A. Tinea versicolor is common, in young and middle-aged adults. The condition is caused by the lipophilic yeasts, Pityrosporum orbiculare and Pityrosporum ovale. P orbiculare is known as Malassezia furfur. Tinea versicolor is also referred to as pityriasis versicolor. B. Tinea versicolor is typically found on the upper trunk, neck, and arms. The characteristic finding is skin depigmentation, but lesions can range from red to hypopigmented to hyperpigmented. C. Tinea versicolor usually does not clear spontaneously and may persist for many years. “Spotty body” often presents in adolescence and is associated with itching. Tinea versicolor has a high rate of recurrence, and periodic retreatment may be needed. D. Differential diagnosis includes vitiligo, tinea corporis, pityriasis rosea, pityriasis alba, and secondary syphilis. E. Tinea versicolor responds to topical therapies, such as terbinafine, econazole, ketoconazole, and selenium sulfide lotion or shampoo (Exsel, Head & Shoulders, Selsun). Recurrences may be less frequent if a short course of oral itraconazole (Sporanox) is instituted. VIII. Cutaneous Candidiasis A. Cutaneous candidiasis is caused by C albicans. Other candidiasis infections include angular cheilitis (perlèche), erosio interdigitalis blastomycetica, candidal intertrigo, balanitis, vaginitis, and paronychia. Involvement of the skinfolds is most common, but any area of the skin with increased moisture is susceptible. B. Wearing of occlusive clothing, obesity or disorders affecting the immune system (eg, diabetes, AIDS) may increase susceptibility to candidal infection. C. Candidal skin infection often presents with erythema, cracking, or maceration. When maceration develops in the web spaces of the fingers, the skin can become soft and white. Candidal skin infection is characterized by irregular (serrated) edges, tissue erythema, and satellite lesions. D. In patients with normal immunity, candidiasis is most often treated with topical therapy. Commonly used topical agents include nystatin (Mycostatin), ketoconazole, miconazole, and clotrimazole. Therapy with oral fluconazole (Diflucan) is highly effective. References, see page 360. Common Skin Diseases I. Alopecia Areata A. Alopecia areata is characterized by asymptomatic, noninflammatory, non-scarring areas of complete hair loss, most commonly involving the scalp, but the disorder may involve any area of hair-bearing skin. B. Auto-antibodies to hair follicles are the most likely cause. Emotional stress is sometimes a precipitating factor. The younger the patient and the more wide- spread the disease, and the poorer the prognosis. C. Regrowth of hair after the first attack takes place in 6 months in 30% of cases, with 50% regrowing within 1 year, and 80% regrowing within 5 years. Ten to 30% of patients will not regrow hair; 5% progress to total hair loss. D. Lesions are well defined, single or multiple round or oval areas of total hair loss. Typical “exclamation point” hairs (3-10 mm in size with a tapered, less pigmented proximal shaft) are seen at the margins. E. Differential diagnosis includes tinea capitis, trichotillomania, secondary syphilis, and lupus erythematosus. F. A VDRL or RPR test for syphilis should be obtained. A CBC, SMAC, sedimentary rate, thyroid function tests, and antinuclear antibody should be completed to screen for pernicious anemia, chronic active hepatitis, thyroid disease, lupus erythematosus, and Addison's disease. G. Therapy. Topical steroids, intralesional steroids, and topical minoxidil may be somewhat effective. 1. Intralesional glucocorticoid injection is the most common therapy for limited involvement. Triamcino- lone in a dosage of 10 mg per mL, is the preferred agent. 2. Topical therapy may be beneficial when it is com- bined with minoxidil, anthralin or injected steroids. 3. Topical minoxidil, 5 percent solution, is 40% effec- tive in stimulating hair growth on the scalp, eye- brows and beard area. Minoxidil solution is applied twice daily and stimulates hair growth within 12 weeks. 4. Anthralin cream is commonly used in children. New hair growth may occur within two to three months after initiation of topical anthralin therapy. In one study, 25 percent of patients had cosmetically acceptable results by six months. Side effects of anthralin include redness, itching and scaling. Removal of the cream after application for 20 to 60 minutes is often recommended. However, overnight application has been shown to be well tolerated by some patients. 5. The investigational technique called topical immunotherapy, or contact sensitization, may be effective. II. Scabies A. Scabies is an extremely pruritic eruption usually accentuated in the groin, axillae, navel, breasts and finger webs, with sparing the head. B. Scabies is spread by skin to skin contact. The diagno- sis is established by finding the mite, ova, or feces in scrapings of the skin, usually of the finger webs or genitalia. C. Treatment of choice for nonpregnant adults and children is lindane (Kwell), applied for 12 hours, then washed off. D. Elimite, a 5% permethrin cream, applied liberally head to toe and rinsed off in 12 hours, is more effective but more expensive than lindane (Kwell). E. Treatment should be given to all members of an infected household simultaneously. Clothing and sheets must be washed on the day of treatment. III.Acne Rosacea A. This condition commonly presents in fair-skinned individuals and is characterized by papules, erythema, and telangiectasias. B. Initial treatment consists of doxycycline or tetracycline. Once there has been some clearing, topical metronidazole gel (Metro-gel) can prevent remission. Sunblock should be used because sunlight can exacer- bate the condition. IV. Drug Eruptions A. Drug eruptions may be type I, type II, type III, or type IV immunologic reactions. Cutaneous drug reactions may start within 7 days of initiation of the drug or within 4-7 days after the offending drug has been stopped. B. The cutaneous lesions usually become more severe and widespread over the following several days to 1 week and then clear over the next 7-14 days. C. Lesions most often start first and clear first from the head and upper extremities to the trunk and lower legs. Palms, soles, and mucous membranes may be in- volved. D. Most drug reactions appear as a typical maculopapular drug reaction. Tetracycline is associated with a fixed drug eruption. Thiazide diuretics have a tendency for photosensitivity eruptions. E. Treatment of drug eruptions 1. Oral anti hi stami nes are very useful . Diphenhydramine (Benadryl), 25-50 mg q4-6h. Soothing, tepid water baths in Aveeno or corn starch or cool compresses are useful. 2. Severe signs and symptoms. A 2-week course of systemic steroids (prednisone starting at 60 mg/day and then tapering) will usually stop the symptoms. F. Erythema Multiforme 1. Erythema multiforme presents as dull red macules or papules on the back of hands, palms, wrists, feet, elbows and knees. The periphery is red and the center becomes blue or darker red, hence the characteristic target or iris lesion. 2. The rash is most commonly a drug reaction caused by sulfa medications or phenytoin (Dilantin). It is also seen as a reaction to herpes simplex virus infections, mycoplasma, and Hepatitis B. 3. Erythema multiforme major or Steven’s Johnson syndrome is diagnosed when mucous membrane or eye involvement is present. 4. Prednisone 30-60 mg/day is often given with a 2-4 week taper. 5. For HSV-driven erythema multiforme, acyclovir may be helpful. Ophthalmologic consultation is obtained for ocular involvement. V. Pityriasis Rosea A. Pityriasis rosea is an acute inflammatory dermatitis characterized by self-limited lesions distributed on the trunk and extremities. A viral cause is hypothesized. It is most common between the ages of 10 and 35. B. Clinical manifestations 1. The initial lesion, called the "herald patch," can appear anywhere on the body, and is 2-6 cm in size, and begins a few days to several weeks before the generalized eruption. The hands, face, and feet are usually spared. 2. The lesions are oval, and the long axes follow the lines of cleavage. Lesions are 2 cm or less, pink, tan, or light brown. The borders of the lesions have a loose rim of scales, peeling peripherally, called the "collarette." Pruritus is usually minimal. C. Differential diagnosis. Secondary syphilis (a VDRL is indicated for atypical rashes), drug eruptions, viral exanthems, acute papular psoriasis, tinea corporis. D. Treatment. Topical antipruritic emollients (Caladryl) relieve itching. Ultraviolet therapy may be used. The disease usually resolves in 2-14 weeks and recur- rences are unusual. References, see page 360. Bacterial Infections of the Skin Bacterial skin infections most commonly include cellulitis, impetigo, and folliculitis. I. Cellulitis A. Cellulitis is a painful, erythematous infection of the dermis and subcutaneous tissues that is characterized by warmth, edema, and advancing borders. Cellulitis commonly occurs near breaks in the skin, such as surgical wounds, trauma, tinea infections, or ulcer- ations. Patients may have a fever and an elevated white blood cell count. The most common sites of cellulitis are the legs and digits, followed by the face, feet, hands, torso, neck, and buttocks. B. In otherwise healthy adults, isolation of an etiologic agent is difficult and unrewarding. If the patient has diabetes, an immunocompromising disease, or persis- tent inflammation, blood cultures or aspiration of the area of maximal inflammation may be useful. C. Empiric treatment of infection in patients without diabetes: 1. Penicillinase-resistant penicillin: Dicloxacillin (Pathocil) 40 mg/kg/day in 4 divided doses for 7-12 days; adults: 500 mg qid or 2. First-generation cephalosporin: Cephalexin (Keflex) 50 mg/kg/day PO in 4 divided doses for 7- 10 days; adults: 500 mg PO qid or 3. Amoxicillin/clavulanate (Augmentin) 500 mg tid or 875 mg bid for 7-10 days. 4. Azithromycin (Zithromax) 500 mg on day 1, then 250 mg PO qd for 4 days. 5. Erythromycin ethylsuccinate 40 mg/kg/day in 3 divided doses for 7-10 days; adults: 250-500 mg qid. 6. Limited disease can be treated orally, but more extensive disease requires parenteral therapy. Marking the margins of erythema with ink is helpful in following the progression or regression of cellulitis. 7. Outpatient therapy with injected ceftriaxone (Rocephin) provides 24 hours of parenteral cover- age and may be an option for some patients. Descriptions of Bacterial Skin Infections Disease Description Carbuncle A network of furuncles connected by sinus tracts Cellulitis Painful, erythematous infection of deep skin with poorly demarcated borders Erysipelas Fiery red, painful infection of superficial skin with sharply demarcated borders Folliculitis Papular or pustular inflammation of hair folli- cles Furuncle Painful, firm or fluctuant abscess originating from a hair follicle Impetigo Large vesicles and/or honey-crusted sores D. Antibiotics should be maintained for at least three days after the resolution of acute inflammation. Adjunctive therapy includes cool compresses; appropriate analge- sics for pain; tetanus immunization; and immobilization and elevation of the affected extremity. E. A parenteral second- or third-generation cephalosporin (with or without an aminoglycoside) should be consid- er ed i n pat i ent s who have di abet es, immunocompromised patients, those with unrespon- sive infections, or in young children. The patient may also require a plain radiograph of the area or surgical debridement to evaluate for gas gangrene, osteomyelitis, or necrotizing fasciitis. F. Periorbital cellulitis is caused by the same organisms that cause other forms of cellulitis and is treated with warm soaks, oral antibiotics, and close follow-up. Children with periorbital or orbital cellulitis often have underlying sinusitis. If the child is febrile and appears toxic, blood cultures should be performed and lumbar puncture considered. G. Orbital cellulitis occurs when the infection passes the orbital septum and is manifested by proptosis, orbital pain, restricted eye movement, visual disturbances, and concomitant sinusitis. This ocular emergency requires intravenous antibiotics, otorhinolaryngology, and ophthalmologic consultation. II. Erysipelas A. Erysipelas usually presents as an intensely erythematous infection with clearly demarcated raised margins and lymphatic streaking. Common sites are the legs and face. B. Erysipelas is caused almost exclusively by beta-hemolytic streptococcus and thus can be treated with oral or intravenous penicillin, or this infection may be treated the same as cellulitis. Adjunctive treatment and complications are the same as for cellulitis. III. Impetigo A. Impetigo is most commonly seen in children aged two to five years and is classified as bullous or nonbullous. The nonbullous type predominates and presents with an erosion (sore), cluster of erosions, or small vesicles or pustules that have a honey-yellow crust. Impetigo usually appears in areas where there is a break in the skin, such as a wound, herpes simplex infection, or angular cheilitis. B. The bullous form of impetigo presents as a large thin-walled bulla (2 to 5 cm) containing serous yellow fluid. It often ruptures leaving a denuded area. Both forms of impetigo are primarily caused by S. aureus with Streptococcus usually being involved in the nonbullous form. C. An oral antibiotic with activity against S. aureus and group A beta-hemolytic streptococcus is warranted in nonlocalized cases. 1. Azithromycin (Zithromax) for five days and cephalexin (Keflex) for 10 days have been shown to be effective and well-tolerated. 2. Dicloxacillin (Pathocil), 500 mg PO qid for 2 weeks. 3. Oxacillin (Prostaphlin) 1-2 gm IV q4-6h. 4. Cephalexin (Keflex) 250-500 mg PO qid. 5. Amoxicillin/clavulanate (Augmentin) 500 mg tid or 875 mg bid for 7-10 days. 6. Broad-spectrum fluoroquinolones have also been shown to be effective for treating skin and soft tissue infections. These medications have excellent skin penetration and good bioavailability. IV.Folliculitis A. The most common form is superficial folliculitis that manifests as a tender or painless pustule that heals without scarring. Multiple or single lesions can appear on any skin bearing hair including the head, neck, trunk, buttocks, and extremities. S. aureus is the most likely pathogen. Topical therapy with erythromycin, clindamycin (Cleocin T gel), mupirocin (Bactroban), or benzoyl peroxide can be administered to accelerate the healing process. B. Staphylococci will occasionally invade the deeper portion of the follicle, causing swelling and erythema. These lesions are painful and may scar. This inflam- mation of the entire follicle or the deeper portion of the hair follicle is called deep folliculitis. Oral antibiotics are usually used and include first-generation cephalosporins, penicillinase-resistant penicillins, macrolides, and fluoroquinolones. C. Gram-negative folliculitis usually involves the face and affects patients with a history of long-term antibiotic therapy for acne. Pathogens include Klebsiella, Enterobacter, and Proteus species. It can be treated as severe acne with isotretinoin (Accutane). V. Furuncles and Carbuncles A. Furuncles and carbuncles occur as a follicular infection progresses deeper and extends out from the follicle. Commonly known as an abscess or boil, a furuncle is a tender, erythematous, firm or fluctuant mass of walled-off purulent material, arising from the hair follicle. The pathogen is usually S. aureus. Typically, the furuncle will develop into a fluctuant mass and eventually open to the skin surface. B. Carbuncles are an aggregate of infected hair follicles that form broad, swollen, erythematous, deep, and painful masses that usually open and drain through multiple tracts. Fever and malaise, are commonly associated with these lesions. With both of these lesions, gentle incision and drainage is indicated when lesions “point” (fluctuant). The wound may be packed (usually with iodoform gauze) to encourage further drainage. In severe cases, parenteral antibiotics such as cloxacillin (Tegopen), or a first-generation cephalosporin, such as cefazolin (Ancef), are required. References, see page 360. Psoriasis Approximately 1 percent of the population is affected by psoriasis. The typical clinical findings of erythema and scaling are the result of hyperproliferation and abnormal differentiation of the epidermis, plus inflammatory cell infiltrates and vascular changes. I. Clinical Manifestations A. Plaque type psoriasis usually presents in young adults with symmetrically distributed plaques involving the scalp, extensor elbows, knees, and back. The plaques are erythematous with sharply defined, raised margins. A thick silvery scale is usually present. The lesions can range from less than 1 cm to more than 10 cm in diameter. The plaques typically are asymptomatic, although some patients complain of pruritus. Inspection may reveal pitting of the nail plates and involvement of intertriginous areas, such as the umbilicus and intergluteal cleft. B. Clinical course. Most patients with psoriasis tend to have the disease for life. However, there may be marked variability in severity over time, and remissions at some stage are seen in 25 percent of cases. Pruri- tus may be severe and arthritis can be disabling. C. Diagnosis. The diagnosis of psoriasis is made by physical examination and in some cases skin biopsy. The scalp, umbilicus, intergluteal cleft, and nails should be examined. II. Treatment A. Topical emollients. Keeping psoriatic skin soft and moist minimizes itching. The most effective are oint- ments such as petroleum jelly or thick creams. B. Topical corticosteroids 1. Topical corticosteroids remain the mainstay of topical psoriasis treatment despite the development of newer agents. 2. In the scalp, potent steroids in an alcohol solution (eg, fluocinonide 0.05 percent) are frequently indicated. On the face and intertriginous areas, a low-potency cream (eg, hydrocortisone 1 percent) should be used. 3. For thick plaques on extensor surfaces, potent steroid ointments (eg, betamethasone 0.05 percent) with added occlusion by tape or plastic wrap may be required. 4. The typical regimen consists of twice-daily applica- tion of topical corticosteroids. Generics include, in order of increasing potency, hydrocortisone (Hytone) 1 percent, triamcinolone (Aristocort) 0.1 percent, fluocinonide (Lidex) 0.05 percent, and betamethasone dipropionate (Diprosone) 0.05 percent. 5. Betamethasone valerate in a foam (Luxiq) has superior efficacy for scalp psoriasis. Types of Psoriasis, Associated Findings and Treat- ment Options Type of psoriasis Clinical fea- tures Differential diagnosis Treatment options Plaque-type psoriasis Red, thick, scaly lesions with silvery scale Atopic der- matitis, irri- tant dermati- tis, cutane- ous T-cell lymphoma, pityriasis rubra pilaris, seborrheic dermatitis Localized: topi- cal therapy with corticosteroids, calcipotriene (Dovonex), coal tars, anthralin (Anthra-Derm) or tazarotene (Tazorac). Generalized: phototherapy, systemic agents, combi- nation therapy Guttate psoriasis Teardrop-sh aped, pink to salmon, scaly plaques; usu- ally on the trunk, with sparing of palms and soles Pityriasis rosea, sec- ondary syphi- lis, drug erup- tion Ultraviolet B phototherapy, natural sunlight Pustular psoriasis, localized Erythematou s papules or plaques stud- ded with pus- tules; usually on palms or soles (palmoplanta r pustular psoriasis) Pustular drug eruption, dyshidrotic eczema, subcorneal pustular dermatosis Same as for plaque-type psoriasis Pustular psoriasis, generalized Same as lo- calized with a more general involvement; may be asso- ciated with systemic symptoms such as fe- ver, malaise and diarrhea Pustular drug eruption, subcorneal pustular dermatosis Systemic ther- apy and/or hospitalization usually re- quired Erythroder mic psoria- sis Severe, in- tense, gener- alized ery- thema and scaling cov- ering entire body; often associated with systemic symptoms; may or may not have had preexisting psoriasis Drug erup- tion, eczema- tous dermati- tis, mycosis fungoides, pityriasis rubra pilaris Systemic ther- apy and/or hospitalization usually re- quired C. Calcipotriol 1. Calcipotriol (Dovonex) has become an established therapy in psoriasis. Calcipotriol affects the growth of keratinocytes via its action at the level of vitamin D receptors. Calcipotriol is at least as effective as potent topical corticosteroids. Skin irritation is the main adverse effect. Topical calcipotriol may be used as an alternative to topical steroid therapy. Twice-daily application is indicated. Other than skin irritation, side effects are usually minimal; the risk of hypercalcemia is low. However, topical calcipotriol is more expensive than potent steroids. 2. Tazarotene (Tazorac) is a topical retinoid that appears to be safe and effective for the treatment of mild to moderate plaque psoriasis. Once-daily administration of tazarotene gel, 0.05 or 0.1 per- cent, compared favorably with topical fluocinonide. D. Methotrexate 1. Methotrexate is usually administered in an intermit- tent low-dose regimen, such as once weekly. Administration can be oral, intravenous, intramuscu- lar, or subcutaneous; the usual dose range is between 7.5 mg and 25 mg per week. 2. Folic acid, 1 mg daily, protects against some of the common side effects seen with low-dose MTX such as stomatitis. Monitoring for bone marrow suppres- sion and hepatotoxicity are necessary. E. Retinoids. Systemic retinoids (derivatives of Vitamin A) are indicated in patients with severe psoriasis. The retinoid of choice in psoriasis is acitretin (Soriatane). The usual dose of acitretin is 50 mg daily. Monitoring for hypertriglyceridemia and hepatotoxicity are required with retinoid therapy. Side effects include cheilitis and alopecia. Acitretin is teratogenic and is only indicated in men and in women of nonreproductive potential. F. Cyclosporine is effective in patients with severe psoriasis. Usual doses are in the range of 3 to 5 mg/kg per day orally. Improvement is generally observed within four weeks. Renal toxicity and hypertension are common. G. Alefacept (Amevive), the first biologic agent for treatment of psoriasis, is fairly effective in moderate to severe disease. Alefacept must be given parenterally (once a week). References, see page 360. Allergic Rhinitis Allergic rhinitis is characterized by paroxysms of sneezing, rhinorrhea, nasal obstruction, and itching of the eyes, nose, and palate. It is also frequently associated with postnasal drip, cough, irritability, and fatigue. Allergic rhinitis is classi- fied as seasonal if symptoms occur at a particular time of the year, or perennial if symptoms occur year round. I. Pathophysiology A.Common allergens causing seasonal allergic rhinitis are tree, grass, and weed pollens, and fungi. Dust mites, cockroaches, animal proteins, and fungi are frequently associated with perennial rhinitis. B.Perennial allergic rhinitis is associated with nasal symptoms, which occur for more than nine months of the year. Perennial allergic rhinitis usually reflects allergy to indoor allergens like dust mites, cockroaches, or animal dander. C.Nine to 40 percent of the population may have some form of allergic rhinitis. The prevalence of allergic rhinitis has a bimodal peak in the early school and early adult years, and declines thereafter. II.Clinical manifestations A.The intense nasal itching that occurs in allergic rhinitis is associated with nose rubbing, pushing the tip of the nose up with the hand (the “allergic salute”), and a transverse nasal crease. B.Adults and older children frequently have clear mucus. Young children have persistent rhinorrhea and often snort, sniff, cough, and clear their throats. Mouth breathing is common. Allergic rhinitis occurs in associa- tion with sinusitis, asthma, eczema and allergic con- junctivitis. III. Evaluation A.Nasal examination. The nasal mucosa frequently displays a pale bluish hue or pallor along with turbinate edema. In nonallergic or vasomotor rhinitis, the nasal turbinates are erythematous and boggy. B.Identification of allergens. For patients in whom symptoms are not well controlled with medications and in whom the cause of rhinitis is not evident from the history, skin testing may provide an in vivo assessment of IgE antibodies. C.Skin tests. Immediate hypersensitivity skin testing is a quick, inexpensive, and safe way to identify the pres- ence of allergen specific IgE. IV. Management of allergic rhinitis (rhinosinusitis) A.Allergen identification and avoidance. The history frequently identifies involvement of pollens, molds, house dust mites and insects, such as fleas and cockroaches, or animal allergens B.Allergen avoidance measures: 1. Maintaining the relative humidity at 50 percent or less to limit house dust mite and mold growth and avoid- ing exposure to irritants, such as cigarette smoke. 2. Air conditioners decrease concentrations of pollen, mold, and dust mite allergens in indoor air. 3. Avoiding exposure to the feces of the house dust mite is facilitated by removing carpets and furry pets, and washing bedding in hot water once weekly. 4. HEPA filters may help reduce animal allergens. Ordinary vacuuming and dusting have little effect. C.Pharmacologic treatment 1. Nasal decongestant sprays are not recommended in the treatment of allergic rhinitis. Tachyphylaxis develops after three to seven days, rebound nasal congestion results, and continued use causes rhinitis medicamentosa. 2. Intranasal corticosteroids. Topical intranasal steroid therapy is presently the most effective single maintenance therapy for allergic rhinitis and causes few side effects. Topical nasal steroids are more effective than cromolyn and second generation antihistamines. Most studies show no effect on growth at recommended doses. a. The addition of antihistamine or antihistamine- decongestant combination to nasal corticosteroids offers little additional clinical benefit. b. Topical nasal steroids are available in both aque- ous and freon-propelled preparations. The aque- ous preparations may be particularly useful in patients in whom freon preparations cause mucosal drying, crusting, or epistaxis. Rarely, nasal steroids are associated with nasal septal perforation. c. As needed use appears to be almost as effective as daily use in patients with episodic symptoms. d. The preparations requiring once-daily dosing are preferred. These include triamcinolone, budesonide, fluticasone, or mometasone. Mometasone is approved for use in children older than two years. For children, mometasone (Nasonex) is the preferred as first-line therapy. Budesonide and fluticasone propionate are ap- proved for use in children older than six years. Drugs for Allergic Rhinitis Drug Trade name Dose Corticosteroid Nasal Sprays Triamcinolone Nasacort Two sprays qd Budesonide Rhinocort AQ Two sprays qd Fluticasone Flonase Two sprays qd Mometasone Nasonex Two sprays qd Beclomethasone Beconase Vancenase Beconase AQ Vancenase AQ One spray two to qid One spray bid-qid One to two sprays bid One to two sprays bid Flunisolide Nasalide Two sprays bid Oral H 1 -receptor Blockers Citrizine Zyrtec Zyrtec-D 5 or 10 mg once/d Cetirizine 5 mg, pseudoephedrine 120 mg; 1 tablet bid Desloratadine Clarinex 5 mg once/d Fexofenadine Allegra 60 mg bid or 180 mg once/d Loratadine Claritin Claritin Reditabs Alavert Claritin-D 10 mg once/d Loratadine 5 mg, pseudoephedrine 120 m; 1 tab qAM Leukotriene Modifier Montelukast Singulair 10 mg once/d D. Antihistamines 1. Antihistamines are clearly less effective than topical nasal steroids. Antihistamines typically reduce itching, sneezing, and rhinorrhea, but may not completely eliminate the symptoms of nasal con- gestion. 2. Two second-generation antihistamines are currently available in syrup for young children. Cetirizine (Zyrtec) is approved for children >6 months of age. Loratadine (Claritin) is approved for use in children >2 years of age and is available over the counter. Second-generation antihistamines and nasal corticosteroids are not approved for children under two and three years of age, respectively. Rondec (carbinoxamine maleate-pseudoephedrine) drops are approved for children one month and older. 3. In relieving symptoms, second-generation drugs are less efficacious than corticosteroids and equally or more efficacious than cromolyn. The addition of antihistamines to topical nasal steroids may be useful in patients with concomitant allergic conjunc- tivitis. Oral antihistamine combinations that contain the decongestant, pseudoephedrine, provide better symptom relief than that associated with antihista- mine alone. 4. Adverse effects. a. First-generation antihistamines easily cross the blood brain barrier and cause sedation, making them relatively less desirable. Sedation occurs uncommonly with second-generation antihista- mines other than cetirizine and azelastine. b. Metabolites of second-generation antihista- mines, such as the metabolite of terfenadine, fexofenadine (Allegra), and desloratadine (Clarinex) are classified as “third-generation antihistamines.” These compounds avoid poten- tial cardiotoxic effects of the second-generation compounds. c. Cetirizine, fexofenadine, desloratadine, and loratadine have not been associated with QT prolongation. However, coadministration with P450-active drugs increases loratadine levels. In addition, licorice ingestion prolongs QT-intervals and may potentially have additive effects. 5. Second-generation antihistamines may be prefera- ble in patients with mild symptoms, or those prefer- ring pills over nose sprays, especially if allergic conjunctivitis is also present. Cetirizine (Zyrtec) is reserved for those who fail loratadine (Claritin) or fexofenadine (Allegra), as cetirizine has sedative properties. E. Cromolyn and nedocromil decrease allergic inflam- mation by inhibiting mast cell mediator release. Cromolyn, but not nedocromil, is available in the United States. Cromolyn is less effective than topical nasal steroids. F. Allergen immunotherapy 1. Allergen immunotherapy involves the subcutaneous administration of increasing doses of therapeutic vaccines of allergens. 2. Efficacy. Allergen immunotherapy to tree, grass and ragweed pollens, Alternaria mold and house dust mite is efficacious in allergic rhinitis. Immunotherapy should be considered in patients in whom pharmacotherapy and avoidance of allergens have failed to resolve symptoms. References, see page 360. Renal Disorders Acute Renal Failure Acute renal failure is defined as a sudden decrease in renal function sufficient to increase the concentration of nitroge- nous wastes in the blood. It is characterized by an increasing BUN and creatinine. I. Clinical presentation of acute renal failure A. Oliguria is a common indicator of acute renal failure, and it is marked by a decrease in urine output to less than 30 mL/h. Acute renal failure may be oliguric (<500 L/day) or nonoliguric (>30 mL/h). Anuria (<100 mL/day) does not usually occur in renal failure, and its presence suggests obstruction or a vascular cause. B. Acute renal failure may also be manifest by encephalopathy, volume overload, pericarditis, bleed- ing, anemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidemia. II. Clinical causes of renal failure A. Prerenal insult 1. Prerenal insult is the most common cause of acute renal failure, accounting for 70% of cases. Prerenal failure is usually caused by reduced renal perfusion secondary to extracellular fluid loss (diarrhea, diuresis, GI hemorrhage) or secondary to extracellular fluid sequestration (pancreatitis, sep- si s), i nadequate cardi ac output, renal vasoconstriction (sepsis, liver disease, drugs), or inadequate fluid intake or replacement. 2. Most patients with prerenal azotemia have oliguria, a history of large fluid losses (vomiting, diarrhea, burns), and evidence of intravascular volume de- pletion (thirst, weight loss, orthostatic hypotension, tachycardia, flat neck veins, dry mucous mem- branes). Patients with congestive heart failure may have total body volume excess (distended neck veins, pulmonary and pedal edema) but still have compromised renal perfusion and prerenal azotemia because of diminished cardiac output. 3. Causes of prerenal failure are usually reversible if recognized and treated early; otherwise, prolonged renal hypoperfusion can lead to acute tubular necrosis and permanent renal insufficiency. B. Intrarenal insult 1. Acute tubular necrosis (ATN) is the most common intrinsic renal disease leading to ARF. a. Prolonged renal hypoperfusion is the most common cause of ATN. b. Nephrotoxic agents (aminoglycosides, heavy metals, radiocontrast media, ethylene glycol) represent exogenous nephrotoxins. ATN may also occur as a result of endogenous nephrotoxins, such as intratubular pigments (hemoglobinuri a), i ntratubul ar protei ns (myeloma), and intratubular crystals (uric acid). 2. Acute interstitial nephritis (AIN) is an allergic reaction secondary to drugs (NSAIDs, β-lactams). 3. Arteriolar injury occurs secondary to hypertension, vasculitis, microangiopathic disorders. 4. Glomerulonephritis secondary to immunologically mediated inflammation may cause intrarenal dam- age. C. Postrenal insult results from obstruction of urine flow. Postrenal insult is the least common cause of acute renal failure, accounting for 10%. Postrenal insult may be caused by obstruction secondary to prostate can- cer, benign prostatic hypertrophy, or renal calculi. Postrenal insult may be caused by amyloidosis, uric acid crystals, multiple myeloma, methotrexate, or acyclovir. III. Clinical evaluation of acute renal failure A. Initial evaluation of renal failure should determine whether the cause is decreased renal perfusion, obstructed urine flow, or disorders of the renal paren- chyma. Volume status (orthostatic pulse, blood pres- sure, fluid intake and output, daily weights, hemodynamic parameters), nephrotoxic medications, and pattern of urine output should be assessed. B. Prerenal azotemia is likely when there is a history of heart failure or extracellular fluid volume loss or deple- tion. C. Postrenal azotemia is suggested by a history of decreased size or force of the urine stream, anuria, flank pain, hematuria or pyuria, or cancer of the blad- der, prostate or pelvis. D. Intrarenal insult is suggested by a history of pro- longed volume depletion (often post-surgical), pigmenturia, hemolysis, rhabdomyolysis, or nephrotoxins. Intrarenal insult is suggested by recent radiocontrast, aminoglycoside use, or vascular catheterization. Interstitial nephritis may be implicated by a history of medication rash, fever, or arthralgias. E. Chronic renal failure is suggested by diabetes mellitus, normochromic normocytic anemia, hypercalcemia, and hyperphosphatemia. IV. Physical examination A. Cardiac output, volume status, bladder size, and systemic disease manifestations should be assessed. B. Prerenal azotemia is suggested by impaired cardiac output (neck vein distention, pulmonary rales, pedal edema). Volume depletion is suggested by orthostatic blood pressure changes, weight loss, low urine output, or diuretic use. C. Flank, suprapubic, or abdominal masses may indicate an obstructive cause. D. Skin rash suggests drug-induced interstitial nephritis; palpable purpura suggests vasculitis; nonpalpable purpura suggests thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. E. Bladder catheterization is useful to rule out sus- pected bladder outlet obstruction. A residual volume of more than 100 mL suggests bladder outlet obstruction. F. Central venous monitoring is used to measure cardiac output and left ventricular filling pressure if prerenal failure is suspected. V. Laboratory evaluation A. Spot urine sodium concentration 1. Spot urine sodium can help distinguish between prerenal azotemia and acute tubular necrosis. 2. Prerenal failure causes increased reabsorption of salt and water and will manifest as a low spot urine sodium concentration <20 mEq/L and a low frac- tional sodium excretion <1%, and a urine/plasma creatinine ration of >40. Fractional excretion of sodium (%) = ([urine sodium/plasma sodium] ÷ [urine creatinine/plasma creatinine] x 100). 3. If tubular necrosis is the cause, the spot urine concentration will be >40 mEq/L, and fractional excretion of sodium will be >1%. B. Urinalysis 1. Normal urine sediment is a strong indicator of prerenal azotemia or may be an indicator of obstruc- tive uropathy. 2. Hematuria, pyuria, or crystals may be associated with postrenal obstructive azotemia. 3. Abundant cells, casts, or protein suggests an intrarenal disorder. 4. Red cells alone may indicate vascular disorders. RBC casts and abundant protein suggest glomeru- lar disease (glomerulonephritis). 5. White cell casts and eosinophilic casts indicate interstitial nephritis. 6. Renal epithelial cell casts and pigmented granu- lar casts are associated with acute tubular necrosis. C. Ultrasound is useful for evaluation of suspected postrenal obstruction (nephrolithiasis). The presence of small (<10 cm in length), scarred kidneys is diagnostic of chronic renal insufficiency. VI. Management of acute renal failure A. Reversible disorders, such as obstruction, should be excluded, and hypovolemia should be corrected with volume replacement. Cardiac output should be main- tained. In critically ill patients, a pulmonary artery catheter should be used for evaluation and monitoring. B. Extracellular fluid volume expansion. Infusion of a 1-2 liter crystalloid fluid bolus may confirm suspected volume depletion. C. If the patient remains oliguric despite euvolemia, IV diuretics may be administered. A large single dose of furosemide (100-200 mg) may be administered intrave- nously to promote diuresis. If urine flow is not im- proved, the dose of furosemide may be doubled. Furosemide may be repeated in 2 hours, or a continu- ous IV infusion of 10-40 mg/hr (max 1000 mg/day) may be used. D. The dosage or dosing intervals of renally excreted drugs should be modified. E. Hyperkalemia is the most immediately life-threatening complication of renal failure. Serum potassium values greater than 6.5 mEq/L may lead to arrhythmias and cardiac arrest. Potassium should be removed from IV solutions. Hyperkalemia may be treated with sodium polystyrene sulfonate (Kayexalate), 30-60 gm PO/PR every 4-6 hours. F. Hyperphosphatemia can be controlled with aluminum hydroxide antacids (eg, Amphojel or Basaljel), 15-30 ml or one to three capsules PO with meals, should be used. G. Fluids. After normal volume has been restored, fluid intake should be reduced to an amount equal to urinary and other losses plus insensible losses of 300-500 mL/day. In oliguric patients, daily fluid intake may need to be restricted to less than 1 L. H. Nutritional therapy. A renal diet consisting of daily high biologic value protein intake of 0.5 gm/kg/d, sodium 2 g, potassium 40-60 mg/day, and at least 35 kcal/kg of nonprotein calories is recommended. Phos- phorus should be restricted to 800 mg/day I. Dialysis. Indications for dialysis include uremic pericarditis, severe hyperkalemia, pulmonary edema, persistent severe metabolic acidosis (pH less than 7.2), and symptomatic uremia. References, see page 360. Hematuria Hematuria may be a sign of urinary tract malignancy or renal parenchymal disease. Up to 18% of normal persons excrete red blood cells into the urine, averaging 2 RBCs per high- power field (HPF). I. Clinical evaluation of hematuria A. Dipstick testing detects hemoglobin and myoglobin; therefore, microscopic examination of the urinary sediment is required before a diagnosis of hematuria can be made. B. The patient should be asked about frequency, dysuria, pain, colic, fever, fatigue, anorexia, abdominal, flank, or perineal pain. Exercise, jogging, menstruation, or a history of kidney stones should be sought. C. The patient should be examined for hypertension, edema, rash, heart murmurs, or abdominal masses (renal tumor, hydronephrosis from obstruction). Costovertebral-angle tenderness may be a sign of renal calculus or pyelonephritis. D. Genitourinary examination may reveal a foreign body in the penile urethra or cervical carcinoma invading the urinary tract. Prostatitis, carcinoma, or benign prostatic hyperplasia may be found. II. Laboratory evaluation A. At least one of the following criteria should be met before initiating a workup for hematuria. 1. More than 3 RBCs/HPF on two of three properly collected clean-catch specimens (abstain from exercise for 48 hours before sampling; not during menses). 2. One episode of gross hematuria. 3. One episode of high-grade microhematuria (>100 RBCs HPF). B. A properly collected, freshly voided specimen should be examined for red blood cell morphology; the char- acter of the sediment and the presence of proteinuria should be determined. C. RBC casts are pathognomonic of glomerulonephritis. WBC casts and granular casts are indicative of pyelonephritis. D. Urine culture should be completed to rule out urinary tract infection, which may cause hematuria. E. Serum blood urea nitrogen and creatinine levels should be evaluated to rule out renal failure. Impaired renal function is seen more commonly with medical causes of hematuria. F. Fasting blood glucose levels should be obtained to rule out diabetes; a complete blood count should be obtained to assess severity of blood loss. G. Serum coagulation parameters should be measured to screen for coagulopathy. A skin test for tuberculosis should be completed if risk factors are present. A sickle cell prep is recommended for all African-Ameri- can patients. III. Classification of hematuria A. Medical hematuria is caused by a glomerular lesion. Plasma proteins are present in the urine out of propor- tion to the amount of hematuria. Medical hematuria is characterized by glomerular RBCs, which are distorted with crenated membranes and an uneven hemoglobin distribution. Microscopic hematuria and a urine dipstick test of 2+ protein is more likely to have a medical cause. B. Urologic hematuria is caused by urologic lesions, such as urolithiasis or bladder cancer. It is character- ized by minimal proteinuria. Non-glomerular RBCs (disk shaped) and an absence of casts are character- istic. IV. Diagnostic evaluation of medical hematuria A. Renal ultrasound is used to evaluate kidney size and rule out hydronephrosis or cystic disease. B. 24-hour urine. Creatinine, creatinine clearance and protein should be measured to assess renal failure. C. Immunologic studies that may suggest a diagnosis include third and fourth complement components, antinuclear antibodies, cryoglobulins, anti-basement membrane antibodies; serum and urine protein elec- trophoresis (to rule out IgA nephropathy). D. Audiogram should be obtained if there is a family history of Alport syndrome. E. Skin biopsy can reveal dermal capillary deposits of IgA in 80% of patients with Berger's disease (IgA nephropathy), which is the most common cause of microhematuria in young adults. V. Diagnostic evaluation of urologic hematuria A. Intravenous pyelography is the best screening test for upper tract lesions if the serum creatinine is normal. It is usually contraindicated in renal insufficiency. If renal insufficiency is present, renal ultrasound and cystoscopy with retrograde pyelogram should be used to search for stones or malignancy. If the IVP Is normal, cystoscopy with washings for cytology may reveal the cause of bleeding. B. Other tests. Lesions in the kidney visualized on IVP can be evaluated by renal ultrasound to assess cystic or solid character. CT-guided aspiration of cysts may be considered. Filling defects in the ureter should be evaluated by retrograde pyelogram and ureteral washings. VI.Idiopathic hematuria A. Idiopathic hematuria is a diagnosis of exclusion. Five to 10% of patients with significant hematuria will have no diagnosis. Suspected urologic hematuria with a negative initial workup should be followed every 6-12 months with a urinalysis and urine cytology. An IVP should be done every 2-3 years. B. Renal function and proteinuria should be monitored. If renal function declines or if proteinuria exceeds 1 gm/day, renal biopsy is indicated. References, see page 360. Hyperkalemia Body potassium is 98% intracellular. Only 2% of total body potassium, about 70 mEq, is in the extracellular fluid, with the normal concentration of 3.5-5 mEq/L. I. Pathophysiology of potassium homeostasis A. The normal upper limit of plasma K is 5-5.5 mEq/L, with a mean K level of 4.3. B. External potassium balance. Normal dietary K intake is 1-1.5 mEq/kg in the form of vegetables and meats. The kidney is the primary organ for preserving external K balance, excreting 90% of the daily K burden. C. Internal potassium balance. Potassium transfer to and from tissues, is affected by insulin, acid-base status, catecholamines, aldosterone, plasma osmolality, cellular necrosis, and glucagon. II. Clinical disorders of external potassium balance A. Chronic renal failure. The kidney is able to excrete the dietary intake of potassium until the glomerular filtration rate falls below 10 cc/minute or until urine output falls below 1 L/day. Renal failure is advanced before hyperkalemia occurs. B. Impaired renal tubular function. Renal diseases may cause hyperkalemia, and the renal tubular acidosis caused by these conditions may worsen hyperkalemia. C. Primary adrenal insufficiency (Addison's disease) is now a rare cause of hyperkalemia. Diagnosis is indicated by the combination of hyperkalemia and hyponatremia and is confirmed by a low aldosterone and a low plasma cortisol level that does not respond to adrenocorticotropic hormone treatment. D. Drugs that may cause hyperkalemia include nonsteroidal anti-inflammatory drugs, angiotensin- converting enzyme inhibitors, cyclosporine, and potassium-sparing diuretics. Hyperkalemia is especially common when these drugs are given to patients at risk for hyperkalemia (diabetics, renal failure, advanced age). E. Excessive potassium intake 1. Long-term potassium supplementation results in hyperkalemia most often when an underlying impair- ment in renal excretion already exists. 