Harrison's Manual of Medicine 18th Edition PDF

 GLOSSARY A2 aortic second sound Dx diagnosis ABGs arterial blood gases EBV Epstein-Barr virus ACE angiotensin converting ECG electrocardiogram enzyme EEG electroencephalogram AF atrial fibrillation ELISA enzyme-li...

 GLOSSARY A2 aortic second sound Dx diagnosis ABGs arterial blood gases EBV Epstein-Barr virus ACE angiotensin converting ECG electrocardiogram enzyme EEG electroencephalogram AF atrial fibrillation ELISA enzyme-linked AIDS acquired immunodeficiency immunosorbent assay syndrome EMG electromyogram ALS amyotrophic lateral ENT ear, nose, and throat sclerosis EOM extraocular movement ANA antinuclear antibody ESR erythrocyte sedimentation ARDS adult respiratory distress rate syndrome FDA US Food and Drug bid two times daily Administration biw twice a week FEV1 forced expiratory volume bp blood pressure in first second BUN blood urea nitrogen GRF glomerular filtration rate CAPD continuous ambulatory GI gastrointestinal peritoneal dialysis G6PD glucose-6-phosphate CBC complete blood count dehydrogenase CF complement fixation Hb hemoglobin CHF congestive heart failure Hct hematocrit CLL chronic lymphocytic HDL high-density lipoprotein leukemia HIV human immunodeficiency CML chronic myeloid virus leukemia hs at bedtime CMV cytomegalovirus HSV herpes simplex virus CNS central nervous system Hx history CPK creatine phosphokinase ICU intensive care unit CSF cerebrospinal fluid IFN interferon CT computed tomography Ig immunoglobulin CVP central venous pressure IL interleukin CXR chest x-ray IM intramuscular DIC disseminated intravascular IV intravenous coagulation IVC inferior vena cava DVT deep venous thrombosis IVP intravenous pyelogram  18th Edition TM MANUAL OF MEDICINE  EDITORS Dan L. Longo, MD Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts; Adjunct Investigator, National Institute on Aging, National Institutes of Health, Bethesda, Maryland Anthony S. Fauci, MD, ScD(HON) Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Dennis L. Kasper, MD, MA(HON) William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Stephen L. Hauser, MD Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California J. Larry Jameson, MD, PhD Robert G. Dunlop Professor of Medicine; Dean, University of Pennsylvania Perelman School of Medicine; Executive Vice-President, University of Pennsylvania Health System, Philadelphia, Pennsylvania Joseph Loscalzo, MD, PhD Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts  18th Edition TM MANUAL OF MEDICINE EDITORS Dan L. Longo, MD Anthony S. Fauci, MD Dennis L. Kasper, MD Stephen L. Hauser, MD J. Larry Jameson, MD, PhD Joseph Loscalzo, MD, PhD New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto Copyright © 2013, 2009, 2005, 2002, 1998, 1995, 1991, 1988 by The McGraw-Hill Companies, Inc. All rights reserved. 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This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.  CONTENTS Contributors................................................. xiii Preface..................................................... xv Acknowledgments........................................... xvii SECTION 1 Care of the Hospitalized Patient 1 Initial Evaluation and Admission Orders for the General Medicine Patient............................... 1 2 Electrolytes/Acid-Base Balance............................. 3 3 Diagnostic Imaging in Internal Medicine...................... 26 4 Procedures Commonly Performed by Internists................. 30 5 Principles of Critical Care Medicine.......................... 35 6 Pain and Its Management................................. 40 7 Assessment of Nutritional Status............................ 46 8 Enteral and Parenteral Nutrition............................. 49 9 Transfusion and Pheresis Therapy........................... 51 10 Palliative and End-of-Life Care.............................. 54 SECTION 2 Medical Emergencies 11 Cardiovascular Collapse and Sudden Death.................... 65 12 Shock................................................. 69 13 Sepsis and Septic Shock.................................. 74 14 Acute Pulmonary Edema.................................. 78 15 Acute Respiratory Distress Syndrome........................ 80 16 Respiratory Failure....................................... 83 17 Confusion, Stupor, and Coma............................... 86 18 Stroke................................................ 93 19 Subarachnoid Hemorrhage................................ 103 20 Increased Intracranial Pressure and Head Trauma.............. 105 21 Spinal Cord Compression................................. 112 22 Hypoxic-Ischemic Encephalopathy.......................... 114 23 Status Epilepticus...................................... 116 v vi CONTENTS 24 Diabetic Ketoacidosis and Hyperosmolar Coma................ 118 25 Hypoglycemia.......................................... 122 26 Infectious Disease Emergencies............................ 125 27 Oncologic Emergencies.................................. 133 28 Anaphylaxis........................................... 138 29 Bites, Venoms, Stings, and Marine Poisonings................. 139 30 Hypothermia and Frostbite................................ 151 31 Altitude Illness......................................... 155 32 Poisoning and Drug Overdose............................. 159 33 Bioterrorism........................................... 191 SECTION 3 Common Patient Presentations 34 Fever, Hyperthermia, and Rash............................. 209 35 Generalized Fatigue..................................... 214 36 Weight Loss........................................... 218 37 Chest Pain............................................ 221 38 Palpitations........................................... 225 39 Dyspnea.............................................. 226 40 Cyanosis............................................. 229 41 Cough and Hemoptysis.................................. 231 42 Edema............................................... 235 43 Abdominal Pain........................................ 239 44 Nausea, Vomiting, and Indigestion.......................... 244 45 Dysphagia............................................ 248 46 Diarrhea, Constipation, and Malabsorption.................... 253 47 Gastrointestinal Bleeding................................. 261 48 Jaundice and Evaluation of Liver Function.................... 266 49 Ascites............................................... 275 50 Lymphadenopathy and Splenomegaly....................... 278 51 Anemia and Polycythemia................................ 283 52 Azotemia and Urinary Abnormalities........................ 287 53 Pain and Swelling of Joints............................... 294 54 Back and Neck Pain..................................... 298 55 Headache............................................. 307  CONTENTS vii 56 Syncope.............................................. 316 57 Dizziness and Vertigo.................................... 320 58 Acute Visual Loss and Double Vision........................ 324 59 Weakness and Paralysis................................. 328 60 Tremor and Movement Disorders........................... 332 61 Aphasia.............................................. 335 62 Sleep Disorders........................................ 337 SECTION 4 Ophthalmology and Otolaryngology 63 Common Disorders of Vision and Hearing.................... 343 64 Sinusitis, Pharyngitis, Otitis, and Other Upper Respiratory Tract Infections.......................... 353 SECTION 5 Dermatology 65 General Examination of the Skin........................... 363 66 Common Skin Conditions................................. 367 SECTION 6 Hematology and Oncology 67 Examination of Blood Smears and Bone Marrow............... 375 68 Red Blood Cell Disorders................................. 377 69 Leukocytosis and Leukopenia............................. 384 70 Bleeding and Thrombotic Disorders......................... 387 71 Cancer Chemotherapy................................... 395 72 Myeloid Leukemias, Myelodysplasia, and Myeloproliferative Syndromes............................. 403 73 Lymphoid Malignancies.................................. 414 74 Skin Cancer........................................... 428 75 Head and Neck Cancer................................... 432 76 Lung Cancer........................................... 433 77 Breast Cancer......................................... 441 78 Tumors of the Gastrointestinal Tract........................ 447 79 Genitourinary Tract Cancer................................ 460 80 Gynecologic Cancer..................................... 464 81 Prostate Hyperplasia and Carcinoma........................ 469 viii CONTENTS 82 Cancer of Unknown Primary Site........................... 473 83 Paraneoplastic Endocrine Syndromes....................... 477 84 Neurologic Paraneoplastic Syndromes....................... 480 SECTION 7 Infectious Diseases 85 Diagnosis of Infectious Diseases........................... 485 86 Antibacterial Therapy.................................... 496 87 Health Care–Associated Infections.......................... 505 88 Infections in the Immunocompromised Host.................. 511 89 Infective Endocarditis.................................... 521 90 Intraabdominal Infections................................. 532 91 Infectious Diarrheas..................................... 536 92 Sexually Transmitted and Reproductive Tract Infections.......... 551 93 Infections of the Skin, Soft Tissues, Joints, and Bones........... 569 94 Pneumococcal Infections................................. 580 95 Staphylococcal Infections................................. 584 96 Streptococcal/Enterococcal Infections, Diphtheria, and Other Infections Caused by Corynebacteria and Related Species........................................ 592 97 Meningococcal and Listerial Infections...................... 603 98 Infections Caused by Haemophilus, Bordetella, Moraxella, and HACEK Group Organisms..................... 608 99 Diseases Caused by Gram-Negative Enteric Bacteria, Pseudomonas, and Legionella............................. 615 100 Infections Caused by Miscellaneous Gram-Negative Bacilli....... 627 101 Anaerobic Infections.................................... 635 102 Nocardiosis and Actinomycosis............................ 644 103 Tuberculosis and Other Mycobacterial Infections............... 649 104 Lyme Disease and Other Nonsyphilitic Spirochetal Infections..... 663 105 Rickettsial Diseases..................................... 670 106 Mycoplasma Infections.................................. 680 107 Chlamydial Infections.................................... 681 108 Herpesvirus Infections................................... 685 109 Cytomegalovirus and Epstein-Barr Virus Infections............. 694 110 Influenza and Other Viral Respiratory Diseases................ 699  CONTENTS ix 111 Rubeola, Rubella, Mumps, and Parvovirus Infections............ 708 112 Enteroviral Infections.................................... 714 113 Insect- and Animal-Borne Viral Infections.................... 718 114 HIV Infection and AIDS................................... 728 115 Fungal Infections....................................... 744 116 Pneumocystis Infections................................. 759 117 Protozoal Infections..................................... 763 118 Helminthic Infections and Ectoparasite Infestations............. 778 SECTION 8 Cardiology 119 Physical Examination of the Heart.......................... 795 120 Electrocardiography..................................... 800 121 Noninvasive Examination of the Heart....................... 805 122 Congenital Heart Disease in the Adult....................... 811 123 Valvular Heart Disease................................... 815 124 Cardiomyopathies and Myocarditis......................... 822 125 Pericardial Disease...................................... 828 126 Hypertension.......................................... 834 127 Metabolic Syndrome.................................... 842 128 ST-Segment Elevation Myocardial Infarction (STEMI)............ 844 129 Unstable Angina and Non-ST-Elevation Myocardial Infarction..... 855 130 Chronic Stable Angina................................... 858 131 Bradyarrhythmias....................................... 864 132 Tachyarrhythmias....................................... 867 133 Heart Failure and Cor Pulmonale........................... 879 134 Diseases of the Aorta.................................... 887 135 Peripheral Vascular Disease............................... 890 136 Pulmonary Hypertension.................................. 