2. Intravenous administration of 0.5 mEq/kg over 1 hour increases serum levels by 0.6 mEq/L. Hyperkalemia often results when infusions of greater than 40 mEq/hour are given. III. Clinical disorders of internal potassium balance A. Diabetic patients are at particular risk for severe hyperkalemia because of renal insufficiency and hyporeninemic hypoaldosteronism. B. Systemic acidosis reduces renal excretion of potas- sium and moves potassium out of cells, resulting in hyperkalemia. C. Endogenous potassium release from muscle injury, tumor lysis, or chemotherapy may elevate serum potassium. IV. Manifestations of hyperkalemia A. Hyperkalemia, unless severe, is usually asymptomatic. The effect of hyperkalemia on the heart becomes significant above 6 mEq/L. As levels increase, the initial ECG change is tall peaked T waves. The QT interval is normal or diminished. B. As K levels rise further, the PR interval becomes prolonged, then the P wave amplitude decreases. The QRS complex eventually widens into a sine wave pattern, with subsequent cardiac standstill. C. At serum K is >7 mEq/L, muscle weakness may lead to a flaccid paralysis. Sensory abnormalities, impaired speech and respiratory arrest may follow. V. Pseudohyperkalemia A. Potassium may be falsely elevated by hemolysis during phlebotomy, when K is released from ischemic muscle distal to a tourniquet, and because of erythrocyte fragility disorders. B. Falsely high laboratory measurement of serum potas- sium may occur with markedly elevated platelet counts (>10 6 platelet/mm 3 ) or white blood cell counts (>50,000/mm 3 ). VI. Diagnostic approach to hyperkalemia A. The serum K level should be repeat tested to rule out laboratory error. If significant thrombocytosis or leukocytosis is present, a plasma potassium level should be determined. B. The 24-hour urine output, urinary K excretion, blood urea nitrogen, and serum creatinine should be mea- sured. Renal K retention is diagnosed when urinary K excretion is less than 20 mEq/day. C. High urinary K, excretion of >20 mEq/day, is indicative of excessive K intake as the cause. VII. Renal hyperkalemia A. If urinary K excretion is low and urine output is in the oliguric range, and creatinine clearance is lower than 20 cc/minute, renal failure is the probable cause. Prerenal azotemia resulting from volume depletion must be ruled out because the hyperkalemia will respond to volume restoration. B. When urinary K excretion is low, yet blood urea nitro- gen and creatinine levels are not elevated and urine volume is at least 1 L daily and renal sodium excretion is adequate (about 20 mEq/day), then either a defect in the secretion of renin or aldosterone or tubular resistance to aldosterone is likely. Low plasma renin and aldosterone levels, will confirm the diagnosis of hyporeninemic hypoaldosteronism. Addison's disease is suggested by a low serum cortisol, and the diagnosis is confirmed with a ACTH (Cortrosyn) stimulation test. C. When inadequate K excretion is not caused by hypoaldosteronism, a tubular defect in K clearance is suggested. Urinary tract obstruction, renal transplant, lupus, or a medication should be considered. VIII. Extrarenal hyperkalemia A. When hyperkalemia occurs along with high urinary K excretion of >20 mEq/day, excessive intake of K is the cause. Potassium excess in IV fluids, diet, or medica- tion should be sought. A concomitant underlying renal defect in K excretion is also likely to be present. B. Blood sugar should be measured to rule out insulin deficiency; blood pH and serum bicarbonate should be measured to rule out acidosis. C. Endogenous sources of K, such as tissue necrosis, hypercatabolism, hematoma, gastrointestinal bleeding, or intravascular hemolysis should be excluded. IX. Management of hyperkalemia A. Acute treatment of hyperkalemia 1. Calcium a. If the electrocardiogram shows loss of P waves or widening of QRS complexes, calcium should be given IV; calcium reduces the cell membrane threshold potential. b. Calcium chloride (10%) 2-3 g should be given over 5 minutes. In patients with circulatory com- promise, 1 g of calcium chloride IV should be given over 3 minutes. c. If the serum K level is greater than 7 mEq/L, calcium should be given. If digitalis intoxication is suspected, calcium must be given cautiously. Coexisting hyponatremia should be treated with hypertonic saline. 2. Insulin: If the only ECG abnormalities are peaked T waves and the serum level is under 7 mEq/L, treat- ment should begin with insulin (regular insulin, 5-10 U by IV push) with 50% dextrose water (D50W) 50 mL IV push. Repeated insulin doses of 10 U and glucose can be given every 15 minutes for maximal effect. 3. Sodium bicarbonate promotes cellular uptake of K. It should be given as 1-2 vials (50-mEq/vials) IV push. 4. Potassium elimination measures a. Sodium polystyrene sulfonate (Kayexalate) is a cation exchange resin which binds to potassium in the lower GI tract. Dosage is 30-60 gm pre- mixed with sorbitol 20% PO/PR. b. Furosemide (Lasix) 100 mg IV should be given to promote kaliuresis. c. Emergent hemodialysis for hyperkalemia is rarely necessary except when refractory metabolic acidosis is present. References, see page 360. Hypokalemia Hypokalemia is characterized by a serum potassium concen- tration of less than 3.5 mEq/L. Ninety-eight percent of K is intracellular. I. Pathophysiology of hypokalemia A. Cellular redistribution of potassium. Hypokalemia may result from the intracellular shift of potassium by insulin, beta-2 agonist drugs, stress induced catecholamine release, thyrotoxic periodic paralysis, and alkalosis-induced shift (metabolic or respiratory). B. Nonrenal potassium loss 1. Gastrointestinal loss can be caused by diarrhea, laxative abuse, villous adenoma, biliary drainage, enteric fistula, clay ingestion, potassium binding resin ingestion, or nasogastric suction. 2. Sweating, prolonged low-potassium diet, hemodialysis and peritoneal dialysis may also cause nonrenal potassium loss. C. Renal potassium loss 1. Hypertensive high renin states. Malignant hyper- tension, renal artery stenosis, renin-producing tumors. 2. Hypertensive low renin, high aldosterone states. Primary hyperaldosteronism (adenoma or hyperpla- sia). 3. Hypertensive low renin, low aldosterone states. Congenital adrenal hyperplasia (11 or 17 hydroxy- lase deficiency), Cushing's syndrome or disease, exogenous mineralocorticoids (Florinef, licorice, chewing tobacco), Liddle's syndrome. 4. Normotensive states a. Metabolic acidosis. Renal tubular acidosis (type I or II) b. Metabolic alkalosis (urine chloride <10 mEq/day). Vomiting c. Metabolic alkalosis (urine chloride >10 mEq/day). Bartter's syndrome, diuretics, magne- sium depletion, normotensive hyperaldo- steronism 5. Drugs associated with potassium loss include amphotericin B, ticarcillin, piperacillin, and loop diuretics. II. Clinical effects of hypokalemia A. Cardiac effects. The most lethal consequence of h yp o k a l e mi a i s c a r d i a c a r r h yt h mi a . Electrocardiographic effects include a depressed ST segment, decreased T-wave amplitude, U waves, and a prolonged QT-U interval. B. Musculoskeletal effects. The initial manifestation of K depletion is muscle weakness, which can lead to paralysis. In severe cases, respiratory muscle paralysis may occur. C. Gastrointestinal effects. Nausea, vomiting, constipa- tion, and paralytic ileus may develop. III. Diagnostic evaluation A. The 24-hour urinary potassium excretion should be measured. If >20 mEq/day, excessive urinary K loss is the cause. If <20 mEq/d, low K intake, or non-urinary K loss is the cause. B. In patients with excessive renal K loss and hyperten- sion, plasma renin and aldosterone should be mea- sured to differentiate adrenal from non-adrenal causes of hyperaldosteronism. C. If hypertension is absent and serum pH is acidotic, renal tubular acidosis should be considered. If hyper- tension is absent and serum pH is normal to alkalotic, a high urine chloride (>10 mEq/d) suggests hypokalemia secondary to diuretics or Bartter's syn- drome. A low urine chloride (<10 mEq/d) suggests vomiting. IV. Emergency treatment of hypokalemia A. I ndi cat i ons f or urgent repl acement . Electrocardiographic abnormalities, myocardial infarc- tion, hypoxia, digitalis intoxication, marked muscle weakness, or respiratory muscle paralysis. B. Intravenous potassium therapy 1. Intravenous KCL is usually used unless concomitant hypophosphatemia is present, where potassium phosphate is indicated. 2. The maximal rate of intravenous K replacement is 30 mEq/hour. The K concentration of IV fluids should be 80 mEq/L or less if given via a peripheral vein. Frequent monitoring of serum K and constant electrocardiographic monitoring is recommended when potassium levels are being replaced. V.Non-emergent treatment of hypokalemia A. Attempts should be made to normalize K levels if <3.5 mEq/L. B. Oral supplementation is significantly safer than IV. Liquid formulations are preferred due to rapid oral absorption, compared to sustained release formula- tions, which are absorbed over several hours. 1. KCL elixir 20-40 mEq qd-tid PO after meals. 2. Micro-K, 10 mEq tabs, 2-3 tabs tid PO after meals (40-100 mEq/d). References, see page 360. Hypermagnesemia Serum magnesium has a normal range of 0.8-1.2 mmol/L. Magnesium homeostasis is regulated by renal and gastroin- testinal mechanisms. Hypermagnesemia is usually iatrogenic and is frequently seen in conjunction with renal insufficiency. I. Clinical evaluation of hypermagnesemia A. Causes of hypermagnesemia 1. Renal. Creatinine clearance <30 mL/minute. 2. Nonrenal. Excessive use of magnesium cathartics, especially with renal failure; iatrogenic overtreatment with magnesium sulfate. B. Cardiovascular manifestations of hypermagnesemia 1. Hypermagnesemia <10 mEq/L. Delayed interventricular conduction, first-degree heart block, prolongation of the Q-T interval. 2. Levels greater than 10 mEq/L. Low-grade heart block progressing to complete heart block and asystole occurs at levels greater than 12.5 mmol/L (>6.25 mmol/L). C. Neuromuscular effects 1. Hyporeflexia occurs at a magnesium level >4 mEq/L (>2 mmol/L); diminution of deep tendon reflexes is an early sign of magnesium toxicity. 2. Respiratory depression due to respiratory muscle paralysis, somnolence and coma occur at levels >13 mEq/L (6.5 mmol/L). 3. Hypermagnesemia should always be considered when these symptoms occur in patients with renal failure, in those receiving therapeutic magnesium, and in laxative abuse. II.Treatment of hypermagnesemia A. Asymptomatic, hemodynamically stable patients. Moderate hypermagnesemia can be managed by elimination of intake. B. Severe hypermagnesemia 1. Furosemide 20-40 mg IV q3-4h should be given as needed. Saline diuresis should be initiated with 0.9% saline, infused at 120 cc/h to replace urine loss. 2. If ECG abnormalities (peaked T waves, loss of P waves, or widened QRS complexes) or if respiratory depression is present, IV calcium gluconate should be given as 1-3 ampules (10% solution, 1 gm per 10 mL amp), added to saline infusate. Calcium gluconate can be infused to reverse acute cardiovas- cular toxicity or respiratory failure as 15 mg/kg over a 4-hour period. 3. Parenteral insulin and glucose can be given to shift magnesium into cells. Dialysis is necessary for patients who have severe hypermagnesemia. References, see page 360. Hypomagnesemia Magnesium deficiency occurs in up to 11% of hospitalized patients. The normal range of serum magnesium is 1.5 to 2.0 mEq/L, which is maintained by the kidney, intestine, and bone. I. Pathophysiology A. Decreased magnesium intake. Protein-calorie malnu- trition, prolonged parenteral fluid administration, and catabolic illness are common causes of hypomagnesemia. B. Gastrointestinal losses of magnesium may result from prolonged nasogastric suction, laxative abuse, and pancreatitis. C. Renal losses of magnesium 1. Renal loss of magnesium may occur secondary to renal tubular acidosis, glomerulonephritis, interstitial nephritis, or acute tubular necrosis. 2. Hyper t hyr oi di sm, hyper cal cemi a, and hypophosphatemia may cause magnesium loss. 3. Agents that enhance renal magnesium excretion include alcohol, loop and thiazide diuretics, amphotericin B, aminoglycosides, cisplatin, and pentamidine. D. Alterations in magnesium distribution 1. Redistribution of circulating magnesium occurs by extracellular to intracellular shifts, sequestration, hungry bone syndrome, or by acute administration of glucose, insulin, or amino acids. 2. Magnesium depletion can be caused by large quanti- ties of parenteral fluids and pancreatitis-induced sequestration of magnesium. II.Clinical manifestations of hypomagnesemia A. Neuromuscular findings may include positive Chvostek's and Trousseau's signs, tremors, myoclonic jerks, seizures, and coma. B. Cardiovascular. Ventricular tachycardia, ventricular fibrillation, atrial fibrillation, multifocal atrial tachycardia, ventricular ectopic beats, hypertension, enhancement of digoxin-induced dysrhythmias, and cardiomyopathies. C. ECG changes include ventricular arrhythmias (extra- systoles, tachycardia) and atrial arrhythmias (atrial fibrillation, supraventricular tachycardia, torsades de Pointes). Prolonged PR and QT intervals, ST segment depression, T-wave inversions, wide QRS complexes, and tall T-waves may occur. III. Clinical evaluation A. Hypomagnesemia is diagnosed when the serum magnesium is less than 0.7-0.8 mmol/L. Symptoms of magnesium deficiency occur when the serum magne- sium concentration is less than 0.5 mmol/L. A 24-hour urine collection for magnesium is the first step in the evaluation of hypomagnesemia. Hypomagnesia caused by renal magnesium loss is associated with magnesium excretion that exceeds 24 mg/day. B. Low urinary magnesium excretion (<1 mmol/day), with concomitant serum hypomagnesemia, suggests magne- sium deficiency due to decreased intake, nonrenal losses, or redistribution of magnesium. IV. Treatment of hypomagnesemia A. Asymptomatic magnesium deficiency 1. In hospitalized patients, the daily magnesium require- ments can be provided through either a balanced diet, as oral magnesium supplements (0.36-0.46 mEq/kg/day), or 16-30 mEq/day in a parenteral nutrition formulation. 2. Magnesium oxide is better absorbed and less likely to cause diarrhea than magnesium sulfate. Magnesium oxide preparations include Mag-Ox 400 (240 mg elemental magnesium per 400 mg tablet), Uro-Mag (84 mg elemental magnesium per 400 mg tablet), and magnesium chloride (Slo-Mag) 64 mg/tab, 1-2 tabs bid. B. Symptomatic magnesium deficiency 1. Serum magnesium <0.5 mmol/L requires IV magne- sium repletion with electrocardiographic and respira- tory monitoring. 2. Magnesium sulfate 1-6 gm in 500 mL of D5W can be infused IV at 1 gm/hr. An additional 6-9 gm of MgSO 4 should be given by continuous infusion over the next 24 hours. References, see page 360. Disorders of Water and Sodium Bal- ance I. Pathophysiology of water and sodium balance A. Volitional intake of water is regulated by thirst. Mainte- nance intake of water is the amount of water sufficient to offset obligatory losses. B. Maintenance water needs = 100 mL/kg for first 10 kg of body weight + 50 mL/kg for next 10 kg + 20 mL/kg for weight greater than 20 kg C. Clinical signs of hyponatremia. Confusion, agitation, lethargy, seizures, and coma. D. Pseudohyponatremia 1. Elevation of blood glucose may creates an osmotic gradient that pulls water from cells into the extracellular fluid, diluting the extracellular sodium. The contribution of hyperglycemia to hyponatremia can be estimated using the following formula: Expected change in serum sodium = (serum glu- cose - 100) x 0.016 2. Marked elevation of plasma lipids or protein can also result in erroneous hyponatremia because of laboratory inaccuracy. The percentage of plasma water can be estimated with the following formula: % plasma water = 100 - [0.01 x lipids (mg/dL)] - [0.73 x protein (g/dL)] II. Diagnostic evaluation of hyponatremia A. Pseudohyponatremia should be excluded by repeat testing. The cause of the hyponatremia should be determined based on history, physical exam, urine osmolality, serum osmolality, urine sodium and chlo- ride. An assessment of volume status should deter- mine if the patient is volume contracted, normal volume, or volume expanded. B. Classification of hyponatremic patients based on urine osmolality 1. Low-urine osmolality (50-180 mOsm/L) indicates primary excessive water intake (psychogenic water drinking). 2. High-urine osmolality (urine osmolality >serum osmolality) a. High-urine sodium (>40 mEq/L) and volume contraction indicates a renal source of sodium loss and fluid loss (excessive diuretic use, salt- wasting nephropathy, Addison's disease, os- motic diuresis). b. High-urine sodium (>40 mEq/L) and normal volume is most likely caused by water retention due to a drug effect, hypothyroidism, or the syndrome of inappropriate antidiuretic hormone secretion. In SIADH, the urine sodium level is usually high. SIADH is found in the presence of a malignant tumor or a disorder of the pulmonary or central nervous system. c. Low-urine sodium (<20 mEq/L) and volume contraction, dry mucous membranes, de- creased skin turgor, and orthostatic hypotension indicate an extrarenal source of fluid loss (gas- trointestinal disease, burns). d. Low-urine sodium (<20 mEq/L) and volume- expansion, and edema is caused by congestive heart failure, cirrhosis with ascites, or nephrotic syndrome. Effective arterial blood volume is decreased. Decreased renal perfusion causes increased reabsorption of water. Drugs Associated with SIADH Acetaminophen Barbiturates Carbamazepine Chlorpropamide Clofibrate Cyclophosphamide Indomethacin Isoproterenol Prostaglandin E 1 Meperidine Nicotine Tolbutamide Vincristine III. Treatment of water excess hyponatremia A. Determine the volume of water excess Water excess = total body water x ([140/measured sodium] -1) B. Treatment of asymptomatic hyponatremia. Water intake should be restricted to 1,000 mL/day. Food alone in the diet contains this much water, so no liquids should be consumed. If an intravenous solution is needed, an isotonic solution of 0.9% sodium chlo- ride (normal saline) should be used. Dextrose should not be used in the infusion because the dextrose is metabolized into water. C. Treatment of symptomatic hyponatremia 1. If neurologic symptoms of hyponatremia are pres- ent, the serum sodium level should be corrected with hypertonic saline. Excessively rapid correction of sodium may result in a syndrome of central pontine demyelination. 2. The serum sodium should be raised at a rate of 1 mEq/L per hour. If hyponatremia has been chronic, the rate should be limited to 0.5 mEq/L per hour. The goal of initial therapy is a serum sodium of 125- 130 mEq/L, then water restriction should be contin- ued until the level normalizes. 3. The amount of hypertonic saline needed is esti- mated using the following formula: Sodium needed (mEq) = 0.6 x wt in kg x (desired sodium - measured sodium) 4. Hypertonic 3% sodium chloride contains 513 mEq/L of sodium. The calculated volume required should be administered over the period required to raise the serum sodium level at a rate of 0.5-1 mEq/L per hour. Concomitant administration of furosemide may be required to lessen the risk of fluid overload. IV.Hypernatremia A. Clinical manifestations of hypernatremia: Clinical manifestations include tremulousness, irritability, ataxia, spasticity, mental confusion, seizures, and coma. B. Causes of hypernatremia 1. Net sodium gain or net water loss will cause hypernatremia 2. Failure to replace obligate water losses may cause hypernatremia, as in patients unable to obtain water because of an altered mental status or severe debilitating disease. 3. Diabetes insipidus: If urine volume is high but urine osmolality is low, diabetes insipidus is the most likely cause. Drugs Associated with Diabetes Insipidus Ethanol Phenytoin Chlorpromazine Lithium Glyburide Amphotericin B Colchicine Vinblastine C. Diagnosis of hypernatremia 1. Assessment of urine volume and osmolality are essential in the evaluation of hyperosmolality. The usual renal response to hypernatremia is the excre- tion of the minimum volume (<500 mL/day) of maximally concentrated urine (urine osmolality >800 mOsm/kg). These findings suggest extrarenal water loss. 2. Diabetes insipidus generally presents with polyuria and hypotonic urine (urine osmolality <250 mOsm/kg). V. Management of hypernatremia A. If there is evidence of hemodynamic compromise (eg, orthostatic hypotension, marked oliguria), fluid deficits should be corrected initially with isotonic saline. Once hemodynamic stability is achieved, the remaining free water deficit should be corrected with 5% dextrose water or 0.45% NaCl. B. The water deficit can be estimated using the following formula: Water deficit = 0.6 x wt in kg x (1 - [140/measured sodium]). C. The change in sodium concentration should not exceed 1 mEq/liter/hour. One-half of the calculated water deficit can be administered in the first 24 hours, followed by correction of the remaining deficit over the next 1-2 days. The serum sodium concentration and ECF volume status should be evaluated every 6 hours. Excessively rapid correction of hypernatremia may lead to lethargy and seizures secondary to cerebral edema. D. Maintenance fluid needs from ongoing renal and insensible losses must also be provided. If the patient is conscious and able to drink, water should be given orally or by nasogastric tube. E. Treatment of diabetes insipidus 1. Vasopressin (Pitressin) 5-10 U IV/SQ q6h; fast onset of action with short duration. 2. Desmopressin (DDAVP) 2-4 mcg IV/SQ q12h; slow onset of action with long duration of effect. VI.Mixed disorders A. Water excess and saline deficit occurs when severe vomiting and diarrhea occur in a patient who is given only water. Clinical signs of volume contraction and a low serum sodium are present. Saline deficit is re- placed and free water intake restricted until the serum sodium level has normalized. B. Water and saline excess often occurs with heart failure, manifesting as edema and a low serum so- dium. An increase in the extracellular fluid volume, as evidenced by edema, is a saline excess. A marked excess of free water expands the extracellular fluid volume, causing apparent hyponatremia. However, the important derangement in edema is an excess of sodium. Sodium and water restriction and use of furosemide are usually indicated in addition to treat- ment of the underlying disorder. C. Water and saline deficit is frequently caused by vomiting and high fever and is characterized by signs of volume contraction and an elevated serum sodium. Saline and free water should be replaced in addition to maintenance amounts of water. References, see page 360. Endocrinologic Disorders Diabetic Ketoacidosis Diabetic ketoacidosis is defined by hyperglycemia, metabolic acidosis, and ketosis. I. Clinical presentation A. Diabetes is newly diagnosed in 20% of cases of diabetic ketoacidosis. In patients with known diabetes, precipitating factors include infection, noncompliance with insulin, myocardial infarction, and gastrointestinal bleeding. B. Symptoms of DKA include polyuria, polydipsia, fatigue, nausea, and vomiting, developing over 1 to 2 days. Abdominal pain is prominent in 25%. II. Physical examination 1. Patients are typically flushed, tachycardic, tachypneic, and volume depleted with dry mucous membranes. Kussmaul's respiration (rapid, deep breathing and air hunger) occurs when the serum pH is between 7.0 and 7.24. 2. A fruity odor on the breath indicates the presence of acetone, a byproduct of diabetic ketoacidosis. 3. Fever, although seldom present, indicates infection. Eighty percent of patients with diabetic ketoacidosis have altered mental status. Most are awake but confused; 10% are comatose. B. Laboratory findings 1. Serum glucose level >300 mg/dL 2. pH <7.35, pCO2 40 mm Hg 3. Bicarbonate level below normal with an elevated anion gap 4. Presence of ketones in the serum III. Differential diagnosis A. Differential diagnosis of ketosis-causing condi- tions 1. Alcoholic ketoacidosis occurs with heavy drinking and vomiting. It does not cause an elevated glu- cose. 2. Starvation ketosis occurs after 24 hours without food and is not usually confused with DKA because glucose and serum pH are normal. B. Differential diagnosis of acidosis-causing condi- tions 1. Metabolic acidoses are divided into increased anion gap (>14 mEq/L) and normal anion gap; anion gap = sodium - (CI- + HCO 3- ). 2. Anion gap acidoses can be caused by ketoacidoses, lactic acidosis, uremia, salicylate, methanol, ethanol, or ethylene glycol poisoning. 3. Non-anion gap acidoses re associated with a normal glucose level and absent serum ketones. Causes of non-anion gap acidoses include renal or gastrointestinal bicarbonate loss. C. Hyperglycemia caused by hyperosmolar nonketotic coma occurs in patients with type 2 diabetes with severe hyperglycemia. Patients are usually elderly and have a precipitating illness. Glu- cose level is markedly elevated (>600 mg/dL), osmolarity is increased, and ketosis is minimal. IV.Treatment of diabetic ketoacidosis A. Fluid resuscitation 1. Fluid deficits average 5 liters or 50 mL/kg. Resusci- tation consists of 1 liter of normal saline over the first hour and a second liter over the second and third hours. Thereafter, 1/2 normal saline should be infused at 100-120 mL/hr. 2. When the glucose level decreases to 250 mg/dL, 5% dextrose should be added to the replacement fluids to prevent hypoglycemia. If the glucose level declines rapidly, 10% dextrose should be infused along with regular insulin until the anion gap nor- malizes. B. Insulin 1. An initial loading dose consists of 0.1 U/kg IV bolus. Insulin is then infused at 0.1 U/kg per hour. The biologic half-life of IV insulin is less than 20 min- utes. The insulin infusion should be adjusted each hour so that the glucose decline does not exceed 100 mg/dL per hour. 2. The insulin infusion rate may be decreased when the bicarbonate level is greater than 20 mEq/L, the anion gap is less than 16 mEq/L, or the glucose is <250 mg/dL. C. Potassium 1. The most common preventable cause of death in patients with DKA is hypokalemia. The typical deficit is between 300 and 500 mEq. 2. Potassium chloride should be started when fluid therapy is started. In most patients, the initial rate of potassium replacement is 20 mEq/h, but hypokalemia requires more aggressive replacement (40 mEq/h). 3. All patients should receive potassium replacement, except for those with renal failure, no urine output, or an initial serum potassium level greater than 6.0 mEq/L. D. Sodium. For every 100 mg/dL that glucose is ele- vated, the sodium level should be assumed to be higher than the measured value by 1.6 mEq/L. E. Phosphate. Diabetic ketoacidosis depletes phosphate stores. Serum phosphate level should be checked after 4 hours of treatment. If it is below 1.5 mg/dL, potassium phosphate should be added to the IV solution in place of KCl. F. Bicarbonate therapy is not required unless the arterial pH value is <7.0. For a pH of <7.0, add 50 mEq of sodium bicarbonate to the first liter of IV fluid. G. Magnesium. The usual magnesium deficit is 2-3 gm. If the patient's magnesium level is less than 1.8 mEq/L or if tetany is present, magnesium sulfate is given as 5g in 500 mL of 0.45% normal saline over 5 hours. H. Additional therapies 1. A nasogastric tube should be inserted in semicon- scious patients to protect against aspiration. 2. Deep vein thrombosis prophylaxis with subcuta- neous heparin should be provided for patients who are elderly, unconscious, or severely hyperosmolar (5,000 U every 12 hours). V. Monitoring of therapy A. Serum bicarbonate level and anion gap should be monitored to determine the effectiveness of insulin therapy. B. Glucose levels should be checked at 1-2 hour inter- vals during IV insulin administration. C. Electrolyte levels should be assessed every 2 hours for the first 6-8 hours, and then q8h. Phosphorus and magnesium levels should be checked after 4 hours of treatment. D. Plasma and urine ketones are helpful in diagnosing diabetic ketoacidosis, but are not necessary during therapy. VI.Determining the underlying cause A. Infection is the underlying cause of diabetic ketoacidosis in 50% of cases. Infection of the urinary tract, respiratory tract, skin, sinuses, ears, or teeth should be sought. Fever is unusual in diabetic ketoacidosis and indicates infection when present. If infection is suspected, antibiotics should be promptly initiated. B. Omission of insulin doses is often a precipitating factor. Myocardial infarction, ischemic stroke, and ab- dominal catastrophes may precipitate DKA. VII. Initiation of subcutaneous insulin A. When the serum bicarbonate and anion gap levels are normal, subcutaneous regular insulin can be started. B. Intravenous and subcutaneous administration of insulin should overlap to avoid redevelopment of ketoacidosis. The intravenous infusion may be stopped 1 hour after the first subcutaneous injection of insulin. C. Estimation of subcutaneous insulin requirements 1. Multiply the final insulin infusion rate times 24 hours. Two-thirds of the total dose is given in the morning as two-thirds NPH and one-third regular insulin. The remaining one-third of the total dose is given before supper as one-half NPH and one-half regular insulin. 2. Subsequent doses should be adjusted according to the patient's blood glucose response. References, see page 360. Diabetes Up to 4 percent of Americans have diabetes. Vascular disease accounts for over 70 percent of deaths in adults with diabetes. I. Classification and pathophysiology A. Type 1 diabetes mellitus primarily occurs in children and adolescents. Patients with type 1 diabetes have an absolute deficiency of endogenous insulin and require exogenous insulin for survival. B. Type 2 diabetes accounts for 90% of individuals with diabetes mellitus, and the incidence increases in frequency with age, obesity and physical inactivity. The initial problem in type 2 diabetes is resistance to the action of insulin at the cellular level. II. Screening A. All adults should be screened for diabetes at regular intervals. Factors that confer an increased risk for development of diabetes include impaired glucose tolerance, hypertension, lipid disorders, coronary artery disease, obesity, and physical inactivity. B. A fasting plasma glucose test is recommended for screening. A level of 110 to 125 mg/dL is considered “impaired fasting glucose,” and a value of greater than or equal to 126 mg/dL, if confirmed on repeat testing, establishes the diagnosis of diabetes. If a patient is found to have a random plasma glucose level over 160 mg/dL, more formal testing with a fasting plasma glucose should be considered. Criteria for Diagnosis of Diabetes in Nonpregnant Adults Fasting plasma glucose 126 mg/dL or higher or Random plasma glucose 200 mg/dL or higher with symptoms of diabetes (fatigue, weight loss, polyuria, polyphagia, polydipsia) or Abnormal two-hour 75-g oral glucose tolerance test result, with glucose 200 mg/dL or higher at two hours Any abnormal test result must be repeated on a subsequent occasion to establish the diagnosis III. Screening for microvascular complications in diabet- ics A. Retinopathy. Diabetic retinopathy and macular de- generation are the leading causes of blindness in diabetes. Adults with diabetes should receive annual dilated retinal examinations beginning at the time of diagnosis. B. Nephropathy. Diabetes-related nephropathy affects 40% of patients with type 1 disease and 10-20% of those with type 2 disease. Microalbuminuria can be detected with annual urine screening for albu- min/creatinine ratio. C. Peripheral neuropathy affects many patients with diabetes and causes nocturnal or constant pain, tingling and numbness. The feet should be evaluated regularly for sensation, pulses and sores. D. Autonomic neuropathy is found in many patients with long-standing diabetes, resulting in diarrhea, constipa- tion, gastroparesis, vomiting, orthostatic hypotension, and erectile or ejaculatory dysfunction. Routine Diabetes Care History Review physical activity, diet, self-monitored blood glucose readings, medications Assess for symptoms of coronary heart disease Evaluate smoking status, latest eye examination results, foot care Physical examination Weight Blood pressure Foot examination Pulse Sores or callus Monofilament test for sensation Insulin injection sites Refer for dilated retinal examination annually Laboratory studies HbA1c every three to six months Annual fasting lipid panel Annual urine albumin/creatinine ratio Annual serum creatinine IV. Treatment of type 2 diabetes mellitus A. The patient should monitor his fasting blood glucose. Some readings should also be obtained after meals and at other times during the day, and when hypoglycemia is suspected. American Diabetes Association goals for the treat- ment of diabetes Preprandial blood glucose level 80 to 120 mg/dL Bedtime blood glucose level 100 to 140 mg/dL Normal hemoglobin A 1c (HbA 1c ) level 4% to 6% Target HbA 1c level <7% “Take action” HbA 1c level >8% V. Sulfonylureas A. Sulfonylureas promote increased pancreatic insulin secretion. Sulfonylureas can lead to hypoglycemia and weight gain. All members of this drug class appear to be equally efficacious, with a decrease in fasting plasma glucose concentration of 60 to 70 mg/dL and a drop in HbA 1c levels of about 1.5% to 2%. B. Most patients who are of normal weight or only moder- ately obese should initially take a sulfonylurea. A typical initial sulfonylurea regimen consists of 2.5 mg of glipizide (Glucotrol) or glyburide (Micronase) taken before breakfast. If adequate glycemic control is not attained in the next two to four weeks, the dose can be increased to 5 mg and then 10 mg. VI. Meglitinides A. The mechanism of action of the meglitinides is similar to that of the sulfonylureas. Unlike sulfonylureas, however, meglitinides have a “quick on-quick off” action that offers improved postprandial control and reduces the incidence of late postprandial hypoglycemia. B. The efficacy of the meglitinides is similar to that of the sulfonylureas, leading to a decrease in the fasting plasma glucose level of 60 mg/dL and in HbA 1c of 1.7% to 1.9%. The main disadvantages of the meglitinides are their frequent dosing requirements and the risk for hypoglycemia and hyperinsulinemia, which is the same as with the sulfonylureas. C. Repaglinide (Prandin) is taken shortly before each meal in doses ranging from 0.5 to 4 mg, up to three or four times a day. It may benefit patients with unpredict- able meal schedules or large postprandial glucose excursions. D. Nateglinide (Starlix) is a derivative of phenylalanine. Nateglinide appears to have a faster onset and disap- pearance of action than repaglinide but a somewhat reduced efficacy. 60-120 mg tid before meals. VII. Biguanides A. Metformin (Glucophage), a biguanide, decreases hepatic glucose production. Gastrointestinal distress is common (eg, abdominal pain, nausea, diarrhea), most prominent during initiation of therapy. The incidence of lactic acidosis from metformin is only 0.03 per 1,000 patient-years. B. Metformin lowers fasting plasma glucose levels by 60 to 70 mg/dL and HbA 1c by 1.5% to 2.0%. It is equally efficacious in non-obese patients. It is an appropriate first-line therapy for patients of any weight. Contraindications to metformin therapy Renal dysfunction Serum creatinine level >1.5 mg/dL in men, >1.4 mg/dL in women Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular admin- istration of iodinated contrast materials. Treatment may be restarted 48 hours after the procedure when normal renal function is documented. Treatment should be carefully initiated in patients >80 years of age after measurement of creatinine clearance demonstrates that renal function is not reduced. Congestive heart failure that requires pharmacologic therapy Hepatic dysfunction Dehydration Acute or chronic metabolic acidosis (diabetic ketoacidosis) Known hypersensitivity to metformin VIII. Alpha-glucosidase inhibitors A. The alpha-glucosidase inhibitors slow the rate of absorption of carbohydrates. The use of acarbose (Precose) and miglitol (Glyset) is limited by both their relatively mild efficacy and the high frequency of gastrointestinal distress. These drugs may be suitable for mild diabetes or for those taking other oral agents who continue to have large postprandial blood glucose increases. They must be taken with each meal to reduce the rise of postprandial plasma glucose levels. B. Alpha-glucosidase inhibitors decrease postprandial plasma glucose levels by 40 to 60 mg/dL, fasting plasma glucose levels by 20 to 30 mg/dL, and HbA 1c levels by 0.5% to 1.0%. Many patients experience abdominal bloating, cramping, and flatulence during initial therapy. C. Acarbose (Precose) is available as 50 and 100 mg tablets which should be taken with the first bite of each meal; 50 mg three times daily. D. Miglitol (Glyset) may be started at 50 mg tid with the first bite of each meal. IX.Thiazolidinediones A. Thiazolidinediones increase insulin sensitivity in muscle resulting in lower circulating glucose concentrations. Thiazolidinediones, rosiglitazone (Avandia) and pioglitazone (Actos), decrease fasting plasma glu- cose by 30 to 60 mg/dL and decrease HbA 1c level by 1% to 1.5%. Pioglitazone is given once daily and rosiglitazone once or twice daily. Rosiglitazone and pioglitazone may be used for monotherapy or in combination with metformin or a sulfonylurea or insulin. Thiazolidinediones are no more effective than metformin, and they should be used only in patients who have contraindications to metformin. B. Adverse effects of thiazolidinedione therapy include weight gain and peripheral edema. Expansion of the extracellular fluid space can occur, and anemia is occasionally seen. Therapy is contraindicated in advanced congestive heart failure. X. Choice of agent A. Diet, weight loss, and exercise remain the most important initial steps in the management of type 2 diabetes. Pharmacologic therapy is mandatory for patients who are unable to achieve glycemic control with lifestyle modifications or who have significant symptoms. B. Lean patients with type 2 diabetes usually have insulin deficiency as the predominant feature, and a sulfonylurea is recommended in this subgroup. If control remains suboptimal, metformin or an al- pha-glucosidase inhibitor may be added. First-line therapy with metformin is also reasonable, especially if glucose levels are only mildly elevated, because risk of hypoglycemia in these patients is increased with sulfonylurea therapy. C. Overweight patients. Metformin should be considered the first-line agent because of the weight loss and lack of hypoglycemia. If control is suboptimal with metformin, the addition of a thiazolidinedione may be beneficial. If adequate control cannot be achieved with two drugs, the addition of a third oral agent should be considered. Alternatively, insulin could be added or substituted entirely (a patient who is 20 percent above ideal body weight and has a fasting blood glucose of 180 mg/dL should be started on a total dose of 21 units per day). Pharmacotherapy of Type 2 Diabetes Agent Starting dose Maximum dose Comments Sulfonylurea s Glipizide (Glucotrol) Glyburide (DiaBeta, Micronase ) Glimepirid e (Amaryl) 5 mg daily 2.5 mg daily 1 mg daily 20 mg twice daily 10 mg twice daily 8 mg daily May cause hypoglycemia, weight gain. Maximum dose should be used only in combi- nation with insu- lin therapy Biguanide Metformin (Glucopha ge) 500 mg daily 850 mg three times daily Do not use if serum creatinine is greater than 1.4 mg/dL in women or 1.5 mg/dL in men or in the presence of heart failure, chronic obstruc- tive pulmonary disease or liver disease; may cause lactic acidosis Glyburide/ metformin (Glucovance ) 25 mg/250 mg; 2.5 mg/500 mg; 5 mg/500 mg 1 tab qAM- bid Thiazolidine- diones Pioglitazon e (Actos) Rosiglitazo ne (Avandia) 15 mg daily 4 mg daily 45 mg per day 4 mg twice daily Should be used only in patients who have con- traindications to metformin Alpha- glucosidase inhibitor Acarbose (Precose) Miglitol (Glyset) 50 mg tid 50 mg tid 100 mg three times daily 100 mg three times daily Flatulence; start at low dose to minimize side effects; take at mealtimes Meglitamide Repaglinid e (Prandin) Nateglinid e (Starlix) 0.5 mg be- fore meals 120 mg tid before meals or 60 mg tid be- fore meals 4 mg tid-qid 120 mg tid Take at meal- times XI.Treatment of type 1 diabetes mellitus Goals of intensive diabetes treatment Premeal blood glu- cose level Postpran- dial (ie, mealtime) glucose level Bedtime glucose level Hemoglobin A 1c (HbA 1c ) level 90 to 130 mg/dL 120 to 180 mg/dL 110 to 150 mg/dL Less than 6.5% A. Basics of insulin use 1. Tighter control is recommended for pregnant women. Looser control may be appropriate in young children; elderly patients with active cardiac, cognitive, or visual disorders; and patients who (1) have hypoglycemic unawareness or recurrent severe hypoglycemia, (2) abuse alcohol or drugs, (3) have poor social support, or (4) have diabetes resulting from combined exocrine and endocrine pancreatic failure. Looser control is also indicated in patients in whom a hypoglycemic event might put them or others in danger (eg, bus drivers). 2. Starting insulin dose in otherwise healthy patients in whom type 1 diabetes was recently diagnosed, during the “honeymoon period” is typically 10 to 15 U/day (or 0.2 to 0.6 U/kg per day). Two-thirds of the total dose of intermediate-acting isophane insulin suspension (NPH, or N) is given in the morning and one-third at dinnertime. Short-acting regular insulin or a more rapid-acting insulin, such as lispro (LP) or aspart (as insulin analogue), is given with breakfast and dinner. 3. Over time, patients who have type 1 diabetes without intercurrent illness typically need 0.5 to 1 U/kg per day. Higher doses may be required during pregnancy and the adolescent growth spurt. If the patient's condition is unstable because of diabetic ketoacidosis, the insulin requirements may rise in the short term to 1 to 1.5 U/kg per day or higher. Initiating Insulin Therapy in a Patient with Newly Diagnosed Type 1 Diabetes The total daily insulin dosage is 0.3 unit per kg of body weight. Two-thirds of the total daily insulin dose may be given 20 to 30 minutes before breakfast and one-third of the dose may be given 20 to 30 minutes before the evening meal. NPH insulin and regular insulin can be given in a 2:1 ratio for the breakfast dose and a 1:1 ratio for the evening-meal dose. As more complete insulin deficiency develops this regimen becomes less effective. Pharmacokinetic properties of types of insulin Type of insulin Onset Peak effect Dura- tion of ac- tion Dosing interval Mealtime Insulin Lispro (Humalog) (rapid-acting ) 5-15 min 30 min-1.5 hr 2 to 4 hours Mealtime Aspart (Novolog) (rapid-acting ) 5-15 min 1-2 hr Mealtime Regular (Humulin R) (short-acting ) 30-60 min 2-4 hr 5 to 8 hours 20-45 min be- fore meals Background Insulin Isophane insulin sus- pension (NPH) (Humulin N) (intermedi- ate-acting) 45 min-3 hr 4.5-7 hr 18 to 28 hours Twice daily Lente (Humulin L) (intermedi- ate-acting) 1-3 hr 6-8 hr 13 to 20 hours Twice daily Type of insulin Onset Peak effect Dura- tion of ac- tion Dosing interval Glargine (Lantus) (long-acting) 1.5-2 hr No peak 13 to 18 hours Once daily 4. In patients with type 2 diabetes in whom oral agents have failed, the starting dose of N insulin is 0.15 U/kg at bedtime (when oral agents are continued) or a total multidose regimen of 0.3 to 0.7 U/kg per day (when all oral agents are discontinued). The total insulin dose required in obese patients with type 2 diabetes averages 1.2 U/kg per day. 5. Lispro insulin is superior to regular insulin in controlling postprandial glucose spikes when given in addition to a background insulin. Other advan- tages of lispro insulin are that it can be injected anytime from 15 minutes before to shortly after the meal, and it carries less risk of hypoglycemia and weight gain. 6. Glargine insulin is a human insulin that is slowly released, resulting in a relatively constant concen- tration over 24 hours with no pronounced peak. When patients are switched to glargine from twice-daily N insulin, it is suggested that 10% to 20% less glargine be given than the previous daily total dose of N insulin. Patients require regular, lispro, or aspart insulin boluses with each meal. Because of its consistency and prolonged action, glargine is a superior background insulin. Other peakless long-acting analogues (eg, Determir) will be available soon. B. Multiple-dose strategies 1. Near-normoglycemia usually requires two to four daily injections or use of the insulin pump. 2. The most physiologic ratio of mealtime insulin to background insulin is 50:50. However, some active adolescents do best on a 60:40 ratio, whereas more sedentary adults might need a 40:60 ratio. Conventional and intensive insulin regimes No. of injec- tions Regi- men 8 AM/Noo n/6 PM/10P M Morn- ing dose Noon dose Din- ner dose Bed- time dose Two injections 40% meal- time N+R/0/ N+R/0 or 20% R or LP - 20% R or LP - 60% back- ground N+LP/0/ N+LP/0 40% N - 20% N - Three injections 40% meal- time N+LP/0/ LP/N or 20% LP or R - 20% LP or R - 60% back- ground N+R/0/ R/N 40% N - - 20% N Three injections 50% meal- time U+R/R/ U+R/0 or 15% R or LP 15% R or LP 20% R or LP - 50% back- ground U+LP/L P/U+LP/ 0 20% U - 30% - References, see page 360. Hypothyroidism Hypothyroidism is second only to diabetes mellitus as the most common endocrine disorder, and its prevalence may be as high as 18 cases per 1,000 persons in the general population. The disorder becomes increasingly common with advancing age, affecting about 2 to 3 percent of older women. I. Etiology A. Primary hypothyroidism 1. The most common cause of hypothyroidism is Hashimoto's (chronic lymphocytic) thyroiditis. Most patients who have Hashimoto's thyroiditis have symmetrical thyroid enlargement, although many older patients with the disease have atrophy of the gland. Anti-thyroid peroxidase (TPO) antibodies are present in almost all patients. Some patients have blocking antibodies to the thyroid-stimulating hor- mone (TSH) receptor. 