895 SECTION 9 Pulmonology 137 Respiratory Function and Pulmonary Diagnostic Procedures...... 899 138 Asthma............................................... 907 139 Environmental Lung Diseases............................. 911 140 Chronic Obstructive Pulmonary Disease...................... 915 x CONTENTS 141 Pneumonia, Bronchiectasis, and Lung Abscess................ 920 142 Pulmonary Thromboembolism and Deep-Vein Thrombosis....... 929 143 Interstitial Lung Disease................................. 933 144 Diseases of the Pleura and Mediastinum..................... 939 145 Disorders of Ventilation.................................. 945 146 Sleep Apnea........................................... 947 SECTION 10 Nephrology 147 Approach to the Patient With Renal Disease.................. 949 148 Acute Renal Failure..................................... 954 149 Chronic Kidney Disease and Uremia........................ 960 150 Dialysis.............................................. 963 151 Renal Transplantation.................................... 965 152 Glomerular Diseases.................................... 968 153 Renal Tubular Disease................................... 978 154 Urinary Tract Infections and Interstitial Cystitis................ 986 155 Renovascular Disease................................... 991 156 Nephrolithiasis......................................... 998 157 Urinary Tract Obstruction................................ 1001 SECTION 11 Gastroenterology 158 Peptic Ulcer and Related Disorders........................ 1005 159 Inflammatory Bowel Diseases............................ 1011 160 Colonic and Anorectal Diseases........................... 1016 161 Cholelithiasis, Cholecystitis, and Cholangitis................. 1021 162 Pancreatitis.......................................... 1026 163 Acute Hepatitis........................................ 1032 164 Chronic Hepatitis...................................... 1039 165 Cirrhosis and Alcoholic Liver Disease....................... 1051 166 Portal Hypertension.................................... 1057 SECTION 12 Allergy, Clinical Immunology, and Rheumatology 167 Diseases of Immediate-Type Hypersensitivity................ 1061 168 Primary Immune Deficiency Diseases...................... 1066  CONTENTS xi 169 SLE, RA, and Other Connective Tissue Diseases............... 1070 170 Vasculitis............................................ 1078 171 Ankylosing Spondylitis.................................. 1082 172 Psoriatic Arthritis...................................... 1085 173 Reactive Arthritis...................................... 1087 174 Osteoarthritis......................................... 1089 175 Gout, Pseudogout, and Related Diseases.................... 1091 176 Other Musculoskeletal Disorders.......................... 1096 177 Sarcoidosis.......................................... 1100 178 Amyloidosis.......................................... 1102 SECTION 13 Endocrinology and Metabolism 179 Disorders of the Anterior Pituitary and Hypothalamus.......... 1105 180 Diabetes Insipidus and SIADH............................ 1113 181 Thyroid Gland Disorders................................. 1116 182 Adrenal Gland Disorders................................. 1126 183 Obesity.............................................. 1134 184 Diabetes Mellitus...................................... 1137 185 Disorders of the Male Reproductive System................. 1144 186 Disorders of the Female Reproductive System............... 1150 187 Hypercalcemia and Hypocalcemia......................... 1159 188 Osteoporosis and Osteomalacia........................... 1167 189 Hypercholesterolemia and Hypertriglyceridemia.............. 1172 190 Hemochromatosis, Porphyrias, and Wilson’s Disease........... 1180 SECTION 14 Neurology 191 The Neurologic Examination.............................. 1187 192 Neuroimaging......................................... 1197 193 Seizures and Epilepsy.................................. 1199 194 Dementia............................................ 1212 195 Parkinson’s Disease.................................... 1221 196 Ataxic Disorders....................................... 1227 197 ALS and Other Motor Neuron Diseases...................... 1231 198 Autonomic Nervous System Disorders...................... 1235 xii CONTENTS 199 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders................................. 1243 200 Spinal Cord Diseases................................... 1251 201 Tumors of the Nervous System........................... 1257 202 Multiple Sclerosis (MS)................................. 1262 203 Acute Meningitis and Encephalitis......................... 1270 204 Chronic Meningitis..................................... 1283 205 Peripheral Neuropathies Including Guillain-Barré Syndrome (GBS)........................... 1292 206 Myasthenia Gravis (MG)................................. 1302 207 Muscle Diseases...................................... 1306 SECTION 15 Psychiatry and Substance Abuse 208 Psychiatric Disorders................................... 1315 209 Psychiatric Medications................................. 1324 210 Eating Disorders....................................... 1333 211 Alcoholism........................................... 1336 212 Narcotic Abuse........................................ 1340 SECTION 16 Disease Prevention and Health Maintenance 213 Routine Disease Screening.............................. 1345 214 Immunization and Recommendations for Travelers............ 1350 215 Cardiovascular Disease Prevention........................ 1361 216 Prevention and Early Detection of Cancer................... 1365 217 Smoking Cessation.................................... 1372 218 Women’s Health....................................... 1375 SECTION 17 Adverse Drug Reactions 219 Adverse Drug Reactions................................. 1379 SECTION 18 Laboratory Values 220 Laboratory Values of Clinical Importance.................... 1393 Index.................................................... 