2. Hypothyroidism also occurs after treatment of hyperthyroidism by either surgical removal or radioiodine ablation. Less common causes of h y p o t h y r o i d i s m i n c l u d e c o n g e n i t a l dyshormonogenesis, external radiotherapy, infiltrative diseases, such as amyloidosis, and peripheral resistance to thyroid hormone action. B. Secondary and central hypothyroidism. Pituitary and hypothalamic dysfunction can lead to hypothyroidism. Pituitary adenomas, craniopharyngiomas, pinealomas, sarcoidosis, histiocytosis X, metastatic disease, primary central nervous system (CNS) neoplasms (eg, menin- gioma), and head trauma all may cause hypothyroidism. C. Transient hypothyroidism. Subacute thyroiditis is frequently associated with a hyperthyroid phase of 4 to 12 weeks' duration; a 2- to 16-week hypothyroid phase follows, before recovery of thyroid function. Subacute granulomatous (de Quervain's) thyroiditis and subacute lymphocytic (painless) thyroiditis are viral and autoim- mune disorders, respectively; the latter condition may occur post partum. II. Diagnosis A. Symptoms and signs of hypothyroidism include fatigue, weight gain, muscle weakness and cramps, fluid retention, constipation, and neuropathy (eg, carpal tunnel syndrome). Severe hypothyroidism may be associated with carotenemia, loss of the lateral aspect of the eyebrows, sleep apnea, hypoventilation, bradycardi a, peri cardi al effusi on, anemi a, hyponatremia, hyperprolactinemia, hypercholesterol- emia, hypothermia, and coma. B. In patients with primary hypothyroidism, the thy- roid-stimulating hormone (TSH) level is elevated, and free thyroid hormone levels are depressed. In contrast, patients with secondary hypothyroidism have a low or undetectable TSH level. C. TSH results have to be interpreted in light of the pa- tient's clinical condition. A low TSH level should not be misinterpreted as hyperthyroidism in the patient with clinical manifestations of hypothyroidism. When symp- toms are nonspecific, a follow-up assessment of the free thyroxine (T 4 ) level can help distinguish between primary and secondary hypothyroidism. Laboratory Values in Hypothyroidism TSH level Free T 4 level Free T 3 level Likely diagnosis High Low Low Primary hypothyroidism High (>10 μU per mL) Nor- mal Nor- mal Subclinical hypothyroidism with high risk for future development of overt hypothyroidism High (6 to 10 μU per mL) Nor- mal Nor- mal Subclinical hypothyroidism with low risk for future de- velopment of overt hypothyroidism High High Low Congenital absence of T 4 -T 3 ―converting en- zyme; amiodarone (Cordarone) effect on T 4 -T 3 conversion High High High Peripheral thyroid hor- mone resistance Low Low Low Pituitary thyroid defi- ciency or recent with- drawal of thyroxine after excessive re- placement therapy Causes of Hypothyroidism Primary hypothyroidism (95% of cases) Idiopathic hypothyroidism Hashimoto's thyroiditis Irradiation of the thyroid subsequent to Graves' disease Surgical removal of the thyroid Late-stage invasive fibrous thyroiditis Iodine deficiency Drug therapy (eg, lithium, interferon) Infiltrative diseases (eg, sarcoidosis, amyloidosis, scleroderma, hemochromatosis) Secondary hypothyroidism (5% of cases) Pituitary or hypothalamic neoplasms Congenital hypopituitarism Pituitary necrosis (Sheehan's syndrome) III. Treatment of hypothyroidism A. Initiating thyroid hormone replacement 1. Most otherwise healthy adult patients with hypothyroidism require thyroid hormone replace- ment in a dosage of 1.7 mcg per kg per day, with requirements falling to 1 mcg per kg per day in the elderly. Thus, (Synthroid) in a dosage of 0.10 to 0.15 mg per day is needed to achieve euthyroid status. For full replacement, children may require up to 4 mcg per kg per day. 2. In young patients without risk factors for cardiovas- cular disease, thyroid hormone replacement can start close to the target goal. In most healthy young adults, replacement is initiated using levothyroxine in a dosage of 0.075 mg per day, with the dosage increased slowly as indicated by continued eleva- tion of the TSH level. 3. Levothyroxine (Synthroid) should be initiated in a low dosage in older patients and those at risk for cardiovascular compromise; the usual starting dosage is 0.025 mg per day, increased in incre- ments of 0.025 to 0.050 mg every four to six weeks until the TSH level returns to normal. Commonly Prescribed Thyroid Hormone Prepara- tions Generic Name Brand Name(s) Approxi- mate Equiv- alent Dose Prepara- tions Levothyroxin e Synthroid Levothroid Levoxyl Eltroxin 100 mcg Tablets: 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, 300 mcg IV. Monitoring thyroid function A. In patients with an intact hypothalamic-pituitary axis, the adequacy of thyroid hormone replacement can be followed with serial TSH assessments. The TSH level should be evaluated no earlier than four weeks after an adjustment in the levothyroxine dosage. The full effects of thyroid hormone replacement on the TSH level may not become apparent until after eight weeks of therapy. B. In patients with pituitary insufficiency, measurements of free T 4 and T 3 levels can be performed to deter- mine whether patients remain euthyroid. TSH or free T 4 levels are monitored annually in most patients with hypothyroidism. V. Subclinical Hypothyroidism A. The TSH level can be mildly elevated when the free T 4 and T 3 levels are normal, a situation that occurs most often in women and becomes increasingly common with advancing age. This condition has been termed “subclinical hypothyroidism.” B. In patients at higher risk for osteoporosis or fractures, the deleterious effects of excessive thyroid hormone can be avoided by withholding replacement until the free T 4 and T 3 levels drop below normal. References, see page 360. Obesity Obesity is a risk factor for many medical illnesses, and a modest reduction of 5% to 10% of body weight can modify risk factors for heart disease, including lipid levels, glycemic control, and blood pressure. Obesity is defined as a body mass index (BMI) of 30 kg per m 2 or more. Overweight is defined as a BMI of 25 to 29.9 kg per m 2 . I. Diagnosis of obesity begins with the determination of BMI. The BMI can be ascertained by measuring the patient's height and weight and then using a BMI table to find the BMI value. The distribution of fat based on the waist circumference or the waist-to-hip circumference ratio (WHR) and investigations for comorbid conditions such as diabetes mellitus, dyslipidemia, hypertension, and heart disease should be determined. II. Management A. For most patients, the initial weight loss objective should be a 10 percent reduction from baseline body weight over a period of about four to six months. After six months, the rate of weight loss often stabilizes or slows. B. An overweight individual with a BMI of less than 30 kg per m 2 and no health risk factors should have a target, six-month BMI in the range of 20 to 27. A decrease of 300 to 500 kcal per day will produce weight losses of 0.5 to 1 lb per week (10 percent reduction at six months). C. Nutrition therapy 1. A meal plan that creates an energy deficit of 500 to 1,000 kcal per day less than the individual's average daily intake will usually be suitable for weight reduc- tion. Along with caloric reduction, a reduction in total fat consumption should be recommended. Caloric restrictions for the treatment of overweight and obesity can be classified as follows: a. Moderate deficit diet (all health risk groups). Women: 1200+ kcal per day; men: 1400+ kcal per day b. Low-calorie diet (moderate to extremely high health risk groups). Women: 800 to 1200 kcal per day; men: 800 to 1400+ kcal per day c. Very low-calorie diet (high to extremely high- health risk groups). Less than 800 kcal per day. 2. Among patients treated with a moderate deficit diet, weight losses average about 1 lb (0.45 kg) per week. D. Physical activity. Although most weight loss is achieved through decreased caloric intake, physical activity is the primary factor responsible for increased caloric expenditure. The long-term physical activity goal of most adults should be to perform 30 or more min- utes of physical activity each day. III.Treatment of obesity A. Obesity is a chronic condition requiring long-term therapy. If obesity is not treated for the duration of the patient's life, obesity re-emerges as a potent comorbid risk factor for disability or premature death. B. Candidates for use of weight loss drugs are patients who have failed to lose weight with diet and exercise therapy, have a body mass index greater than 27 to 30, or have risk factors or medical conditions caused by obesity. Weight loss medications should not be used by pregnant or lactating women. Any medical condition (eg, cardiovascular disease) should be stable before these drugs are prescribed. Anorexiants are contraindi- cated in patients with glaucoma. C. Goals of therapy. Weight loss should exceed 2 kg during the first month of drug therapy, fall more than 5 percent below baseline by three to six months, and remain at this level to be considered effective. Weight loss of 10 to 15 percent is considered a good response and loss exceeding 15 percent is considered an excellent response. Weight loss may lower blood pressure and serum lipid concentrations, increase insulin sensitivity, and reduce hyperglycemia. Anorectic Medication for Obesity Treatment Medica- tion Sc he dul e Trade Name(s ) Dosage (mg) Common Use Phenter mine IV 8, 15, 30 Initial dose: 8-15 mg/d Higher dose: 15 mg bid or 30 mg q AM Adipex- P 37.5 Initial dose: ½ tablet/d Higher dose: ½ tablet bid or 37.5- mg tablet q AM Fastin 30 1 capsule q AM Phenter mine resin IV Ionamin 15, 30 Initial dose: 15 mg/d Higher dose: 15 mg bid or 30 mg q AM Medica- tion Sc he dul e Trade Name(s ) Dosage (mg) Common Use Diethylpr opion IV Tenuat e Tenuat e Dospan (sus- tained-r elease form) 25 75 25 mg tid 75 mg qd Sibutrami ne IV Meridia 5, 10, 15 Initial dose: 5-10 mg/d Higher dose: 15- 25 mg/d Orlistat IV Xenical 120 Initial dose: 1 cap- sule with a fatty meal qd; bid; or tid D. Anorexiant therapy 1. Anorexiants that have low potential for abuse are phentermine (eg, Adipex-P, Fastin, Ionamin), mazindol (Mazanor, Sanorex), and diethylpropion (Tenuate). 2. Anorexiants may cause patients to feel nervous or experience insomnia and dry mouth. Patients should expect to lose about 0.5 lb per week. E. Orlistat (Xenical) therapy 1. Orlistat inhibits gastrointestinal lipases. Minor gastrointestinal side effects of steatorrhea, oily spotting, and fecal urgency usually resolve with continued use. One-fourth to one-half of motivated patients have success with orlistat therapy in that it prevents weight regain after dieting or it decreases weight by 5% to 10%. 2. Orlistat should be prescribed as 120 mg three times daily with meals, along with a diet restricted to 30% of calories obtained from fat. A multivitamin should be taken daily. F. Sibutramine (Meridia, Reductil) therapy 1. Si but r ami ne i s a s er ot oni n and norepinephrine-uptake inhibitor that increases energy expenditure and satiety. Treatment with 10 to 15 mg/day of sibutramine results in weight loss between 10.6 to 13.4 lb. Sibutramine also has been shown to maintain weight loss attained by dieting. 2. Side effects include insomnia, dizziness, constipa- tion, and dry mouth. Sibutramine increases heart rate 4 or 5 beats per minute and blood pressure by 1 to 3 mm Hg. Pre-existing hypertension should be controlled before sibutramine is prescribed. G. Metformin (Glucophage) has been used for weight loss in patients who are overweight without diabetes. Women who combine metformin with a low-calorie and reduced carbohydrate diet can lose 20 to 30 pounds in one year. Metformin helps maintain weight loss. Initial dose is 500 mg BID with meals, increasing to 1500 mg/day. IV. Surgical therapy A. Surgical therapy should be considered in patients with severe obesity meeting the following criteria: 1. A BMI of 40 kg per m 2 or more and have failed in attempts at medical treatment, or 2. A BMI of 35 kg per m 2 or more with coexisting morbidities or other complicating risk factors. References, see page 360. Rheumatic and Hematologic Disorders Osteoarthritis Approximately 40 million Americans of all ages are affected by osteoarthritis and 70 to 90 percent of Americans older than 75 years have at least one involved joint. The preva- lence of osteoarthritis ranges from 30 to 90 percent. Clinical Features of Osteoarthritis Symptoms Joint pain Morning stiffness lasting less than 30 minutes Joint instability or buckling Loss of function Pattern of joint involvement Axial: cervical and lumbar spine Peripheral: distal interphalangeal joint proximal interphalangeal joint first carpometacarpal joints, knees, hips Signs Bony enlargement at affected joints Limitation of range of motion Crepitus on motion Pain with motion Malalignment and/or joint deformity I. Clinical evaluation A. Pathogenesis. Osteoarthritis is caused by a combina- tion of mechanical, cellular, and biochemical processes leading to changes in the composition and mechanical properties of the articular cartilage and degenerative changes and an abnormal repair response. B. The typical patient with osteoarthritis is middle-aged or elderly and complains of pain in the knee, hip, hand or spine. The usual presenting symptom is pain involving one or only a few joints. Joint involvement is usually symmetric. The patient usually has pain, stiffness, and some limitation of function. Pain typically worsens with use of the affected joint and is alleviated with rest. Morning stiffness lasting less than 30 minutes is common. (morning stiffness in rheumatoid arthritis lasts longer than 45 minutes.) C. Patients with osteoarthritis of the hip may complain of pain in the buttock, groin, thigh or knee. Hip stiffness is common, particularly after inactivity. Involvement of the apophyseal or facet joints of the lower cervical spine may cause neck symptoms, and involvement of the lumbar spine may cause pain in the lower back. Pa- tients may have radicular symptoms, including pain, weakness and numbness. D. The physical examination should include an assess- ment of the affected joints, surrounding soft tissue and bursal areas. Joint enlargement may become evident. Crepitus, or a grating sensation in the joint, is a late manifestation. E. Laboratory work may include erythrocyte sedimentation rate and rheumatoid factor. Synovial fluid analysis may be conducted to help exclude other diagnoses. F. Radiographic findings consistent with osteoarthritis include presence of joint space narrowing, osteophyte formation, pseudocyst in subchondral bone, and increased density of subchondral bone. The absence of radiographic changes does not exclude the diagno- sis of osteoarthritis. Radiographs are recommended for patients with trauma, joint pain at night, progressive joint pain, significant family history of inflammatory arthritis, and children younger than 18 years. Distinction Between Rheumatoid Arthritis and Osteoarthritis Feature Rheumatoid ar- thritis Osteoarthritis Primary joints af- fected Metacarpophalang eal Proximal interphalangeal Distal interphalangeal Carpometacarpal Heberden’ s nodes Absent Frequently pres- ent Joint char- acteristics Soft, warm, and tender Hard and bony Stiffness Worse after rest- ing (eg, morning stiffness) Worse after effort Laboratory findings Positive rheuma- toid factor Elevated ESR and C reactive protein Rheumatoid fac- tor negative Normal ESR and C reactive pro- tein II. Treatment of osteoarthritis A. Analgesics. Acetaminophen at doses of up to 4 g/day is the drug of choice for pain relief. Hepatotoxicity is primarily seen only in patients who consume excessive amounts of alcohol. Combination analgesics (eg, acetaminophen with aspirin) increase the risk for renal failure. 1. Opioid analgesics, such as codeine, oxycodone, or propoxyphene may be beneficial for short-term use. 2. Tramadol (Ultram) alone or in combination with acetaminophen are useful when added to an NSAID or COX-2 inhibitor. The combination of tramadol and acetaminophen (37.5 mg/325 mg) is roughly equiva- lent to 30 mg codeine and 325 mg of acetaminophen. B. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be indicated in patients with noninflammatory OA who fail to respond to acetaminophen. NSAIDs are more efficacious than acetaminophen. Gastrointestinal symptoms were more frequent with use of nonselective NSAIDs than with acetaminophen. Nonacetylated salicylates (salsalate, choline magnesium trisalicylate), sulindac, and perhaps nabumetone appear to have less renal toxicity. The nonacetylated salicylates and nabumetone (Relafen) have less antiplatelet activity. Low-dose ibuprofen (less than 1600 mg/day) may have less serious gastrointestinal toxicity. C. COX-2 inhibitors have a 200 to 300 fold selectivity for inhibition of COX-2 over COX-1. Celecoxib (Celebrex) is available. Two other selective COX-2 inhibitors, rofecoxib (Vioxx) and valdecoxib (Bextra), were with- drawn from the worldwide market because of an increased risk of serious cardiovascular adverse events. 1. Selective COX-2 inhibitors are an option for patients with a history of peptic ulcer, gastrointestinal bleed- ing, or gastrointestinal intolerance to NSAIDs (includ- ing salicylates). These agents are contraindicated in cardiovascular disease or with multiple risk factors for atherosclerotic coronary heart disease. An alternative approach is the use of a nonselective NSAID and misoprostol or a proton pump inhibitor. Selective COX-2 and nonselective NSAIDs should be avoided in renal disease, congestive heart failure, cirrhosis, and volume depletion. Celecoxib dosage is 100 mg twice daily and 200 mg once daily. D. Adverse effects. NSAID use is often limited by toxicity. Among the side effects that can occur are: 1. Rash and hypersensitivity reactions. 2. Abdominal pain and gastrointestinal bleeding. 3. Impairment of renal, hepatic, and bone marrow function, and platelet aggregation. 4. Central nervous system dysfunction in the elderly. 5. NSAIDs are contraindicated in patients with active peptic ulcer disease. Non-specific COX inhibitors should be avoided in patients with a history of peptic ulcer disease. Specific COX-2 inhibitors are pre- ferred in these individuals. 6. Non-specific COX-2 inhibitors must be used with caution in patients on warfarin. NSAID-induced platelet dysfunction can increase the risk of bleeding. Specific COX-2 inhibitors can be used in this setting. 7. Patients with intrinsic renal disease, congestive heart failure, and those receiving diuretic therapy are at risk for developing reversible renal failure while using an NSAID, resulting in an elevation in the plasma creatinine. Nonacetylated salicylates and sulindac (Clinoril) in low doses appear to relatively spare renal prostaglandin synthesis and can be used in these settings. 8. NSAIDs may interfere with the control of hyperten- sion, usually resulting in a modest rise in blood pressure of 5 mm Hg. 9. Some patients with diminished cardiac function may develop overt congestive heart failure when given NSAIDs. 10. NSAIDs can be safely used in combination with low-dose aspirin (81 to 325 mg/day) that is pre- scribed for cardiovascular protection. NSAIDs should be avoided in patients with aspirin sensitiv- ity. Dose and cost nonsteroidal anti-inflammatory drugs (NSAIDs) Agent Brand name( s) Dos ing Daily use Specific benefits Salicylates Aspirin Choline magne- sium trisalicy late Salsala te Trilisate Disalcid , Salflex, Monog esic BID- QID BID- QID BID- QID 500- 4000 mg 975- 3600 mg 975- 3600 mg Titrate dose by serum levels Decreased GI toxicity, titrate dose by serum levels Decreased GI toxicity, titrate dose by serum levels Short half-life NSAID Fenopr ofen calcium Ibuprof en Indome thacin Ketopro fen Meclofe namate sodium Tolmeti n Nalfon Motrin, Advil, Midol, Nuprin Indocin Orudis Meclom en Tolectin TID- QID TID- QID TID- QID TID- QID TID- QID TID- QID 900- 2400 mg 600- 3600 mg 75-200 mg 75-300 mg 150-400 mg 600- 2000 mg Generally fewer side effects Excellent effi- cacy if tolerated Dialyzable Intermediate half-life NSAID Diclofe nac Catafla m, Voltare n BID- QID 100-200 mg Etodola c Lodine BID- QID 400- 1200 mg Flurbipr ofen Ansaid BID- QID 100-300 mg Naprox en Naprox yn, Napron X BID- TID 500- 1500 mg Naprox en-so- dium Anapro x, Aleve BID- TID 550- 1650 mg Sulinda c Clinoril BID 150- 1000 mg Decreased re- nal prostaglan- din effect Diflunis al Dolobid BID 500- 1000 mg Most uricosuric NSAID Long half-life NSAID Nabum etone Relafen QD- BID 1000- 2000 mg Decreased GI side effects Oxapro zin Daypro QD- BID 600- 1800 mg Piroxic am Felde ne QD 10-20 mg E. Choice of NSAID 1. None of the available NSAIDs is more effective than any other. It is preferable to use a NSAID on a periodic basis in patients with noninflammatory OA since the presence and intensity of symptoms usually vary with time; a short-acting agent is ideal in this setting. Continuous therapy with a long-acting agent is indicated if this regimen does not provide ade- quate symptom control. 2. A short-acting NSAID is generally used initially. An over-the-counter agent (ibuprofen or naproxen) is a reasonable choice. If there is inadequate control with the initial dose, then the dose should be gradually increased toward the maximum for that drug. If one NSAID is not effective after two to four weeks on a maximal dosage, then another NSAID or nonacetylated salicylate should be tried. If there is a history of gastroduodenal disease, a specific COX-2 inhibitor is preferred 3. Misoprostol (Cytotec) can also be used as prophy- laxis for the development of upper gastrointestinal bleeding in patients who receive non-specific COX-2 inhibitors. Misoprostol is usually given in a dose of 100 µg twice daily. F. Intraarticular corticosteroid injections may be appropriate in patients with OA who have one or several joints that are painful despite the use of a NSAIDs and in patients with monoarticular or pauciarticular inflam- matory osteoarthritis in whom NSAIDs are contraindi- cated. Intraarticular corticosteroids are effective for short-term pain relief. 1. Common corticosteroid suspensions used for intraarticular injection include triamcinolone acetonide, hexacetonide, and Depo-Medrol. The amount of these agents generally used depends upon joint size: a. 10 mg for small joints (interphalangeal, metacarpophalangeal and metatarsophalangeal joints). b. 20 mg for medium-sized joints (wrists, elbows, ankles). c. 40 mg for larger joints (shoulders, knees, hips). d. Corticosteroid injections in a weight-bearing joint should be limited to three to four per year. G. Intraarticular hyaluronic acid derivatives are more efficacious than intraarticular placebo. However, the magnitude of the benefit is modest. A series of three or five injections may be beneficial to some patients with knee OA. H. Joint irrigation may be warranted in patients with inflammatory symptoms who are refractory to NSAIDs or intraarticular corticosteroid injections. Office-based arthroscopic irrigation can be accomplished on knees and shoulders. I. Colchicine may be a reasonable treatment option in patients with inflammatory OA who have symptoms that are unresponsive to nonpharmacologic interventions and NSAIDs. J. Arthroscopic debridement. Patients who will benefit from arthroscopic lavage and debridement have pre- dominantly mechanical symptoms, mild-to-moderate roentgenographic disease, and shorter disease dura- tion. K. Surgical intervention should be considered in patients with severe symptomatic OA who have failed to respond to medical management (including arthroscopic proce- dures, and who have marked limitations in activities of daily living. Total joint arthroplasty replacement (arthroplasty) provides marked pain relief and functional improvement in patients with severe hip or knee OA. Most patients with total hip or knee arthroplasty for severe OA have improvement in pain which takes one year. L. Exercise. The goals of an exercise program are to maintain range of motion, muscle strength and general health. Management of Osteoarthritis of the Knee 1. Patient education, exercise, weight loss, joint protection 2. Acetaminophen (Tylenol), up to 4 g per day. 3. Add topical capsaicin cream (eg ArthriCare) applied four times daily if needed. 4. If joint effusion is present consider aspiration and intra-articular injection of triamcinolone (Aristocort) 40 mg. 5. If more pain or symptom control is needed add an NSAID, 400 mg of ibuprofen (eg Advil) taken four times daily or a nonacetylated salicylate such as choline magnesium trisalicylate (Trilisate), 500-1500 mg bid, or salsalate (Disalcid), 500-1000 mg tid. 6. If more pain or symptom control is needed use the full dos- age of an NSAID plus misoprostol (Cytotec) or a proton pump inhibitor if the patient is at risk for upper gastrointesti- nal tract bleeding or ulcer disease, or substitute a cyclo-oxygenase-2 inhibitor for the NSAID; some patients may benefit from intra-articular injections of a hyaluronic acid-like product. 7. If the response is inadequate, consider joint lavage, arthro- scopic debridement osteotomy, or joint replacement. Risk Factors for Ulcer Complications Induced by Nonsteroidal Anti-inflammatory Drugs Definite risk factors Patient older than 65 years of age Previous ulcer disease or upper gastrointestinal tract bleeding Use of a high dosage of one of these drugs Concomitant oral corticosteroid therapy Concomitant anticoagulant therapy Duration of therapy (risk is higher in first three months of treatment) Possible risk factors Female gender Smoking Alcohol consumption Helicobacter pylori infection M. The risk of NSAID-induced renal and hepatic toxicity is increased in older patients and in patients with preex- isting renal or hepatic insufficiency. Thus, it is impor- tant to monitor renal and liver function. Choline magne- sium trisalicylate (Trilisate) and salsalate (Disalcid) cause less renal toxicity. Liver function tests and serum hemoglobin, creatinine and potassium measurements should be performed before NSAID therapy is initiated and again after six months of treatment. Nonsteroidal Anti-inflammatory Drugs Drug Usual dosage for adults Formulations Acetic acids Diclofenac po- tassium (Cataflam) 100 to 200 mg daily 50 mg Diclofenac so- dium Immedi- ate-release (Voltaren) 100 to 200 mg daily 25, 50, 75 mg Delayed-release (Voltaren XR) 100 to 200 mg daily 100 mg With misoprostol (Arthrotec) 50 mg three times daily 50 mg three or four times daily for rheumatoid arthritis 50 mg diclofenac sodium with 200 μg misoprostol 75 mg diclofenac sodium with 200 μg misoprostol Etodolac Immedi- ate-release (Lodine) 600 to 1,000 mg daily given in two divided doses 200 mg 300 mg 400 mg 500 mg Ex- tended-release (Lodine XL) 400 to 1,000 mg daily 400 mg 500 mg 600 mg Sulindac (Clinoril) 150 mg twice daily (maximum dosage: 400 mg daily) 150, 200 mg Propionic acids Flurbiprofen (Ansaid) 200 to 300 mg daily given in two to four divided doses 50, 100 mg Ibuprofen (Motrin) 400 to 800 mg three or four times daily (maxi- mum dosage: 3,200 mg daily) 200 mg 400 mg 600 mg 800 mg Ketoprofen Immedi- ate-release (Orudis) 150 to 300 mg daily given in three to four di- vided doses 25 mg 50 mg 75 mg Ex- tended-release (Oruvail) 150 to 300 mg daily given in three or four di- vided doses 100 mg 150 mg 200 mg Over-the-counter (Orudis KT) 12.5 mg every 4 to 6 hours 12.5 mg Naproxen Imme- diate-release (Naprosyn) 250 to 500 mg twice daily 250 mg 375 mg 500 mg Drug Usual dosage for adults Formulations Delayed-release (EC Naprosyn) 750 or 1,000 mg daily 375 mg 500 mg Naproxen so- dium Immedi- ate-release (Anaprox, Anaprox DS) 275 or 550 mg twice daily 275 mg 550 mg Ex- tended-release (Naprelan) 750 or 1,000 mg daily 375 mg 500 mg Over-the-counter (Aleve) 220 mg every 8 to 12 hours 220 mg Oxaprozin (Daypro) 1,200 mg daily 600 mg Nonacidic agents Nabumetone (Relafen) 1,000 to 2,000 mg given once daily or twice daily in divided doses 500 mg 750 mg Cyclooxygenase-2 inhibitors Celecoxib (Celebrex) 100 mg twice daily or 200 mg daily for osteoarthritis 100 to 200 mg twice daily for rheumatoid arthri- tis 100 mg 200 mg N. Local analgesics. Capsaicin (eg, ArthriCare) has been shown to be better than placebo in osteoarthritis. Capsaicin cream is available over the counter in concentrations of 0.025, 0.075 and 0.25 percent. O. Intra-articular corticosteroid injections. Patients with a painful flare of osteoarthritis of the knee may benefit from intra-articular injection of triamcinolone (Aristocort) or prednisone 8-20 mg. Intra-articular steroid injections should not be administered more than three to four times per year. Knee injections significantly reduce pain for up to four weeks. P. Intra-articular injections of hyaluronic acid-like products. Hyaluronate (Hyalgan) and hylan G-F 20 (Synvisc) injections are useful for the treatment of osteoarthritis of the knee. Hylan G-F 20 injections are at least as effective as continuous NSAID therapy. Q. Surgery. Patients whose symptoms are not adequately controlled with medical therapy and who have moder- ate to severe pain and functional impairment are candidates for surgery. Osteoarthritis of the knee may be treated with arthroscopic debridement or joint lavage. References, see page 360. Low Back Pain Approximately 90 percent of adults experience back pain at some time in life, and 50 percent of persons in the working population have back pain every year. I. Evaluation of low back pain A. A comprehensive history and physical examination can identify the small percentage of patients with serious conditions such as infection, malignancy, rheumatologic diseases and neurologic disorders. B. The history and review of systems include patient age, constitutional symptoms and the presence of night pain, bone pain or morning stiffness. The patient should be asked about the occurrence of visceral pain, claudication, numbness, weakness, radiating pain, and bowel and bladder dysfunction. History and Physical Examination in the Patient with Acute Low Back Pain History Onset of pain (eg, time of day, activity) Location of pain (eg, specific site, radiation of pain) Type and character of pain (sharp, dull) Aggravating and relieving factors Medical history, including previous injuries Psychosocial stressors at home or work "Red flags": age greater than 50 years, fever, weight loss Incontinence, constipation Physical examination Informal observation (eg, patient's posture, expressions, pain behavior) Physical examination, with attention to specific areas as indi- cated by the history Neurologic evaluation Back examination Palpation Range of motion or painful arc Stance Gait Mobility (test by having the patient sit, lie down and stand up) Straight leg raise test C. Specific characteristics and severity of the pain, a history of trauma, previous therapy and its efficacy, and the functional impact of the pain on the patient's work and activities of daily living should be assessed. D. The most common levels for a herniated disc are L4-5 and L5-S1. The onset of symptoms is characterized by a sharp, burning, stabbing pain radiating down the posterior or lateral aspect of the leg, to below the knee. Pain is generally superficial and localized, and is often associated with numbness or tingling. In more ad- vanced cases, motor deficit, diminished reflexes or weakness may occur. E. If a disc herniation is responsible for the back pain, the patient can usually recall the time of onset and contributing factors, whereas if the pain is of a gradual onset, other degenerative diseases are more probable than disc herniation. F. Rheumatoid arthritis often begins in the appendicular skeleton before progressing to the spine. Inflammatory arthritides, such as ankylosing spondylitis, cause generalized pain and stiffness that are worse in the morning and relieved somewhat throughout the day. G. Cauda equina syndrome. Only the relatively uncom- mon central disc herniation provokes low back pain and saddle pain in the S1 and S2 distributions. A central herniated disc may also compress nerve roots of the cauda equina, resulting in difficult urination, incontinence or impotence. If bowel or bladder dys- function is present, immediate referral to a specialist is required for emergency surgery to prevent permanent loss of function. II. Physical and neurologic examination of the lumbar spine A. External manifestations of pain, including an abnor- mal stance, should be noted. The patient's posture and gait should be examined for sciatic list, which is indica- tive of disc herniation. The spinous processes and interspinous ligaments should be palpated for tender- ness. B. Range of motion should be evaluated. Pain during lumbar flexion suggests discogenic pain, while pain on lumbar extension suggests facet disease. Ligamentous or muscular strain can cause pain when the patient bends contralaterally. C. Motor, sensory and reflex function should be assessed to determine the affected nerve root level. Muscle strength is graded from zero (no evidence of contractility) to 5 (motion against resistance). D. Specific movements and positions that reproduce the symptoms should be documented. The upper lumbar region (L1, L2 and L3) controls the iliopsoas muscles, which can be evaluated by testing resistance to hip flexion. While seated, the patient should attempt to raise each thigh while the physician's hands are placed on the leg to create resistance. Pain and weakness are indicative of upper lumbar nerve root involvement. The L2, L3 and L4 nerve roots control the quadriceps muscle, which can be evaluated by manu- ally trying to flex the actively extended knee. The L4 nerve root also controls the tibialis anterior muscle, which can be tested by heel walking. Indications for Radiographs in the Patient with Acute Low Back Pain History of significant trauma Neurologic deficits Systemic symptoms Temperature greater than 38EC (100.4EF) Unexplained weight loss Medical history Cancer Corticosteroid use Drug or alcohol abuse Ankylosing spondylitis suspected Differential Diagnosis of Acute Low Back Pain Dis- ease or con- dition Pa- tient age (year s) Loca- tion of pain Quality of pain Aggravat- ing or re- lieving factors Signs Back strain 20 to 40 Low back, but- tock, pos- terior thigh Ache, spasm Increased with activ- ity or bending Local tender- ness, limited spinal motion Acute disc hernia tion 30 to 50 Low back to lower leg Sharp, shoot- ing or burning pain, paresth esia in leg Decreased with stand- ing; in- creased with bend- ing or sit- ting Positive straight leg raise test, weak- ness, asym- metric reflexes Oste o- arthri- tis or spinal steno- sis >50 Low back to lower leg; often bilat- eral Ache, shoot- ing pain, "pins and nee- dles" sensa- tion Increased with walk- ing, espe- cially up an incline; decreased with sitting Mild de- crease in extension of spine; may have weak- ness or asym- metric reflexes Spon dy- lolisth esis Any age Back, pos- terior thigh Ache Increased with activ- ity or bending Exagger- ation of the lum- bar curve, palpable "step off" (defect between spinous pro- cesses), tight ham- strings Anky- losing spond ylitis 15 to 40 Sa- croilia c joints, lum- bar spine Ache Morning stiffness De- creased back mo- tion, ten- derness over sa- croiliac joints Infec- tion Any age Lum- bar spine, sa- crum Sharp pain, ache Varies Fever, percus- sive ten- derness; may have neuro- logic ab- normalitie s or de- creased motion Malig- nancy >50 Af- fecte d bone( s) Dull ache, throb- bing pain; slowly progres- sive Increased with re- cumbency or cough May have localized tender- ness, neuro- logic signs or fever Waddell Signs: Nonorganic Signs Indicating the Presence of a Functional Component of Back Pain Superficial, nonanatomic tenderness Pain with simulated testing (eg, axial loading or pelvic rotation) Inconsistent responses with distraction (eg, straight leg raises while the patient is sitting) Nonorganic regional disturbances (eg, nondermatomal sen- sory loss) Overreaction Location of Pain and Motor Deficits in Association with Nerve Root Involvement Disc level Location of pain Motor deficit T12-L1 Pain in inguinal re- gion and medial thigh None L1-2 Pain in anterior and medial aspect of up- per thigh Slight weakness in quadriceps; slightly diminished supra- patellar reflex L2-3 Pain in anterolateral thigh Weakened quadriceps; dimin- ished patellar or suprapatellar reflex L3-4 Pain in posterolateral thigh and anterior tibial area Weakened quadriceps; dimin- ished patellar reflex L4-5 Pain in dorsum of foot Extensor weakness of big toe and foot L5-S1 Pain in lateral aspect of foot Diminished or absent Achilles reflex E. The L5 nerve root controls the extensor hallucis longus, which can be tested with the patient seated and moving both great toes in a dorsiflexed position against resistance. The L5 nerve root also innervates the hip abductors, which are evaluated by the Trendelenburg test. This test requires the patient to stand on one leg; the physician stands behind the patient and puts his or her hands on the patient's hips. A positive test is characterized by any drop in the pelvis and suggests L5 nerve root pathology. F. Cauda equina syndrome can be identified by unex- pected laxity of the anal sphincter, perianal or perineal sensory loss, or major motor loss in the lower extremi- ties. G. Nerve root tension signs are evaluated with the straight-leg raising test in the supine position. The physician raises the patient's legs to 90 degrees. If nerve root compression is present, this test causes severe pain in the back of the affected leg and can reveal a disorder of the L5 or S1 nerve root. H. The most common sites for a herniated lumbar disc are L4-5 and L5-S1, resulting in back pain and pain radiating down the posterior and lateral leg, to below the knee. I. A crossed straight-leg raising test may suggest nerve root compression. In this test, straight-leg raising of the contralateral limb reproduces more specific but less intense pain on the affected side. In addition, the femoral stretch test can be used to evaluate the reproducibility of pain. The patient lies in either the prone or the lateral decubitus position, and the thigh is extended at the hip, and the knee is flexed. Reproduction of pain suggests upper nerve root (L2, L3 and L4) disorders. J. Laboratory tests 1. Evaluation may include a complete blood count, determination of erythrocyte sedimentation rate. 2. Radiographic evaluation. Plain-film radiography is rarely useful in the initial evaluation of patients with acute-onset low back pain. Plain-film radiographs are normal or equivocal in more than 75 percent of patients with low back pain. Views of the spine uncover useful information in fewer than 3 percent of patients. Anteroposterior and lateral radiographs should be considered in patients who have a history of trauma, neurologic deficits, or systemic symp- toms. 3. Magnetic resonance imaging and computed tomographic scanning a. Magnetic resonance imaging (MRI) and computed tomographic (CT) scanning often demonstrate abnormalities in "normal" asymptomatic people. Thus, positive findings in patients with back pain are frequently of questionable clinical signifi- cance. b.MRI is better at imaging soft tissue (eg, herniated discs, tumors). CT scanning provides better imaging of bone (eg, osteoarthritis). MRI has the ability to demonstrate disc damage. MRI or CT studies should be considered in patients with worsening neurologic deficits or a suspected systemic cause of back pain such as infection or neoplasm. 4. Bone scintigraphy or bone scanning, can be useful when radiographs of the spine are normal, but the clinical findings are suspicious for osteomyelitis, bony neoplasm or occult fracture. 5. Physiologic assessment. Electrodiagnostic as- sessments such as needle electromyography and nerve conduction studies are useful in differentiating peripheral neuropathy from radiculopathy or myopathy. III. Management of acute low back pain A. Pharmacologic therapy 1. The mainstay of pharmacologic therapy for acute low back pain is acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). If no medical contraindications are present, a two- to four-week course of medication at anti-inflammatory levels is suggested. 2. Naproxen (Naprosyn) 500 mg, followed by 250 mg PO tid-qid prn [250, 375,500 mg]. 3. Naproxen sodium (Aleve) 200 mg PO tid prn. 4. Naproxen sodium (Anaprox) 550 mg, followed by 275 mg PO tid-qid prn. 5. Ibuprofen (Motrin, Advil) 800 mg, then 400 mg PO q4-6h prn. 6. Diclofenac (Voltaren) 50 mg bid-tid or 75 mg bid. 7. Gastrointestinal prophylaxis, using a histamine H 2 antagonist or misoprostol (Cytotec), should be prescribed for patients who are at risk for peptic ulcer disease. 8. Celecoxib (Celebrex) are NSAIDs with selective cyclo-oxygenase-2 inhibition. These agents have fewer gastrointestinal side effects. 9. Celecoxib (Celebrex) is given as 200 mg qd or 100 mg bid. 10. For relief of acute pain, short-term use of a nar- cotic may be considered. B. Rest. Two to three days of bed rest in a supine posi- tion may be recommended for patients with acute radiculopathy. C. Physical therapy modalities 1. Superficial heat, ultrasound (deep heat), cold packs and massage are useful for relieving symptoms in the acute phase after the onset of low back pain. 2. No convincing evidence has demonstrated the long- term effectiveness of lumbar traction and transcutaneous electrical stimulation. D. Aerobic exercise has been reported to improve or prevent back pain. Exercise programs that facilitate weight loss, trunk strengthening and the stretching of musculotendinous structures appear to be most helpful. Exercises should promote the strengthening of muscles that support the spine. E. Trigger point injections can provide extended relief for localized pain sources. An injection of 1 to 2 mL of 1 percent lidocaine (Xylocaine) without epinephrine is usually administered. Epidural steroid injection therapy has been reported to be effective in patients with lumbar disc herniation. F. Indications for herniated disc surgery. Most patients with a herniated disc may be effectively treated conser- vatively. Indications for referral include the following: (1) cauda equina syndrome, (2) progressive neurologic deficit, (3) profound neurologic deficit and (4) severe and disabling pain refractory to four to six weeks of conservative treatment. References, see page 360. Gout Gout comprises a heterogeneous group of disorders charac- terized by deposition of uric acid crystals in the joints and tendons. Gout has a prevalence of 5.0 to 6.6 cases per 1,000 men and 1.0 to 3.0 cases per 1,000 women. I. Clinical features A. Asymptomatic hyperuricemia is defined as an abnormally high serum urate level, without gouty arthritis or nephrolithiasis. Hyperuricemia is defined as a serum urate concentration greater than 7 mg/dL. Hyperuricemia predisposes patients to both gout and nephrolithiasis, but therapy is generally not warranted in the asymptomatic patient. B. Acute gout is characterized by the sudden onset of pain, erythema, limited range of motion and swelling of the involved joint. The peak incidence of acute gout occurs between 30 and 50 years of age. First attacks are monoarticular in 90 percent. In more than one-half of patients, the first metatarsophalangeal joint is the initial joint involved, a condition known as podagra. Joint involvement includes the metatarsophalangeal joint, the instep/forefoot, the ankle, the knee, the wrist and the fingers. C. Intercritical gout consists of the asymptomatic phase of the disease following recovery from acute gouty arthritis. D. Recurrent gouty arthritis. Approximately 60 percent of patients have a second attack within the first year, and 78 percent have a second attack within two years. E. Chronic tophaceous gout. Tophi are deposits of sodium urate that are large enough to be seen on radiographs and may occur at virtually any site. Com- mon sites include the joints of the hands or feet, the helix of the ear, the olecranon bursa, and the Achilles tendon. II. Diagnosis A. Definitive diagnosis of gout requires aspiration and examination of synovial fluid for monosodium urate crystals. Monosodium urate crystals are identified by polarized light microscopy. B. If a polarizing microscope is not available, the charac- teristic needle shape of the monosodium urate crystals, especially when found within white blood cells, can be identified with conventional light microscopy. The appearance resembles a toothpick piercing an olive. III. Treatment of gout A. Asymptomatic hyperuricemia. Urate-lowering drugs should not be used to treat patients with asymptomatic hyperuricemia. If hyperuricemia is identified, associated factors such as obesity, hypercholesterolemia, alcohol consumption and hypertension should be addressed. B. Acute gout 1. NSAIDs are the preferred therapy for the treatment of acute gout. Indomethacin (Indocin), ibuprofen (Motrin), naproxen (Naprosyn), sulindac (Clinoril), piroxicam (Feldene) and ketoprofen (Orudis) are effective. More than 90 percent of patients have a resolution of the attack within five to eight days. Drugs Used in the Management of Acute Gout Drug Dosage Side ef- fects/comments NSAIDS Indomethacin (Indocin) Naproxen (Naprosyn) Ibuprofen (Motrin) Sulindac (Clinoril) Ketoprofen (Orudis) 25 to 50 mg four times daily 500 mg two times daily 800 mg four times daily 200 mg two times daily 75 mg four times daily Contraindicated with peptic ulcer disease or systemic anticoagulation; side effects include gastropathy, nephropathy, liver dysfunction, and re- versible platelet dys- function; may cause fluid overload in pa- tients with heart fail- ure Corticosteroids Oral Prednisone, 0.5 mg per kg on day 1, taper by 5.0 mg each day thereafter Fluid retention; im- paired wound healing Intramuscular Triamcinolone acetonide (Kenalog), 60 mg intramuscu- larly, repeat in 24 hours if nec- essary May require repeat injections; risk of soft tissue atrophy Intra-articular Large joints: 10 to 40 mg Small joints: 5 to 20 mg Preferable route for monoarticular involve- ment ACTH 40 to 80 IU intra- muscularly; re- peat every 8 hours as neces- sary Repeat injections are commonly needed; requires intact pitu- itary-adrenal axis; stimulation of mineralocorticoid re- lease may cause vol- ume overload Drug Dosage Side ef- fects/comments Colchicine 0.5 to 0.6 mg PO every hour until relief or side effects oc- cur, or until a maximum dos- age of 6 mg is reached Dose-dependent gas- trointestinal side ef- fects; improper intra- venous dosing has caused bone marrow suppression, renal failure and death 2. Corticosteroids a. Intra-articular, intravenous, intramuscular or oral corticosteroids are effective in acute gout. In cases where one or two joints are involved, intra-articular injection of corticosteroid can be used. b. Intramuscular triamcinolone acetonide (60 mg) is as effective as indomethacin in relieving acute gouty arthritis. Triamcinolone acetonide is especially useful in patients with contraindications to NSAIDs. c. Oral prednisone is an option when repeat dosing is anticipated. Prednisone, 0.5 mg per kg on day 1 and tapered by 5 mg each day is very effective. 3. Colchicine is effective in treating acute gout; however, 80 percent of patients experience gastro- intestinal side effects, including nausea, vomiting and diarrhea. Intravenous colchicine is available but is highly toxic and not recommended. C. Treatment of intercritical gout 1. Prophylactic colchicine (from 0.6 mg to 1.2 mg) should be administered at the same time urate-lowering drug therapy is initiate. Colchicine should be used for prophylaxis only with concurrent use of urate-lowering agents. Colchicine is used for prophylaxis until the serum urate concentration is at the desired level and the patient has been free from acute gouty attacks for three to six months. 2. Urate-lowering agents a. After the acute gouty attack is treated and pro- phylactic therapy is initiated, sources of hyperuricemia should be eliminated to lower the serum urate level without the use of medication. b. Medications that may aggravate the patient's condition (eg, diuretics) should be discontinued; purine-rich foods and alcohol consumption should be curtailed, and the patient should gradually lose weight, if obese. Purine Content of Foods and Beverages High Avoid: Liver, kidney, anchovies, sardines, herring, mussels, bacon, codfish, scallops, trout, haddock, veal, venison, turkey, alcoholic beverages Moderate May eat occasionally: Asparagus, beef, bouillon, chicken, crab, duck, ham, kidney beans, lentils, lima beans, mush- rooms, lobster, oysters, pork, shrimp, spinach 3. 24-hour urine uric acid excretion measurement is essential to identify the most appropriate urate-lowering medication and to check for signifi- cant preexisting renal insufficiency. a. Uricosuric agents should be used in most patients with gout because most are "underexcretors" of uric acid. Inhibitors of uric acid synthesis are more toxic and should be reserved for use in "overproducers" of urate (urine excretion >800 mg in 24 hours). b. Urate-lowering therapy should not be initiated until the acute attack has resolved, since they may exacerbate the attack. Urate-Lowering Drugs for the Treatment of Gout and Hyperuricemia Drug Dosage Indica- tions Side ef- fects/comments Proben ecid (Bene- mid) Begin with 250 mg twice daily, gradually titrating up- ward until the serum urate level is <6 mg per dL; maximum: 3 g per day Recurrent gout may be com- bined with allopurinol in resistant hyperurice mia Uricosuric agent; creatinine clearance must be >60 mL per minute; therapeutic effect reversed by as- pirin therapy; avoid concurrent daily aspirin use; contraindicated in urolithiasis; may pre- cipitate gouty attack at start of therapy; rash or gastrointestinal side effects may occur Allopuri nol (Zylopri m) Begin with 50 to 100 mg daily, gradually titrating up- ward until the serum urate level is <6 mg per dL; typi- cal dosage: 200 to 300 mg daily Chronic gouty ar- thritis; sec- ondary hyper- uricemia related to the use of cytolytics in the treatment of hematologi c malig- nancies; gout com- plicated by renal dis- ease or renal cal- culi Inhibits uric acid syn- thesis; side effects in- clude rash, gastroin- testinal symptoms, headache, urticaria and interstitial nephri- tis; rare, potentially fatal hypersensitivity syndrome 4. Probenecid (Benemid) is the most frequently used uricosuric medication. Candidates for probenecid therapy must have hyperuricemia attributed to undersecretion of urate (ie, <800 mg in 24 hours), a creatinine clearance of >60 mL/minute and no history of nephrolithiasis. Probenecid should be initiated at a dosage of 250 mg twice daily and increased as needed, up to 3 g per day, to achieve a serum urate level of less than 6 mg per dL. Side effects include precipitation of an acute gouty attack, renal calculi, rash, and gastrointestinal problems. 5. Allopurinol (Zyloprim) is an inhibitor of uric acid synthesis. Allopurinol is initiated at a dosage of 100 mg per day and increased in increments of 50 to 100 mg per day every two weeks until the urate level is <6 mg per dL. Side effects include rash, gastroin- testinal problems, headache, urticaria and interstitial nephritis. A hypersensitivity syndrome associated with fever, bone marrow suppression, hepatic toxicity, renal failure and a systemic hypersensitivity vasculitis is rare. References, see page 360. Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic, polyarticular, symmet- ric, inflammatory disease that affects about 2.5 million people in the United States. The disease has a predilection for small proximal joints, although virtually every peripheral joint in the body can be involved. RA strikes women, usually of childbearing age, three times more often than it does men. This process causes the immune system to attack the synovium of various joints, leading to synovitis. I. Clinical manifestations A. RA is a chronic, symmetric polyarthritis. The polyarthritis is often deforming. About 80% of patients describe a slowly progressive onset over weeks or months. B. Inflammatory features 1. The joints in RA are swollen, tender, slightly warm, and stiff. Synovial fluid is cloudy and has an in- creased number of inflammatory white blood cells. 2. Patients with RA usually have profound and pro- longed morning stiffness. Fatigue, anemia of chronic disease, fever, vasculitis, pericarditis, and myocarditis, are common. C. Joint involvement. RA may begin in one or two joints, but it almost invariably progresses to affect 20 or more. In some cases, joint involvement is nearly symmetric. Initially, the disease typically involves the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints, either alone or in combination with others. D. Proliferative/erosive features. The inflamed synovial tissue evolves into a thickened, boggy mass known as a pannus. Pannus can eat through joint cartilage and into adjacent bone. E. Joint deformity. Deformities of RA are more likely to be the result of damage to ligaments, tendons, and joint capsule. II. Diagnosis A. RA is a clinical diagnosis. The presence of arthritis excludes the many forms of soft tissue rheumatism (eg, tendinitis, bursitis). The degree of inflammation excludes osteoarthritis and traumatic arthritis. Polyarticular involvement of the appropriate joints makes the spondyloarthropathies unlikely. The pannus is often palpable as a rubbery mass of tissue around a joint. B. Rheumatoid factor testing helps to confirm the diagnosis of RA. Rheumatoid factor serves as a marker for RA, but it is not reliable because 1-2% of the normal population have rheumatoid factor. Chronic infections, other inflammatory conditions and malig- nancies may trigger formation of rheumatoid factor. Conversely, 15% of patients with RA are seronegative for rheumatoid factor. C. Radiography. Typical erosions around joint margins help confirm the diagnosis of RA. III. Treatment of mild disease rheumatoid arthritis A. NSAIDs. Appropriate initial therapy of patients with mild disease consists of an NSAID at full therapeutic dose. 1. Initial therapy consists of an NSAID rather than a salicylate, because fewer tablets are required each day. Full anti-inflammatory doses should be admin- istered, such as the equivalent of 3200 mg of ibuprofen,1000 mg of naproxen (Naprosyn), or 200 mg of celecoxib (Celebrex) per day in divided doses, or a single-daily dose of longer-acting agents, such as piroxicam (Feldene,10 mg bid or 20 mg qd) may be used. 2. Selective COX-2 inhibitors, which have equivalent efficacy to NSAIDs but markedly lower gastroduodenal toxicity, are recommended for patients with a history of peptic ulcer, gastrointesti- nal bleeding, or gastrointestinal intolerance to NSAIDs (including salicylates); celecoxib (Celebrex) 100-200 bid. B. Disease modifying anti-rheumatic drugs (DMARDs). The addition of hydroxychloroquine (200 mg BID) or sulfasalazine (1000 mg BID or TID) is frequently employed for mild disease. Sulfasalazine is utilized among those with active synovitis. C. Adjunctive therapies. Additional initial therapies may include: 1. Acetaminophen for pain relief 2. Patient education concerning joint protection 3. Physical therapy to enhance muscle tone and help maintain full range of motion 4. Intraarticular injection of steroids. When the disease is oligoarticular, joint injection with a depo- corticosteroid preparation, such as triamcinolone hexacetonide, may lead to prolonged local disease control IV. Treatment of moderate disease rheumatoid arthritis A. Patients presenting with moderate disease should receive DMARD therapy in addition to an NSAID. B. NSAIDs. Full anti-inflammatory doses should be administered, such as the equivalent of 3200 mg of ibuprofen,1000 mg of naproxen (Naprosyn), or 200 mg of celecoxib (Celebrex) per day in divided doses, or a single-daily dose of longer-acting agents, such as piroxicam (Feldene) may be used. C. DMARDs 1. Hydroxychloroquine (200 mg BID) is initiated if the disease is more mild, or sulfasalazine 1000 BID-TID if the disease is intermediate. 2. Methotrexate (MTX) is commonly selected as early therapy for active disease. Methotrexate is used, except in women who may become pregnant and patients with liver disease. The dose is 7.5 mg per week. Folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5 mg per week, 8 to 12 hours after methotrexate) should be administered concurrently to reduce potential MTX toxicity. 3. For those with contraindications to the use of methotrexate, the following agents can be consid- ered: a. Leflunomide (Arava) alone b. Etanercept (Enbrel) alone c. Adalimumab (Humira) alone d. Infliximab (Remicade) alone e. Combination of hydroxychloroquine and sulfasalazine f. Anakinra (Kineret) alone D. Begin with either leflunomide or TNF-alpha-blockade in this setting. Leflunomide can cause fetal harm and is contraindicated in women who are or may become pregnant. Etanercept, adalimumab, and infliximab are contraindicated in women who are pregnant or nursing, patients with active infection, and those at high risk of reactivation of tuberculosis unless given prophylactic antituberculous therapy. E. Anticytokine therapy. Etanercept, infliximab, adalimumab, or anakinra alone are alternatives for the patient in whom methotrexate is contraindicated. Addition of one of these agents to ongoing methotrexate therapy is an option for patients with moderate disease. Antirheumatic drugs used in treatment of rheuma- toid arthritis Drug Deliv- ery Dose Side effects Methotrex- ate (Rheumatre x Dose Pack) PO or SC 5-20 mg/wk Marrow suppression, mucositis, hepatotoxicity, pulmonary disease, sus- ceptibility to infection Cyclospor- ine (Neoral) PO 2-4 mg/kg daily Marrow suppression, re- nal toxicity, hyperuricemia, suscepti- bility to infection Azathioprine (Imuran) PO 50-250 mg/day Marrow suppression, GI intolerance, hepatotoxicity, tumors, susceptibility to infection Chloram- bucil (Leukeran) PO 2-8 mg/day Marrow suppression (par- ticularly thrombocytopenia), tu- mors, susceptibility to infection Cyclophos- phamide (Cytoxan, Neosar) PO 25-150 mg/day Marrow suppression, hemorrhagic cystitis, tran- sitional cell carcinoma and other tumors, sus- ceptibility to infection Leflunomide (Arava) PO 100 mg/day for 3 days, then 20 mg/day Diarrhea, dyspepsia, rash, alopecia, hepatotoxicity, marrow suppression Infliximab (Remicade) IV 10 mg/kg infu- sions sporadi- cally Susceptibility to infection, autoimmune phenome- non, diarrhea, rash, infu- sion reactions Etanercept (Enbrel) SC 25 mg twice/wk Injection site reactions, upper respiratory tract infections; theoretically, sepsis or tumors Adalimumab (Humira) SC 40 mg, every other week Injection site reactions, upper respiratory tract infections; theoretically, sepsis or tumors F. Adjunctive therapies 1. If the disease remains active (as demonstrated by inflamed joints) and/or the NSAID has produced toxicity, consider the following: 2. Change NSAID G. Add prednisone or prednisolone 1. Administer intraarticular steroids 2. Prednisone can be added at a dose of up to 7.5 mg/day. V. Severe disease A. NSAIDs. Therapy initially involves a NSAID in full antiinflammatory doses. B. DMARDs 1. Unless contraindicated, methotrexate (MTX) is the DMARD of first choice for those with severe dis- ease. The dose is 7.5 mg per week. 2. Folic acid that can competitively inhibit the binding of dihydrofolic acid. Folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5 mg per week, 8 to 12 hours after methotrexate) should be administered concur- rently to reduce potential toxicity. C. Anticytokine therapy 1. Etanercept (Enbrel). Etanercept is extremely effective in controlling symptoms and slowing the rate of radiographic progression in early severe RA (10 or 25 mg twice a week). Etanercept is contrain- dicated in women who are pregnant or nursing, and in patients with active infection. 2. Infliximab (Remicade.) Unlike etanercept, which may be used alone, infliximab, a chimeric anti-TNF monoclonal antibody, is generally given in combina- tion with methotrexate. It is therefore usually re- served for use in patients with moderate or severe disease who tolerate, but have had an inadequate response to, methotrexate. 3. Adalimumab (Humira). The fully human anti-TNF monoclonal antibody, adalimumab, administered subcutaneously every two weeks is efficacious and can be used alone or combined with methotrexate treatment for RA. 4. Anakinra (Kineret). Anakinra, a human interleukin- 1 receptor antagonist, also may be of value in patients with active RA. It can be given alone or in combination with methotrexate. However, anakinra should not be given with anti-TNF therapy due to an increased risk of serious infections. D. Prednisone. If the patient is febrile, toxic or experienc- ing a rapid decline in function, prednisone (5 to 20 mg/day) is frequently added to the regimen of an NSAID and an DMARD. However, once the patient responds sufficiently, the dose of prednisone should be tapered as rapidly as possible to less than 10 mg/day (usually by 8 to 12 weeks). References, see page 360. Deep Vein Thrombosis The incidence of venous thromboembolism (VTE) is 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age. There is no antecedent trauma, surgery, immobilization, or diagnosis of cancer in 48 percent of VTE events. Most of the cases of secondary VTE are associated with more than one underlying condition, includ- ing cancer (48 percent), hospitalization (52 percent), surgery (42 percent), and major trauma (6 percent). The following factors are associated with an increased risk for VTE: Presence of an acute infectious disease, age greater than 75 years, cancer, and history of prior VTE. I. Initial approach A. Risk factors for DVT should be sought in all pa- tients 1.History of immobilization or prolonged hospitaliza- tion/bed rest. 2.Recent surgery. 3.Obesity. 4.Prior episode(s) of venous thromboembolism. 5.Lower extremity trauma. 6.Malignancy. 7.Use of oral contraceptives or hormone replacement therapy. 8.Pregnancy or postpartum status. 9.Stroke. B. History 1.Symptoms of DVT include swelling, pain, and discolor- ation in the involved extremity. History should include the time of onset, location of prior thromboses, and results of objective diagnostic studies documenting thrombotic episodes in the patient. A history of venous thrombosis in one or more first-degree relatives strongly suggests the presence of a hereditary defect. 2.Precipitating conditions, such as surgical procedures, trauma, pregnancy, heart failure, and immobility. Women should be questioned regarding use of oral contraceptives or hormone replacement therapy as well as their obstetric history. 3.Recurrent fetal loss suggests the possible presence of an inherited thrombophilia or antiphospholipid antibod- ies. Collagen-vascular disease, myeloproliferative disease, atherosclerotic disease, nephrotic syndrome or drugs which can induce antiphospholipid antibodies (hydralazine, procainamide, and phenothiazines) should be sought. 4.A past history of cancer, and the results of mammogra- phy, colonoscopy, and pelvic examinations should be assessed. Other findings that may suggest an underly- ing malignancy are constitutional symptoms such as loss of appetite, weight loss, fatigue, pain, hematochezia, hemoptysis, and hematuria. C. Physical examination may reveal a palpable cord (reflecting a thrombosed vein), ipsilateral edema, warmth, and/or superficial venous dilation. However, the clinical diagnosis of DVT is not sufficiently accu- rate, since the symptoms and findings are often nonspecific. 1.The vascular system, extremities (eg, looking for signs of superficial or deep vein thrombosis), chest, heart, abdominal organs, and skin (eg, skin necrosis, livedo reticularis) should be examined. There may be pain and tenderness in the thigh along the course of the major veins (“painful deep vein syndrome”). 2.Tenderness on deep palpation of the calf muscles is suggestive, but not diagnostic. Homan’s sign is unreli- able. 3.The respective values for the following local symptoms are: a. Edema — 33-70%. b. Pain — 19-58%. c. Warmth — 48-62%. 4.Since venous thromboembolism may be the first manifestation of an underlying malignancy, rectal examination and stool testing for occult blood should be performed and women should undergo a pelvic examination. Venous thromboembolism may also be a manifestation of physical immobility and cardiovascu- lar disorders such as heart failure. 5.Signs of hepatic vein thrombosis, Budd-Chiari syn- drome, may include ascites and hepatomegaly. Edema is suggestive of nephrotic syndrome. Causes of Venous Thrombosis Inherited thrombophilia. May be present in 24% of cases Factor V Leiden mutation Prothrombin gene mutation Protein S deficiency Protein C deficiency Antithrombin (AT) deficiency Rare disorders Dysfibrinogenemia Increased factor VIII coagulant activity Acquired disorders Malignancy Tissue factor Cancer procoagulant Presence of a central venous catheter Surgery, especially or- thopedic Trauma Pregnancy Oral contraceptives Hormone replacement therapy Tamoxifen Immobilization Congestive heart failure Hyperhomocyst(e)inemia Antiphospholipid anti- body syndrome Myeloproliferative disor- ders Polycythemia vera Essential thrombocythemia Paroxysmal nocturnal hemoglobinuria Inflammatory bowel dis- ease Nephrotic syndrome Hyperviscosity Waldenstrom’s macroglobulinemia Multiple myeloma Polycythemia vera Marked leukocytosis in acute leukemia Sickle cell anemia II.Laboratory testing should include a complete blood count, coagulation studies (eg, prothrombin time, activated partial thromboplastin time, D-dimer, fibrinogen), serum chemistries including liver and renal function tests, and urinalysis. A prostate-specific antigen measurement should b e obtained in men over the age of 50. A. Elevations in the hematocrit or platelet count should lead to consideration of polycythemia vera or essential thrombocythemia. B. Secondary polycythemia or secondary (reactive) thrombocytosis suggests underlying occult neoplasm that may be the predisposing factor to thrombosis. C. A leukoerythroblastic picture with nucleated red blood cells and immature white cells suggests the possibility of bone marrow involvement by tumor or a myeloproliferative disorder. D. Anemia, leukopenia, and thrombocytopenia are often found in paroxysmal nocturnal hemoglobinuria, a rare hematologic disorder characterized by chronic intravascular hemolysis and thrombotic complications. E. Thrombosis and thrombocytopenia concurrent with heparin therapy should prompt consideration of the diagnosis of heparin-induced thrombocytopenia. An unexplained prolongation of the activated partial thromboplastin time, which does not correct on 1:1 dilution with normal plasma, is suggestive of the antiphospholipid antibody syndrome. F. A peripheral blood smear demonstrating red cell fragmentation or schistocytes suggests disseminated intravascular coagulation (DIC) and the thrombotic microangiopathies (eg, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome). Although bleeding is the most common coagulation problem in DIC, patients with malignancy can have a low-grade or compensated consumptive coagulopathy and develop venous or arterial thrombosis. III. Differential diagnosis A. Popliteal (Baker’s) cyst. The majority of popliteal cysts are due to either distention of a bursa by fluid originat- ing from a knee joint lesion or posterior herniation of the joint capsule due to increased intraarticular pressure. It can cause leg swelling via compression of the popliteal vein and may result in DVT if the vein is compressed sufficiently. B. Internal derangement of the knee. Pain, inflammation, and swelling can accompany knee joint pathology. C. Drug-induced edema. Leg swelling is a side effect of some drugs, such as calcium channel blockers. The edema is usually bilateral but can be asymmetric if there is underlying venous pathology; signs of inflam- mation are not present. D. Calf muscle pull or tear is frequently induced by unaccustomed physical activity. There may be signs of bleeding within muscle compartments. E. Superficial thrombophlebitis is most likely in the presence of palpable, tender superficial veins. F. Venous valvular insufficiency. Chronic venous insufficiency is the most common cause of chronic unilateral leg edema and is usually associated with a past history of DVT. G. Lymphedema is a cause of chronic, rather than acute, edema of the extremities. IV. Diagnosis OF DVT A. Compression ultrasonography is the noninvasive approach of choice for the diagnosis of patients with suspected DVT. B. D-dimer levels below 500 ng/mL by ELISA or a negative SimpliRED assay in conjunction with a low clinical probability or other negative noninvasive tests may be useful in excluding DVT. C. A positive noninvasive study in patients with a first episode of DVT usually establishes the diagnosis, with positive predictive values for compression ultrasonography of 94 percent. If the initial study is negative and the clinical suspicion of DVT is high, a repeat study should be obtained on day 5 to 7. Venography is used only when noninvasive testing is not clinically feasible or the results are equivocal. D. Screening for a hypercoagulable state. A cause of thrombosis can be identified in over 60 percent of patients with DVT. 1. A thrombophilic state leading to venous thrombosis can be inherited or acquired: a. Congenital/inherited (eg, factor V Leiden, protein C deficiency). b. Acquired (eg, following orthopedic surgery, antiphospholipid antibody). c. Associated with systemic disease (eg, malignancy). Indications for testing for hypercougalable state. d. When thrombosis occurs in association with use of oral contraceptives, hormone replacement therapy, or pregnancy. e. When thrombosis occurs in unusual vascular beds such as portal, hepatic, mesenteric, or cerebral veins. f. In patients with a history of warfarin-induced skin necrosis. g. In patients with unprovoked upper extremity venous thrombosis (eg, in the absence of an indwelling central venous catheter, upper ex- tremity trauma). V. Treatment of DVT A. Anticoagulant therapy is indicated for patients with symptomatic proximal DVT, since pulmonary embolism will occur in 50 percent of untreated individuals, most often within days or weeks of the event. B. Patients with DVT or pulmonary embolism should be treated acutely with low-molecular-weight (LMW) heparin, unfractionated intravenous heparin, or adjusted-dose subcutaneous heparin. C. When unfractionated heparin is used, the dose should be sufficient to prolong the activated partial thromboplastin time (aPTT) to 1.5 to 2.5 times the mean of the control value, or the upper limit of the normal aPTT range. Weight-based nomograms are used for unfractionated heparin dosing. D. Treatment with LMW heparin or heparin should be continued for at least five days and oral anticoagulation should be overlapped with LMW heparin or unfractionated heparin for at least four to five days. Warfarin can be initiated simultaneously with the heparin, at an initial dose of not more than 5 to 10 mg PO. The heparin product can be discontinued on day five or six if the INR has been therapeutic for two consecutive days. 1. Thrombocytopenia. A platelet count should be obtained between day three and day five of therapy. If heparin is continued beyond this period, another platelet count should be obtained between days 7 and 10, and another at day 14. The heparin product should be stopped if any one of the following oc- curs: a precipitous or sustained fall in the platelet count, or a platelet count <100,000/µL. Management of Deep Venous Thrombosis Superficial Venous Thrombosis • Use duplex scan to screen for involvement of deep sys- tem • Elevation, nonsteroidal anti-inflammatory drugs Deep Venous Thrombosis • Begin warfarin on the first hospital day • Low-molecular-weight heparin--more effective and safer than standard heparin Phlegmasia Dolens • Enoxaparin 1.0 mg/kg SQ q12h • Heparin 80 U/kg load, 18 U/kg/hr drip • Thrombolysis for severe disease in young adults • Vena cava filter if thrombosis in presence of adequate anticoagulation Exclusions for Home Treatment for DVT Medical Exclusions Concurrent Pulmonary Embolism (PE) Serious co-morbid condition Cancer, infection, stroke Prior DVT or PE Contraindications to anticoagulation Familial bleeding disorder Known deficiency of Antithrombin Ill, Protein C, Protein S Pregnancy Social Exclusions No phone Lives far from hospital Unable to understand instructions or comply with follow-up Family or patient resistance to home therapy Low Molecular Weight Heparin Protocol Subcutaneous enoxaparin 1 mg/kg q12hours for a minimum of five days and achieving INR of 2-3 (from warfarin therapy) Warfarin to be started on first day of therapy INR should be monitored during outpatient treatment Warn patients to return immediately for shortness of breath, hemorrhage, or clinical decomposition Weight-Based Nomogram for Intravenous Heparin Infusions Initial dose 80 U/kg bolus, then 18 U/kg per hour aPTT <35 sec (<1 .2 x con- trol) 80 U/kg bolus, then increase infusion rate by 4 U/kg per hour aPTT 35-45 sec (1 .2-1 .5 x control) 40 U/kg bolus, then increase infusion rate by 2 U/kg per hour aPTT 46-70 sec (1.5-2.3 x control) No change aPTT 71-90 sec (2.3-3.0 x control) Decrease infusion rate by 2 U/kg per hour aPTT >90 sec (>3.0 x con- trol) Hold infusion 1 hour, then decrease infusion rate by 3 U/kg per hour E. Thrombolytic agents may be appropriate for hemodynamically unstable PE or massive iliofemoral thrombosis in patients who are at low risk to bleed. F. Inferior vena caval filter placement is recommended when there is a contraindication to, or a complication of, anticoagulant therapy in an individual with, or at high risk for, proximal vein thrombosis or PE. It is also recommended i n pati ents wi th recurrent thromboembolism despite adequate anticoagulation, for chronic recurrent embolism with pulmonary hyperten- sion, and with the concurrent performance of surgical pul monar y embol ect omy or pul monar y thromboendarterectomy. G. Oral anticoagulation with warfarin should prolong the INR to a target of 2.5 (range: 2.0 to 3.0). If oral antico- agulants are contraindicated or inconvenient, long-term therapy can be undertaken with either low molecular weight heparin or adjusted-dose unfractionated heparin. H. Patients with a first thromboembolic event in the context of a reversible or time-limited risk factor should be treated for at least three months, whereas those with an idiopathic first thromboembolic event should be treated for a minimum of six to twelve months. Patients with recurrent idiopathic VTE or a continuing risk factor (eg, cancer, antithrombin deficiency, anticardiolipin antibody syndrome) should be treated for 12 months or longer. I. Once warfarin/heparin have been started and the patient’s symptoms (ie, pain, swelling) are under control, the patient is encouraged to ambulate. References, see page 360. Pulmonary Embolism More than 500,000 patients are diagnosed with pulmonary emboli annually, resulting in 200,000 deaths. Pulmonary embolism is associated with a mortality rate of 30 percent if untreated. Accurate diagnosis with ventilation/perfusion lung scanning or pulmonary angiography followed by therapy with anticoagulants significantly decreases the mortality rate to 2 to 8 percent. I. Pathophysiology A. Pulmonary emboli usually arise from thrombi in the deep venous system of the lower extremities; however, they may also originate in the pelvic, renal, or upper extremity veins and in the right heart B. Risk factors. Patients with pulmonary emboli usually have risk factors for the development of venous throm- bosis. 1. Immobilization. 2. Surgery within the last three months. 3. History of venous thromboembolism. 4. Malignancy is an increased risk associated with obesity (relative risk 2.9), heavy cigarette smoking 25 to 34 cigarettes per day, and hypertension. C. Patients with pulmonary emboli without identifiable risk factors (idiopathic or primary venous thromboembolism) may have unsuspected underlying abnormalities that favor the development of thromboembolic disease. Factor V Leiden mutation should be particularly sus- pected in this setting, being seen in up to 40 percent of cases. High concentrations of factor VIII are present in 11 percent and confer a sixfold risk for venous thromboembolism. D. When idiopathic venous thromboembolism recurs, occult malignancy should also be suspected, being present in 17 percent of such patients. Venous thromboembolism may be the presenting sign of pancreatic or prostate cancers, breast, lung, uterine, or brain malignancies. II.Clinical manifestations. Sixty-five to 90 percent of pulmonary emboli arise from the lower extremities. How- ever, the majority of patients with pulmonary embolism have no leg symptoms. A. The most common symptoms are dyspnea (73 percent), pleuritic pain (66 percent), cough (37 percent) and hemoptysis (13 percent). B. The most common signs are tachypnea (70 percent), rales (51 percent), tachycardia (30 percent), a fourth heart sound (24 percent), and an accentuated pulmonic component of the second heart sound (23 percent). C. The syndrome of pleuritic pain or hemoptysis without cardiovascular collapse is the most commonly recog- nized syndrome (65 percent); isolated dyspnea is observed in 22 percent. Circulatory collapse is uncom- mon (8 percent). D. Fever, usually with a temperature <102.0ºF, occurs in 14 percent of patients with pulmonary embolism. Frequency of Symptoms and Signs in Pulmonary Embolism Symptoms Freq- uency (%) Signs Freq- uency (%) Dyspnea Pleuritic chest pain Apprehension Cough Hemoptysis Sweating Non-pleuritic chest pain 84 74 59 53 30 27 14 Tachypnea (>16/min) Rales Accentuated S2 Tachycardia Fever (>37.8EC) Diaphoresis S3 or S4 gallop Thrombophlebit is 92 58 53 44 43 36 34 32 III. Laboratory abnormalities are nonspecific and include leukocytosis, an increase in the erythrocyte sedimenta- tion rate (ESR), and an elevated serum LDH or AST (SGOT) with a normal serum bilirubin. Arterial blood gases usually reveal hypoxemia, hypocapnia, and respiratory alkalosis. A. Massive pulmonary embolus with hypotension and respiratory collapse can lead to hypercapnia and a combined respiratory and metabolic acidosis. Addition- ally, the PaO 2 is between 85 and 105 mm Hg in 18 percent of patients with pulmonary embolism, and up to 6 percent may have a normal alveolar-arterial gradient for oxygen. Arterial blood gas measurements do not play a major role in excluding or establishing the diagnosis of pulmonary embolism. B. Serum troponin I and troponin T are elevated in 30 to 50 percent of patients with a moderate to large pulmo- nary embolism because of acute right heart overload. Although not useful for diagnosis, elevated troponins are predictive of an adverse prognosis, being associ- ated with marked increases in the incidence of pro- longed hypotension and in-hospital mortality. C. Electrocardiography is often abnormal (70 percent); however, the findings are insensitive and nonspecific. The most common abnormalities are nonspecific ST segment and T wave changes (49 percent). The pres- ence of T-wave inversion in the precordial leads may correlate with more severe right ventricular dysfunction. D. Chest radiography. The most frequent radiographic abnormalities are atelectasis, observed in 69 percent of pulmonary emboli. Pleural effusion is noted in 47 percent. IV. Diagnostic evaluation A. Ventilation/perfusion lung scanning is the most frequently used test to aid in the diagnosis of PE in patients in whom a careful physical examination and routine diagnostic tests have failed to reveal a specific diagnosis to explain the pulmonary symptoms. B. A high probability lung scan indicates a high likelihood of emboli, particularly in patients with a high pretest probability of pulmonary emboli (95 percent). High probability lung scans, however, are not very sensitive for PE (42 percent sensitivity). The majority of pulmo- nary emboli produce lung scan defects that are interme- diate (41 percent of emboli) or low probability (16 percent). C. Noninvasive lower extremity tests. Noninvasive assessment for deep venous thrombosis may be helpful in the evaluation of patients with intermediate clinical and scan probabilities for pulmonary emboli. Color-flow Doppler with compression ultrasound has high sensitiv- ity (89 to 100 percent) and specificity (89 to 100 per- cent) for the detection of a first episode of proximal venous thrombosis. D. D-dimers are detectable at levels greater than 500 ng/mL in nearly all patients with PE. However, an elevated D-dimer concentration is insufficient to estab- lish the diagnosis of PE because such values are nonspecific and are commonly present in hospitalized patients, particularly those with malignancy or recent surgery. E. Pulmonary angiography. Many patients require angiography to confirm or exclude PE with certainty. Angiography is the definitive diagnostic technique. A negative pulmonary angiogram with magnification excludes clinically relevant pulmonary embolism. F. Helical CT scanning. Initial reports suggested that the technique had a very high sensitivity, but subsequent studies found sensitivities ranging from 53 to 87 per- cent. Pretest Probability of Pulmonary Embolism High probability - 90 percent Presence of at least one of three symptoms (sudden onset dyspnea, chest pain, fainting) not otherwise explained and associated with: (1) any two of the following abnormalities: electrocardiographic signs of right ventricular overload, radiographic signs of oligemia, amputation of a hilar artery, or pulmonary consolidation compatible with infarction; (2) any one of the above three radiographic abnormalities. Intermediate probability - 50 percent Presence of at least one of the above symptoms, not explained otherwise, but not associated with the above electrocardiographic and radiographic abnor- malities, or associated with electrocardiographic signs of right ventricular overload only. Low probability - 10 percent Absence of the above three symptoms, or identifica- tion of an alternative diagnosis that may account for their presence (eg, exacerbation of COPD, pneumo- nia, lung edema, myocardial infarction, pneumothorax, and others) V. Recommendations. The combination of clinical assess- ment, lung scanning, D-dimer testing, and venous ultra- sound will confirm or exclude acute pulmonary emboli in many patients. A. In patients with suspected pulmonary embolism and leg symptoms, initial testing with venous ultrasonography should be considered. B. Anticoagulation can be safely withheld from patients with a low pretest clinical probability and a negative D- dimer. C. Anticoagulation also can be safely withheld from patients with low or moderate pretest clinical probabil- ity, a non-high probability lung scan, and either nega- tive serial venous ultrasounds or a negative D-dimer. Weight-based nomogram for intravenous heparin infusion Initial dose 80 U/kg bolus, then 18 U/kg per hour aPTT* <35 sec (<1.2 x control) 80 U/kg bolus, then increase infu- sion rate by 4 U/kg per hour aPTT 40 U/kg per hour, then increase infusion by 2 U/kg per hour aPTT No change aPTT Decrease infusion rate by 2q U/kg per hour aPTT Hold infusion 1 hour, then de- crease infusion rate by 3 U/kg per hour *aPTT = activated partial thromboplastin time References, see page 360. Anemia The prevalence of anemia is about 29 to 30 cases per 1,000 females of all ages and six cases per 1,000 males under the age of 45 Deficiencies of iron, vitamin B12 and folic acid are the most common causes. I. Clinical manifestations. Severe anemia may be toler- ated well if it develops gradually. Patients with an Hb of less than 7 g/dL will have symptoms of tissue hypoxia (fatigue, headache, dyspnea, light-headedness, angina). Pallor, syncope and tachycardia may signal hypovolemia and impending shock. II. History and physical examination A. The evaluation should determine if the anemia is of acute or chronic onset, and clues to any underlying systemic process should be sought. A history of drug exposure, blood loss, or a family history of anemia should be sought. B. Lymphadenopathy, hepatic or splenic enlargement, jaundice, bone tenderness, neurologic symptoms or blood in the feces should be sought. III.Laboratory evaluation A. Hemoglobin and hematocrit serve as an estimate of the RBC mass. B. Reticulocyte count reflects the rate of marrow produc- tion of RBCs. Absolute reticulocyte count = (% reticulocytes/100) × RBC count. An increase of reticulocytes to greater than 100,000/mm 3 suggests a hyperproliferative bone marrow. C. Mean corpuscular volume (MCV) is used in classify- ing anemia as microcytic, normocytic or macrocytic. Normal Hematologic Values Age of patient Hemoglobin Hemato crit (%) Mean corpus- cular volume (pm 3 ) One to three days 14.5-22.5 g per dL 45-67 95-121 Six months to two years 10.5-13.5 g per dL 33-39 70-86 12 to 18 years (male) 13.0-16.0 g per dL 37-49 78-98 12 to 18 years (female) 12.0-16.0 g per dL 36-46 78-102 >18 years (male) 13.5-17.5 g per dL 41-53 78-98 >18 years (fe- male) 12.0-16.0 g per dL 36-46 78-98 IV. Iron deficiency anemia A. Iron deficiency is the most common cause of anemia. In children, the deficiency is typically caused by diet. In adults, the cause should be considered to be a result of chronic blood loss until a definitive diagnosis is established. B. Laboratory results 1. The MCV is normal in early iron deficiency. As the hematocrit falls below 30%, hypochromic microcytic cells appear, followed by a decrease in the MCV. 2. A serum ferritin level of less than 10 ng/mL in women or 20 ng/mL in men is indicative of low iron stores. A serum ferritin level of more than 200 ng/mL indicates adequate iron stores. C. Treatment of iron deficiency anemia 1. Ferrous salts of iron are absorbed much more readily and are preferred. Commonly available oral preparations include ferrous sulfate, ferrous gluconate and ferrous fumarate (Hemocyte). All three forms are well absorbed. Ferrous sulfate is the least expensive and most commonly used oral iron supplement. Oral Iron Preparations Preparation Elemental iron (%) Typical dosage Elemental iron per dose Ferrous sulfate 20 325 mg three times daily 65 mg Ferrous sulfate, exsiccated (Feosol) 30 200 mg three times daily 65 mg Ferrous gluconate 12 325 mg three times daily 36 mg Ferrous fumarate (Hemocyte) 33 325 mg twice daily 106 mg 2. For iron replacement therapy, a dosage equivalent to 150 to 200 mg of elemental iron per day is recommended. 3. Ferrous sulfate, 325 mg of three times a day, will provide the necessary elemental iron for replace- ment therapy. Hematocrit levels should show improvement within one to two months. 4. Depending on the cause and severity of the ane- mia, replacement of low iron stores usually requires four to six months of iron supplementation. A daily dosage of 325 mg of ferrous sulfate is necessary for maintenance therapy. 5. Side effects from oral iron replacement therapy are common and include nausea, constipation, diarrhea and abdominal pain. Iron supplements should be taken with food; however, this may decrease iron absorption by 40 to 66 percent. Changing to a different iron salt or to a controlled-release prepara- tion may also reduce side effects. 6. For optimum delivery, oral iron supplements must dissolve rapidly in the stomach so that the iron can be absorbed in the duodenum and upper jejunum. Enteric-coated preparations are ineffective since they do not dissolve in the stomach. 7. Causes of resistance to iron therapy include contin- uing blood loss, ineffective intake and ineffective absorption. Continuing blood loss may be overt (eg, menstruation, hemorrhoids) or occult (e.g., gastroin- testinal malignancies, intestinal parasites, nonsteroidal anti-inflammatory drugs). V. Vitamin B12 deficiency anemia A. Since body stores of vitamin B12 are adequate for up to five years, deficiency is generally the result of failure to absorb it. Pernicious anemia, Crohn's disease and other intestinal disorders are the most frequent causes of vitamin B12 deficiency. B. Symptoms are attributable primarily to anemia, al- though glossitis, jaundice, and splenomegaly may be present. Vitamin B12 deficiency may cause decreased vibratory and positional sense, ataxia, paresthesias, confusion, and dementia. Neurologic complications may occur in the absence of anemia and may not resolve completely despite adequate treatment. Folic acid deficiency does not cause neurologic disease. C. Laboratory results 1. A macrocytic anemia usually is present, and leukopenia and thrombocytopenia may occur. Lactate dehydrogenase (LDH) and indirect bilirubin typically are elevated. 2. Vitamin B12 levels are low. RBC folate levels should be measured to exclude folate deficiency. D. Treatment of vitamin B12 deficiency anemia. Intramuscular, oral or intranasal preparations are available for B12 replacement. In patients with severe vitamin B12 deficiency, daily IM injections of 1,000 mcg of cyanocobalamin are recommended for five days, followed by weekly injections for four weeks. Hematologic improvement should begin within five to seven days, and the deficiency should resolve after three to four weeks. Vitamin B12 and Folic Acid Preparations Preparation Dosage Cyanocobalamin tablets 1,000 μg daily Cyanocobalamin injection 1,000 μg weekly Cyanocobalamin nasal gel (Nascobal) 500 μg weekly Folic acid (Folvite) 1 mg daily VI. Folate deficiency anemia A. Folate deficiency is characterized by megaloblastic anemia and low serum folate levels. Most patients with folate deficiency have inadequate intake. Lactate dehydrogenase (LDH) and indirect bilirubin typically are elevated, reflecting ineffective erythropoiesis and premature destruction of RBCs. B. RBC folate and serum vitamin B 12 levels should be measured. RBC folate is a more accurate indicator of body folate stores than is serum folate, particularly if measured after folate therapy has been initiated. C. Treatment of folate deficiency anemia 1. A once-daily dosage of 1 mg of folic acid given PO will replenish body stores in about three weeks. 