1451  CONTRIBUTORS ASSOCIATE EDITORS GERHARD P. BAUMANN, MD Professor of Medicine Emeritus Division of Endocrinology, Metabolism, and Molecular Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois S. ANDREW JOSEPHSON, MD Assistant Professor of Neurology, Director, Neurohospitalist Program University of California, San Francisco San Francisco, California CAROL A. LANGFORD, MD, MHS Director, Center for Vasculitis Care and Research Department of Rheumatic and Immunologic Diseases Cleveland Clinic Cleveland, Ohio LEONARD S. LILLY, MD Professor of Medicine Harvard Medical School Chief, Brigham and Women’s/Faulkner Cardiology Brigham and Women’s Hospital Boston, Massachusetts DAVID B. MOUNT, MD Assistant Professor of Medicine Harvard Medical School Associate Physician, Renal Division, Brigham and Women’s Hospital Staff Physician, Renal Division, VA Boston Healthcare System Boston, Massachusetts EDWIN K. SILVERMAN, MD, PhD Associate Professor of Medicine Chief, Channing Division of Network Medicine Department of Medicine, Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts xiii xiv CONTRIBUTORS SECTION 00 Infectious Diseases NEERAJ K. SURANA, MD, PhD Instructor in Pediatrics Harvard Medical School Assistant in Medicine Boston Children’s Hospital Boston, Massachusetts Numbers indicate the chapters written or co-written by the contributor. GERHARD P. BAUMANN, MD 1, 3, 4, 7, 8, 24, 25, 30, 32, 35, 36, 127, 179–190, 210, 213, 218, 220 ANTHONY S. FAUCI, MD 28, 33, 48, 49, 53, 65, 66, 114, 161–178 STEPHEN L. HAUSER, MD 6, 17–23, 54–63, 84, 191–209, 211, 212, 217 J. LARRY JAMESON, MD, PhD 1, 3, 4, 7, 8, 24, 25, 30, 32, 35, 36, 127, 179–190, 210, 213, 218, 220 S. ANDREW JOSEPHSON, MD 6, 17–23, 54–63, 84, 191–209, 211, 212, 217 DENNIS L. KASPER, MD 13, 26, 29, 31, 34, 64, 85–113, 115–118, 141, 154, 214 CAROL A. LANGFORD, MD 28, 33, 48, 49, 53, 65, 66, 114, 161–178 LEONARD S. LILLY, MD 11, 12, 14, 37, 38, 40, 119–126, 128–136, 215 DAN L. LONGO, MD 9, 10, 27, 43–47, 50, 51, 67–83, 158–160, 216 JOSEPH LOSCALZO, MD, PhD 5, 11, 12, 14–16, 37–42, 52, 119–126, 128–153, 155–157, 215 DAVID B. MOUNT, MD 42, 52, 147–153, 155–157 EDWIN K. SILVERMAN, MD, PhD 5, 15, 16, 39, 41, 137–146 NEERAJ K. SURANA, MD 13, 26, 29, 31, 34, 64, 85–113, 115–118, 141, 154, 214  PREFACE Harrison’s Principles of Internal Medicine (HPIM) provides a comprehensive body of information important to an understanding of the biological and clinical aspects of quality patient care. It remains the premier medical text- book for students and clinicians. With the rapidly expanding base of medi- cal knowledge and the time constraints associated with heavy patient-care responsibilities in modern health care settings, it is not always possible to read a comprehensive account of diseases and their presentations, clinical manifestations, and treatments before or even immediately after encoun- tering the patient. It was for these reasons, among others, that in 1988 the Editors first condensed the clinical portions of HPIM into a pocket-sized volume, Harrison’s Manual of Medicine. Similar to the prior seven editions, this new edition of the Manual, drawn from the 18th edition of HPIM, pres- ents the key features of the diagnosis, clinical manifestations, and treatment of the major diseases that are likely to be encountered on a medical service. The Editors stress that the Manual should not substitute for in-depth anal- ysis of the clinical problem, but should serve as a ready source of well-crafted and informative summaries that will be useful “on-the-spot” and that will prepare the reader for a more in-depth analysis drawn from more extensive reading at a later time. The Manual has met with increasing popularity over the years; its popularity and value relate in part to its abbreviated format, which has proven to be extremely useful for initial diagnosis, brief descrip- tion of pathogenesis, and outline of management in time-restricted clinical settings. The book’s full-color format will increase the speed with which readers can locate and use information within its chapters. The Manual has been written for easy and seamless reference to the full text of the 18th edition of HPIM, and the Editors recommend that the full textbook—or Harrison’s Online—be consulted as soon as time allows. As with previous editions, this latest edition of the Manual attempts to keep up with the continual and sometimes rapid evolution of internal medicine practices. In this regard, every chapter has received a close review and has been updated from the prior edition, with substantial revisions and new chapters provided where appropriate. The format of the book has been further streamlined to reflect more use of abbreviated text, with use of numerous tables and graphics to help guide understanding and decisions at the point of care. In full recogni- tion of the important role of digital information delivery in alleviating the increasing time demands put on clinicians, the 18th edition of the Manual has also been made available in portable format for the smartphone and tablet. We would like to thank our friend and colleague Eugene Braunwald, MD for his many contributions and years of wise advice in shaping the Manual and indeed all the publications in the Harrison’s family. xv This page intentionally left blank  ACKNOWLEDGMENTS The Editors and McGraw-Hill wish to thank their editorial staff whose as- sistance and patience made this edition come out in a timely manner: From the Editors’ offices: Pat Duffey; Gregory K. Folkers; Julie B. McCoy; Elizabeth Robbins, MD; Marie E. Scurti; Kristine Shontz; and Stephanie Tribuna. From McGraw-Hill: James F. Shanahan, Kim J. Davis, and Catherine H. Saggese. The Editors also wish to acknowledge contributors to past editions of this Manual, whose work formed the basis for many of the chapters herein: Eugene Braunwald, MD; Joseph B. Martin, MD, PhD; Kurt Isselbacher, MD; Jean Wilson, MD; Tamar F. Barlam, MD; Daryl R. Gress, MD; Michael Sneller, MD; John W. Engstrom, MD; Kenneth Tyler, MD; Sophia Vinogradov, MD; Dan B. Evans, MD; Punit Chadha, MD; Glenn Chertow, MD; and James Woodrow Weiss, MD. xvii  NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recom- mended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.  SECTION 1 Care of the Hospitalized Patient C H AP TE R 1 Initial Evaluation and Admission Orders for the General Medicine Patient Pts are admitted to the hospital when (1) they present the physician with a complex diagnostic challenge that cannot be safely or efficiently performed in the outpatient setting; or (2) they are acutely ill and require inpatient diagnostic tests, interventions, and treatments. The decision to admit a pt includes identifying the optimal clinical service (e.g., medicine, urology, neurology), the level of care (observation, general floor, telemetry, ICU), and necessary consultants. Admission should always be accompanied by clear communication with the pt and family, both to obtain information and to outline the anticipated events in the hospital. Pts often have multiple physicians, and based on the nature of the clinical problems, they should be contacted to procure relevant medical history and to assist with clinical care during or after admission. Electronic health records promise to facilitate the communication of medical information among physicians, hospitals, and other medical care providers. The scope of illnesses cared for by internists is enormous. During a single day on a typical general medical service, it is not unusual for physicians, espe- cially residents in training, to admit ten pts with ten different diagnoses affect- ing ten different organ systems. Given this diversity of disease, it is important to be systematic and consistent in the approach to any new admission. Physicians are often concerned about making errors of commission. Examples would include prescribing an improper antibiotic for a pt with pneumonia or miscalculating the dose of heparin for a pt with new deep venous thrombosis (DVT). However, errors of omission are also common and can result in pts being denied life-saving interventions. Simple exam- ples include: not checking a lipid panel for a pt with coronary heart disease, not prescribing an angiotensin-converting enzyme (ACE) inhibitor to a diabetic with documented albuminuria, or forgetting to give a pt with an osteoporotic hip fracture calcium, vitamin D, and an oral bisphosphonate. Inpatient medicine typically focuses on the diagnosis and treatment of acute medical problems. However, most pts have multiple medical problems affecting different organ systems, and it is equally important to prevent nosocomial complications. Prevention of common hospital complications, such as DVT, peptic ulcers, line infections, falls, delirium, and pressure ulcers, is an important aspect of the care of all general medicine pts. A consistent approach to the admission process helps to ensure compre- hensive and clear orders that can be written and implemented in a timely manner. Several mnemonics serve as useful reminders when writing admis- sion orders. A suggested checklist for admission orders is shown below; it 1 2 SECTION 1 Care of the Hospitalized Patient includes several interventions targeted to prevent common nosocomial com- plications. Computerized order entry systems are also useful when designed to prompt structured sets of admission orders. However, these should not be used to the exclusion of orders tailored for the needs of an individual pt. Checklist mnemonic: ADMIT VITALS AND PHYSICAL EXAM Admit to: service (Medicine, Oncology, ICU); provide status (acute or observation). Diagnosis: state the working diagnosis prompting this particular hospitalization. MD: name the attending, resident, intern, student, primary care MD, and consultants. Isolation requirements: state respiratory or contact isolation and reason for order. Telemetry: state indications for telemetry and specify monitor parameters. Vital signs (VS): frequency of VS; also specify need for pulse oximetry and orthostatic VS. IV access and IV fluid or TPN orders (Chap. 2). Therapists: respiratory, speech, physical, and/or occupational therapy needs. Allergies: also specify type of adverse reaction. Labs: blood count, chemistries, coagulation tests, type & screen, UA, special tests. Studies: CT scans (also order contrast), ultrasounds, angiograms, endos- copies, etc. Activity: weight bear/ambulating instructions, fall/seizure precautions and restraints. Nursing Orders: call intern if (x/y/z), also order I/Os, daily weights, and blood glucose. Diet: include NPO orders and tube feeding. State whether to resume diet after tests. Peptic ulcer prevention: proton-pump inhibitor or misoprostol for high- risk pts. Heparin or other modality (warfarin, compression boots, support hose) for DVT prophylaxis. Yank all Foley catheters and nonessential central lines to prevent iatro- genic infections. Skin care: prevent pressure sores with heel guards, air mattresses, and RN wound care. Incentive spirometry: prevent atelectasis and hospital-acquired pneumonia. Calcium, vitamin D, and bisphosphonates if steroid use, bone fracture, or osteoporosis. ACE inhibitor and aspirin: use for nearly all pts with coronary disease or diabetes. Lipid panel: assess and treat all cardiac and vascular pts for hyperlipidemia. ECG: for nearly every pt >50 years at the time of admission. X-rays: chest x-ray, abdominal series; evaluate central lines and endotra- cheal tubes. Advance directives: Full code or DNR; specify whether to rescind for any procedures. Medications: be specific with your medication orders.  Electrolytes/Acid-Base Balance CHAPTER 2 3 It may be helpful to remember the medication mnemonic “Stat DRIP” for different routes of administration (stat, daily, round-the-clock, IV, and prn medications). For the sake of cross-covering colleagues, provide relevant prn orders for acetaminophen, diphenhydramine, stool softeners or laxa- tives, and sleeping pills. Specify any stat medications since routine medica- tion orders entered as “once daily” may not be dispensed until the following day unless ordered as stat or “first dose now.” C H AP TE R 2 Electrolytes/Acid-Base Balance SODIUM Disturbances of sodium concentration [Na+] result in most cases from abnormalities of H2O homeostasis, which change the relative ratio of Na+ to H2O. Disorders of Na+ balance per se are, in contrast, associated with changes in extracellular fluid volume, either hypo- or hypervolemia. Maintenance of the “effective circulating volume” is achieved in large part by changes in urinary sodium excretion, whereas H2O balance is achieved by changes in both H2O intake and urinary H2O excretion (Table 2-1). Confusion can result from the coexistence of defects in both H2O and Na+ balance. For example, a hypovolemic pt may have an appropriately low urinary Na+ due to increased renal tubular reabsorption of filtered NaCl; a concomitant increase in circulating arginine vasopressin (AVP)—part of the defense of effective circulating volume (Table 2-1)—will cause the renal retention of ingested H2O and the development of hyponatremia. 