2. Folate supplementation is also recommended for women of child-bearing age to reduce the incidence of fetal neural tube defects. Folic acid should be initiated at 0.4 mg daily before conception. Prenatal vitamins contain this amount. Women who have previously given birth to a child with a neural tube defect should take 4 to 5 mg of folic acid daily. References, see page 360. Gynecologic Disorders Osteoporosis Over 1.3 million osteoporotic fractures occur each year in the United States. The risk of all fractures increases with age; among persons who survive until age 90, 33 percent of women will have a hip fracture. The lifetime risk of hip fracture for white women at age 50 is 16 percent. Osteoporo- sis is characterized by low bone mass, microarchitectural disruption, and increased skeletal fragility. Risk Factors for Osteoporotic Fractures Personal history of fracture as an adult History of fracture in a first- degree relative Current cigarette smoking Low body weight (less than 58 kg [127 lb]) Female sex Estrogen deficiency (meno- pause before age 45 years or bilateral ovariectomy, pro- longed premenopausal amenorrhea [greater than one year]) White race Advanced age Lifelong low calcium intake Alcoholism Inadequate physical activity Recurrent falls Dementia Impaired eyesight despite adequate correction Poor health/frailty I. Screening for osteoporosis and osteopenia A. Normal bone density is defined as a bone mineral density (BMD) value within one standard deviation of the mean value in young adults of the same sex and race. B. Osteopenia is defined as a BMD between 1 and 2.5 standard deviations below the mean. C. Osteoporosis is defined as a value more than 2.5 standard deviations below the mean; this level is the fracture threshold. These values are referred to as T- scores (number of standard deviations above or below the mean value). D. Dual x-ray absorptiometry. In dual x-ray absorptiometry (DXA), two photons are emitted from an x-ray tube. DXA is the most commonly used method for measuring bone density because it gives very precise measurements with minimal radiation. DXA measure- ments of the spine and hip are recommended. E. Biochemical markers of bone turnover. Urinary deoxypyridinoline (DPD) and urinary alpha-1 to alpha-2 N-telopeptide of collagen (NTX) are the most specific and clinically useful markers of bone resorp- tion. Biochemical markers are not useful for the screening or diagnosis of osteoporosis because the values in normal and osteoporosis overlap substan- tially. II. Recommendations for screening for osteoporosis of the National Osteoporosis Foundation A. All women should be counseled about the risk factors for osteoporosis, especially smoking cessation and limiting alcohol. All women should be encouraged to participate in regular weight-bearing and exercise. B. Measurement of BMD is recommended for all women 65 years and older regardless of risk factors. BMD should also be measured in all women under the age of 65 years who have one or more risk factors for osteoporosis (in addition to menopause). The hip is the recommended site of measurement. C. All adults should be advised to consume at least 1,200 mg of calcium per day and 400 to 800 IU of vitamin D per day. A daily multivitamin (which provides 400 IU) is recommended. In patients with documented vitamin D deficiency, osteoporosis, or previous fracture, two multivitamins may be reasonable, particularly if dietary intake is inadequate and access to sunlight is poor. D. Treatment is recommended for women without risk factors who have a BMD that is 2 SD below the mean for young women, and in women with risk factors who have a BMD that is 1.5 SD below the mean. III. Nonpharmacologic therapy of osteoporosis in women A. Diet. An optimal diet for treatment (or prevention) of osteoporosis includes an adequate intake of calories (to avoid malnutrition), calcium, and vitamin D. B. Calcium. Postmenopausal women should be advised to take 1000 to 1500 mg/day of elemental calcium, in divided doses, with meals. C. Vitamin D total of 800 IU daily should be taken. D. Exercise. Women should exercise for at least 30 minutes three times per week. Any weight-bearing exercise regimen, including walking, is acceptable. E. Cessation of smoking is recommended for all women because smoking cigarettes accelerates bone loss. IV.Drug therapy of osteoporosis in women A. Selected postmenopausal women with osteoporosis or at high risk for the disease should be considered for drug therapy. Particular attention should be paid to treating women with a recent fragility fracture, including hip fracture, because they are at high risk for a second fracture. B. Candidates for drug therapy are women who already have postmenopausal osteoporosis (less than -2.5) and women with osteopenia (T score -1 to -2.5) soon after menopause. C. Bisphosphonates 1. Alendronate (Fosamax) (10 mg/day or 70 mg once weekly) or risedronate (Actonel) (5 mg/day or 35 mg once weekly) are good choices for the treatment of osteoporosis. Bisphosphonate therapy increases bone mass and reduces the incidence of vertebral and nonvertebral fractures. 2. Alendronate (5 mg/day or 35 mg once weekly) and risedronate (5 mg/day of 35 mg once weekly) have been approved for prevention of osteoporosis. 3. Alendronate or risedronate should be taken with a full glass of water 30 minutes before the first meal or beverage of the day. Patients should not lie down for at least 30 minutes after taking the dose to avoid the unusual complication of pill-induced esophagitis. 4. Alendronate is well tolerated and effective for at least seven years. 5. The bisphosphonates (alendronate or risedronate) and raloxifene are first-line treatments for prevention of osteoporosis. The bisphosphonates are first-line therapy for treatment of osteoporosis. Bisphosphon- ates are preferred for prevention and treatment of osteoporosis because they increase bone mineral density more than raloxifene. D. Selective estrogen receptor modulators 1. Raloxifene (Evista) (5 mg daily or a once-a-week preparation) is a selective estrogen receptor modu- lator (SERM) for prevention and treatment of osteo- porosis. It increases bone mineral density and reduces serum total and low-density-lipoprotein (LDL) cholesterol. It also appears to reduce the incidence of vertebral fractures and is one of the first-line drugs for prevention of osteoporosis. 2. Raloxifene is somewhat less effective than the bisphosphonates for the prevention and treatment of osteoporosis. Venous thromboembolism is a risk. Treatment Guidelines for Osteoporosis Calcium supplements with or without vitamin D supplements or calcium-rich diet Weight-bearing exercise Avoidance of alcohol tobacco products Alendronate (Fosamax) Risedronate (Actonel) Raloxifene (Evista) Agents for Treating Osteoporosis Medication Dosage Route Calcium 1,000 to 1,500 mg per day Oral Vitamin D 400 IU per day (800 IU per day in winter in northern latitudes) Oral Alendronate (Fosamax) Prevention: 5 mg per day or 35 mg once-a-week Treatment: 10 mg per day or 70 mg once-a-week Oral Risedronate (Actonel) 5 mg daily or 35 mg once weekly Oral Raloxifene (Evista) 60 mg per day Oral Conjugated estrogens 0.3 mg per day Oral E. Monitoring the response to therapy 1. Bone mineral density and a marker of bone turnover should be measured at baseline, followed by a repeat measurement of the marker in three months. 2. If the marker falls appropriately, the drug is having the desired effect, and therapy should be continued for two years, at which time bone mineral density can be measured again. The anticipated three- month decline in markers is 50 percent with alendronate. F. Estrogen/progestin therapy 1. Estrogen-progestin therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women because of increases in the risk of breast cancer, stroke, venous thrombo- embolism, and coronary disease. 2. Indi cati ons for est rogen-progest i n i n postmenopausal women include persistent meno- pausal symptoms and patients with an indication for antiresorptive therapy who cannot tolerate the other drugs. References, see page 360. Management of the Abnormal Papanicolaou Smear The Papanicolaou (Pap) smear is the standard screening test for cervical cancer and premalignant lesions. Refine- ments in processing (eg, ThinPrep) have improved sensitivity and specificity. The Pap smear functions to screen for cellular abnormalities that are associated with an increased risk. Treatment decisions are then made based upon diagnostic results from histologic examination, usually from colposcopically directed biopsies. I. Clinical evaluation A. Pap smear report 1. A description of specimen type. Conventional Pap smear, liquid based cytology, or other. 2. A description of specimen adequacy. 3. A general categorization (optional). Negative, epithelial cell abnormality, or other (see interpreta- tion below). 4. An interpretation/result. Either the specimen is negative for intraepithelial lesions and malignancy (although organisms or reactive changes may be present) or there is an epithelial cell abnormality or there is another finding. 5. A description of any ancillary testing or automated review that was performed (eg, human papillomavirus [HPV], AutoPap). 6. Educational notes and suggestions by the patholo- gist. B. Specimen adequacy. The adequacy of the Pap smear specimen is typically reported as follows. 1. Unsatisfactory. Smears that are "unsatisfactory for evaluation" may have scanty cellular material or may be obscured by inflammation, blood, or debris so that more than 75 percent of the cells are unin- terpretable. Unsatisfactory Pap smears should always be repeated in two to four months. If the cells are obscured by inflammation, an attempt should be made to clear the inflammatory process (eg, treat cervicitis or vaginitis) prior to repeating the smear. 2. Endocervical cells not present. The presence of metaplastic and endocervical cells indicates ade- quate sampling of the transformation zone of the cervix, the area at risk for neoplasia. Most women without an endocervical/transformation zone com- ponent present should be screened with a repeat Pap test in 12 months. However, repeat testing in six months is advised in the following situations: a. A previous Pap smear result of ASC-US or worse without three subsequent negative Pap smears. b. A previous Pap smear with an unexplained glandular abnormality. c. An HPV test result positive for a high-risk type within the previous 12 months. d. Inability to clearly visualize or sample the endocervical canal. e. Immunosuppression. f. Insufficient frequency of previous screening (eg, failure to be screened at least biennially). 3. Blood or inflammation present. Women with partially obscuring blood or inflammation should have a repeat test in six months if they meet any of the above criteria. 4. Intraepithelial abnormalities a. Squamous epithelial cell abnormalities (1) Atypical squamous cells (ASC) may be of undetermined significance (ASC-US) or suspicious for HSIL (ASC-H) (2) Low-grade intraepithelial lesions (LSIL) (3) High-grade intraepithelial lesions (HSIL) b. Glandular cell abnormalities (1) Atypical glandular cells (AGC): may be endocervical, endometrial, or other glandu- lar cells (2) Endocervical adenocarcinoma in situ (AIS) (3) Adenocarcinoma c. The LSIL category includes changes consistent with human papillomavirus (HPV), mild dysplasia, or CIN I (grade 1 cervical intraepithelial neoplasia). HSIL includes changes consistent with moderate or severe dysplasia, CIN II or III, and carcinoma in situ (CIS). 5. Hyperkeratosis or parakeratosis on an otherwise negative Pap smear is not a marker for significant CIN and may be related to infection or trauma with inflammation, such as from use of a diaphragm. The Pap smear should be repeated in 6 to 12 months. Bethesda 2001 Pap Smear Report Interpretation Result Negative for intraepithelial lesion or malignancy Infection (Trichomonas vaginalis, Candida spp., shift in flora suggestive of bacterial vaginosis, Actinomyces spp., cellular changes consistent with Herpes simplex virus) Other Non-neoplastic Findings: Reactive cellular changes associated with inflammation (includes typical repair) radiation, intrauterine contracep- tive device (IUD) Glandular cells status post-hysterectomy Atrophy Other Endometrial cells (in a woman >40 years of age) Epithelial Cell Abnormalities Squamous Cell Atypical squamous cells -of undetermined significance (ASC-US) -cannot exclude HSIL (ASC-H) Low-grade squamous intraepithelial lesion (LSIL) en- compassing: HPV/mild dysplasia/CIN 1 High-grade squamous intraepithelial lesion (HSIL) en- compassing: moderate and severe dysplasia, CIS/CIN 2 and CIN 3 with features suspicious for invasion (if invasion is suspected) Squamous cell carcinoma Glandular Cell Atypical -Endocervical cells (not otherwise specified or specify in comments) -Glandular cell (not otherwise specified or specify in comments) -Endometrial cells (not otherwise specified or specify in comments) -Glandular cells (not otherwise specified or specify in comments) Atypical -Endocervical cells, favor neoplastic -Glandular cells, favor neoplastic Endocervical adenocarcinoma in situ Adenocarcinoma (endocervical, endometrial, extrauterine, not otherwise specified (not otherwise specified) Other Malignant Neoplasms (specify) Management of the Abnormal Papanicolaou Smear Result Action Specimen adequacy Satisfactory for evaluation Routine follow-up Unsatisfactory for evaluation Repeat smear No endocervical cells Follow-up in one year for low- risk women with a previously normal smear; repeat in 4-6 months for high-risk women Atypical cells Atypical squamous cells of undetermined significance (ASC-US) HPV testing with referral to colposcopy if positive for high-risk HPV type; if nega- tive for high-risk HPV type, then repeat cytology in 12 months Special circumstances Postmenopausal women with atrophic epitheliium may be treated with topical estrogen followed by repeat cervical cytology one week after com- pleting treatment ASC-H Immediate referral to colposcopy Atypical glandular cells (AGS) Immediate referral to colposcopy with sampling of the endocervical canal. Women over age 35 and any woman with unexplained vaginal bleeding should also have an endometrial biopsy Intraepithelial neoplasia High grade Immediate referral for colposcopy Low grade Immediate referral for colposcopy, except adoles- cents and postmenopausal women Result Action Endometrial cells Endometrial biopsy in se- lected cases Other malignant cells Referral to a gynecologic oncologist II. Atypical squamous cells (ASC) is divided into ASC-US, which are qualified as "of undetermined significance," and ASC-H, in which a high-grade squamous intraepithelial lesion (HSIL) cannot be excluded. A. ASC requires further evaluation, but it does not require treatment. This cytologic diagnosis is common and frequently associated with spontaneously resolv- ing, self-limited disease. The risk of invasive cancer is low, 0.1 to 0.2 percent. However, 5 to 17 percent of patients with ASC and 24 to 94 percent of those with ASC-H will have CIN II or III at biopsy; therefore, further investigation is necessary to determine if underlying high-grade dysplasia is present. B. Evaluation of ASC-US. Reflex HPV testing is the preferred approach. Reflex testing refers to concurrent collection of cytology and HPV samples with actual testing for HPV only if indicated by cytology results. If liquid-based cytology is used, reflex HPV testing can be performed on the same specimen. 1. Women with a positive test for high- (including intermediate) risk type HPV DNA are evaluated by colposcopy. The sensitivity of this approach for detection of CIN II/III is 83 to 100 percent. 2. Women who test negative for high-risk HPV DNA can be followed with a repeat cervical cytology in 12 months. Management of Women with Combined Test Screening Results of cytol- ogy/HPV Recommended follow- up Negative/Negative Negative/Negative ASCUS/Negative ASCUS/Positive Greater than ASCUS/ Posi- tive or negative Routine screening in 3 years Repeat combined test in 6-12 months* Repeat cytology in 12 months** Colposcopy Colposcopy *If Negative/Negative, then resume screening in 3 years If ASCUS/Negative, then repeat combined test in 12 months If greater than ASCUS/Negative, then colposcopy If any cytology result/Positive, the colposcopy **Follow-up depends on cytology results HPV = Human Papillomarvirus. Positive means high-risk types are present. Negative means high-risk types are not present C. Special circumstances 1. Infection or reactive changes. When an infec- tious organism is identified, the patient should be contacted to determine if she is symptomatic. Antibiotic therapy is indicated for symptomatic infection. Asymptomatic trichomonas infection should be treated. Most patients with only reactive changes due to inflammation will not have an organism identified on Pap smear. The Pap smear does not need to be repeated unless the patient is HIV positive. 2. Atrophic epithelium (a normal finding in postmenopausal women) is often characterized by nuclear enlargement, which meets one of the pathologic criteria for ASC. Administration of estrogen (eg, 0.3 mg conjugated estrogen applied as vaginal cream nightly for four weeks [1/8th of the applicator]) causes atypical atrophic epithelium to mature into normal squamous epithelium. a. Hormonal therapy given for vaginal atrophy should be followed by repeat cervical cytology one week after completing treatment. If nega- tive, cytology should be repeated again in four to six months. If both tests are negative, the woman can return to routine screening intervals, but if either test is positive for ASC-US or greater, she should be referred for colposcopy. 3. Immunosuppressed women, including all women who are HIV positive, with ASC-US should be referred for immediate colposcopy. D. Management after col poscopy/ bi opsy. Colposcopy/biopsy of women with ASC-US will either yield a histologic abnormality (eg, CIN II or III), which should be treated as appropriate or show no abnormal findings. In the latter case, if HPV testing was not performed or showed a low-risk type, then follow-up cytological testing in 12 months is recommended. 1. Management of women who test positive for high- risk HPV types, but have CIN I or less on colposcopy/biopsy consists of HPV testing at 12 months postprocedure with repeat colposcopic referral if the HPV results are positive for high-risk types. E. Women with ASC-H on cytological examination should be referred for colposcopy. Biopsy proven CIN is treated. If no lesion is identified, the cytology sam- ple, colposcopy, and any biopsy specimens should be reviewed. If review of cytology confirms ASC-H, follow- up HPV DNA testing in 12 months is acceptable. Colposcopy should be repeated for ASC-US or greater on cytology or a positive test for high-risk HPV DNA. III. Low- and high-grade intraepithelial neoplasia. All women who present with lower genital tract intraepithelial lesions should be offered HIV testing because of the high incidence of neoplasia in this population. A. Low-grade squamous intraepithelial lesions 1. Immediate referral for colposcopy is the recom- mended management for LSIL (see exceptions for postmenopausal women, adolescents, and preg- nant women below). 2. Endocervical curettage should be done in nonpregnant women in whom: the transformation zone cannot be fully visualized, the lesion extends into the endocervical canal, or no lesion is identi- fied on colposcopy. It is also an acceptable proce- dure in nonpregnant women in whom a lesion is identified in the transformation zone. B. Special circumstances 1. Postmenopausal women may forgo immediate colposcopy and be managed by HPV DNA testing at 12 months with referral to colposcopy for positive results (high- risk HPV DNA types). Women with LSIL who have clinical or cytologic evidence of atrophy may be treated with intravaginal estrogen, followed by repeat cytology seven days after completion of therapy, with referral to colposcopy if an abnormality persists. If repeat cytology is normal, then another cytology test should be obtained in four to six months. The woman can return to routine surveillance if both tests are normal, but should be referred for colposcopy if either test is ASC-US or worse. 2. Adolescents. Initial colposcopy may be deferred in adolescents. Instead, they may be managed with HPV DNA testing at 12 months with referral to colposcopy for positive results (high-risk HPV DNA types). 3. Pregnant women with LSIL are managed in a similar fashion to those with HSIL (see below). Colposcopy should be performed, with biopsy and endocervical curettage performed for any lesion suspicious for HSIL or more severe disease. C. High-grade squamous intraepithelial lesions 1. HSIL may also be referred to as CIN II or III, severe dysplasia, or carcinoma in situ (CIS). All women with HSIL should be referred for colposcopy and endocervical curettage. 2. If colposcopy reveals no lesion or only biopsy proven CIN I, then cytology, colposcopy, and biopsies should be reviewed. A cytological diagno- sis of HSIL without colposcopic or histologic confir- mation of significant dysplasia (CIN II or above) requires a diagnostic excisional procedure in nonpregnant women. IV. Atypical glandular cells A. A report of atypical glandular cells (AGC) indicates the presence of glandular cells that could originate from the endocervical or endometrial region. AGC is divided into two subcategories: 1. AGC (specify endocervical, endometrial, or glandu- lar cells not otherwise specified [NOS]). 2. AGC, favor neoplastic (specify endocervical or NOS). B. Additional categories for glandular cell abnormalities are: 1. Endocervical adenocarcinoma in situ (AIS). 2. Adenocarcinoma. C. Significance. A smear with adenocarcinoma in situ is associated with a premalignant or malignant lesion of the endocervix or endometrium in 10 to 39 percent of cases. D. Evaluation 1. All women with atypical endocervical or glandular cells or AIS should be referred for colposcopy and sampling of the endocervical canal. Women over age 35 and younger women with AGC and unex- plained or anovulatory bleeding also need an endometrial biopsy. 2. Women with only atypical endometrial cells on cytology can be initially evaluated with endometrial biopsy only, rather than colposcopy. 3. Positive findings, such as any grade of CIN on biopsy, should be managed as appropriate. 4. Negative colposcopy/endocervical curettage a. AGC not otherwise specified. Women with AGC NOS who have a normal initial colposcopic evaluation and endocervical biopsy can be followed with cervical cytology at four to six month intervals until four consecutive tests are negative for intraepithelial lesions or malig- nancy. They are then followed with routine surveillance. b. AGC favor neoplasia or AIS. A cold-knife conization is the best procedure for subsequent evaluation of AGC lesions at high risk of asso- ciated adenocarcinoma, such as AGC favor neoplasia or AIS. 5. Endocervical adenocarcinoma in situ (AIS) and adenocarcinoma are separate categories of glan- dular cell abnormality. Colposcopy with directed biopsy is required. A diagnostic excisional proce- dure is also needed. 6. Endometrial cells. Occasionally, normal appear- ing endometrial cells will be reported on a Pap smear. The presence of these cells is reported only in women >40 years of age. In these cases, endo- metrial biopsy should be performed. E. Follow-up after treatment. Follow-up Pap smears are recommended every three to four months for the first year after any treatment for dysplasia. Women with cervical dysplasia present at the LEEP or cone margin or in the concomitant endocervical curettage also need follow-up colposcopy with endocervical sampling every six months for one year. Routine surveillance can be resumed if there is no recurrence after the first year. Surveillance consists of Pap smears on a yearly basis for most women and on a twice-yearly basis for high-risk women (ie, HIV posi- tive). References, see page 360. Sexually Transmissible Infections Approximately 12 million patients are diagnosed with a sexually transmissible infection (STI) annually in the United States. Sequella of STIs include infertility, chronic pelvic pain, ectopic pregnancy, and other adverse pregnancy outcomes. Diagnosis and Treatment of Bacterial Sexually Transmissible Infections Organ- ism Diagnostic Methods Recommended Treatment Alternative Chlamy- dia tracho- matis Direct fluo- rescent antibody, enzyme immuno- assay, DNA probe, cell culture, DNA ampli- fication Doxycycline 100 mg PO 2 times a day for 7 days or Azithromycin (Zithromax) 1 g PO Ofloxacin (Floxin) 300 mg PO 2 times a day for 7 days Neisser- ia gonor- rhoeae Culture DNA probe Ceftriaxone (Rocephin) 125 mg IM or Cefixime 400 mg PO or Ciprofloxacin (Cipro) 500 mg PO or Ofloxacin (Floxin) 400 mg PO plus Doxycycline 100 mg 2 times a day for 7 days or azithromycin 1 g PO Levofloxacin (Levaquin) 250 mg PO once Spectinomycin 2 g IM once Organ- ism Diagnostic Methods Recommended Treatment Alternative Trepo- nema pallidum Clinical appear- ance Dark-field microscopy Nontrepon emal test: rapid plasma reagin, VDRL Treponem al test: MHA-TP, FTA-ABS Primary and sec- ondary syphilis and early latent syphilis (<1 year duration): benzathine peni- cillin G 2.4 million units IM in a sin- gle dose. Penicillin allergy in patients with pri- mary, secondary, or early latent syphilis (<1 year of dura- tion): doxycycline 100 mg PO 2 times a day for 2 weeks. Diagnosis and Treatment of Viral Sexually Transmis- sible Infections Organ- ism Diagnostic Methods Recommended Treatment Regi- mens Herpes simplex virus Clinical ap- pearance Cell culture confirmation First episode: Acyclovir (Zovirax) 400 mg PO 5 times a day for 7-10 days, or famciclovir (Famvir) 250 mg PO 3 times a day for 7-10 days, or valacyclovir (Valtrex) 1 g PO 2 times a day for 7-10 days. Recurrent episodes: acyclovir 400 mg PO 3 times a day for 5 days, or 800 mg PO 2 times a day for 5 days or famciclovir 125 mg PO 2 times a day for 5 days, or valacyclovir 500 mg PO 2 times a day for 5 days Daily suppressive therapy: acyclovir 400 mg PO 2 times a day, or famciclovir 250 mg PO 2 times a day, or valacyclovir 250 mg PO 2 times a day, 500 mg PO 1 time a day, or 1000 mg PO 1 time a day Human papillom a virus Clinical ap- pearance of condyloma papules Cytology External warts: Patient may apply podofilox 0.5% solution or gel 2 times a day for 3 days, followed by 4 days of no therapy, for a total of up to 4 cycles, or imiquimod 5% cream at bedtime 3 times a week for up to 16 weeks. Cryotherapy with liquid nitro- gen or cryoprobe, repeat every 1-2 weeks; or podophyllin, repeat weekly; or TCA 80-90%, repeat weekly; or surgical removal. Vaginal warts: cryotherapy with liquid nitrogen, or TCA 80-90%, or podophyllin 10-25% Human immuno- defi- ciency virus Enzyme immunoassay Western blot (for confirma- tion) Polymerase chain reaction Antiretroviral agents Treatment of Pelvic Inflammatory Disease Reg- imen Inpatient Outpatient A Cefotetan (Cefotan) 2 g IV q12h; or cefoxitin (Mefoxin) 2 g IV q6h plus doxycycline 100 mg IV or PO q12h. Ofloxacin (Floxin) 400 mg PO bid for 14 days plus metronidazole 500 mg PO bid for 14 days. B Clindamycin 900 mg IV q8h plus gentamicin load- ing dose IV or IM (2 mg/kg of body weight), followed by a mainte- nance dose (1.5 mg/kg) q8h. Ceftriaxone (Rocephin) 250 mg IM once; or cefoxitin 2 g IM plus probenecid 1 g PO; or other parenteral third-gen- eration cephalosporin (eg, ceftizoxime, cefotaxime) plus doxycycline 100 mg PO bid for 14 days. I. Chlamydia Trachomatis A. Chlamydia trachomatis is the most prevalent STI in the United States. Chlamydial infections are most common in women age 15-19 years. B. Routine screening of asymptomatic, sexually active adolescent females undergoing pelvic examination is recommended. Annual screening should be done for women age 20-24 years who are either inconsistent users of barrier contraceptives or who acquired a new sex partner or had more than one sexual partner in the past 3 months. II. Gonorrhea. Gonorrhea has an incidence of 800,000 cases annually. Routine screening for gonorrhea is recommended among women at high risk of infection, including prostitutes, women with a history of repeated episodes of gonorrhea, women under age 25 years with two or more sex partners in the past year, and women with mucopurulent cervicitis. III. Syphilis A. Syphilis has an incidence of 100,000 cases annually. The rates are highest in the South, among African Americans, and among those in the 20- to 24-year-old age group. B. Prostitutes, persons with other STIs, and sexual contacts of persons with active syphilis should be screened. IV.Herpes simplex virus and human papillomavirus A. An estimated 200,000-500,000 new cases of herpes simplex occur annually in the United States. New infections are most common in adolescents and young adults. B. Human papillomavirus affects about 30% of young, sexually active individuals. References, see page 360. Vaginitis Approximately 8-18% of women reported an episode of vaginal symptoms in the previous year. The etiology of vaginal complaints includes infection of the vagina, cervix, and upper genital tract, chemicals or irritants (eg, spermi- cides or douching), hormone deficiency, and rarely systemic diseases. I. Clinical evaluation A. Symptoms of vaginitis include vaginal discharge, pruritus, irritation, soreness, odor, dyspareunia and dysuria. Dyspareunia is a common feature of atrophic vaginitis. Abdominal pain is suggestive of pelvic inflam- matory disease and suprapubic pain is suggestive of cystitis. B. A new sexual partner increases the risk of acquiring sexually transmitted diseases, such as trichomonas, chlamydia, or Neisseria gonorrheae. Trichomoniasis often occurs during or immediately after the menstrual period; candida vulvovaginitis often occurs during the premenstrual period. C. Antibiotics and high-estrogen oral contraceptive pills may predispose to candida vulvovaginitis; increased physiologic discharge can occur with oral contracep- tives; pruritus unresponsive to antifungal agents suggests vulvar dermatitis. II. Physical examination A. The vulva usually appears normal in bacterial vaginosis. Erythema, edema, or fissure formation suggest candidiasis, trichomoniasis, or dermatitis. Trichomonas is associated with a purulent discharge; candidiasis is associated with a thick, adherent, “cot- tage cheese-like” discharge; and bacterial vaginosis is associated with a thin, homogeneous, “fishy smelling” discharge. The cervix in women with cervicitis is usually erythematous and friable, with a mucopurulent dis- charge. Abdominal or cervical motion tenderness is suggestive of PID. III. Diagnostic studies A. Vaginal pH. Measurement of vaginal pH should always be determined. The pH of the normal vaginal secre- tions is 4.0 to 4.5. A pH above 4.5 suggests bacterial vaginosis or trichomoniasis (pH 5 to 6), and helps to exclude candida vulvovaginitis (pH 4 to 4.5). B. Saline microscopy should look for candidal buds or hyphae, motile trichomonads, epithelial cells studded with adherent coccobacilli (clue cells), and polymorphonuclear cells (PMNs). The addition of 10% potassium hydroxide to the wet mount is helpful in diagnosing candida vaginitis. Culture for candida and trichomonas may be useful if microscopy is negative. C. Cervical culture. A diagnosis of cervicitis, typically due to Neisseria gonorrhoeae or Chlamydia trachomatis, must always be considered in women with purulent vaginal discharge. The presence of high-risk behavior or any sexually transmitted disease requires screening for HIV, hepatitis B, and other STDs. Clinical Manifestations of Vaginitis Candidal Vagi- nitis Nonmalodorous, thick, white, "cottage cheese- like" discharge that adheres to vaginal walls Hyphal forms or budding yeast cells on wet- mount Pruritus Normal pH (<4.5) Bacterial Vaginosis Thin, dark or dull grey, homogeneous, mal- odorous discharge that adheres to the vaginal walls Elevated pH level (>4.5) Positive KOH (whiff test) Clue cells on wet-mount microscopic evalua- tion Trichomonas Vaginalis Copious, yellow-gray or green, homogeneous or frothy, malodorous discharge Elevated pH level (>4.5) Mobile, flagellated organisms and leukocytes on wet-mount microscopic evaluation Vulvovaginal irritation, dysuria Atrophic Vagi- nitis Vaginal dryness or burning IV. Bacterial vaginosis A. Incidence. Bacterial vaginosis is the most common cause of vaginitis in women of childbearing age, with prevalence of 5-60%. B. Microbiology and risk factors. Bacterial vaginosis represents a change in vaginal flora characterized by a reduction of lactobacilli and an increase of Gardnerella vaginalis, Mobiluncus species, Mycoplasma hominis, anaerobic gram-negative rods, and Peptostreptococcus species. Risk factors for bacterial vaginosis include multiple or new sexual partners, early age of first coitus, douching, cigarette smoking, and use of an intrauterine contraceptive device. C. Clinical features. Symptoms include a “fishy smelling” discharge that is more noticeable after unprotected intercourse. The discharge is off-white, thin, and homo- geneous. Pruritus and inflammation are absent. D. Complications 1. Pregnant women appear to be at higher risk of preterm delivery. 2. Bacterial vaginosis may cause plasma-cell endometritis, postpartum fever, post-hysterectomy vaginal-cuff cellulitis, and postabortal infection. 3. Bacterial vaginosis is a risk factor for HIV acquisition and transmission. E. Diagnosis. Three of the four criteria listed below are necessary for diagnosis. 1. Homogeneous, grayish-white discharge 2. Vaginal pH greater than 4.5 3. Positive whiff-amine test, defined as the presence of a fishy odor when 10% KOH is added to vaginal discharge samples 4. Clue cells on saline wet mount (epithelial cells studded with coccobacilli) F. Therapy. Treatment is indicated in women with symp- tomatic infection and those with asymptomatic infection prior to abortion or hysterectomy. 1. Metronidazole or clindamycin administered either orally or intravaginally will result in a high rate of clinical cure (70-80% at 4 weeks of follow-up). Oral medication is more convenient, but associated with a higher rate of systemic side effects than vaginal administration. 2. The oral regimen is 500 mg twice daily for 7 days. Topical vaginal therapy with 0.75% metronidazole gel (MetroGel, 5 g once daily for 5 days) is as effective as oral metronidazole. 3. Single-dose therapy with 2 g of metronidazole achieves a similar immediate rate of clinical response and is considered an alternative, slightly less effec- tive regimen. 4. Side effects of metronidazole include a metallic taste, nausea, a disulfiram-like effect with alcohol, interac- tion with warfarin, and peripheral neuropathy. 5. Topical vaginal therapy with 2% clindamycin cream (5 g once daily for 7 days) appears to be less effec- tive than the metronidazole regimens but is a reason- able choice. Pseudomembranous colitis has been reported with topical clindamycin. Clindamycin cream should not be used with condoms, which may be weakened. G. Relapse 1. Approximately 30% of patients have a recurrence within three months. Recurrence usually reflects a failure to eradicate the offending organisms. Man- agement of symptomatic relapse includes prolonged therapy for 10 to 14 days. 2. Most women with a history of recurrent infection benefit from suppressive therapy with metronidazole gel 0.75% for 10 days, followed by twice-weekly applications for three to six months. V. Candida vulvovaginitis A. Incidence. Candida vulvovaginitis accounts for one- third of vaginitis. Up to 75% of women report having had at least one episode of candidiasis. The condition is rare before menarche. It is less common in postmenopausal women, unless they are taking estrogen replacement therapy. B. Microbiology and risk factors. Candida albicans is responsible for 80-92% of vulvovaginal candidiasis. Sporadic attacks of vulvovaginal candidiasis usually occur without an identifiable precipitating factor. 1. Antibiotics. A minority of women are prone to vulvovaginal candidiasis while taking antibiotics. 2. Intrauterine devices have been associated with vulvovaginal candidiasis. 3. Pregnancy. Symptomatic infection is more common in pregnancy. C. Clinical features. Vulvar pruritus is the dominant feature. Women may also complain of dysuria (external rather than urethral), soreness, irritation, and dyspareunia. There is often little or no discharge; that which is present is typically white and clumpy. Physical examination often reveals erythema of the vulva and vaginal mucosa. The discharge is thick, adherent, and “cottage cheese-like.” D. Diagnosis 1. The vaginal pH is typically 4 to 4.5, which distin- guishes candidiasis from Trichomonas or bacterial vaginosis. The diagnosis is confirmed by finding the organism on a wet mount; adding 10% potassium hydroxide facilitates recognition of budding yeast and hyphae. Microscopy is negative in 50% of patients with vulvovaginal candidiasis. 2. Empiric therapy is often considered in women with typical clinical features, a normal vaginal pH, and no other pathogens visible on microscopy. Culture should be performed in patients with persistent or recurrent symptoms. E. Therapy 1. Women with mild infection usually respond to treat- ment within a couple of days. More severe infections require a longer course of therapy and may take up to 14 days to fully resolve. 2. Uncomplicated infection. Both oral and topical antimycotic drugs achieve comparable clinical cure rates that are in excess of 80%. 3. Oral azole agents are more convenient. Side effects of single-dose fluconazole (150 mg) tend to be mild and infrequent, including gastrointestinal intolerance, headache, and rash. Treatment regimens for yeast vaginitis* 1-day regimens Clotrimazole vaginal tablets (Mycelex G), 500 mg hs** Fluconazole tablets (Diflucan), 150 mg PO Itraconazole capsules (Sporanox), 200 mg PO bid Tioconazole 6.5% vaginal ointment (Vagistat-1), 4.6 g hs** [5 g] 3-day regimens Butoconazole nitrate 2% vaginal cream (Femstat 3), 5 g hs [28 g] Clotrimazole vaginal inserts (Gyne-Lotrimin 3), 200 mg hs** Miconazole vaginal suppositories (Monistat 3), 200 mg hs** Terconazole 0.8% vaginal cream (Terazol 3), 5 g hs Terconazole vaginal suppositories (Terazol 3), 80 mg hs Itraconazole capsules (Sporanox), 200 mg PO qd (4) 5-day regimen Ketoconazole tablets (Nizoral), 400 mg PO bid (4) 7-day regimens Clotrimazole 1% cream (Gyne-Lotrimin, Mycelex-7, Sweet'n Fresh Clotrimazole-7), 5 g hs** Clotrimazole vaginal tablets (Gyne-Lotrimin, Mycelex-7, Sweet'n Fresh Clotrimazole-7), 100 mg hs** Miconazole 2% vaginal cream (Femizol-M, Monistat 7), 5 g hs** Miconazole vaginal suppositories (Monistat 7), 100 mg hs** Terconazole 0.4% vaginal cream (Terazol 7), 5 g hs 14-day regimens Nystatin vaginal tablets (Mycostatin), 100,000 U hs Boric acid No. 0 gelatin vaginal suppositories, 600 mg bid (2) *Suppositories can be used if inflammation is predominantly vaginal; creams if vulvar; a combination if both. Cream-supposi- tory combination packs available: clotrimazole (Gyne-Lotrimin, Mycelex); miconazole (Monistat, M-Zole). If diagnosis is in doubt, consider oral therapy to avoid amelioration of symptoms with use of creams. Use 1-day or 3-day regimen if compliance is an issue. Miconazole nitrate may be used during pregnancy. **Nonprescription formulation. If nonprescription therapies fail, use terconazole 0.4% cream or 80-mg suppositories at bedtime for 7 days. 4. Complicated infections. Factors that predispose to complicated infection include uncontrolled diabetes, immunosuppression, and a history of recurrent vulvovaginal candidiasis. Women with severe inflam- mation or complicated infection require seven to 14 days of topical therapy or two doses of oral therapy 72 hours apart. Management options for complicated or recurrent yeast vaginitis Extend any 7-day regimen to 10 to 14 days Eliminate use of nylon or tight-fitting clothing Consider discontinuing oral contraceptives Consider eating 8 oz yogurt (with Lactobacillus acidophilus culture) per day Improve glycemic control in diabetic patients For long-term suppression of recurrent vaginitis, use ketoconazole, 100 mg (½ of 200-mg tablet) qd for 6 months 5. Partner treatment is not necessary since this is not a primary route of transmission. 6. Pregnancy. Topical azoles applied for seven days are recommended for treatment during pregnancy. F. Women with recurrent infections should receive longer initial therapy (10 to 14 days of a topical agent or fluconazole 150 mg orally with a repeat dose three days later). Antifungal maintenance suppressive therapy that should be taken for six months after an initial induction regimen include ketoconazole (100 mg per day), itraconazole (100 mg per day or 400 mg once monthly), fluconazole (100 to 150 mg once per week), and clotrimazole (500 mg vaginal suppository once per week). Alternatively, fluconazole 200 mg orally may be given every three days until the patient is asymptomatic, with redosing weekly, tapered to every two weeks, and then every three to four weeks. Redosing once per month just before menses may be effective because this is when most patients flare. Patients receiving long-term ketoconazole should be monitored for hepatotoxicity. VI. Trichomoniasis A. Trichomoniasis, the third most common cause of vaginitis, is caused by the flagellated protozoan, Trichomonas vaginalis. The disorder is virtually always sexually transmitted. B. Clinical features. Trichomoniasis in women ranges from an asymptomatic state to a severe, acute, inflam- matory disease. Signs and symptoms include a puru- lent, malodorous, thin discharge (70%) with associated burning, pruritus, dysuria, and dyspareunia. Physical examination reveals erythema of the vulva and vaginal mucosa; the classic green-yellow frothy discharge is observed in 10-30%. Punctate hemorrhages may be visible on the vagina and cervix in 2%. C. Complications. Infection is associated with premature rupture of the membranes and prematurity; however, treatment of asymptomatic infection has not been shown to reduce these complications. Trichomoniasis is a risk factor for development of post-hysterectomy cellulitis. The infection facilitates transmission of the human immunodeficiency virus. D. Diagnosis 1. The presence of motile trichomonads on wet mount is diagnostic of infection, but this occurs in only 50- 70% of cases. Other findings include an elevated vaginal pH (>4.5) and an increase in polymorphonuclear leukocytes on saline microscopy. 2. Culture on Diamond's medium has a 95% high sensitivity and should be considered in patients with elevated vaginal pH, increased numbers of polymorphonuclear leukocytes, and an absence of motile trichomonads and clue cells; rapid diagnostic kits using DNA probes and monoclonal antibodies have a sensitivity of 90%. 3. Trichomonads are often seen on conventional Papanicolaou smears, but false positive results are not uncommon (30%). Thus, asymptomatic women with Trichomonas identified on conventional Pap smear should not be treated until the diagnosis is confirmed by wet mount. Treatment of asymptomatic women with trichomonads noted on liquid-based cervical cytology is recommended. E. Therapy is indicated in all nonpregnant women diag- nosed with Trichomonas vaginitis and their sexual partner(s). Intercourse should not resume until both partners have completed treatment. 1. Metronidazole is the treatment of choice. Oral is preferred to local vaginal therapy since systemic administration achieves therapeutic drug levels in the urethra and periurethral glands. Sexual partners should also be treated. 2. Similar cure rates are obtained with oral metronidazole in a dose of 500 mg twice a day for seven days (cure rate, 85-90%) and a single 2 g oral dose (82-88%). Patients should be advised not to take alcohol for the duration of 48 hours after treat- ment because of the disulfiram-like (Antabuse effect) reaction. Treatment options for trichomoniasis Initial measures Metronidazole (Flagyl, Protostat), 2 g PO in a single dose, or metronidazole, 500 mg PO bid X 7 days, or metronidazole, 375 mg PO bid X 7 days Treat male sexual partners Measures for treatment failure Treatment sexual contacts Re-treat with metronidazole, 500 mg PO bid X 7 days If infection persists, confirm with culture and re-treat with metronidazole, 2-4 g PO qd X 3-10 days 3. Pregnancy. Metronidazole is the drug of choice in pregnancy. Metronidazole 500 mg twice daily for 5-7 days is preferred to the 2 g single-dose regimen, but both regimens are acceptable. Treatment of asymp- tomatic infections is not recommended during preg- nancy because it does not prevent preterm delivery. 4. Refractory cases. If treatment failure occurs, retreatment with metronidazole (500 mg PO twice a day for seven days) is recommended. If treatment failure recurs again, the woman should be treated with a single oral 2 g dose of oral metronidazole daily for 3-5 days. VII. Other causes of vaginitis and vaginal discharge A. Atrophic vaginitis 1. Reduced endogenous estrogen causes thinning of the vaginal epithelium. Symptoms include vaginal soreness, postcoital burning, dyspareunia, and occasional spotting. The vaginal mucosa is thin with diffuse erythema, occasional petechiae or ecchymoses, and few or no vaginal folds. There may be a serosanguineous or watery discharge with a pH of 5.0-7.0. 2. Treatment consists of topical vaginal estrogen. Vaginal ring estradiol (Estring), a silastic ring impregnated with estradiol, is the preferred means of delivering estrogen to the vagina. The silastic ring delivers 6 to 9 µg of estradiol to the vagina daily. The rings are changed once every three months. Con- comitant progestin therapy is not necessary. 3. Conjugated estrogens (Premarin), 0.5 gm of cream, or one-eighth of an applicatorful daily into the vagina for three weeks, followed by twice weekly thereafter is also effective. Concomitant progestin therapy is not necessary. 4. Estrace cream (estradiol) can also by given by vaginal applicator at a dose of one-eighth of an applicator or 0.5 g (which contains 50 µg of estradiol) daily into the vagina for three weeks, followed by twice weekly thereafter. Concomitant progestin therapy is not necessary. 5. Oral estrogen (Premarin) 0.3 mg qd should also provide relief. B. Desquamative inflammatory vaginitis 1. Chronic purulent vaginitis usually occurs perimenopausally, with diffuse exudative vaginitis, massive vaginal-cell exfoliation, purulent vaginal discharge, and occasional vaginal and cervical spotted rash. Laboratory findings included an ele- vated pH, increased numbers of parabasal cells, the absence of gram-positive bacilli and their replace- ment by gram-positive cocci on Gram staining. Clindamycin 2% cream is usually effective. C. Noninfectious vaginitis and vulvitis 1. Noninfectious causes of vaginitis include irritants (eg, minipads, spermicides, povidone-iodine, topical antimycotic drugs, soaps and perfumes) and contact dermatitis (eg, latex condoms and antimycotic creams). 2. Typical symptoms, including pruritus, irritation, burning, soreness, and variable discharge, are most commonly confused with acute candida vaginitis. The diagnosis should be suspected in symptomatic women who do not have an otherwise apparent infectious cause. 