䡵 HYPONATREMIA This is defined as a serum [Na+] 6% for any surgeon, the benefit is lost. Endovascular stenting is an emerging option; there remains controversy as to who should receive a stent or undergo endarterectomy. Surgical results in pts with asymptomatic carotid stenosis are less robust, and medical therapy for reduc- tion of atherosclerosis risk factors plus antiplatelet medications is generally recommended in this group.  Subarachnoid Hemorrhage CHAPTER 19 103 For a more detailed discussion, see Smith WS, English JD, Johnston SC: Cerebrovascular Diseases, Chap. 370, p. 3270, in HPIM-18. C H AP TE R 19 Subarachnoid Hemorrhage Excluding head trauma, the most common cause of subarachnoid hem- orrhage (SAH) is rupture of an intracranial (saccular) aneurysm; other etiologies include bleeding from a vascular malformation (arteriovenous malformation or dural arterial-venous fistula), infective (mycotic) aneurysms, and extension into the subarachnoid space from a primary intracerebral hemorrhage. Approximately 2% of the population harbor aneurysms, and 25,000–30,000 cases of aneurysmal rupture producing SAH occur each year in the United States; rupture risk for aneurysms 5 min.  Status Epilepticus CHAPTER 23 117 䡵 CLINICAL FEATURES Has numerous subtypes: GCSE (e.g., persistent, generalized electrographic seizures, coma, and tonic-clonic movements), and nonconvulsive status epilepticus (e.g., persistent absence seizures or focal seizures, confusion, or partially impaired consciousness, and minimal motor abnormalities). GCSE is obvious when overt convulsions are present, but after 30–45 min of unin- terrupted seizures, the signs may become increasingly subtle (mild clonic movements of the fingers; fine, rapid movements of the eyes; or paroxysmal episodes of tachycardia, pupillary dilatation, and hypertension). EEG may be the only method of diagnosis with these subtle signs; therefore, if a pt remains comatose after a seizure, EEG should be performed to exclude ongoing status epilepticus. GCSE is life-threatening when accompanied by cardiorespiratory dysfunction, hyperthermia, and metabolic derangements such as acidosis (from prolonged muscle activity). Irreversible neuronal injury may occur from persistent seizures, even when a pt is paralyzed from neuromuscular blockade. 䡵 ETIOLOGY Principal causes of GCSE are antiepileptic drug withdrawal or noncompli- ance, metabolic disturbances, drug toxicity, CNS infections, CNS tumors, refractory epilepsy, and head trauma. TREATMENT OF GENERALIZED TONIC-CLONIC STATUS EPILEPTICUS IN ADULTS Lorazepam 0.1–0.15 mg/kg IV over 1–2 min Additional emergent drug therapy (repeat x 1 if no response after 5 min) may not be required if seizures stop and the etiology of status epilepticus is rapidly corrected Fosphenytoin 20 mg/kg PE IV 150 mg/min or phenytoin 20 mg/kg IV 50 mg/min Seizures continuing Consider valproate 25 mg/kg IV in pts. Fosphenytoin 7–10 mg/kg PE IV 150 mg/min normally taking or phenytoin 7–10 mg/kg IV 50 mg/min valproate and who may be subtherapeutic Seizures continuing Consider valproate 25 mg/kg IV No immediate access to ICU Phenobarbital 20 mg/kg IV 60 mg/min Admit Seizures continuing to ICU Phenobarbital 10 mg/kg IV 60 mg/min IV anesthesia with propofol or midazolam or pentobarbital FIGURE 23-1 Pharmacologic treatment of generalized tonic-clonic status epilepticus in adults. The horizontal gray bars indicate the approximate duration of drug infusions. IV, intravenous; PE, phenytoin equivalents. 118 SECTION 2 Medical Emergencies TREATMENT Status Epilepticus GCSE is a medical emergency and must be treated immediately. First attend to any acute cardiorespiratory problems or hyperthermia. Perform a brief medical and neurologic exam, establish venous access, and send labs to screen for metabolic abnormalities includ- ing anticonvulsant levels if pt has a history of epilepsy. Anticonvulsant therapy should then begin without delay (Fig. 23-1) In parallel, it is essential to determine the cause of the seizures to prevent recurrence and treat any underlying abnormalities. The treatment of nonconvulsive status epilepticus is somewhat less urgent since the ongoing seizures are not accompanied by the severe metabolic disturbances of GCSE; however, evidence points to local cellular injury in the region of the seizure focus, so the condition should be treated as promptly as possible using the general approach for GCSE. 䡵 PROGNOSIS The mortality rate is 20% in GCSE, and the incidence of permanent neuro- logic sequelae is 10–50%. For a more detailed discussion, see Lowenstein DH: Seizures and Epilepsy, Chap. 369, p. 3251, in HPIM-18. CHAP T E R 24 Diabetic Ketoacidosis and Hyperosmolar Coma Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are acute complications of diabetes mellitus (DM). DKA is seen primarily in individuals with type 1 DM and HHS in individuals with type 2 DM. Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and altered mental status. The metabolic similarities and differ- ences in DKA and HHS are summarized in Table 24-1. DIABETIC KETOACIDOSIS 䡵 ETIOLOGY DKA results from insulin deficiency with a relative or absolute increase in glucagon and may be caused by inadequate insulin administration, infection (pneumonia, urinary tract infection, gastroenteritis, sepsis), infarction (cerebral, coronary, mesenteric, peripheral), surgery, trauma,  Diabetic Ketoacidosis and Hyperosmolar Coma CHAPTER 24 119 TABLE 24-1 LABORATORY VALUES IN DIABETIC KETOACIDOSIS (DKA) AND HYPERGLYCEMIC HYPEROSMOLAR STATE (HHS) (REPRESENTATIVE RANGES AT PRESENTATION) DKA HHS a Glucose, mmol/L (mg/dL) 13.9–33.3 (250–600) 33.3–66.6 (600–1200)c Sodium, meq/L 125–135 135–145 Potassium,a meq/L Normal to ↑b Normal Magnesiuma Normalb Normal Chloridea Normal Normal Phosphatea Normal to ↓b Normal Creatinine, μmol/L (mg/dL) Slightly ↑ Moderately ↑ Osmolality (mOsm/mL) 300–320 330–380 Plasma ketonesa ++++ ± Serum bicarbonate,a meq/L 7.3 Arterial PCO2,a mmHg 20–30 Normal Anion gapa ↑ Normal to slightly ↑ [Na – (Cl + HCO3)], meq/L a Large changes occur during treatment of DKA. b Although plasma levels may be normal or high at presentation, total-body stores are usually depleted. c Large changes occur during treatment drugs (cocaine), or pregnancy. A common precipitating scenario is the pt with type 1 DM who erroneously stops administering insulin because of anorexia/lack of food intake caused by a minor illness, followed by lipolysis and progressive ketosis leading to DKA. 䡵 CLINICAL FEATURES The initial symptoms of DKA include anorexia, nausea, vomiting, poly- uria, and thirst. Abdominal pain, altered mental function, or frank coma may ensue. Classic signs of DKA include Kussmaul respirations and an acetone odor on the pt’s breath. Volume depletion can lead to dry mucous membranes, tachycardia, and hypotension. Fever and abdominal tender- ness may also be present. Laboratory evaluation reveals hyperglycemia, ketosis (β-hydroxybutyrate > acetoacetate), and metabolic acidosis (arterial pH 6.8–7.3) with an increased anion gap (Table 24-1). The fluid deficit is often 3–5 L and can be greater. Despite a total-body potassium deficit, the serum potassium at presentation may be normal or mildly high as a result of acidosis. Similarly, phosphate may be normal at presentation despite total body phosphate depletion. Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are common. Hyperamylasemia is usually of salivary origin but may suggest a diagnosis of pancreatitis. The measured serum 120 SECTION 2 Medical Emergencies sodium is reduced as a consequence of osmotic fluid shifts due to hyper- glycemia [1.6-meq reduction for each 5.6-mmol/L (100-mg/dL) rise in the serum glucose]. TREATMENT Diabetic Ketoacidosis The management of DKA is outlined in Table 24-2. TABLE 24-2 MANAGEMENT OF DIABETIC KETOACIDOSIS 1. Confirm diagnosis ( plasma glucose, positive serum ketones, metabolic acidosis). 2. Admit to hospital; intensive-care setting may be necessary for frequent monitoring or if pH 5.2 meq/L, do not supplement K+ until the potassium is corrected. 6. Assess pt: What precipitated the episode (noncompliance, infection, trauma, infarction, cocaine)? Initiate appropriate workup for precipitating event (cultures, chest x-ray, ECG). 7. Measure capillary glucose every 1–2 h; measure electrolytes (especially K+, bicarbonate, phosphate) and anion gap every 4 h for first 24 h. 8. Monitor blood pressure, pulse, respirations, mental status, fluid intake and output every 1–4 h. 9. Replace K+: 10 meq/h when plasma K+ 1 h after ingestion. Activated charcoal has comparable or greater efficacy, fewer contraindications and complications, and is less invasive than gastric lavage and is the preferred method of GI decontamination in most situations. Activated charcoal is prepared as a suspension in water, either alone or with a cathartic. It is given orally via a nippled bottle (for infants), or via a cup, straw, or small-bore nasogastric tube. The recommended dose is 1 g/kg body weight, using 8 mL of diluent per gram of charcoal if a premixed formulation is not available. Charcoal may inhibit absorption of other orally administered agents and is contraindicated in pts with corrosive ingestion. When indicated, gastric lavage is performed using a 28F orogastric tube in children and a 40F orogastric tube in adults. Saline or tap water may be used in adults or children. (Use saline in infants.) Place pt in Trendelenburg and left lateral decubitus position to minimize aspiration (occurs in 10% of pts). Repeated administration of fluid (5 mL/kg) followed by aspiration results in progressive removal of gastric content. Lavage is contraindicated in pts resisting the procedure, and with ingested corrosives and petroleum distillate hydrocarbons because of risk of aspiration-induced pneumonia and gastroesophageal perforation. Syrup of ipecac, once the most commonly used decontamination procedure, has no role in the hospital setting and is no longer recom- mended for the management of poisoning. 166 TABLE 32-3 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Stimulated Sympathetics (see also HPIM-18 Chap. 394) Sympathomimetics α1-Adrenergic Stimulation of central Physiologic stimulation Phentolamine, a nonselective α1-adrenergic agonists (deconges- and peripheral sympa- (HPIM-18 Table e50-2); receptor antagonist, for severe hypertension due tants): phenylephrine, thetic receptors directly reflex bradycardia can occur to α1-adrenergic agonists; propranolol, a non- phenylpropanolamine or indirectly (by pro- with selective α1 agonists; selective β blocker, for hypotension and tachy- β2-Adrenergic agonists moting the release or β agonists can cause hypo- cardia due to β2 agonists; labetalol, a β blocker (bronchodilators): alb- inhibiting the reuptake tension and hypokalemia. with α-blocking activity, or phentolamine with uterol, terbutaline of norepinephrine and esmolol, metoprolol, or other cardioselective sometimes dopamine) β blocker for hypertension with tachycardia due to Nonspecific adrenergic nonselective agents (β blockers, if used alone, can agonists: amphetamines, exacerbate hypertension and vasospasm due to cocaine, ephedrine unopposed a stimulation); benzodiazepines; propofol. Ergot alkaloids Ergotamine, methyser- Stimulation and inhibi- Physiologic stimulation Nitroprusside or nitroglycerine for severe vaso- gide, bromocriptine, tion of serotonergic and (HPIM-18 Table e50-2); spasm; prazosin (an α1 blocker), captopril, nife- pergolide α-adrenergic receptors; formication; vasospasm with dipine, and cyproheptadine (a serotonin receptor stimulation of dopamine limb (isolated or generalized), antagonist) for mild to moderate limb ischemia; receptors myocardial, and cerebral isch- dopamine receptor antagonists (antipsychotics) for emia progressing to gangrene hallucinations and movement disorders. or infarction; hypotension, bradycardia, and involuntary movements can also occur.  