3. Management of noninfectious vaginitis includes identifying and eliminating the offending agent. Sodium bicarbonate sitz baths and topical vegetable oils may provide some local relief. Topical cortico- steroids are not recommended. References, see page 360. Breast Cancer Screening and Diagno- sis Breast cancer is the second most commonly diagnosed cancer among women, after skin cancer. Approximately 182,800 new cases of invasive breast cancer are diagnosed in the United States per year. The incidence of breast cancer increases with age. White women are more likely to develop breast cancer than black women. The incidence of breast cancer in white women is about 113 cases per 100,000 women and in black women, 100 cases per 100,000. I. Risk factors Risk Factors for Breast Cancer Age greater than 50 years Prior history of breast can- cer Family history Early menarche, before age 12 Late menopause, after age 50 Nulliparity Age greater than 30 at first birth Obesity High socioeconomic status Atypical hyperplasia on bi- opsy Ionizing radiation exposure A. Family history is highly significant in a first-degree relative (ie, mother, sister, daughter), especially if the cancer has been diagnosed premenopausally. Women who have premenopausal first-degree rela- tives with breast cancer have a three- to fourfold increased risk of breast cancer. Having several second-degree relatives with breast cancer may further increase the risk of breast cancer. Most women with breast cancer have no identifiable risk factors. B. Approximately 8 percent of all cases of breast cancer are hereditary. About one-half of these cases are attributed to mutations in the BRCA1 and BRCA2 genes. Hereditary breast cancer commonly occurs in premenopausal women. Screening tests are available that detect BRCA mutations. II. Diagnosis and evaluation A. Clinical evaluation of a breast mass should assess duration of the lesion, associated pain, relationship to the menstrual cycle or exogenous hormone use, and change in size since discovery. The presence of nipple discharge and its character (bloody or tea- colored, unilateral or bilateral, spontaneous or ex- pressed) should be assessed. B. Menstrual history. The date of last menstrual period, age of menarche, age of menopause or surgical removal of the ovaries, previous pregnancies should be determined. C. History of previous breast biopsies, cyst aspiration, dates and results of previous mammograms should be determined. D. Family history should document breast cancer in relatives and the age at which family members were diagnosed. III. Physical examination A. The breasts should be inspected for asymmetry, deformity, skin retraction, erythema, peau d'orange (breast edema), and nipple retraction, discoloration, or inversion. B. Palpation 1. The breasts should be palpated while the patient is sitting and then supine with the ipsilateral arm extended. The entire breast should be palpated systematically. The mass should be evaluated for size, shape, texture, tenderness, fixation to skin or chest wall. 2. mass that is suspicious for breast cancer is usually solitary, discrete and hard. In some instances, it is fixed to the skin or the muscle. A suspicious mass is usually unilateral and nontender. Sometimes, an area of thickening may represent cancer. Breast cancer is rarely bilateral. The nipples should be expressed for discharge. 3. The axillae should be palpated for adenopathy, with an assessment of size of the lymph nodes, number, and fixation. C. Mammography. Screening mammograms are recom- mended every year for asymptomatic women 40 years and older. Unfortunately, only 60 percent of cancers are diagnosed at a local stage. Screening for Breast Cancer in Women Age American Cancer Society guidelines 20 to 39 years Clinical breast examination every three years Monthly self-examination of breasts Age 40 years and older Annual mammogram Annual clinical breast examination Monthly self-examination of breasts IV.Methods of breast biopsy A. Palpable masses. Fine-needle aspiration biopsy (FNAB) has a sensitivity ranging from 90-98%. Nondiagnostic aspirates require surgical biopsy. 1. The skin is prepped with alcohol and the lesion is immobilized with the nonoperating hand. A 10 mL syringe, with a 14 gauge needle, is introduced in to the central portion of the mass at a 90E angle. When the needle enters the mass, suction is ap- plied by retracting the plunger, and the needle is advanced. The needle is directed into different areas of the mass while maintaining suction on the syringe. 2. Suction is slowly released before the needle is withdrawn from the mass. The contents of the needle are placed onto glass slides for pathologic examination.Excisional biopsy is done when needle biopsies are negative but the mass is clinically suspected of malignancy. B. Stereotactic core needle biopsy. Using a computer- driven stereotactic unit, the lesion is localized in three dimensions, and an automated biopsy needle obtains samples. The sensitivity and specificity of this tech- nique are 95-100% and 94-98%, respectively. C. Nonpalpable lesions 1. Needle localized biopsy a. Under mammographic guidance, a needle and hookwire are placed into the breast parenchyma adjacent to the lesion. The patient is taken to the operating room along with mammograms for an excisional breast biopsy. b. The skin and underlying tissues are infiltrated with 1% lidocaine with epinephrine. For lesions located within 5 cm of the nipple, a periareolar incision may be used or use a curved incision located over the mass and parallel to the areola. Incise the skin and subcutaneous fat, then pal- pate the lesion and excise the mass. c. After removal of the specimen, a specimen x-ray is performed to confirm that the lesion has been removed. The specimen can then be sent fresh for pathologic analysis. d. Close the subcutaneous tissues with a 4-0 chro- mic catgut suture, and close the skin with 4-0 subcuticular suture. 2. Ultrasonography. Screening is useful to differenti- ate between solid and cystic breast masses when a palpable mass is not well seen on a mammogram. Ultrasonography is especially helpful in young women with dense breast tissue when a palpable mass is not visualized on a mammogram. Ultrasonography is not used for routine screening because microcalcifications are not visualized and the yield of carcinomas is negligible. References, see page 360. Secondary Amenorrhea Amenorrhea (absence of menses) can be a transient, intermittent, or permanent condition resulting from dysfunc- tion of the hypothalamus, pituitary, ovaries, uterus, or vagina. Amenorrhea is classified as either primary (absence of menarche by age 16 years) or secondary (absence of menses for more than three cycles or six months in women who previously had menses). Pregnancy is the most com- mon cause of secondary amenorrhea. I. Diagnosis of secondary amenorrhea A. Step 1: Rule out pregnancy. A pregnancy test is the first step in evaluating secondary amenorrhea. Mea- surement of serum beta subunit of hCG is the most sensitive test. B. Step 2: Assess the history 1. Recent stress; change in weight, diet or exercise habits; or illnesses that might result in hypothalamic amenorrhea should be sought. 2. Drugs associated with amenorrhea, systemic ill- nesses that can cause hypothalamic amenorrhea, recent initiation or discontinuation of an oral contra- ceptive, androgenic drugs (danazol) or high-dose progestin, and antipsychotic drugs should be evalu- ated. 3. Headaches, visual field defects, fatigue, or polyuria and polydipsia may suggest hypothalamic-pituitary disease. 4. Symptoms of estrogen deficiency include hot flashes, vaginal dryness, poor sleep, or decreased libido. 5. Galactorrhea is suggestive of hyperprolactinemia. Hirsutism, acne, and a history of irregular menses are suggestive of hyperandrogenism. 6. A history of obstetrical catastrophe, severe bleeding, dilatation and curettage, or endometritis or other infection that might have caused scarring of the endometrial lining suggests Asherman's syndrome. C. Step 3: Physical examination. Measurements of height and weight, signs of other illnesses, and evidence of cachexia should be assessed. The skin, breasts, and genital tissues should be evaluated for estrogen deficiency. The breasts should be palpated, including an attempt to express galactorrhea. The skin should be examined for hirsutism, acne, striae, acanthosis nigricans, vitiligo, thickness or thinness, and easy bruisability. D. Step 4: Basic laboratory testing. In addition to measurement of serum hCG to rule out pregnancy, minimal laboratory testing should include measure- ments of serum prolactin, thyrotropin, and FSH to rule out hyperprolactinemia, thyroid disease, and ovarian failure (high serum FSH). If there is hirsutism, acne or irregular menses, serum dehydroepiandrosterone sulfate (DHEA-S) and testosterone should be mea- sured. Causes of Primary and Secondary Amenorrhea Abnormality Causes Pregnancy Anatomic abnormalities Congenital abnormality in Müllerian development Isolated defect Testicular feminization syn- drome 5-Alpha-reductase deficiency Vanishing testes syndrome Defect in testis determining factor Congenital defect of uro- genital sinus development Agenesis of lower vagina Imperforate hymen Acquired ablation or scar- ring of the endometrium Asherman’s syndrome Tuberculosis Disorders of hypothalamic- pituitary ovarian axis Hypothalamic dysfunction Pituitary dysfunction Ovarian dysfunction Causes of Amenorrhea due to Abnormalities in the Hypothalamic-Pituitary-Ovarian Axis Abnormality Causes Hypothalamic dys- function Functional hypothalamic amenorrhea Weight loss, eating disorders Exercise Stress Severe or prolonged illness Congenital gonadotropin-releasing hormone deficiency Inflammatory or infiltrative diseases Brain tumors - eg, craniopharyngioma Pituitary stalk dissection or compres- sion Cranial irradiation Brain injury - trauma, hemorrhage, hydrocephalus Other syndromes - Prader-Willi, Laurence-Moon-Biedl Pituitary dysfunction Hyperprolactinemia Other pituitary tumors- acromegaly, corticotroph adenomas (Cushing's disease) Other tumors - meningioma, germinoma, glioma Empty sella syndrome Pituitary infarct or apoplexy Ovarian dysfunction Ovarian failure (menopause) Spontaneous Premature (before age 40 years) Surgical Abnormality Causes Other Hyperthyroidism Hypothyroidism Diabetes mellitus Exogenous androgen use Drugs Associated with Amenorrhea Drugs that Increase Prolactin Antipsychotics Tricyclic antidepressants Calcium channel blockers Drugs with Estro- genic Activity Digoxin, marijuana, oral contracep- tives Drugs with Ovarian Toxicity Chemotherapeutic agents E. Step 5: Follow-up laboratory evaluation 1.High serum prolactin concentration. Prolactin secretion can be transiently increased by stress or eating. Therefore, serum prolactin should be measured at least twice before cranial imaging is obtained, particularly in those women with small elevations (<50 ng/mL). These women should be screened for thyroid disease with a TSH and free T4 because hypothyroidism can cause hyperprolactinemia. 2.Women with verified high serum prolactin values should have a cranial MRI unless a very clear explana- tion is found for the elevation (eg, antipsychotics). Imaging should rule out a hypothalamic or pituitary tumor. 3.High serum FSH concentration. A high serum FSH concentration indicates the presence of ovarian failure. This test should be repeated monthly on three occa- sions to confirm. A karyotype should be considered in most women with secondary amenorrhea age 30 years or younger. 4.High serum androgen concentrations. A high serum androgen value may suggest the diagnosis of polycystic ovary syndrome or may suggest an androgen-secreting tumor of the ovary or adrenal gland. Further testing for a tumor might include a 24- hour urine collection for cortisol and 17-ketosteroids, determination of serum 17-hydroxyprogesterone after intravenous injection of corticotropin (ACTH), and a dexamethasone suppression test. Elevation of 17- ketosteroids, DHEA-S, or 17-hydroxyprogesterone is more consistent with an adrenal, rather than ovarian, source of excess androgen. 5.Normal or low serum gonadotropin concentrations and all other tests normal a. This result is one of the most common outcomes of laboratory testing in women with amenorrhea. Women with hypothalamic amenorrhea (caused by marked exercise or weight loss to more than 10 percent below the expected weight) have normal to low serum FSH values. Cranial MRI is indicated in all women without an a clear explanation for hypo- gonadotropic hypogonadism and in most women who have visual field defects or headaches. No further testing is required if the onset of amenorrhea is recent or is easily explained (eg, weight loss, excessive exercise) and there are no symptoms suggestive of other disease. b. High serum transferrin saturation may indicate hemochromatosis, high serum angiotensin-convert- ing enzyme values suggest sarcoidosis, and high fasting blood glucose or hemoglobin A1c values indicate diabetes mellitus. 6.Normal serum prolactin and FSH concentrations with history of uterine instrumentation preceding amenorrhea a. Evaluation for Asherman's syndrome should be completed. A progestin challenge should be per- formed (medroxyprogesterone acetate 10 mg for 10 days). If withdrawal bleeding occurs, an outflow tract disorder has been ruled out. If bleeding does not occur, estrogen and progestin should be adminis- tered. b. Oral conjugated estrogens (0.625 to 2.5 mg daily for 35 days) with medroxyprogesterone added (10 mg daily for days 26 to 35); failure to bleed upon cessa- tion of this therapy strongly suggests endometrial scarring. In this situation, a hysterosalpingogram or hysteroscopy can confirm the diagnosis of Asherman syndrome. II.Treatment A. Athletic women should be counseled on the need for increased caloric intake or reduced exercise. Resump- tion of menses usually occurs. B. Nonathletic women who are underweight should receive nutritional counseling and treatment of eating disorders. C. Hyperprolactinemia is treated with a dopamine agonist. Cabergoline (Dostinex) or bromocriptine (Parlodel) are used for most adenomas. Ovulation, regular menstrual cycles, and pregnancy may usually result. D. Ovarian failure should be treated with hormone replacement therapy. E. Hyperandrogenism is treated with measures to reduce hirsutism, resume menses, and fertility and preventing endometrial hyperplasia, obesity, and metabolic defects. F. Asherman's syndrome is treated with hysteroscopic lysis of adhesions followed by long-term estrogen administration to stimulate regrowth of endometrial tissue. References, see page 360. Abnormal Vaginal Bleeding Menorrhagia (excessive bleeding) is most commonly caused by anovulatory menstrual cycles. Occasionally it is caused by thyroid dysfunction, infections or cancer. I. Pathophysiology of normal menstruation A. In response to gonadotropin-releasing hormone from the hypothalamus, the pituitary gland synthesizes follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which induce the ovaries to produce estrogen and progesterone. B. During the follicular phase, estrogen stimulation causes an increase in endometrial thickness. After ovulation, progesterone causes endometrial matura- tion. Menstruation is caused by estrogen and proges- terone withdrawal. C. Abnormal bleeding is defined as bleeding that occurs at intervals of less than 21 days, more than 36 days, lasting longer than 7 days, or blood loss greater than 80 mL. II. Clinical evaluation of abnormal vaginal bleeding A. A menstrual and reproductive history should include last menstrual period, regularity, duration, frequency; the number of pads used per day, and intermenstrual bleeding. B. Stress, exercise, weight changes and systemic dis- eases, particularly thyroid, renal or hepatic diseases or coagulopathies, should be sought. The method of birth control should be determined. C. Pregnancy complications, such as spontaneous abortion, ectopic pregnancy, placenta previa and abruptio placentae, can cause heavy bleeding. Preg- nancy should always be considered as a possible cause of abnormal vaginal bleeding. III. Puberty and adolescence--menarche to age 16 A. Irregularity is normal during the first few months of menstruation; however, soaking more than 25 pads or 30 tampons during a menstrual period is abnormal. B. Absence of premenstrual symptoms (breast tender- ness, bloating, cramping) is associated with anovulatory cycles. C. Fever, particularly in association with pelvic or abdomi- nal pain may, indicate pelvic inflammatory disease. A history of easy bruising suggests a coagulation defect. Headaches and visual changes suggest a pituitary tumor. D. Physical findings 1. Pallor not associated with tachycardia or signs of hypovolemia suggests chronic excessive blood loss secondary to anovulatory bleeding, adenomyosis, uterine myomas, or blood dyscrasia. 2. Fever, leukocytosis, and pelvic tenderness suggests PID. 3. Signs of impending shock indicate that the blood loss is related to pregnancy (including ectopic), trauma, sepsis, or neoplasia. 4. Pelvic masses may represent pregnancy, uterine or ovarian neoplasia, or a pelvic abscess or hematoma. 5. Fine, thinning hair, and hypoactive reflexes suggest hypothyroidism. 6. Ecchymoses or multiple bruises may indicate trau- ma, coagulation defects, medication use, or dietary extremes. E. Laboratory tests 1. CBC and platelet count and a urine or serum preg- nancy test should be obtained. 2. Screening for sexually transmitted diseases, thyroid function, and coagulation disorders (partial thromboplastin time, INR, bleeding time) should be completed. 3. Endometrial sampling is rarely necessary for those under age 20. F. Treatment of infrequent bleeding 1. Therapy should be directed at the underlying cause when possible. If the CBC and other initial laboratory tests are normal and the history and physical exami- nation are normal, reassurance is usually all that is necessary. 2. Ferrous gluconate, 325 mg bid-tid, should be pre- scribed. G. Treatment of frequent or heavy bleeding 1. Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) improves platelet aggregation and in- creases uterine vasoconstriction. NSAIDs are the first choice in the treatment of menorrhagia because they are well tolerated and do not have the hor- monal effects of oral contraceptives. a. Mefenamic acid (Ponstel) 500 mg tid during the menstrual period. b. Naproxen (Anaprox, Naprosyn) 500 mg loading dose, then 250 mg tid during the menstrual period. c. Ibuprofen (Motrin, Nuprin) 400 mg tid during the menstrual period. d. Gastrointestinal distress is common. NSAIDs are contraindicated in renal failure and peptic ulcer disease. 2. Iron should also be added as ferrous gluconate 325 mg tid. H. Patients with hypovolemia or a hemoglobin level below 7 g/dL should be hospitalized for hormonal therapy and iron replacement. 1. Hormonal therapy consists of estrogen (Premarin) 25 mg IV q6h until bleeding stops. Thereafter, oral contraceptive pills should be administered q6h x 7 days, then taper slowly to one pill qd. 2. If bleeding continues, IV vasopressin (DDAVP) should be administered. Hysteroscopy may be necessary, and dilation and curettage is a last resort. Transfusion may be indicated in severe hemorrhage. 3. Iron should also be added as ferrous gluconate 325 mg tid. IV. Primary childbearing years – ages 16 to early 40s A. Contraceptive complications and pregnancy are the most common causes of abnormal bleeding in this age group. Anovulation accounts for 20% of cases. B. Adenomyosis, endometriosis, and fibroids increase in frequency as a woman ages, as do endometrial hyper- plasia and endometrial polyps. Pelvic inflammatory disease and endocrine dysfunction may also occur. C. Laboratory tests 1. CBC and platelet count, Pap smear, and pregnancy test. 2. Screening for sexually transmitted diseases, thyroid- stimulating hormone, and coagulation disorders (partial thromboplastin time, INR, bleeding time). 3. If a non-pregnant woman has a pelvic mass, ultrasonography or hysterosonography (with uterine saline infusion) is required. D. Endometrial sampling 1. Long-term unopposed estrogen stimulation in anovulatory patients can result in endometrial hyperplasia, which can progress to adeno- carcinoma; therefore, in perimenopausal patients who have been anovulatory for an extended interval, the endometrium should be biopsied. 2. Biopsy is also recommended before initiation of hor- monal therapy for women over age 30 and for those over age 20 who have had prolonged bleeding. 3. Hysteroscopy and endometrial biopsy with a Pipelle aspirator should be done on the first day of men- struation (to avoid an unexpected pregnancy) or anytime if bleeding is continuous. E. Treatment 1. Medical protocols for anovulatory bleeding (dysfunc- tional uterine bleeding) are similar to those de- scribed above for adolescents. 2. Hormonal therapy a. In women who do not desire immediate fertility, hormonal therapy may be used to treat menorrhagia. b. A 21-day package of oral contraceptives is used. The patient should take one pill three times a day for 7 days. During the 7 days of therapy, bleeding should subside, and, following treatment, heavy flow will occur. After 7 days off the hormones, another 21-day package is initiated, taking one pill each day for 21 days, then no pills for 7 days. c. Alternatively, medroxyprogesterone (Provera), 10-20 mg per day for days 16 through 25 of each month, will result in a reduction of menstrual blood loss. Pregnancy will not be prevented. d. Patients with severe bleeding may have hypotension and tachycardia. These patients require hospitalization, and estrogen (Premarin) should be administered IV as 25 mg q4-6h until bleeding slows (up to a maximum of four doses). Oral contraceptives should be initiated concur- rently as described above. 3. Iron should also be added as ferrous gluconate 325 mg tid. 4. Surgical treatment can be considered if childbearing is completed and medical management fails to provide relief. V. Pr emenopausal , per i menopausal , and postmenopausal years--age 40 and over A. Anovulatory bleeding accounts for about 90% of abnormal vaginal bleeding in this age group. How- ever, bleeding should be considered to be from cancer until proven otherwise. B. History, physical examination and laboratory testing are indicated as described above. Menopausal symptoms, personal or family history of malignancy and use of estrogen should be sought. A pelvic mass requires an evaluation with ultrasonography. C. Endometrial carcinoma 1. In a perimenopausal or postmenopausal woman, amenorrhea preceding abnormal bleeding sug- gests endometrial cancer. Endometrial evaluation is necessary before treatment of abnormal vaginal bleeding. 2. Before endometrial sampling, determination of endometri al thi ckness by transvagi nal ultrasonography is useful because biopsy is often not required when the endometrium is less than 5 mm thick. D. Treatment 1. Cystic hyperplasia or endometrial hyperplasia without cytologic atypia is treated with depo- medroxyprogesterone, 200 mg IM, then 100 to 200 mg IM every 3 to 4 weeks for 6 to 12 months. Endometrial hyperplasia requires repeat endometrial biopsy every 3 to 6 months. 2. Atypical hyperplasia requires fractional dilation and curettage, followed by progestin therapy or hyster- ectomy. 3. If the patient's endometrium is normal (or atrophic) and contraception is a concern, a low-dose oral contraceptive may be used. If contraception is not needed, estrogen and progesterone therapy should be prescribed. 4. Surgical management a. Vaginal or abdominal hysterectomy is the most absolute curative treatment. b. Dilatation and curettage can be used as a temporizing measure to stop bleeding. c. Endometrial ablation and resection by laser, electrodiathermy “rollerball,” or excisional resec- tion are alternatives to hysterectomy. References, see page 360. Menopause Menopause is diagnosed by the presence of amenorrhea for six to twelve months, together with the occurrence of symptoms such as hot flashes. If the diagnosis is uncertain, a high serum concentration of follicle-stimulating hormone (FSH) can confirm the diagnosis. I. Perimenopausal transition A. Perimenopause is defined as the two to eight years preceding menopause and the one year after the last menstrual period. It is characterized by a normal ovulatory cycle interspersed with anovulatory cycles. Menses become irregular, and heavy breakthrough bleeding can occur. Some women complain of hot flashes and vaginal dryness. B. Chronic anovulation and progesterone deficiency in this transition period may lead to long periods of unopposed estrogen exposure and endometrial hyperplasia. Oligomenorrhea (irregular cycles) for six or more months or an episode of heavy dysfunctional bleeding is an indication for endometrial surveillance. Endometrial biopsy is the standard to rule out endometrial hyperplasia, but screening with vaginal ultrasonography is acceptable. Biopsy can be de- ferred if endometrial thickness is 4 mm or less. C. Irregular bleeding and menopausal symptoms during this perimenopausal transition may be treated by estrogen-progestin replacement therapy. However, some women still require contraception. In this case, menopausal symptoms may be effectively treated with a low-dose oral contraceptive if the woman does not smoke and has no other contraindications to oral contraceptive therapy. D. The oral contraceptive can be continued until the onset of menopause, determined by a high serum FSH concentration after six days off the pill. Estrogen replacement therapy can be started at this point. E. In women with no symptoms of estrogen deficiency but with dysfunctional uterine bleeding who smoke or have other reasons to avoid an oral contraceptive, monthly withdrawal bleeding can be induced with medroxyprogesterone acetate (5 to 10 mg daily for 10 to 14 days per month). II. Menopause occurs at a mean age of 51 years in normal women. Menopause occurring after age 55 is defined as late menopause. The age of menopause is reduced by about two years in women who smoke. III. Short-term effects of estrogen deficiency A. Hot flashes. The most common symptom of meno- pause is the hot flash, which occurs in 75 percent of women. Flashes are self-limited, with 50 to 75 percent of women having cessation of hot flashes within five years. B. Hot flashes typically begin as the sudden sensation of heat centered on the face and upper chest, which rapidly becomes generalized. The sensation of heat lasts from two to four minutes, is often associated with profuse perspiration and occasionally palpitations, and is often followed by chills and shivering. Hot flashes usually occur several times per day. C. Treatment of menopausal symptoms with estro- gen 1. Estrogen therapy remains the gold standard for relief of menopausal symptoms, and is a reason- able option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous venous thromboembolic event or stroke, or those at high risk for these complications. Estrogen therapy should be used for shortest duration possible (eg, 6 months to 5 years). 2. Dose. A low-dose estrogen is recommended when possible (eg, 0.3 mg conjugated estrogens or 0.5 mg estradiol). 3. Adding a progestin. Endometrial hyperplasia and cancer can occur with unopposed estrogen ther- apy; therefore, a progestin should be added in women who have not had a hysterectomy. Medroxyprogesterone (Provera), 1.5 mg, is usually given every day of the month. Prempro 0.3/1.5 (0.3 mg of conjugated estrogens and 1.5 mg of medroxyprogesterone) or Prempro 0.45/1.5 (0.45 mg of conjugated estrogens and 1.5 mg of medroxyprogesterone), taken daily. 4. Low-dose oral contraceptives. A low-estrogen oral contraceptive (20 µg of ethinyl estradiol) remai ns an appropri ate treatment for perimenopausal women who seek relief of meno- pausal symptoms. Most of these women are be- tween the ages of 40 and 50 years and are still candidates for oral contraception. For them, an oral contraceptive pill containing 20 µg of ethinyl estradiol provides symptomatic relief while provid- ing better bleeding control than conventional estrogen-progestin therapy because the oral contraceptive contains higher doses of both estro- gen and progestin. D. Treatment of vasomotor instability in women not taking estrogen: Venlafaxine (Effexor), at doses of 75 mg daily, reduces hot flashes by 61 percent. Mouth dryness, anorexia, nausea, and constipation are common. E. Urogenital changes. Menopause has been associ- ated with decreased sexual function and an increased incidence of urinary incontinence and urinary tract infection. 1. Sexual function a. Estrogen deficiency leads to a decrease in blood flow to the vagina and vulva, causing decreased vaginal lubrication and sexual function. b. Dyspareunia in postmenopausal women should be treated with estrogen. Systemic estrogen therapy is usually adequate in women who desire estrogen therapy for reasons in addition to genitourinary symptoms. Vaginal estrogens are a good choice for women who want to mini- mize systemic effects. 2. Urinary incontinence a. Low estrogen production after the menopause results in atrophy of the urethral epithelium and irritation; these changes predispose to stress and urge urinary incontinence. b. Estrogen therapy should be attempted in women with stress or urge urinary incontinence. Urinary incontinence may be treated with systemic or vaginal estrogen. 3. Urinary tract infection. Recurrent urinary tract infections are a problem for many postmenopausal women. 4. Treatment of urogenital atrophy in women not taking systemic estrogen a. Moisturizers and lubricants. Regular use of a vaginal moisturizing agent (Replens) and lubri- cants during intercourse are helpful. Water soluble lubricants such as Astroglide are more effective than lubricants that become more viscous after application such as K-Y jelly. A more effective treatment is vaginal estrogen therapy. b. Low-dose vaginal estrogen (1) Vaginal ring estradiol (Estring), a silastic ring impregnated with estradiol, is the pre- ferred means of delivering estrogen to the vagina. The silastic ring delivers 6 to 9 µg of estradiol to the vagina daily for a period of three months. The rings are changed once every three months by the patient. Concomi- tant progestin therapy is not necessary. (2) Conjugated estrogens (Premarin), 0.5 gm of cream, or one-eighth of an applicatorful daily into the vagina for three weeks, fol- lowed by twice weekly thereafter. Concomi- tant progestin therapy is not necessary. (3) Estrace cream (estradiol) can also by given by vaginal applicator at a dose of one- eighth of an applicator or 0.5 g (which con- tains 50 µg of estradiol) daily into the vagina for three weeks, followed by twice weekly thereafter. Concomitant progestin therapy is not necessary. (4) Estradiol (Vagifem). A tablet containing 25 micrograms of estradiol is available and is inserted into the vagina twice per week. Concomitant progestin therapy is not neces- sary. IV.Prevention and treatment of osteoporosis A. Screening for osteoporosis. Measurement of BMD is recommended for all women 65 years and older regardless of risk factors. BMD should also be mea- sured in all women under the age of 65 years who have one or more risk factors for osteoporosis (in addition to menopause). B. Bisphosphonates 1. Alendronate (Fosamax) has effects comparable to those of estrogen for both the treatment of osteoporosis (10 mg/day or 70 mg once a week) and for its prevention (5 mg/day). Alendronate (in a dose of 5 mg/day or 35 mg/week) can also prevent osteoporosis in postmenopausal women. 2. Risedronate (Actonel), a bisphosphonate, has been approved for prevention and treatment of osteoporosis at doses of 5 mg/day or 35 mg once per week. Its efficacy and side effect profile are similar to those of alendronate. C. Raloxifene (Evista) is a selective estrogen receptor modulator. It is available for prevention and treatment of osteoporosis. At a dose of 60 mg/day, bone density increases by 2.4 percent in the lumbar spine and hip over a two year period. This effect is slightly less than with bisphosphonates. D. Calcium. Maintaining a positive calcium balance in postmenopausal women requires a daily intake of 1500 mg of elemental calcium; to meet this most women require a supplement of 1000 mg daily. E. Vitamin D. All postmenopausal women should take a multivitamin containing at least 400 IU vitamin D daily. F. Exercise for at least 20 minutes daily reduces the rate of bone loss. Weight bearing exercises are preferable. References, see page 360. Urologic Disorders Male Sexual Dysfunction Male sexually competency requires adequate sexual desire (libido), adequate blood flow into the penis, (erection) ejaculation, and the ability to experience a sense of pleasure (orgasm). Impotence is defined as the inability to develop or sustain erection 75 percent of the time. It is a common abnormality and may be due to psychological causes, medications, hormonal abnormalities, neurologic, or vascular problems. I. Evaluation of male sexual dysfunction A. Mechanisms of sexual dysfunction in men: 1. Libido declines with androgen deficiency, depres- sion, and with the use of prescription and recre- ational drugs. 2. Erectile dysfunction may reflect inadequate arterial blood flow into or accelerated venous drainage. 3. Disorders of ejaculation occur if the bladder neck sphincter is damaged during prostate surgery. Failure to ejaculate in men with adequate erectile function is also a common side effect of antidepres- sant medication or unresolved patient/partner con- flict. B. Rapidity of onset. Sexually competent men who had report sudden onset of complete impotence usually have psychogenic impotence. Psychologic counseling is the preferred therapy. Men suffering from impotence of any other cause complain of gradual onset of sexual dysfunction. C. Erectile reserve 1. In men presenting with inability to develop erections, the presence or absence of spontaneous erections is an important clue to diagnosis. Most men experi- ence spontaneous erections during REM sleep, and often wake up with an erection, attesting to the integrity of neurogenic reflexes and blood flow. 2. Nonsustained erection with detumescence after penetration is most commonly due to anxiety or the vascular steal syndrome. Sensate focus exercises are effective in patients with anxiety. In the vascular steal syndrome, blood is diverted from the engorged corpora cavernosae to the thrusting pelvis. Vascular surgery is usually effective. D. Unexpressed interpersonal conflict is one of the more common causes of male sexual dysfunction. Couples counseling can restore sexual function in 25 percent of cases. E. Impotence risk factors include cigarette smoking, diabetes mellitus, hypertension, alcoholism, drug abuse, obesity, and depression. Drugs (such as sympathetic blockers), endocrine abnormalities, and psychogenic causes account for 25 percent of cases, with diabetes, other neurologic problems, and urologic disease accounting for the rest. F. Bicycling. Erectile dysfunction is associated with bicycling because of pressure on the pudendal and cavernosal nerves resulting in penile numbness and impotence. G. Drugs 1. Spironolactone. 2. Sympathetic blockers, such as clonidine, guanethidine, or methyldopa. 3. Thiazide diuretics. 4. Most antidepressants. 5. Ketoconazole. 6. Cimetidine, but not ranitidine or famotidine. 7. Alcohol, methadone, heroin and cocaine. Agents That May Cause Erectile Dysfunction Antidepressants Monoamine oxidase in- hibitors Selective serotonin reuptake inhibitors Tricyclic antidepressants Antihypertensives Beta blockers Centrally acting alpha agonists Diuretics Antipsychotics Anxiolytics Miscellaneous Cimetidine (Tagamet) Corticosteroids Finasteride (Proscar) Gemfibrozil (Lopid) Drugs of abuse Alcohol Anabolic steroids Heroin Marijuana Clinical clues to causes of male sexual dysfunction Finding Cause Rapid onset Psychogenic Genitourinary trauma (eg, radical prostatectomy) Nonsustained erection Anxiety Vascular steal Depression or use of certain drugs Depression Drug induced Complete loss of nocturnal erections Vascular disease Neurologic disease II.Physical examination A. If femoral and peripheral pulses are normal, the pres- ence of femoral bruits implies possible pelvic blood occlusion. B. Visual field defects suggest a pituitary tumor. C. Gynecomastia suggests Klinefelter's syndrome. D. Penile strictures are indicative of Peyronie's disease. E. Examination of the testicles looking for atrophy, asym- metry or masses. F. The cremasteric reflex is an index of the integrity of the thoracolumbar erection center. The reflex is elicited by stroking the inner thighs and observing ipsilateral contraction of the scrotum. III. Laboratory studies and diagnostic tests A. Hormonal testing. Measurements of serum testoster- one, prolactin and thyroid function tests are recom- mended in all men with erectile dysfunction. Twenty- nine percent of impotent men have hormonal disorders, i ncl udi ng hypogonadi sm i n 19 percent , hyperprolactinemia in 4 percent, and either hypothyroidism or hyperthyroidism in 6 percent. B. Nocturnal penile tumescence testing measures tumescence and rigidity of erectile episodes a man experiences as he sleeps. Impotent men with normal NPT are considered to have psychogenic impotence whereas those with impaired NPT are considered to have "organic" impotence usually due to vascular or neurologic disease. Testosterone deficient hypogonadal men are still capable of exhibiting some erectile activity during nocturnal penile tumescence studies. C. Duplex Doppler imaging is indicated in men with impaired NPT to identify areas of arterial obstruction or venous leak that might be amenable to surgical recon- struction. IV. Treatment of male sexual dysfunction A. Phosphodiesterase-5 (PDE-5)inhibitors include vardenafil (Levitra), sildenafil (Viagra), and tadalafil (Cialis). All act to increase intracavernosal cyclic GMP levels, and each one has been proven to be effective in restoring erectile function. Oral Treatments for Male Sexual Dysfunction Medica- tion Mecha- nism Pros and cons Dosing Vardenafil (Levitra) Inhibits phospho- diesterase 5, allowing cyclic GMP to accumu- late within penis No visual side effects Side effects: headaches, dyspepsia, vasodilation, diarrhea. Contraindi- cated if us- ing nitrates Taken one hour before sex and ef- fective up to four hours. Stimulation needed for erection. Dose: 2.5 to 20 mg Sildenafil (Viagra) Same as vardenafil Similar effi- cacy/side effects to vardenafil but blue tinge to vi- sion. 100 mg ef- fective in 75 percent of men. Similar on- set and du- ration as vardenafil Dose: 25 to 100 mg Tadalafil (Cialis) Same as vardenafil Similar effi- cacy/side effects to vardenafil but no vi- sual side effects Similar on- set of action as vardenafil. Duration of action is up to 36 hours. Dose: 2.5 to 20 mg Medica- tion Mecha- nism Pros and cons Dosing SSRIs Inhibits se- rotonin reuptake by neurons May help patients with premature ejaculation, depression Sertraline (Zoloft) 50 mg/day. Paroxetine (Paxil) 20 mg as needed 3 hours be- fore inter- course. Trazodone Alpha- blocker component. May caused priapism Used for psychogenic ED. Treats depression. Dizziness, lethargy are side effects 50-100 mg/day Pharmacokinetic Characteristics of PDE-5 Inhibi- tors Parameter Varden afil (Levitra ) Sildenafil (Viagra) Tadalaf il (Cialis) Oral dose 20 mg 100 mg 20 mg Onset of action 30 min 30 min 24 hours Duration of action 16 hours 4 hours 3 days Food interaction Minimal with low- fat foods; delay in time to peak concen- tration with high- fat foods With high- fat foods; possible with low-fat foods None Alcohol interac- tion None None Maybe Age >65 yr In- creased half-life dose adjust- ment not needed Increased half-life, dose ad- justment may be needed In- creased half-life dose ad- justment may not be needed 1. Vardenafil (Levitra) is available as a 10 and 20 mg dose, taken one hour before sex. a. A phase III clinical trial enrolled 440 men with erectile dysfunction. After 12 weeks of vardenafil (Levitra), 71% of the men had improved erections. And men experiencing depression reported fewer symptoms of depression. In a trial of 805 men with erectile dysfunction of various etiologies randomly assigned to receive vardenafil or placebo as needed, vardenafil was more effective than pla- cebo for improving penetration (80 percent) and maintenance of erections (50 to 67 versus 32 percent). b. Vardenafil (Levitra) is biochemically more potent than sildenafil and tadalafil. Vardenafil (Levitra) is faster-acting, reaching maximum concentration in 30 minutes, with the effects lasting about 16 hours. Sildenafil (Viagra) takes effect in about 30 minutes and the effects last only 4 hours. Tadalafil (Cialis) reaches maximum concentration in 24 hours, and the effects last for about 3 days.Vardenafil (Levitra) is also more effective than placebo for men with erectile dysfunction due to diabetes mellitus. c. High-fat meals may lower vardenafil’s peak serum concentration by 18 percent, and delay its absorp- tion by one hour . A slight prolongation of the QT interval may occur, which is not clinically impor- tant. Vardenafil should not be used in men with congenital QT prolongation or in those taking quinidine, procainamide, amiodarone, or sotalol.Side effects are similar to those seen with sildenafil, and include headache, flushing, and rhinitis, in 13, 10, 10 and 5 percent, respectively. Side effects decrease over time . Vardenafil (Levitra) does not cause changes in color vision (blue vision), which occur with sildenafil. Nitrates should be avoided for at least 48 hours after the last vardenafil dose. se of potent CYP3A4 inhibi- tors should be avoided as described below for sildenafil. d. The addition of exogenous testosterone to vardenafil (Levitra) therapy may be useful in men with serum total testosterone concentrations <400 ng/dL who do not respond to vardenafil alone. 2. Sildenafil (Viagra) a. Efficacy. 69 percent of all attempts at sexual intercourse were successful in the men who took sildenafil. Headache, flushing, and dyspepsia are the most common adverse effects, occurring in 6 to 18 percent of the men. b. Dose. Sildenafil should be taken orally about one hour before a planned sexual encounter. The initial dose should be 50 mg, and it should be reduced to 25 mg if side effects occur. If the erectile response is not fully satisfactory, the dose can be increased to 100 mg. c. Cardiovascular effects (1) Sildenafil is a vasodilator that lowers the blood pressure by about 8 mm Hg; this change typically produces no symptoms. The combination of sildenafil and nitrates can lead to severe hypotension (eg, more than 50/25 mm Hg) and syncope. Sildenafil is contraindi- cated in patients taking nitrates of any form, regularly or intermittently. If a man who has taken sildenafil has an acute ischemic syn- drome, nitrates should not be prescribed within 24 hours (or longer in patients with renal or hepatic dysfunction). (2) Sildenafil is safe for men with stable coronary artery disease who are not taking nitrates. The vasodilator properties of sildenafil may cause hypotension in hypertrophic cardiomyopathy. (3) Side effects associated with sildenafil are related to its vasodilatory properties. These include headache, lightheadedness, dizzi- ness, flushing, distorted vision, and, in some cases, syncope. (4) Retinal effects. Sildenafil causes blue vision in 3 percent of men. This effect lasts two to three hours and disappears spontaneously. (5) Drug interactions. Sildenafil should be avoided in patients taking drugs that can prolong the half-life of sildenafil by blocking CYP3A4 ( i ncl udi ng er yt hr omyci n, ketoconazole, protease inhibitors, and grape- fruit juice); drugs that induce CYP3A4 such as rifampin and phenytoin can be expected to reduce the effectiveness of a dose of sildenafil. (6) Alpha-adrenergic antagonists are contraindi- cated (due to potential hypotension with com- bination therapy). d. Tadalafil (Cialis) (1) Tadalafil also appears to be as effective as sildenafil but has a longer duration of action. The recommended starting dose is 10 mg, with 5 and 20 mg options available depending on efficacy and tolerability. Food does not interfere with absorption.59 percent of inter- course attempts were successful at 36 hours with tadalafil (20 mg) compared with 28 per- cent with placebo. (2) Side effects are similar to those seen with vardenafil and sildenafil, with headache, dyspepsia, flushing, and rhinitis occurring in 8 to 14, 5 to 10, 4 to 6, and 5 percent, respec- tively. Back pain occurs in six percent of patients taking the 20 mg dose. Visual side effects have not been described. (3) Nitrates should be avoided for at least 48 hours after the last tadalafil dose. (4) Excessive alcohol intake (5 or more drinks) in combination with tadalafil administration may potentiate the hypotensive effect of tadalafil. Use of potent CYP3A4 inhibitors should be avoided as described above for sildenafil. 3. Summary. Sildenafil, vardenafil, and tadalafil appear to be equally effective, but vardenafil and sildenafil have a rapid onset. Vardenafil (Levitra) is fast-acting, reaching maximum concentration in 30 to 40 min- utes, with the effects lasting about 16 hours. Sildenafil (Viagra) takes effect in about 30 minutes, and the effects last only 4 hours. Tadalafil (Cialis) reaches maximum concentration in 24 hours, and the effects last for about 3 days. Tadalafil absorption is less affected by high fat meals and alcohol. Sildenafil (Viagra) and vardenafil (Levitra) must be taken on an empty stomach, while tadalafil can be taken without regard to food. Vardenafil (Levitra) is the lowest price PDE-5 inhibitor, costing $87.99 for ten tablets. The price of tadalafil (Cialis) is $89.99 for ten tablets. The price of sildenafil is $90.99 for ten tablets. B. Penile self-injection. Intrapenile injection therapy with alprostadil (prostaglandin E1, Caverject), papaverine, or alprostadil with papaverine and phentolamine (Tri-Mix) have all been used for purposes of inducing erection. Papaverine is more reliable than phentolamine in producing an erection. Alprostadil and papaverine remain popular as monotherapy, and all three drugs can be given together. Despite the relatively high success rate of 87 percent, there is a very high attrition rate with self-injection. Suppositories, Injections, and Devices for Sexual Dysfunction Treat- ment Effect Pros and cons Usage pattern Suppository MUSE (alprostadil) Alprostadil (prostaglan- din E1) in gel form delivered by applicator into meatus of penis Can be used twice daily. Not recom- mended with preg- nant part- ners Inserted 5- 10 minutes before sex. Effects last one hour Penile injection Alprostadil (Caverject and Edex) Prostaglan- din E1 in- jected into base of pe- nis. Effective in 50-85 per- cent of cases. May be painful and not rec- ommended for daily use. Priapism occurs un- commonly Inject 10-20 minutes be- fore sex. Erections may last hours Invicorp (VIP and phentolamin e) VIP and alpha- blocker, phentolamin e. Possibly more effec- tive than alprostadil. Causes less pain. Priapism rare Inject 10-20 minutes be- fore sex. Requires stimulation to have erection Device Vacuum pump Creates a vacuum, drawing blood into cavernosae. Elastic tour- niquet at base. Safe if erec- tion not maintained more than one hour. May inter- fere with ejaculation Inflated just before sex- ual activity. Erection lasts until elastic ring removed C. Intraurethral alprostadil (MUSE) provides a less invasive alternative to intrapenile injection. Two-thirds of men responded to intraurethral alprostadil with an erection sufficient for intercourse. Vacuum-assisted erection devices encourage increased arterial inflow and occlusive rings to discourage venous egress from the penile corpora cavernosae. Dexterity is required to use these devices effectively, but once men become comfortable with using the vacuum and restraining rings they can create an erection sufficient for vaginal pene- tration and sexual intercourse. They cannot, however, ejaculate externally because the occlusive rings that prevent venous drainage also compress the penile urethra sufficiently to prevent seminal fluid from reach- ing and traversing the urethral meatus. Vacuum devices successfully create erections in 67 percent of patients. D. Penile prostheses. Drug and penile injection therapy has greatly reduced the need for surgical implants of penile prostheses as treatment for men with erectile dysfunction. This treatment is an option for those men who do not respond to sildenafil and find penile injection or vacuum erection therapy distasteful. E. Androgen replacement therapy is indicated for hypogonadism and requires either injections of long- acting testosterone esters, one of three available testosterone patches, or testosterone gel (Androgel). One patch (Testoderm) is applied once a day to the scrotum. Androderm and Testoderm TTS are applied daily to the torso or extremities. Androgel is applied as one packet once a day to the upper arm, chest, or abdomen. F. Treatment of premature ejaculation. Premature ejaculation is defined as an inability to control ejacula- tion so that both partners enjoy sexual intercourse. Approximately 20 percent of men complain of prema- ture ejaculation, most of whom have no underlying physical abnormality. 1. Sertraline (Zoloft), 50 mg/day. 2. Intermittent use of SSRIs may be as effective as continuous use. Paroxetine(Paxil) is given as 20 mg as needed three to four hours before planned inter- course. References, see page 360. Benign Prostatic Hyperplasia More than 80 percent of men older than 80 years have benign prostatic hyperplasia (BPH). When symptoms of urinary obstruction interfere with quality of life, treatment is warranted. Sequelae of BPH include urinary retention, detrusor instability, infection, stone formation, bladder diverticula, and upper tract dilation with renal insufficiency. I. Clinical evaluation A. Obstructive symptoms, such as nocturia, a slow urine stream, intermittency, and double voiding, are generally evaluated through focused history taking, and a digital rectal examination, with or without serum PSA testing. B. Symptoms of BPH may be obstructive, which are secondary to bladder outlet obstruction or impaired bladder contractility, or irritative, which result from decreased vesicle compliance and increased bladder instability. Obstructive symptoms include a weak stream, hesitancy, abdominal straining, terminal drib- bling, an intermittent stream, and retention; irritative symptoms are frequency, nocturia, urgency, and pain during urination. C. Physical examination should include a digital rectal examination, and a focused neurologic examination to rule out a neurologic cause of symptoms. D. Laboratory assessment 1. Urinalysis and a serum creatinine assay are useful to ascertain there is no infection, hematuria, or decreased renal function. 2. Prostate-specific antigen (PSA) testing may be offered to patients at risk for prostate cancer who prefer to be screened for the malignancy. PSA testing and rectal examination should be offered annually to men 50 years of age and older if they are expected to live at least 10 more years. Black men and men who have a first-degree relative with pros- tate cancer are at high risk for prostate cancer. These men should be offered screening at 45 years of age. BPH Symptom Score For each question, circle the answer that best describes your situation. Add the circled number together to get your total score. See the key at the bottom of this form to determine the overall rating of your symptoms. Not at all Less than one in five times Less than half of the time About half of the time More than half of the time Almost always In the past month, how often have you had a sensa- tion of not emptying your bladder com- pletely after you finished voiding? 0 1 2 3 4 5 In the past month, how often have you had to urinate again less than 2 hours after you finished urinating be- fore? 0 1 2 3 4 5 In the past month, how often have you found you stopped and started again several times when you uri- nated? 0 1 2 3 4 5 In the past month, how often have you found it difficult to postpone urination? 0 1 2 3 4 5 In the past month, how often have you had a weak urinary stream? 0 1 2 3 4 5 Not at all Less than one in five times Less than half of the time About half of the time More than half of the time Almost always In the past month, how often have you had to push or strain to begin urination? 0 1 2 3 4 5 In the past month, how many times did you typically get up to uri- nate from the time you went to bed until you arose in the morning? 0 1 2 3 4 5 II. Treatment options A. Watchful Waiting is appropriate in patients with a low AUA symptom score (zero to seven) because studies have shown that medications are not significantly more effective than placebo in these patients. B. Medical treatments 1. Nonselective alpha-blockers a. Doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin) reduce prostatic smooth muscle tone and, thus, have an immediate effect on urinary flow. These medications quickly improve BPH symptoms. b. Side effects such as dizziness, postural hypotension, fatigue, and asthenia affect from 7 to 9 percent of patients treated with nonselective alpha blockers. Side effects can be minimized by bedtime administration and slow titration of the dosage. Alpha-blockers can be used with other therapies as needed. Prazosin has the cost advantage of generic availability; however, unlike doxazosin and terazosin, it is not available in a once-daily formulation. c. Therapy for BPH with terazosin (Hytrin) is usually begun with a daily dosage of 1 mg hs. Dosage is raised to 2 mg, 5 mg, and 10 mg. Clinical re- sponse may not be seen for 4-6 weeks, even at the 10-mg dosage. Doxazosin (Cardura) is usually given at dosages of 1-4 mg qd. Starting dosages of alpha-blocking agents for managing benign prostatic hypertrophy Drug Starting dosage Afuzosin (Uroxatral) 10 mg qd Tamsulosin (Flomax) 0.4 mg qd Terazosin (Hytrin) 1 mg qd, adjusted up to 5 mg qd Doxazosin mesylate (Cardura) 1 mg qd, adjusted up to 4 mg qd 2. Selective alpha-blockers a. Tamsulosin (Flomax) is a highly selective alpha 1A -adrenergic antagonist that was devel- oped to avoid the side effects of nonselective agents. Some patients who do not respond to nonselective alpha-blockers may respond to tamsulosin and, because of the selectivity, may have fewer side effects, including hypotension. Tamsulosin is initiated in a dosage of 0.4 mg once daily, with a maximum of 0.8 mg per day. Tamsulosin has no antihypertensive effect. b. Afuzosin (Uroxatral) causes less ejaculatory dysfunction than tamsulosin. Dosage is 10 mg qd. Contraindicated in moderate to severe hepatic impairment. 3. 5a-Reductase inhibitors a. Finasteride (Proscan) slowly induces an 80 to 90 percent reducti on i n the serum dihydrotestosterone level. As a result, prostatic volume decreases by about 20 percent over three to six months. Improvements with finasteride are significantly less than those with any al- pha-blocker or surgery. Finasteride may work best in men with a large gland, whereas al- pha-blockers are effective across the range of prostate sizes. Side effects with finasteride are similar to that with placebo, and include de- creased libido, ejaculatory disorder, and impo- tence. The daily dosage is 5 mg. b. Dutasteride (Avodart), 0.5-mg capsule qd, is approved for the treatment of BPH (labeling for male-pattern baldness is pending). This drug has a distinct mechanism of action, in that it blocks both types 1 and 2 5a-reductase. Sexual side effects are similar to those of finasteride. C. Surgical treatments 1. Surgery should be considered in patients who fail medical treatment, have refractory urinary retention, fail catheter removal, or have recurrent urinary tract infections, persistent hematuria, bladder stones, or renal insufficiency. Surgery can also be the initial treatment in patients with high AUA symptom scores who want surgical treatment and are good candi- dates for surgery. 2. Transurethral resection of the prostate (TURP). The most commonly employed surgical procedure for BPH, TURP reduces symptoms in 88 percent of patients. The most frequent complications of the procedure are inability to void, clot retention, and secondary infection. Bleeding occurs in only 1 percent of patients. Long-term complications include retrograde ejaculation (70%), impotence (14%), partial incontinence (6%), and total incontinence (1%). References, see page 360. Acute Epididymoorchitis I. Clinical evaluation of testicular pain A. Epididymoorchitis is indicated by a unilateral painful testicle and a history of unprotected intercourse, new sexual partner, urinary tract infection, dysuria, or discharge. Symptoms may occur following acute lifting or straining. B. The epididymis and testicle are painful, swollen, and tender. The scrotum may be erythematosus and warm, with associated spermatic cord thickening or penile discharge. C. Differential diagnosis of painful scrotal swelling 1. Epididymitis, testicular torsion, testicular tumor, hernia. 2. Torsion is characterized by sudden onset, age <20, an elevated testicle, and previous episodes of scrotal pain. The epididymis is usually located anteriorly on either side, and there is an absence of evidence of urethritis and UTI. 3. Epididymitis is characterized by fever, laboratory evidence of urethritis or cystitis, and increased scrotal warmth. II. Laboratory evaluation of epididymoorchitis A. Epididymoorchitis is indicated by leukocytosis with a left shift; UA shows pyuria and bacteriuria. Midstream urine culture will reveal gram negative bacilli. Chlamydia and Neisseria cultures should be obtained. B. Common pathogens 1. Younger men. Epididymoorchitis is usually associ- ated with sexually transmitted organisms such as Chlamydia and gonorrhea. 2. Older men. Epididymoorchitis is usually associated with a concomitant urinary tract infection or prostatitis caused by E. coli, proteus, Klebsiella, Enterobacter, or Pseudomonas. III. Treatment of epididymoorchitis A. Bed rest, scrotal elevation with athletic supporter, an ice pack, analgesics, and antipyretics are prescribed. Sexual and physical activity should be avoided. B. Sexually transmitted epididymitis in sexually active males 1. Ceftriaxone (Rocephin) 250 mg IM x 1 dose AND doxycycline 100 mg PO bid x 10 days OR 2. Ofloxacin (Floxin) 300 mg bid x 10 days. 3. Treat sexual partners C. Epididymitis secondary to urinary tract infection 1. TMP/SMX DS bid for 10 days OR 2. Ofloxacin (Floxin) 300 mg PO bid for 10 days. References, see page 360. Prostatitis and Prostatodynia Prostatitis is a common condition, with a 5 percent lifetime prevalence to 9 percent. Prostatitis is divided into three subtypes: acute, chronic bacterial prostatitis and chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CNP/CPPS). I. Acute Bacterial Prostatitis A. Acute bacterial prostatitis (ABP) should be considered a urinary tract infection. The most common cause is Escherichia coli. Other species frequently found include Klebsiella, Proteus, Enterococci and Pseudo- monas. On occasion, cultures grow Staphylococcus aureus, Streptococcus faecalis, Chlamydia or Bacteroides species. B. Patients may present with fever, chills, low back pain, perineal or ejaculatory pain, dysuria, urinary frequency, urgency, myalgias and obstruction. The prostate gland is tender and may be warm, swollen, firm and irregular. Vigorous digital examination of the prostate should be avoided because it may induce bacteremia. C. The infecting organism can often be identified by urine culturing. D. Treatment consists of trimethoprim-sulfamethoxazole (TMP-SMX [Bactrim, Septra]), a quinolone or tetracy- cline. Men at increased risk for sexually transmitted disease require antibiotic coverage for Chlamydia. Common Antibiotic Regimens for Acute Bacterial Prostatitis Medication Standard dosage Trimethoprim-sulfamethoxaz ole (Bactrim, Septra) 1 DS tablet (160/800 mg) twice a day Doxycycline (Vibramycin) 100 mg twice a day Ciprofloxacin (Cipro) 500 mg twice a day Norfloxacin (Noroxin) 400 mg twice a day Ofloxacin (Floxin) 400 mg twice a day E. Antibiotic therapy should be continued for three to four weeks. Extremely ill patients should be hospitalized to receive a parenteral broad-spectrum cephalosporin and an aminoglycoside. II. Chronic Bacterial Prostatitis A. Chronic bacterial prostatitis (CBP) is a common cause of recurrent urinary tract infections in men. Men experience irritative voiding symptoms, pain in the back, testes, epididymis or penis, low-grade fever, arthralgias and myalgias. Signs may include urethral discharge, hemospermia and secondary epididymo-orchitis. Often the prostate is normal on rectal examination. B. CBP presents with negative premassage urine culture results, and greater than 10 to 20 white blood cells per high-power field in the pre- and the postmassage urine specimen. Significant bacteriuria in the postmassage urine specimen suggests chronic bacterial prostatitis. C. TMP-SMX is the first-line antibiotic for CBP. Norfloxacin (Noroxin) taken twice a day for 28 days achieves a cure rate in 64 percent. Ofloxacin (Floxin) is also highly effective. Some men require long-term antibiotic suppression with TMP-SMX or nitrofurantoin. III.Chronic Nonbacterial Prostatitis/Chronic Pelvic Pain Syndrome (Prostatodynia) A. Patients with CNP/CPPS have painful ejaculation pain in the penis, testicles or scrotum, low back pain, rectal or perineal pain, and/or inner thigh pain. They often have irritative or obstructive urinary symptoms and decreased libido or impotence. The physical examina- tion is usually unremarkable, but patients may have a tender prostate. B. No bacteria will grow on culture, but leukocytosis may be found in the prostatic secretions. C. Treatment begins with 100 mg of doxycycline (Vibramycin) or minocycline (Minocin) twice daily for 14 days. Other therapies may include Allopurinol (Zyloprim), thrice-weekly prostate massage or transurethral microwave thermotherapy. D. Hot sitz baths and nonsteroidal anti-inflammatory drugs (NSAIDs) may provide some relief. Some men may notice aggravation of symptoms with alcohol or spicy foods and should avoid them. Anticholinergic agents (oxybutynin [Ditropan]) or alpha-blocking agents (doxazosin [Cardura], tamsulosin [Flomax] or terazosin [Hytrin]) may be beneficial. References, see page 360. Psychiatric Disorders Depression The lifetime prevalence of major depression in the United States is 17 percent. In primary care, depression has a prevalence rate of 4.8 to 8.6 percent. I. Diagnosis A. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) includes nine symptoms in the diagnosis of major depression. B. These nine symptoms can be divided into two clusters: (1) physical or neurovegetative symptoms and (2) psychologic or psychosocial symptoms. The nine symptoms are: depressed mood plus sleep distur- bance; interest/pleasure reduction; guilt feelings or thoughts of worthlessness; energy changes/fatigue; concentration/attention impairment; appetite/weight changes; psychomotor disturbances, and suicidal thoughts. Diagnostic Criteria for Major Depression, DSM IV Cluster 1: Physical or neurovegetative symptoms Sleep disturbance Appetite/weight changes Attention/concentration problem Energy-level change/fatigue Psychomotor disturbance Cluster 2: Psychologic or psychosocial symptoms Depressed mood and/or Interest/pleasure reduction Guilt feelings Suicidal thoughts Note: Diagnosis of major depression requires at least one of the first two symptoms under cluster 2 and four of the remain- ing symptoms to be present for at least two weeks. Symptoms should not be accounted for by bereavement. II. Drug Therapy Characteristics of Common Antidepressants Drug Recommended Dos- age Comments Selective Serotonin Reuptake Inhibitors (SSRIs) Escitalopr am (Lexapro) 10 mg qd Minimal sedation, activa- tion, or inhibition of hepatic enzymes, nausea, anorgasmia, headache Citalopra m (Celexa) Initially 20 mg qd; maximum 40 mg/d Fluoxetine (Prozac) 10-20 mg qd initially, taken in AM Anxiety, insomnia, agita- tion, nausea, anorgasmia, erectile dysfunction, head- ache, anorexia. Fluvoxami ne (LuVox) 50-100 mg qhs; max 300 mg/d [50, 100 mg] Headache, nausea, seda- tion, diarrhea Paroxetin e (Paxil) 20 mg/d initially, given in AM; increase in 10-mg/d incre- ments as needed to max of 50 mg/d. [10, 20, 30, 40 mg] Headache, nausea, som- nolence, dizziness, insom- nia, abnormal ejaculation, anxiety, diarrhea, dry mouth. Sertraline (Zoloft) 50 mg/d, increasing as needed to max of 200 mg/d [50, 100 mg] Insomnia, agitation, dry mouth, headache, nausea, anorexia, sexual dysfunc- tion. Secondary Amine Tricyclic Antidepressants Desiprami ne (Norprami n, generics) 100-200 mg/d, gradu- ally increasing to 300 mg/d as tolerated.[10, 25, 50, 75, 100, 150 mg] No sedation; may have stimulant effect; best taken in morning to avoid insom- nia. Nortriptylin e (Pamelor) 25 mg tid-qid, max 150 mg/d. [10, 25, 50, 75 mg] Sedating Tertiary Amine Tricyclics Drug Recommended Dos- age Comments Amitriptyli ne (Elavil, generics) 75 mg/d qhs-bid, in- creasing to 150-200 mg/d. [25, 50, 75, 100, 150 mg] Sedative effect precedes antidepressant effect. High anticholinergic activity. CIomipra mine (Anafranil) 25 mg/d, increasing gradually to 100 mg/d; max 250 mg/d; may be given once qhs [25, 50, 75 mg]. Relatively high sedation, anticholinergic activity, and seizure risk. Protriptylin e (Vivactil) 5-10 mg PO tid-qid; 15-60 mg/d [5, 10 mg] Useful in anxious depres- sion; nonsedating Doxepin (Sinequan , generics) 50-75 mg/d, increas- ing up to 150-300 mg/d as needed [10, 25, 50, 75, 100, 150 mg] Sedating. Also indicated for anxiety. Contraindi- cated in patients with glau- coma or urinary retention. Imipramin e (Tofranil, generics) 75 mg/d in a single dose qhs, increasing to 150 mg/d; 300 mg/d. [10, 25, 50 mg] High sedation and anticholinergic activity. Use caution in cardiovas- cular disease. Miscellaneous Bupropion (Wellbutri n, Wellbutrin SR) 100 mg bid; increase to 100 mg tid [75, 100 mg] Sustained release: 100-200 mg bid [100, 150 mg] Agitation, dry mouth, in- somnia, headache, nau- sea, constipation, tremor. Good choice for patients with sexual side effects from other agents; contra- indicated in seizure disor- ders. Venlafaxin e (Effexor) 75 mg/d in 2-3 di- vided doses with food; increase to 225 mg/d as needed. [25, 37.5, 50, 75, 100 mg]. Extended-release: initially 37.5 mg qAM. The dosage can be increased by 75 mg every four days to a max of 225 mg qd [37.5, 75, 100, 150 mg]. Inhibits norepinephrine and serotonin reuptake. Hypertension, nausea, insomnia, dizziness, ab- normal ejaculation, head- ache, dry mouth, anxiety. Duloxetine (Cymbalta ) 20 mg bid or 60 mg qd or 30 mg bid. Start at a dose of 30 mg and increase the dose to 60 mg daily; up to 120 mg daily [30, 60 mg]. Inhibits norepinephrine and serotonin reuptake. Contraindicated in hepatic or renal insufficiency. Food delays absorption. Nau- sea, dry mouth, constipa- tion. Diarrhea and vomiting less often. Insomnia, dizzi- ness, somnolence, and sweating also seen. Sex- ual side effects may be less common than with the SSRIs. Marketed for physi- cal pain associated with depression. Maprotilin e (Ludiomil) 75 to 225 in single or divided doses [25, 50, 75 mg]. Delays cardiac conduction; high anticholinergic activ- ity; contraindicated in sei- zure disorders. Mirtazapin e (Remeron ) 15 to 45 PO qd [15, 30 mg] High anticholinergic activ- ity; contraindicated in sei- zure disorders. Nefazodo ne (Serzone) Start at 100 mg PO bid, increase to 150- 300 mg PO bid as needed [100, 150, 200, 250 mg]. Headache, somnolence, dry mouth, blurred vision. Postural hypotension, im- potence. Reboxetin e (Vestra) 5 mg bid Selective norepinephrine reuptake inhibitor. Dry mouth, insomnia, constipa- tion, increased sweating Trazodon e (Desyrel, generics) 150 mg/d, increasing by 50 mg/d every 3-4 d 400 mg/d in divided doses [50, 100, 150, 300 mg] Rarely associated with priapism. Orthostatic hypotension in elderly. Sedating. A. Psychotherapy 1. A broad range of psychological interventions appear to be effective for the treatment of depression in both psychiatric and primary care patient popula- tions. The efficacy of cognitive therapy, behavioral therapy, and interpersonal therapy was 46, 55, and 52 percent, respectively, in psychiatric patients with major depression. 2. Cognitive behavioral therapy is as effective as medication use for maintenance therapy (over two years) in patients with major depression. B. Selective serotonin reuptake inhibitors 1. Abnormalities in brain serotonergic activity have been implicated in mood disorders, obsessive- compulsive disorder, and aggressive behaviors. Medications causing increased serotonergic activity are often effective in ameliorating symptoms of depression, anxiety, and obsessive ruminations. 2. The selective-serotonin reuptake inhibitors (SSRIs) block the action of the presynaptic serotonin reuptake pump, thereby increasing the amount of serotonin available in the synapse and increasing postsynaptic serotonin receptor occupancy. 3. The SSRIs all share several other characteris- tics: a. They are all hepatically metabolized. b. They have relatively little affinity for histaminic, dopaminergic, alpha-adrenergic, and cholinergic receptors. c. They tend to have relatively mild side-effect profiles, although they can be associated with sexual dysfunction. d. They are relatively safe in overdose. e. They all produce changes in sleep architecture (decreased REM latency and decreased total REM sleep). 4. The SSRIs differ in potency, receptor selectivity, and pharmacokinetic properties. The overall efficacy of the different SSRIs appears to be similar. Coadministration of any SSRI with a monoamine oxidase inhibitor (MAOI) is contraindicated due to the potential for producing a sometimes fatal “sero- tonin syndrome,” characterized by agitation, hyperthermia, diaphoresis, tachycardia, and rigidity. 5. Fluoxetine (Prozac) has a relatively mild side-effect profile, and the once-daily-dosing schedule makes it a safe and convenient alternative to the tricyclic antidepressants (TCAs) and MAOIs. Fluoxetine is indicated for the treatment of major depressive disorder, obsessive-compulsive disorder, and bulimia. a. Fluoxetine is 95 percent protein bound. It under- goes oxidative metabolism in the liver by the cytochrome P-450 (CYP) enzyme system. The principal CYP enzymes responsible for its metab- olism are CYP2D6 and CYP3A/34. The half-life (t 1/2) of fluoxetine is four to six days. Its active metabolite, norfluoxetine, is formed through demethylation of fluoxetine, is a potent and selective inhibitor of the serotonin reuptake pump, and has a t 1/2 of 7 to 15 days. Fluoxetine is a potent inhibitor of CYP2D6; norfluoxetine is also a mild inhibitor of CYP 3A/34. Drugs metab- olized by CYP2D6 must be used cautiously when coadministered with fluoxetine. b. The clinical antidepressant effect may be delayed three to six weeks from the start of treatment. c. The usual effective dose of fluoxetine is 20 mg daily. Patients who do not respond to this dosage after several weeks can have their dose in- creased by 10 to 20 mg as tolerated up to 80 mg daily. d. Fluoxetine can be administered once weekly to patients who have responded to daily fluoxetine. Fluoxetine is given as 90 mg per week. Seven days should elapse after the last 20 mg daily dose of fluoxetine before beginning the once weekly regimen. e. The most common initial side effects of fluoxetine are nausea, insomnia, and anxiety. These effects usually present at the start of treatment and tend to resolve over one to two weeks. Fluoxetine, like all of the SSRIs, is relatively safe in overdose. 6. Sertraline (Zoloft) is approved for the treatment of depressive illness. Sertraline is approximately 98 percent protein bound. Absorption is increased when taken with food. It is metabolized by the hepatic p450 enzyme system and has an active metabolite that is significantly less potent than the active compound. The t 1/2 of sertraline is 26 hours. As opposed to fluoxetine, which is a potent inhibitor of CYP2D6, sertraline has only mild inhibition of this enzyme. Sertraline has a low likelihood of interac- tions with coadministered medications. a. Sertraline is usually started at 50 mg daily; the effective maintenance dose is typically 50 to 100 mg daily, although doses up to 200 mg daily may be necessary. Clinical effect is usually evident by three to six weeks. b. Common initial side effects of sertraline include nausea, diarrhea, insomnia, and sexual dysfunc- tion. It may be more likely than the other SSRIs to cause nausea. As with fluoxetine, sexual dysfunction can persist. Addition of bupropion (Wellbutrin, 75 to 150 mg/day in divided doses) or buspirone (BuSpar, 10 to 20 mg twice daily) may alleviate decreased libido, diminished sexual arousal, or impaired orgasm. Sertraline is rela- tively safe in overdose. 7. Paroxetine (Paxil) is indicated for the treatment of depression, panic disorder, generalized anxiety disorder, and social phobia. a. Paroxetine is 95 percent protein bound. It inhibits the liver enzyme CYP2D6 and must be used cautiously when coadministered with other drugs metabolized by this enzyme. The t 1/2 is 24 hours. It has a mild affinity for muscarinic recep- tors and can cause more anticholinergic side effects than the other SSRIs (although much less than the tricyclic antidepressants). b. The starting and maintenance dose of paroxetine is 20 mg daily but can be raised to 40 mg daily if necessary. In contrast to fluoxetine and sertraline, which can be activating, paroxetine is mildly sedating. Other side effects include nau- sea, dry mouth, and sexual dysfunction. Sexual dysfunction may be slightly higher with paroxetine than with the other SSRIs. c. An enteric-coated, controlled-release formulation of paroxetine may cause less nausea than the immediate-release formulation. The recom- mended starting dose of Paxil CR is 12.5 mg/day for panic disorder and 25 mg/day for depression; the maximum dose is 75 mg/day. 8. Citalopram (Celexa) has mild p450 2D6 inhibition, but it has significantly less p450 interactions than the other SSRIs, making it an appealing choice in patients who are on other medications where drug- drug interactions are a concern. Citalopram is touted as causing less sexual dysfunction than the other SSRIs. Anxiety symptoms are improved with citalopram compared with sertraline or placebo. a. The usual starting dose of citalopram is 20 mg daily. The therapeutic dose range tends to be 20 to 40 mg daily in a single morning dose. 9. Escitalopram (Lexapro) is a single isomer formula- tion of citalopram. Escitalopram is reported to be a more potent serotonin reuptake inhibitor, and a daily dose of 10 mg is at least comparable to 40 mg of citalopram. There are no clear advantages of escitalopram compared with other SSRIs in terms of efficacy or adverse effects, although, like citalopram, it has little effect on CYP isoenzymes and therefore may prove to have fewer drug interac- tions than other SSRIs such as fluoxetine or paroxetine. C. Heterocyclic antidepressants 1. The cyclic antidepressants are less commonly used as first-line antidepressants with the development of the SSRIs and other newer antidepressants. This is mainly due to the less benign side-effect profile of the cyclic antidepressants. In contrast to the SSRIs, the cyclic antidepressants can be fatal in doses as little as five times the therapeutic dose. The toxicity is usually due to prolongation of the QT interval, leading to arrhythmias. Overdose of cyclic antide- pressants can also cause anticholinergic toxicity and seizures. 2. The cyclic antidepressants tend to have as anticholinergic and orthostatic effects, as well as sedation, weight gain, and sexual dysfunction. In addition, tricyclic antidepressant users have a higher risk of myocardial infarction compared with SSRI users. 3. As with all antidepressants, the cyclic antidepres- sants can take up to three to six weeks before reaching full clinical effect. 4. Tertiary amines are not frequently used as primary antidepressant agents because of their tendency to cause significant sedative and anticholinergic side effects. a. Imipramine (Tofranil). The usual starting dose of imipramine is 25 mg daily. The dose can be increased by 25 to 50 mg every three to four days to a typical therapeutic dose range of 150 to 300 mg daily. Patients with combined blood levels of imipramine and desipramine greater than 225 ng/mL have a superior response. Imipramine is moderately sedating and anticholinergic compared with other cyclic antide- pressants. b. Amitriptyline (Elavil). Amitriptyline is demethylated to nortriptyline, which has antide- pressant effects. The usual starting dose of amitriptyline is 25 mg, typically given at bedtime. Therapeutic doses are generally in the range of 100 to 300 mg daily, but many patients find it difficult to reach these doses due to sedation. Blood levels of amitriptyline plus nortriptyline greater than 95 to 160 ng/mL are ineffective. 5. Secondary amines a. Desipramine (Norpramin) is an active metabo- lite of imipramine. Desipramine differs from the tertiary amines in that it is much more selective in its properties of norepinephrine blockade than in its properties of serotonin reuptake blockade. It tends to have much less sedative and anticholinergic side effects. It does, however, share the side effect of orthostatic hypotension. The usual starting dose of desipramine is 25 mg daily. b. Nortriptyline (Aventyl) is an active metabolite of amitriptyline. Like desipramine, nortriptyline has significantly more effects on norepinephrine than on serotonin receptors. Although nortriptyline has fewer sedative and anticholinergic side effects than the tertiary amines, it has slightly more than desipramine. It is distinctly different from desipramine in that it has very little orthostatic hypotensive effects. Nortriptyline is twice as potent as the other cyclic antidepressants. The starting dose is typically 25 mg daily. 6. Cardiac testing. Before initiating treatment with any of the cyclic antidepressants, patients must be screened for cardiac conduction system disease, which precludes the use of these medications. Patients over age 40 years should have a baseline electrocardiogram (ECG). D. Venlafaxine (Effexor) is a phenylethylamine and is structurally distinct from existing antidepressants. It is a potent inhibitor of serotonin reuptake and an inhibitor of norepinephrine reuptake. Venlafaxine is metabolized in the liver to O-desmethylvenlafaxine, an active metabolite. The t 1/2 of the parent compound plus the active metabolite is 11 hours. There is a slow-release form that allows for once-daily dosing. Venlafaxine is excreted by the kidney, and food does not affect its absorption. Venlafaxine is a weak inhibitor of the p450 2D6 enzyme, but it tends to not interact with most coadministered medications (except MAOIs). 1. Dosing for the immediate-release form of venlafaxine typically begins at 37.5 mg twice daily. The medication can be increased by 75 mg every four days to a maximum dose of 375 mg daily in three divided doses. The extended-release form of venlafaxine is given as a single-morning dose of 37.5 mg. If this is well tolerated, the dose is in- creased to 75 mg in a single daily dose. The medi- cation can be increased by 75 mg every four days to a recommended maximum of 225 mg daily in a single-daily dose. 2. The most common side effects of venlafaxine are nausea, dizziness, insomnia, sedation, and consti- pation. It can also induce sweating in some patients. Venlafaxine may cause blood pressure increases. Three to 7 percent of patients have mild blood pressure elevations (average 1 to 2 mm Hg). Medi- cations that inhibit CYP2D6 can increase the plasma level of venlafaxine. This is sometimes encountered when switching a patient from an SSRI with CYP2D6 inhibiting properties (eg, fluoxetine, paroxetine) to venlafaxine. Venlafaxine overdose is more serious than overdose with SSRIs. Venlafaxine is more likely to cause seizures than tricyclic antidepressants. Rates of serotonin toxicity were also higher with venlafaxine than with tricyclic antidepressants. Venlafaxine should be avoided in patients who are at high risk for deliberate over- dose. 3. Patients who do not respond to other antidepres- sants may respond better to venlafaxine, and venlafaxine may be less likely to lose efficacy over time than other antidepressants. Venlafaxine may be more likely to lead to a remission of depression. E. Duloxetine (Cymbalta) is an inhibitor of both serotonin reuptake and norepinephrine reuptake. 1. Duloxetine is metabolized in the liver and should not be administered with hepatic insufficiency. Metabo- lites are excreted in the urine, and the use of duloxetine is not recommended in end-stage renal disease. Food delays the absorption of duloxetine, and the t 1/2 is 12 hours. Duloxetine is a moderate inhibitor of CYP2D6. 2. Dosage is 20 mg twice daily or 60 mg daily either as a single dose or as 30 mg twice daily. Start at 30 mg daily and increase to 60 mg daily; there may be added benefit to using up to 120 mg daily. 3. Nausea, dry mouth and constipation are common. Diarrhea and vomiting are seen less often. Insom- nia, dizziness, somnolence, and sweating occur. Sexual side effects occur, but may be less common than with the SSRIs. Duloxetine is marketed as a treatment for physical pain associated with depres- sion. Duloxetine has shown efficacy in diabetic neuropathy. 4. Medications that inhibit CYP2D6 (paroxetine and fluoxetine) and medications that inhibit CYP1A2 (fluvoxamine) can increase levels of duloxetine. F. Trazodone (Desyrel) is unrelated to the SSRIs, cyclic antidepressants, or MAOIs. Its overall effect seems to be t hat of modul at i on of serot onergi c neurotransmission. Trazodone is not considered a first- line antidepressant because it may not be as effective as other agents. G. Mirtazapine (Remeron) is a tetracyclic compound (a piperazinoazepine), but it is unrelated to TCAs. It has a unique mechanism of action in that it blocks pre- and postsynaptic alpha-2 receptors, as well as the serotonin receptors 5HT2 and 5HT3. 1. The medication’s antagonism of presynaptic alpha-2 receptors may lead to a significant increase in noradrenergic neurotransmission. This heightened adrenergic neurotransmission, in concert with mirtazapine’s action of increasing serotonin release, is thought to be responsible for the medication’s antidepressant effect. Mirtazapine may also posses anxiolytic effects. It can be particularly helpful in depressed patients with insomnia because of its sedative properties. 2. Mirtazapine is metabolized in the liver primarily by oxidation and demethylation. It is metabolized by several p450 enzymes including 2D6, 1A2, 3A4, and 2C9. Mirtazapine’s t 1/2 is 20 to 40 hours, and it is 85 percent protein bound. 3. Mirtazapine has an unusual dosing profile. Some of the medication’s side effects may be greater at lower doses. Most notably, sedation appears more pronounced at doses of 15 mg daily than at 30 mg daily. Dosing is most frequently started at 15 mg daily and can be increased to 30 mg or 45 mg daily as needed in one- to two-week intervals. Dosing may be initiated at 30 mg or more in order to reduce sedation. 4. The most notable side effects of mirtazapine are sedation, weight gain, and dry mouth. Many patients report a significant increase in appetite. Mirtazapine may have relatively less propensity to cause sexual dysfunction than the SSRIs, TCAs, and MAOIs. Two out of 2796 patients developed agranulocytosis, and a third developed neutropenia. All recovered after the medication was discontinued. There are no FDA recommendations to monitor white blood cell counts. Mild transaminase elevations have been noted in some patients. H. Electroconvulsive therapy. Electroconvulsive therapy (ECT) is highly effective in patients with psychotic depression. Patients who continue to have severe melancholic depression on maximum medical therapy also do well with ETC. The often quick response and low side-effect profile make ECT one of the most effective ways to alleviate the symptoms of major depression. The relapse rate after ECT is high, and drug therapy should continue following cessation of ETC. Indications for Electroconvulsive Therapy Definitely effective Major depression Refractory to antidepressant therapy Need exists for rapid treatment response, such as in pregnancy Medical comorbidities prevent the use of antidepres- sant medication Previous response to ECT Psychotic features Catatonic stupor Severe suicidality Food refusal leading to nutritional compromise Bipolar disorder Mania Atypical psychosis Schizophrenia May be effective Neuroleptic malignant syndrome Organic delusional disorder Organic mood disorder Obsessive-compulsive disorder Neuroleptic-induced Parkinsonism Neuroleptic-induced tardive dyskinesia Catatonia secondary to medical conditions References, see page 360. Generalized Anxiety Disorder Generalized anxiety disorder (GAD) is characterized by excessive worry and anxiety that are difficult to control and cause significant distress and impairment. Commonly patients develop symptoms of GAD secondary to other DSM-IV diagnoses such as panic disorder, major depres- sion, alcohol abuse, or an axis II personality disorder. I. Epidemiology. GAD is a common anxiety disorder. The prevalence is estimated to be 5 percent in the primary care setting. Twice as many women as men have the disorder. GAD may also be associated with substance abuse, post-traumatic stress disorder, and obsessive compulsive disorder. Between 35 and 50 percent of individuals with major depression meet criteria for GAD. II. Clinical manifestations and diagnosis A. The diagnostic criteria for GAD suggest that patients experience excessive anxiety and worry about a number of events or activities, occurring more days than not for at least six months, that are out of propor- tion to the likelihood or impact of feared events. Af- fected patients also present with somatic symptoms, including fatigue, muscle tension, memory loss, and insomnia, and other psychiatric disorders. DSM-IV-PC Diagnostic Criteria for Generalized Anxiety Disorder 1. Excessive anxiety and worry about a number of events or activities, occurring more days than not for at least six months, that are out of proportion to the likelihood or im- pact of feared events. 2. The worry is pervasive and difficult to control. 3. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symp- toms present for more days than not for the past six months): Restlessness or feeling keyed up or on edge Being easily fatigued Difficulty concentrating or mind going blank Irritability Muscle tension Sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep) 4. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. B. Comorbid psychiatric disorders and an organic etiology for anxiety must be excluded by careful history taking, a complete physical examination, and appropri- ate laboratory studies. The medical history should focus upon current medical disorders, medication side effects, or substance abuse to anxiety (or panic) symptoms. C. Psychosocial history should screen for major depres- sion and agoraphobia, stressful life events, family psychiatric history, current social history, substance abuse history (including caffeine, nicotine, and alco- hol), and past sexual, physical and emotional abuse, or emotional neglect. D. Laboratory studies include a complete blood count, chemistry panel, serum thyrotropin (TSH) and urinaly- sis. Urine or serum toxicology measurements or drug levels can be obtained for drugs or medications sus- pected in the etiology of anxiety. Physical Causes of Anxiety-Like Symptoms Cardiovascular Angina pectoris, arrhythmias, congestive heart failure, hyper- tension, hypovolemia, myocardial infarction, syncope (multiple causes), valvular disease, vascular collapse (shock) Dietary Caffeine, monosodium glutamate (Chinese restaurant syn- drome), vitamin-deficiency diseases Drug-related Akathesia (secondary to antipsychotic drugs), anticholinergic toxicity, digitalis toxicity, hallucinogens, hypotensive agents, stimulants (amphetamines, cocaine, related drugs), withdrawal syndromes (alcohol, sedative-hypnotics), bronchodilators (theophylline, sympathomimetics) Hematologic Anemias Immunologic Anaphylaxis, systemic lupus erythematosus Metabolic HyperadrenaIism (Cushing's disease), hyperkalemia, hyperthermia, hyperthyroidism, hypocalcemia, hypoglycemia, hyponatremia, hypothyroidism, menopause, porphyria (acute intermittent) Neurologic Encephalopathies (infectious, metabolic, toxic), essential tremor, intracranial mass lesions, postconcussive syndrome, seizure disorders (especially of the temporal lobe), vertigo Respiratory Asthma, chronic obstructive pulmonary disease, pneumonia, pneumothorax, pulmonary edema, pulmonary embolism Secreting tumors Carcinoid, insulinoma, pheochromocytoma III. Treatment A. Drug therapy. While benzodiazepines have been the most traditionally used drug treatments for GAD, selective serotonin reuptake inhibitors (SSRIs), selec- tive serotonin and norepinephrine reuptake inhibitors (SNRIs, eg venlafaxine), and buspirone are also effective, and because of their lower side effect pro- files and lower risk for tolerance are becoming first-line treatment. B. Antidepressants 1. Venlafaxine SR (Effexor) may be a particularly good choice for patients with coexisting psychiatric illness, such as panic disorder, major depression, or social phobia, or when it is not clear if the patient has GAD, depression, or both. Venlafaxine can be started as venlafaxine XR 37.5 mg daily, with dose increases in increments of 37.5 mg every one to two weeks until a dose of 150 mg to 300 mg is attained. C. Tricyclic antidepressants, SSRIs, or SNRIs may be associated with side effects such as restlessness and insomnia. These adverse effects can be minimized by starting at lower doses and gradually titrating to full doses as tolerated. 1. Selective serotonin reuptake inhibitors a. Paroxetine (Paxil) 5 to 10 mg qd, increasing to 20 to 40 mg. b. Sertraline (Zoloft) 12.5 to 25 mg qd, increasing to 50 to 200 mg. c. Fluvoxamine (Luvox) 25 mg qd, increasing to 100 to 300 mg. d. Fluoxetine (Prozac) 5 mg qd, increasing to 20 to 40 mg. e. Citalopram (Celexa) 10 mg qd, increasing to 20 to 40 mg. f. Side effects of SSRIs include agitation, head- ache, gastrointestinal symptoms (diarrhea and nausea), and insomnia. About 20 to 35 percent of patients develop sexual side effects after several weeks or months of SSRI therapy, especially a decreased ability to have an or- gasm. Addition of bupropion (75 to 150 mg/day in divided doses) or buspirone (10 to 20 mg twice daily) may alleviate decreased libido, diminished sexual arousal, or impaired orgasm. 2. Imipramine (Tofranil), a starting dose of 10 to 20 mg po at night can be gradually titrated up to 75 to 300 mg each night. Imipramine has anticholinergic and antiadrenergic side effects. Desipramine (Norpramin), 25-200 mg qhs, and nortriptyline (Pamelor), 25 mg tid-qid, can be used as alterna- tives. 3. Trazodone (Desyrel) is a serotonergic agent, but because of its side effects (sedation and priapism), it is not an ideal first-line agent. Daily dosages of 200 to 400 mg are helpful in patients who have not responded to other agents. 4. Nefazodone (Serzone) has a similar pharmaco- logic profile to trazodone, but it is better tolerated and is a good alternative; 100 mg bid; increase to 200-300 mg bid. D. Buspirone (BuSpar) appears to be as effective as the benzodiazepines for the treatment of GAD. However, the onset of action can be several weeks, and there are occasional gastrointestinal side effects. Advan- tages of using buspirone instead of benzodiazepines include the lack of abuse potential, physical depend- ence, or withdrawal, and lack of potentiation of alcohol or other sedative-hypnotics. Most patients need to be titrated to doses of 30 to 60 mg per day given in two or three divided doses. E. Benzodiazepines. Several controlled studies have demonstrated the efficacy of benzodiazepines (eg, chlordiazepoxide, diazepam, alprazolam) in the treatment of GAD. 1. Many anxious patients who start on benzodiazepines have difficulty stopping them, particularly since rebound anxiety and withdrawal symptoms can be moderate to severe. Methods of facilitating withdrawal and decreasing rebound symptoms include tapering the medication slowly, converting short-acting benzodiazepines to a long-acting preparation (eg, clonazepam) prior to tapering, and treating the patient with an antide- pressant before attempting to taper. 2. Symptoms of anxiety can be alleviated in most cases of GAD with clonazepam (Klonopin) 0.25 to 0.5 mg po bid titrated up to 1 mg bid or tid, or lora- zepam (Ativan) 0.5 to 1.0 mg po tid titrated up to 1 mg po tid or qid. Often an antidepressant is pre- scribed concomitantly. After six to eight weeks, when the antidepressant begins to have its optimal effects, the benzodiazepine usually should be tapered over months, achieving roughly a 10 percent dose reduction per week. Benzodiazepines Commonly Prescribed for Anxiety Disorders Name Half-life (hours) Dosage range (per day) Initial dos- age Alprazolam (Xanax) 14 1 to 4 mg 0.25 to 0.5 mg four times daily Chlordiazepoxid e (Librium) 20 15 to 40 mg 5 to 10 mg three times daily Clonazepam (Klonopin) 50 0.5 to 4.0 mg 0.5 to 1.0 mg twice daily Clorazepate (Tranxene) 60 15 to 60 mg 7.5 to 15.0 mg twice daily Diazepam (Val- ium) 40 6 to 40 mg 2 to 5 mg three times daily Lorazepam (Ativan) 14 1 to 6 mg 0.5 to 1.0 mg three times daily Oxazepam (Serax) 9 30 to 90 mg 15 to 30 mg three times daily F. Agents with short half-lives, such as oxazepam (Serax), do not cause excessive sedation. These agents should be used in the elderly and in patients with liver disease. They are also suitable for use on an “as-needed” basis. Agents with long half-lives, such as clonazepam (Klonopin), should be used in younger patients who do not have concomitant medical prob- lems. The longer-acting agents can be taken less frequently during the day, patients are less likely to experience anxiety between doses and withdrawal symptoms are less severe. References, see page 360. Panic Disorder Panic disorder is characterized by the occurrence of panic attacks--sudden, unexpected periods of intense fear or discomfort. About 15% of the general population experiences panic attacks; 1.6-3.2% of women and 0.4%-1.7% of men have panic disorder. DSM-IV Criteria for panic attack A discrete period of intense fear or discomfort in which four or more of the following symptoms developed abruptly and reached a peak within 10 minutes. Chest pain or discomfort Choking Depersonalization or derealization Dizziness, faintness, or unsteadiness Fear of "going crazy" or being out of control Fear of dying Flushes or chills Nausea or gastrointestinal distress Palpitations or tachycardia Paresthesias Shortness of breath (or feelings of smothering) Sweating Trembling or shaking Diagnostic criteria for panic disorder without ago- raphobia Recurrent, unexpected panic attacks And At least one attack has been followed by at least 1 month of one (or more) of the following: Persistent concern about experiencing more attacks Worry about the meaning of the attack or its consequences (fear of losing control, having a heart attack, or "going crazy") A significant behavioral change related to the attacks And Absence of agoraphobia And Direct physiological effects of a substance (drug abuse or medication) or general medical condition has been ruled out as a cause of the attacks And The panic attacks cannot be better accounted for by another mental disorder I. Clinical evaluation A. Panic attacks are manifested by the sudden onset of an overwhelming fear, accompanied by feelings of impending doom, for no apparent reason. B. The essential criterion for panic attack is the presence of 4 of 13 cardiac, neurologic, gastrointestinal, or respiratory symptoms that develop abruptly and reach a peak within 10 minutes. The physical symptoms include shortness of breath, dizziness or faintness, palpitations, accelerated heart rate, and sweating. Trembling, choking, nausea, numbness, flushes, chills, or chest discomfort are also common, as are cognitive symptoms such as fear of dying or losing control. C. One third of patients develop agoraphobia, or a fear of places where escape may be difficult, such as bridges, trains, buses, or crowded areas. Medications, sub- stance abuse, and general medical conditions such as hyperthyroidism must be ruled out as a cause of the patient's symptoms. D. The history should include details of the panic attack, its onset and course, history of panic, and any treat- ment. Questioning about a family history of panic disorder, agoraphobia, hypochondriasis, or depression is important. Because panic disorder may be triggered by marijuana or stimulants such as cocaine, a history of substance abuse must be identified. A medication history, including prescription, over-the-counter, and herbal preparations, is essential. E. The patient should be asked about stressful life events or problems in daily life that may have preceded onset of the disorder. The extent of any avoidance behavior that has developed or suicidal ideation, self-medication, or exacerbation of an existing medical disorder should be assessed. II. Management A. Patients should reduce or eliminate caffeine consump- tion, including coffee and tea, cold medications, anal- gesics, and beverages with added caffeine. Alcohol use is a particularly insidious problem because patients may use drinking to alleviate the panic. Pharmacologic treatment of panic disorder Drug Initial dosage (mg/d) Therapeutic dos- age (mg/d) SSRIs Fluoxetine (Prozac) Fluvoxamine (LuVox) Paroxetine (Paxil) Sertraline (Zoloft) Citalopram (Celexa) 5-10 25-50 10-20 25-50 10-20 mg qd 10-60 25-300 20-50 50-200 20-40 Benzodiazepines Alprazolam (Xanax) Alprazolam XR (Xanax XR) Clonazepam (Klonopin) Diazepam (Valium) Lorazepam (Ativan) 0.5 in divided doses, tid-qid 0.5 to 1 mg/day given once in the morning. 0.5 in divided doses, bid-tid 2.0 in divided doses, bid-tid 0.5 in divided doses, bid-tid 1-4 in divided doses, tid-qid 3-6 mg qAM 1-4 in divided doses, bid-tid 2-20 in divided doses, bid 1-4 in divided doses, bid-tid TCAs Amitriptyline (Elavil) Clomipramine (Anafranil) Desipramine (Norpramin) Imipramine (Tofranil) Nortriptyline (Pamelor) 10 25 10 10 10 10-300 25-300 10-300 10-300 10-300 MAOIs Phenelzine (Nardil) Tranylcypromine (Parnate) 1510 15-90 10-30 B. Selective serotonin reuptake inhibitors (SSRIs) are an effective, well-tolerated alternative to benzodiazepines and TCAs. SSRIs are superior to either imipramine or alprazolam. They lack the cardiac toxicity and anticholinergic effects of TCAs. Fluoxetine (Prozac), fluvoxamine (LuVox), paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa) have shown efficacy for the treatment of panic disorder. C. Tricyclic antidepressants (TCAs) have demon- strated efficacy in treating panic. They are, however, associated with a delayed onset of action and side effects--particularly orthostatic hypotension, anticholinergic effects, weight gain, and cardiac toxicity. D. Benzodiazepines 1. Clonazepam (Klonopin), alprazolam (Xanax), and lorazepam (Ativan), are effective in blocking panic attacks. Advantages include a rapid onset of therapeutic effect and a safe, favorable, side-effect profile. Among the drawbacks are the potential for abuse and dependency, worsening of depressive symptoms, withdrawal symptoms on abrupt discon- tinuation, anterograde amnesia, early relapse on discontinuation, and inter-dose rebound anxiety. 2. Benzodiazepines are an appropriate first-line treatment only when rapid symptom relief is needed. The most common use for benzodiazepines is to stabilize severe initial symptoms until another treatment (eg, an SSRI or cognitive behavioral therapy) becomes effective. 3. The starting dose of alprazolam is 0.5 mg bid. Approximately 70% of patients will experience a discontinuance reaction characterized by in- creased anxiety, agitation, and insomnia when alprazolam is tapered. Clonazepam's long duration of effect diminishes the need for multiple daily dosing. Initial symptoms of sedation and ataxia are usually transient. E. Monoamine oxidase inhibitors (MAOIs). MAOIs such phenelzine sulfate (Nardil) may be the most effective agents for blocking panic attacks and for relieving the depression and concomitant social anxiety of panic disorder. Recommended doses range from 45-90 mg/d. MAOI use is limited by adverse effects such as orthostatic hypotension, weight gain, insomnia, risk of hypertensive crisis, and the need for dietary monitoring. MAOIs are often reserved for patients who do not respond to safer drugs. F. Beta-blockers are useful in moderating heart rate and decreasing dry mouth and tremor; they are less effective in relieving subjective anxiety. References, see page 360. Insomnia Insomnia is the perception by patients that their sleep is inadequate or abnormal. Insomnia may affect as many as 69% of adult primary care patients. The incidence of sleep problems increases with age. Younger persons are apt to have trouble falling asleep, whereas older persons tend to have prolonged awakenings during the night. I. Causes of insomnia A. Situational stress concerning job loss or problems often disrupt sleep. Patients under stress may experi- ence interference with sleep onset and early morning awakening. Attempting to sleep in a new place, changes in time zones, or changing bedtimes due to shift work may interfere with sleep. B. Drugs associated with insomnia include antihypertensives, caffeine, diuretics, oral contracep- tives, phenytoin, selective serotonin reuptake inhibitors, protriptyline, corticosteroids, stimulants, theophylline, and thyroid hormone. C. Psychiatric disorders. Depression is a common cause of poor sleep, often characterized by early morning awakening. Associated findings include hopelessness, sadness, loss of appetite, and reduced enjoyment of formerly pleasurable activities. Anxiety disorders and substance abuse may cause insomnia. D. Medical disorders. Prostatism, peptic ulcer, conges- tive heart failure, and chronic obstructive pulmonary disease may cause insomnia. Pain, nausea, dyspnea, cough, and gastroesophageal reflux may interfere with sleep. E. Obstructive sleep apnea syndrome 1. This sleep disorder occurs in 5-15% of adults. It is characterized by recurrent discontinuation of breath- ing during sleep for at least 10 seconds. Abnormal oxygen saturation and sleep patterns result in excessive daytime fatigue and drowsiness. Loud snoring is typical. Overweight, middle-aged men are particularly predisposed. Weight loss can be helpful in obese patients. 2. Diagnosis is by polysomnography. Use of hypnotic agents is contraindicated since they increase the frequency and the severity of apneic episodes. II. Clinical evaluation of insomnia A. Evaluation should include a review of sleep habits, drug and alcohol consumption, medical, psychiatric, and neurologic illnesses, pain, sleep environment, and family history. The physical examination should ex- clude asthma or congestive heart failure, which may contribute to the patient’s sleep problem. B. Sleep history. The onset, frequency, duration, and severity of sleep complaints should be assessed. The progression of symptoms, fluctuations over time, and any possible precipitating events should be evaluated. 1. A sudden onset suggests that a change in sleep environment or a stressful life event may be respon- sible. Persistent insomnia is usually a consequence of medical, neurologic, or psychiatric disease; persistent insomnia can also result from primary sleep disorders, including restless leg syndrome. 2. The evaluation should determine if sleep difficulties involve initiation or maintenance of sleep. 3. Specific symptoms that occur around sleep onset should be sought, including paresthesia or other unpleasant sensations and uncontrollable limb movements of restless leg syndrome; eg, repeated awakenings, snoring, or cessation of breathing in sleep apnea syndromes should be sought; daytime fatigue, irritability, or lack of concentration should be evaluated. 4. Frequent awakenings may be seen when insomnia occurs secondary to drugs or underlying medical conditions; early morning awakenings frequently occur secondary to anxiety or depression. 5. The patient’s functional status and mood during the daytime should be assessed. Episodes of uninten- tional sleep are suggestive of sleep apnea syn- drome or narcolepsy. C. Alcohol and drug history. The patient should be questioned about the use of drugs that can directly cause insomnia (eg, central nervous system stimu- lants, beta blockers, bronchodilators, corticosteroids), and about withdrawal of central nervous system depressant drugs (eg, sedatives, hypnotics, corticosteroids). Alcohol, caffeine, and tobacco con- sumption should also be documented, since they can adversely affect sleep. D. Psychiatric history. Symptoms or history of depres- sion, anxiety, psychosis, or unusually stressful life events. Sleep disorders that occur secondary to psychiatric illness respond in most cases to psychotherapeutic modalities; an additional cause of disturbed sleep or a primary sleep disorder should be suspected if insomnia complaints. E. Medical, neurologic, and family history. A thorough history of medical and neurologic complaints and past illnesses should be obtained to detect potential causes of secondary insomnia. A family history of insomnia may suggest certain primary sleep disorders. A positive family history is found in about one-third of patients with idiopathic restless leg syndrome. F. Physical examination. A careful physical examination may direct attention to medical disorders involving the respiratory, cardiovascular, gastrointestinal, endocrine, or neurologic systems. A wide variety of medical conditions or their treatment may result in insomnia. Medical causes of insomnia Congestive cardiac failure Ischemic heart disease Nocturnal angina Chronic obstructive pulmonary disease (COPD) Bronchial asthma including nocturnal asthma Peptic ulcer disease Reflux esophagitis Rheumatic disorders Lyme disease Acquired immunodeficiency syndrome (AIDS) Chronic fatigue syndrome III. Laboratory evaluation may suggest an underlying medical diagnosis in patients with other suggestive historical or physical findings. A. Polysomnography (PSG). Formal sleep studies are rarely indicated in the initial evaluation of insomnia. PSG may be useful in the following situations: 1. A sleep-related breathing disorder is suspected. 2. Insomnia has been present for more than six months, and medical, neurologic, and psychiatric causes have been excluded. 3. Insomnia has not responded to behavioral or phar- macologic treatment. IV. Pharmacologic management A. Hypnotics are the primary drugs used in the manage- ment of insomnia. These drugs include the benzodiazepines and the benzodiazepine receptor agonists in the imidazopyridine or pyrazolopyrimidine classes. Recommended dosages of hypnotic medications (elderly dosages are in parentheses) Benzodiaz- epine hypnotics Recom- mended dose, mg T max Elimi- nation half- life Rece ptor selec- tivity Benzodiazepine receptor agonists Zolpidem (Ambien) 5-10 (5) 1.6 2.6 Yes Zaleplon (So- nata) 5-10 (5) 1 1 Yes Eszopiclone (Lunesta) 2-3 (1-2) 1 6 Yes Hypnotic Medications Estazolam (ProSom) 1-2 (0.5-1) 2.7 17.1 No Flurazepam (Dalmane) 15-30 (15) 1 47.0- 100 No Triazolam (Halcion) 0.250 (0.125) 1.2 2.6 No Temazepam (Restoril) 7.5-60 (7.5-20) 0.8 8.4 No Quazepam (Doral) 7.5-15.0 (7.5) 2 73 No B. Zolpidem (Ambien) and zaleplon (Sonata) have the advantage of achieving hypnotic effects with less tolerance and fewer adverse effects. C. The safety profile of these benzodiazepines and benzodiazepine receptor agonists is good; lethal overdose is rare, except when benzodiazepines are taken with alcohol. Sedative effects may be en- hanced when benzodiazepines are used in conjunc- tion with other central nervous system depressants. D. Zolpidem (Ambien) is a benzodiazepine agonist with a short elimination half-life that is effective in inducing sleep onset and promoting sleep maintenance. Zolpidem may be associated with greater residual impairment in memory and psychomotor performance than zaleplon. E. Zaleplon (Sonata) is a benzodiazepine receptor agonist that is rapidly absorbed (T MAX = 1 hour) and has a short elimination half-life of 1 hour. Zaleplon does not impair memory or psychomotor functioning at as early as 2 hours after administration, or on morning awakening. Zaleplon does not cause resid- ual impairment when the drug is given in the middle of the night. Zaleplon can be used at bedtime or after the patient has tried to fall asleep naturally. F. Eszopiclone (Lunesta) is a benzodiazepine receptor agonist with a half-life of 6 hours. It is approved for prolonged use; the use of the other agents is re- stricted to 35 days. G. Benzodiazepines with long half-lives, such as flurazepam (Dalmane), may be effective in promoting sleep onset and sustaining sleep. These drugs may have effects that extend beyond the desired sleep period, however, resulting in daytime sedation or functional impairment. Patients with daytime anxiety may benefit from the residual anxiolytic effect of a long-acting benzodiazepine administered at bedtime. Benzodiazepines with intermediate half-lives, such as temazepam (Restoril), facilitate sleep onset and maintenance with less risk of daytime residual ef- fects. H. Benzodiazepines with short half-lives, such as triazolam (Halcion), are effective in promoting the initiation of sleep but may not contribute to sleep maintenance. I. Sedating antidepressants are sometimes used as an alternative to benzodiazepines or benzodiazepine receptor agonists. Amitriptyline (Elavil), 25-50 mg at bedtime, or trazodone (Desyrel), 50-100 mg, are common choices. References, see page 360. Nicotine Dependence Smoking causes approximately 430,000 smoking deaths each year, accounting for 19.5% of all deaths. Daily use of nicotine for several weeks results in physical dependence. Abrupt discontinuation of smoking leads to nicotine with- drawal within 24 hours. The symptoms include craving for nicotine, irritability, frustration, anger, anxiety, restlessness, difficulty in concentrating, and mood swings. Symptoms usually last about 4 weeks. I. Drugs for treatment of nicotine dependance A. Treatment with nicotine is the only method that pro- duces significant withdrawal rates. Nicotine replace- ment comes in three forms: nicotine polacrilex gum (Nicorette), nicotine transdermal patches (Habitrol, Nicoderm, Nicotrol), and nicotine nasal spray (Nicotrol NS) and inhaler (Nicotrol). Nicotine patches provide steady-state nicotine levels, but do not provide a bolus of nicotine on demand as do sprays and gum. B. Bupropion (Zyban) is an antidepressant shown to be effective in treating the craving for nicotine. The symp- toms of nicotine craving and withdrawal are reduced with the use of bupropion, making it a useful adjunct to nicotine replacement systems. Treatments for nicotine dependence Drug Dosage Comments Nicotine gum (Nicorette) 2- or 4-mg piece/30 min Available OTC; poor compliance Nicotine patch (Habitrol, Nicoderm CQ) 1 patch/d for 6-12 wk, then taper for 4 wk Available OTC; local skin reactions Nicotine nasal spray (Nicotrol NS) 1-2 doses/h for 6- 8 wk Rapid nicotine deliv- ery; nasal irritation initially Nicotine in- haler (Nicotrol Inhaler) 6-16 cartridges/d for 12 wk Mimics smoking be- havior; provides low doses of nicotine Bupropion (Zyban) 150 mg/day for 3 d, then titrate to 300 mg Treatment initiated 1 wk before quit day; contraindicated with seizures, anorexia, heavy alcohol use C. Nicotine polacrilex (Nicorette) is available OTC. The patient should use 1-2 pieces per hour. A 2-mg dose is recommended for those who smoke fewer than 25 cigarettes per day, and 4 mg for heavier smokers. It is used for 6 weeks, followed by 6 weeks of tapering. Nicotine gum improves smoking cessation rates by about 40%-60%. Drawbacks include poor compliance and unpleasant taste. D. Transdermal nicotine (Habitrol, Nicoderm, Nicotrol) doubles abstinence rates compared with placebo, The patch is available OTC and is easier to use than the gum. It provides a plateau level of nicotine at about half that of what a pack-a-day smoker would normally obtain. The higher dose should be used for 6-12 weeks followed by 4 weeks of tapering. E. Nicotine nasal spray (Nicotrol NS) is available by prescription and is a good choice for patients who have not been able to quit with the gum or patch or for heavy smokers. It delivers a high level of nicotine, similar to smoking. Nicotine nasal spray doubles the rates of sustained abstinence. The spray is used 6-8 weeks, at 1-2 doses per hour (one puff in each nostril). Tapering over about 6 weeks. Side effects include nasal and throat irritation, headache, and eye water- ing. F. Nicotine inhaler (Nicotrol Inhaler) delivers nicotine orally via inhalation from a plastic tube. It is available by prescription and has a success rate of 28%, similar to nicotine gum. The inhaler has the advantage of avoiding some of the adverse effects of nicotine gum, and its mode of delivery more closely resembles the act of smoking. G. Bupropion (Zyban) 1. Bupropion is appropriate for patients who have been unsuccessful using nicotine replacement. Bupropion reduces withdrawal symptoms and can be used in conjunction with nicotine replacement therapy. The treatment is associated with reduced weight gain. Bupropion is contraindicated with a history of seizures, anorexia, heavy alcohol use, or head trauma. 2. Bupropion is started at a dose of 150 mg daily for 3 days and then increased to 300 mg daily for 2 weeks before the patient stops smoking. Bupropion is then continued for 3 months. When a nicotine patch is added to this regimen, the abstinence rates increase to 50% compared with 32% when only the patch is used. References, see page 360. Alcohol and Drug Addiction The prevalence of alcohol disorders is 16-28%, and the prevalence of drug disorders is 7-9%. Alcoholism is charac- terized by impaired control over drinking, preoccupation with alcohol, use of alcohol despite adverse consequences, and distortions in thinking (denial). Substance abuse is a pattern of misuse during which the patient maintains control. Addiction or substance dependence is a pattern of misuse during which the patient has lost control. I. Clinical assessment of alcohol use and abuse A. The amount and frequency of alcohol use and other drug use in the past month, week, and day should be determined. Whether the patient ever consumes five or more drinks at a time (binge drinking) and previous abuse of alcohol or other drugs should be assessed. B. Effects of the alcohol or drug use on the patient's life may include problems with health, family, job or financial status or with the legal system. History of blackouts, motor vehicle crashes, and the effect of alcohol use on family members or friends should be evaluated. Clinical Clues to Alcohol and Drug Disorders Social history Arrest for driving under the influence Loss of job or sent home from work for alcohol- or drug-related reasons Domestic violence Child abuse/neglect Family instability (divorce, separation) Frequent, unplanned ab- sences Personal isolation Problems at work/school Mood swings Medical history History of addiction to any drug Withdrawal syndrome Depression Anxiety disorder Recurrent pancreatitis Recurrent hepatitis Hepatomegaly Peripheral neuropathy Myocardial infarction at less than age 30 (cocaine) Blood alcohol level greater than 300 mg per dL or greater than 100 mg per dL Alcohol smell on breath or intoxicated during office visit Tremor Mild hypertension Estrogen-mediated signs (telangiectasias, spider angiomas, palmar erythema, muscle atrophy) Gastrointestinal complaints Sleep disturbances Eating disorders Sexual dysfunction DSM-IV Diagnostic Criteria for Substance Depend- ence A maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by 3 or more of the following occurring at any time during the same 12-month period. Tolerance, as defined by one of the following: • A need for markedly increased amounts of the substance to achieve intoxication of the desired effect. • Markedly diminished effect with continued use of the same amount of the substance. Withdrawal, as manifested by one of the following: • The characteristic withdrawal syndrome for the sub- stance. • The same, or a closely related, substance is taken to relieve or avoid withdrawal symptoms. • The substance is often taken in larger amounts or over a longer period than was intended. • There is a persistent desire or unsuccessful efforts to cut down or control substance use. • A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects. • Important social, occupational, or recreational activities are given up or reduced because of substance use. • Substance use is continued despite knowledge of having a persistent or recurrent physical or psychologic problem that is likely caused or exacerbated by the substance. II. Laboratory screening A. Mean corpuscular volume. An elevated mean cor- puscular volume (MCV) level may result from folic acid deficiency, advanced alcoholic liver disease, or the toxic effect of alcohol on red blood cells. MCV has poor sensitivity for predicting addiction. B. Gamma-glutamyltransferase. The sensitivity of GGT for predicting alcohol addiction is higher than that of MCV, but its specificity is low. C. Other liver function test results may be elevated because of heavy alcohol consumption, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). These markers have low sensitivity and specificity. An AST/ALT ratio greater than 2:1 is highly suggestive of alcohol-related liver disease. D. Carbohydrate-deficient transferrin (CDT). Consump- tion of 4 to 7 drinks daily for at least 1 week results in a decrease in the carbohydrate content of transferrin. The sensitivity and specificity of CDT are high. III. Alcohol intoxication. Support is the main treatment for alcohol intoxication. Respiratory depression is frequently the most serious outcome. Unconscious patients should receive thiamine intravenously before receiving glucose. IV. Alcohol withdrawal. Treatment consists of four doses of chlordiazepoxide (Librium), 50 mg every 6 hours, followed by 3 doses of 50 mg every 8 hours, followed by 2 doses of 50 mg every 12 hours, and finally 1 dose of 50 mg at bedtime. Signs and Symptoms of Alcohol Withdrawal Withdrawal is characterized by the development of a combina- tion of any of the following signs and symptoms several hours after stopping a prolonged period of heavy drinking: 1. Autonomic hyperactivity: diaphoresis, tachycardia, elevated blood pressure 2. Tremor 3. Insomnia 4. Nausea or vomiting 5. Transient visual, tactile, or auditory hallucinations or illusions 6. Psychomotor agitation 7. Anxiety 8. Generalized seizure activity Management of Alcohol Withdrawal Clinical Disorder Mild/Moderate AWS, able to take oral Mild/Moder ate AWS, unable to take oral Severe AWS Adrenergic Hyperactivity Lorazepam (Ativan) 2 mg po q2h or Chlordiazepox- ide (Librium) 25-100 mg po q6h Lorazepam 1-2 mg IM/IV q1-2h as needed Lorazepam 1- 2 mg IV q 5- 10 min Dehydration Water or juice po NS 1 liter bolus, then D5NS 150- 200 mL/h Aggressive hydration with NS /D5NS Nutritional Deficiency Thiamine 100 mg po Multivitamins Folate 1 mg po Thiamine 100 mg IV Multivita- mins 1 amp in first liter of IV fluids Folate 1 mg IV in first liter of IV fluids Thiamine 100 mg IV Multivitamins 1 amp in first liter of IV flu- ids Folate 1 mg IV in first liter of IV fluids Hypoglycemi a High fructose solution po 25 mL D50 IV (repeat as neces- sary) 25 mL D50 IV (repeat as necessary) Hyperthermi a Cooling blan- kets Seizures Lorazepam (Ativan) 2 mg IV Lorazepam 2 mg IV Lorazepam 2 mg IV V. Sedative-hypnotic withdrawal. Establishment of physical dependence usually requires daily use of thera- peutic doses of these drugs for 6 months or higher doses for 3 months. Treatment of withdrawal from sedative- hypnotics is similar to that of withdrawal from alcohol; chlordiazepoxide (Librium) and lorazepam (Ativan) are the drugs of choice. VI. Maintenance treatment A. Twelve-step programs make a significant contribu- tion to recovery. Alcoholics Anonymous (AA) is the root of 12-step programs. B. Drugs for treatment of alcohol addiction 1. Disulfiram inhibits aldehyde dehydrogenase. On ingesting alcohol, patients taking disulfiram experi- ence flushing of the skin, palpitations, decreased blood pressure, nausea, vomiting, shortness of breath, blurred vision, and confusion. Death has been reported. Side effects include drowsiness, lethargy, peripheral neuropathy, hepatotoxicity, and hypertension. The usual dose is 250 to 500 mg daily. 2. Naltrexone, an opioid antagonist, reduces drinking. It has diminished effectiveness over time and does not reduce relapse rates. 3. Serotonergic drugs reduce drinking in heavy- drinking, nondepressed alcoholic patients, but only 15% to 20% from pretreatment levels. 4. Acamprosate (calcium acetylhomotaurinate) reduces the craving for alcohol. Acamprosate appears to result in more frequent and longer- lasting periods of abstinence than does naltrexone. VII. Opiates Signs and Symptoms of Opiate Withdrawal 1. Mild elevation of pulse and respiratory rates, blood pressure, and temperature 2. Piloerection (gooseflesh) 3. Dysphoric mood and drug craving 4. Lacrimation and/or rhinorrhea 5. Mydriasis, yawning, and diaphoresis 6. Anorexia, abdominal cramps, vomiting, and diarrhea 7. Insomnia 8. Weakness Agents Used to Treat Opiate Withdrawal Methadone (Dolophine) is a pure opioid agonist restricted to inpatient treatment or specialized outpatient drug treatment programs. Treatment is a 15- to 20-mg daily dose for 2 to 3 days, followed by a 10 to 15 percent reduction in daily dose. Clonidine (Catapres) is an alpha-adrenergic blocker. One 0.2- mg dose every 4 hours to relieve symptoms of withdrawal may be effective. It may be continued for 10 to 14 days, followed by tapering. Buprenorphine (Buprenex) is a partial mu-receptor agonist which can be administered sublingually in doses of 2, 4, or 8 mg every 4 hours for the management of opiate withdrawal symptoms. Naltrexone (ReVia, Trexan)/clonidine involves pretreatment with 0.2 to 0.3 mg of clonidine, followed by 12.5 mg of naltrexone (a pure opioid antagonist). Naltrexone is increased to 25 mg on day 2, 50 mg on day 3, and 100 mg on day 4, with clonidine doses of 0.1 to 0.3 mg 3 times daily. VIII. Stimulant Drugs Signs and Symptoms of Cocaine or Stimulant Withdrawal 1. Dysphoric mood 2. Fatigue, malaise 3. Vivid, unpleasant dreams 4. Sleep disturbance 5. Increased appetite 6. Psychomotor retardation or agitation A. Stimulant withdrawal is treated with bromocriptine (Parlodel). This drug reduces stimulant craving and withdrawal symptoms. Bromocriptine dosage is 0.625 to 2.5 mg taken orally three times daily. B. An alternative protocol uses desipramine to reduce the stimulant craving and postwithdrawal symptoms. Desipramine may be used alone or with bromocriptine. The initial dosage of desipramine is 50 mg per day taken orally. This dosage is increased until a dosage of 150 to 200 mg is achieved. Paranoia or combativeness is treated with lorazepam, 2-mg IM. References, see page 360. Eating Disorders Thirty-five percent of adolescent girls believe that they are overweight and 62 percent attempt to lose weight. Eight percent of adolescent girls report that they had tried vomiting or had taken laxatives to help control their weight. I. Definitions A. Anorexia nervosa. A diagnosis of anorexia nervosa requires four diagnostic criteria as defined in the DSM-IV: 1. Refusal to maintain weight within a normal range for height and age (more than 15 percent below ideal body weight). 2. Fear of weight gain. 3. Severe body image disturbance in which body image is the predominant measure of self-worth with denial of the seriousness of the illness. 4. In postmenarchal females, absence of the men- strual cycle, or amenorrhea (greater than three cycles). B. There are two subtypes of anorexia nervosa: restrict- ing; and binge eating/purging. Patients with the restricting subtype use only restriction of intake to reduce their weight, while those with the binge/purge subtype may either binge or use purging (eg, vomit- ing, laxatives, diuretics) to control their weight. Thus, a patient with anorexia may induce vomiting, yet can still be considered anorexic (rather than bulimic) if she is 15 percent below ideal body weight. DSM-IV Diagnostic Criteria for Anorexia Nervosa • Refusal to maintain body weight at or above a minimally normal weight for age and height (eg, weight loss leading to maintenance of body weight less than 85 percent of that expected; or failure to make expected weight gain during a period of growth, leading to body weight less than 85 per- cent of that expected). • Intense fear of gaining weight or becoming fat, even though underweight. • Disturbance in the way in which one's body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight. • In postmenarchal females, amenorrhea, ie, the absence of at least three consecutive menstrual cycles. (A woman is considered to have amenorrhea if her periods occur only following hormone, eg, estrogen, administration.) Specify type: • Restricting type: During the current episode of anorexia nervosa, the person has not regularly engaged in binge- eating or purging behavior (ie, self-induced vomiting or the misuse of laxatives, diuretics or enemas). • Binge-eating/purging type: During the current episode of anorexia nervosa, the person has regularly engaged in binge-eating or purging behavior (ie, self-induced vomiting or the misuse of laxatives, diuretics or enemas). C. Bulimia nervosa. The DSM-IV criteria for bulimia nervosa include the following: 1. Episodes of binge eating with a sense of loss of control. 2. Binge eating is followed by compensatory behavior of the purging type (self-induced vomiting, laxative abuse, diuretic abuse) or nonpurging type (exces- sive exercise, fasting, or strict diets). 3. Binges and the resulting compensatory behavior must occur a minimum of two times per week for three months. 4. Dissatisfaction with body shape and weight. 5. In addition, the disturbance does not occur exclu- sively during episodes of anorexia nervosa. DSM-IV Diagnostic Criteria for Bulimia Nervosa Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following: Eating, in a discrete period of time (eg, within any two- hour period), an amount of food that is definitely larger than most people would eat during a similar period of time and under similar circumstances. A sense of lack of control over eating during the episode (eg, a feeling that one cannot stop eating or control what or how much one is eating). Recurrent inappropriate compensatory behavior to prevent weight gain such as: self-induce vomiting; misuse of laxatives, diuretics or other medications; fasting; or excessive exercising. The binge eating and inappropriate compensatory behaviors both occur, on average, at least twice a week for three months. Self-evaluation is unduly influenced by body shape and weight. The disturbance does not occur exclusively during episodes of anorexia nervosa. Specify type: Purging type: the person regularly engages in self- induced vomiting or the misuse of laxatives or diuret- ics. Nonpurging type: The person uses other inappropri- ate compensatory behaviors, such as fasting or excessive exercise, but does not regularly engage in self-induced vomiting or the misuse of laxatives or diuretics. D. Binge-eating disorder (BED) is defined as binge eating (eating, in a discrete period of time, an amount of food that is definitely larger than most people would eat in a similar period of time) two days per week for a six month duration. The binge eating is associated with a lack of control over eating, and with distress over the binge eating. The binges associated with BED must have at least three of the following five criteria: 1. Eating much more rapidly than normal. 2. Eating until uncomfortably full. 3. Eating large amounts of food when not feeling physically hungry. 4. Eating alone because of embarrassment. 5. Feeling disgusted, depressed, or very guilty after overeating. II. Epidemiology A. The overall prevalence of anorexia nervosa is 0.27 percent, with a prevalence in 15- to 19-year-olds of 0.48 percent. Rates for men are only 10 percent of those for women. B. Binge-eating disorder (BED) has a prevalence of 2 to 3 percent in obese patients. BED occurs more frequently in females. III. Diagnostic evaluation A. Physical examination 1. Patients with anorexia nervosa require vital sign measurements (heart rate and blood pressure both supine and standing, body temperature), skin and extremity evaluation for dryness, bruising, or lanugo, cardiac examination for bradycardia, arrhythmia, or mitral valve prolapse, examination of the abdomen, and neurologic examination to evaluate for other causes of weight loss or vomiting (eg, brain tumor). 2. Physical examination for the patient with bulimia nervosa should include vital signs and neurologic and abdominal examinations to exclude other causes of vomiting. Patients may have parotid gland hypertrophy from vomiting, and erosion of the enamel of the anterior teeth due to chronic acid exposure from vomiting. B. Laboratory assessment for the patient with an eating disorder should include a complete blood count for anemia, a sedimentation rate (ESR) to rule out chronic illness (in eating disorders the ESR should be low), electrolytes, calcium, magnesium, phosphorous, blood urea nitrogen and creatinine, and beta-hCG to rule out pregnancy in patients with prolonged amenorrhea. 1. A urinalysis is important to assess specific gravity since adolescent girls may water load to falsely elevate weight. Thyroid function tests, serum prolactin and follicle stimulating hormone can be obtained with amenorrhea to rule out prolactinoma, hyperthyroidism, hypothyroidism, or ovarian failure. 2. Abnormal thyroid function tests, when they occur, typically suggest the presence of nonthyroidal illness (eg, low serum concentrations of both thyroxine [T4] and triiodothyronine [T3], low or normal serum thyrotropin [TSH] concentration, high concentration of reverse T3). Hypokalemia or metabolic alkalosis suggests that the patient may be purging with vomiting or diuretic use. Features Associated with Anorexia Nervosa Bulimic episodes Preparation of elaborate meals for others but self-limitation to a narrow selection of low-calo- rie foods Obsessive-compul- sive, behaviors Denial or minimization of ill- ness Delayed psychosexual devel- opment Hypothermia Bradycardia Hypotension Edema Lanugo Overactivity, exercise Early satiety Constipation Skin dryness Hypercarotenemia Hair loss Dehydration IV. Differential diagnosis. Other causes of weight loss or chronic vomiting should be ruled out: A. New onset diabetes mellitus may present with severe weight loss. B. Adrenal insufficiency may present with weight loss, orthostasis, and depression. C. Primary depression with anorexia must be differenti- ated from anorexia nervosa. D. Inflammatory bowel disease or other gastrointestinal diseases must be considered. E. Abdominal masses can cause chronic vomiting. F. Central nervous system lesions can cause vomiting, appetite suppression, and a depressed affect. Medical Complications of Eating Disorders Fluid and electrolyte imbalance Hypokalemia Hyponatremia Hypochloremic alkalosis Elevated BUN Inability to concentrate urine Decreased glomerular filtration rate Ketonuria Dermatologic Acrocyanosis Yellow dry skin (hypercarotenemia) Brittle hair and nails Lanugo Hair loss Russell sign (calluses over the knuckles) Pitting edema Cardiovascular Bradycardia Orthostatic hyperten- sion Dysrhythmias Electrocardiographic abnormalities Prolonged QT in- terval T-wave abnormali- ties Low voltage Conduction defects Ipecac cardiomyopathy Mitral valve prolapse Congestive heart fail- ure Pericardial effusion Endocrine Growth retardation and short stature Delayed puberty Amenorrhea Low T3 syndrome Partial diabetes insipidus Hypercortisolism Medical Complications of Eating Disorders Gastrointestinal Parotid hypertrophy Perimolysis and in- creased incidence of dental caries Constipation Bloody diarrhea Delayed gastric emp- tying Intestinal atony Esophagitis Mallory-Weiss tears Esophageal or stom- ach rupture Barrett esophagus Fatty infiltration and focal necrosis of liver Acute pancreatitis Superior mesenteric artery syndrome Gallstones Skeletal Osteopenia Fractures Hematologic Bone marrow sup- pression Mild anemia Leukopenia Thrombocytopenia Low sedimentation rate Impaired cell-medi- ated immunity Neurologic Seizures Myopathy Peripheral neuropathy Cortical atrophy V. Complications associated with starvation or persis- tent purging: A. Osteoporosis B. Cardiac impairment. C. Cognitive changes. D. Difficulty in psychological functioning. E. Gastrointestinal dysfunction, such as slowed motility, nausea, and bloating. F. Endocrinologic changes (with anorexia nervosa) including low serum LH and FSH concentrations, “sick euthyroid syndrome” with increased levels of reverse T3, low serum dehydroepiandrosterone (DHEA) and insulin-like growth factor-I (IGF-I), and increased serum cortisol and growth hormone concentrations. G. Electrolyte abnormalities, particularly hypokalemia and metabolic alkalosis, in patients who purge by vomiting, laxative abuse, or diuretic abuse. H. Dental erosion and enlarged salivary glands in pa- tients with bulimia nervosa. I. Infertility. J. Osteopenia is one of the most severe complications of anorexia nervosa. Treatment of osteopenia includes weight gain, 1200 to 1500 mg/day of elemental cal- cium, a multivitamin providing 400 IU of vitamin D, and individual assessments for estrogen/progestin replace- ment. K. Cardiac changes. Anorexia nervosa has been associ- ated with mitral valve prolapse, possible QT interval prolongation, and heart failure. The risk of heart failure in patients with an eating disorder is greatest in the first two weeks of refeeding. This risk is reduced by slow refeeding, repletion of phosphorus, and avoid- ance of a high sodium intake. L. Secondary amenorrhea affects more than 90 percent of women with anorexia nervosa. Amenorrhea is caused by low levels of follicle stimulating hormone and luteinizing hormone. Withdrawal bleeding with progesterone challenge or oral contraceptive use does not occur due to the hypoestrogenic state. Menses typically resume within six months of achieving 90 percent of the ideal body weight. I. Treatment of eating disorders A. Medical provider manages medical concerns, such as vital signs stability, electrolyte abnormalities, and hydration status, and also acts as the coordinator of care. Weekly weigh-in and vital sign checks are needed to ensure weight gain and medical stability. B. Nutritional therapy. Expected rates of weight gain are 2 to 3 pounds (0.9 to 1.4 kg) per week for most inpa- tients and 0.5 to 1 pound (0.2 to 0.5 kg) per week for most outpatients. Intake levels usually begin at 30 to 40 kcal/kg (1000 to 1600 kcal/day) and are advanced progressively. For patients with bulimia nervosa, nutritional counseling is recommended. In patients with binge-eating disorder and obesity, dietary ap- proaches, including very low-calorie diets, may be of benefit in reducing binge eating. C. Refeeding syndrome. Patients with moderate to severe anorexia nervosa (ie, more than 10 percent below ideal body weight) are at risk for the refeeding syndrome during the first two to three weeks of refeeding. Manifestations of this syndrome include cardiac arrest and delirium, caused by refeeding- induced hypophosphatemia. Carefully monitoring of electrolytes (including phosphorous) and looking for signs of edema or congestive heart failure are impor- tant during refeeding. Phosphorous replacement during the initial phases of refeeding is acceptable as long as the patient has adequate renal function. Constipation or bloating may be reduced by metoclopramide. D. Psychotherapy. Cognitive behavioral therapy (CBT) emphasizes the relationship of thoughts and feelings to behavior and helps patients learn to recognize the thoughts and feelings that lead to disordered eating. CBT helps the patient manage the anxiety related to eating and poor body image. E. Medication 1. Anorexia nervosa. Antidepressants may help maintain weight gain. Fluoxetine (Prozac) has been used successfully in the therapy of anorexia and bulimia; 20-40 mg PO qAM. Anxiolytic medications may be helpful before meals for the anorexic patient who is having anxiety before eating. Olanzapine (Zyprexa) is useful in patients with severe anorexia nervosa. 2. Bulimia nervosa. A number of trials have shown an improved course in patients with bulimia nervosa who have been treated with fluoxetine. Fluoxetine (Prozac), 20-mg dosage, results in a 45 percent reduction in binge eating. Fluoxetine in a dosage of 60 mg per day produces the best treat- ment response, demonstrating a 67 percent reduc- tion in binge eating. Two other drugs that may be useful in patients with bulimia nervosa are topiramate and ondansetron: a. Topiramate (Topamax) at a dose of 25 to 600 mg/day (median dose 212 mg/day) significantly reduces binge frequency (94 versus 46 percent reduction). b. Ondansetron (Zofran) (24 mg/day) may re- duce binge eating and self-induced vomiting. 3. Binge-eating disorder. SSRI antidepressants, antiepileptics, and appetite suppressants, improve the symptoms of binge-eating disorder. Topiramate (Topamax) may be particularly promising for the treatment of binge-eating disorder. F. Hospitalization. One or more of the following justify hospitalization: 1. Severe malnutrition (weight less than 75 percent of average body weight). 2. Dehydration. 3. El ectrol yte di sturbances (hypokal emi a, hyponatremia, hypophosphatemia). 4. Cardiac dysrhythmia. 5. Physiologic instability (severe bradycardia [heart rate less than 50 beats per minute], hypotension [less than 80/50 mm Hg], hypothermia [less than 96º F], orthostatic changes in pulse [more than 20 beats per minute] or blood pressure [more than 10 mm Hg]). 6. Arrested growth and development. 7. Failure of outpatient treatment. 8. Acute food refusal. 9. Uncontrollable binging and purging. 10.Acute medical complication of malnutrition (eg, syncope, seizures, cardiac failure, pancreatitis). 11.Acute psychiatric emergencies (eg, suicidal ideation, acute psychosis). 12.Comorbid diagnosis that interferes with the treat- ment of eating disorders (eg, severe depression, obsessive-compulsive disorder, severe family dysfunction). G. Management of osteopenia. Osteopenia is one of the most severe complications of anorexia nervosa. The primary therapy is weight gain. Estrogen replace- ment therapy has been used in women with anorexia nervosa. Recommendations include weight gain, 1200 to 1500 mg/day of elemental calcium, and a multivita- min providing 400 IU of vitamin D. Estrogen/progestin replacement in women may be considered. Dual emission X-ray absorptiometry (DEXA) scan should be obtained initially and every 6 to 12 months.