Methylxanthines Caffeine, theophylline Inhibition of adenosine Physiologic stimulation Propranolol, a nonselective β blocker, for tachy- synthesis and adenosine (HPIM-18 Table e50-2); cardia with hypotension; any β blocker for receptor antagonism; pronounced gastrointestinal supraventricular or ventricular tachycardia without stimulation of epine symptoms and β agonist hypotension; elimination enhanced by multiple- phrine and norepineph- effects (see above). Toxicity dose charcoal, hemoperfusion, and hemodialysis; rine release; inhibition occurs at lower drug levels indications for hemoperfusion or hemodialysis of phosphodiesterase in chronic poisoning than in include unstable vital signs, seizures, and a the- resulting in increased acute poisoning. ophylline level of 80–100 μg/mL after acute intracellular cyclic ade- overdose and 40–60 μg/mL with chronic nosine and guanosine exposure. monophosphate Monoamine oxidase Phenelzine, tranylcy- Inhibition of monoamine Delayed or slowly progres- Short-acting agents (e.g., nitroprusside, esmolol) inhibitors promine, selegiline oxidase resulting in sive physiologic stimulation for severe hypertension and tachycardia; direct- impaired metabolism of (HPIM-18 Table e50-2); acting sympathomimetics (e.g., norepinephrine, endogenous catechol- terminal hypotension and epinephrine) for hypotension and bradycardia. amines and exogenous bradycardia in severe cases. sympathomimetic agents (continued ) 167 168 TABLE 32-3 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Anticholinergics Antihistamines Diphenhydramine, Inhibition of central and Physiologic stimulation Physostigmine, an acetylcholinesterase inhibi- doxylamine, pyrilamine postganglionic para- (HPIM-18 Table e50-2); dry tor (see below) for delirium, hallucinations, and Antiparkinsonian Amantadine, trihexy- sympathetic muscarinic skin and mucous mem- neuromuscular hyperactivity. Contraindications agents phenidyl cholinergic receptors. branes, decreased bowel include nonanticholinergic cardiovascular toxicity At high doses, amanta- sounds, flushing, and uri- (e.g., cardiac conduction abnormalities, hypoten- Antipsychotics Chlorpromazine, olan- dine, diphenhydramine, nary retention; myoclonus sion, and ventricular arrhythmias). zapine, quetiapine, orphenadrine, pheno- and picking activity. Central thioridazine thiazines, and tricyclic effects may occur without Antispasmotics Clidinium, dicyclomine antidepressants have significant autonomic Belladonna alkaloids Atropine, hyoscyamine, additional nonanticho- dysfunction. scopolamine linergic activity (see below). Cyclic Amitriptyline, doxepin, antidepressants imipramine Muscle relaxants Cyclobenzaprine, orphenadrine Mushrooms and Amanita muscaria plants and A. pantherina, henbane, jimson weed, nightshade  Depressed Sympatholytics α2-Adrenergic Clonidine, guanabenz, Stimulation of Physiologic depression Dopamine and norepinephrine for hypotension. agonists tetrahydrozoline and α2-adrenergic recep- (HPIM-18 Table e50-2), Atropine for symptomatic bradycardia. Naloxone other imidazoline tors leading to inhibition miosis. Transient initial for CNS depression (inconsistently effective). decongestants, of CNS sympathetic hypertension may be seen. tizanidine and other outflow; activity at non- imidazoline muscle adrenergic imidazoline relaxants binding sites also con- tributes to CNS effects. Antipsychotics Chlorpromazine, Inhibition of α-adrenergic, Physiologic depression Sodium bicarbonate and lidocaine for ventricular clozapine, haloperidol, dopaminergic, (HPIM-18 Table e50-2), tachydysrhythmias associated with QRS prolonga- risperidone, histaminergic, muscarinic, miosis, anticholinergic effects tion. Magnesium, isoproterenol, and overdrive thioridazine and serotonergic (see above), extrapyramidal pacing for torsades de pointes. Avoid class IA, IC, receptors. Some agents reactions (see below), and III antiarrhythmics. IV lipid emulsion therapy also inhibit sodium, tachycardia. Cardiac may be beneficial in some cases. potassium, and calcium conduction delays (increased channels. PR, QRS, JT, and QT intervals) with ventricular tachydys- rhythmias, including torsades des pointes, can sometimes develop. (continued ) 169 170 TABLE 32-3 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Depressed β-Adrenergic Cardioselective (β1) Inhibition of Physiologic depression Glucagon and calcium for hypotension and blockers blockers: atenolol, β-adrenergic receptors (HPIM-18 Table e50-2), symptomatic bradycardia. Atropine, isoproter- esmolol, metoprolol (class II antiarrhythmic atrioventricular block, hypo- enol, amrinone, dopamine, dobutamine, epi- Nonselective (β1 and effect). Some agents glycemia, hyperkalemia, nephrine, and norepinephrine may sometimes β2) blockers: nadolol, have activity at addi- seizures. Partial agonists be effective. High-dose insulin (with glucose propranolol, timolol tional receptors or have can cause hypertension and and potassium to maintain euglycemia and nor- membrane effects (see tachycardia. Sotalol can mokalemia), electrical pacing, and mechanical Partial β agonists: below). cause increased QT interval cardiovascular support for refractory cases. acebutolol, pindolol and ventricular tachydys- α1 Antagonists: carve- rhythmias. Onset may be dilol, labetalol delayed after sotalol and Membrane-active sustained-release formula- agents: acebutolol, tion overdose. propranolol, sotalol Calcium channel Diltiazem, nifedipine Inhibition of slow Physiologic depression Calcium and glucagon for hypotension and blockers and other dihydro- (type L) cardiovascular (HPIM-18 Table e50-2), symptomatic bradycardia. Dopamine, epinephrine, pyridine derivatives, calcium channels atrioventricular block, organ norepinephrine, atropine, and isoproterenol are verapamil (class IV antiarrhythmic ischemia and infarction, less often effective but can be used adjunctively. effect). hyperglycemia, seizures. Amrinone, high-dose insulin (with glucose and  Hypotension is usually potassium to maintain euglycemia and normo- due to decreased vascular kalemia), IV lipid emulsion therapy, electrical resistance rather than to pacing, and mechanical cardiovascular support decreased cardiac output. for refractory cases. Onset may be delayed for ≥12 h after overdose of sus- tained-release formulations. + Cardiac glycosides Digoxin, endogenous Inhibition of cardiac Na , Physiologic depression Digoxin-specific antibody fragments for hemo- cardioactive steroids, K+-ATPase membrane (HPIM-18 Table e50-2); dynamically compromising dysrhythmias, foxglove and other pump. gastrointestinal, psychiat- Mobitz II or third-degree atrioventricular block, plants, toad skin ric, and visual symptoms; hyperkalemia (>5.5 meq/L; in acute poisoning secretions atrioventricular block with or only). Temporizing measures include atropine, (Bufonidae sp.) without concomitant supra- dopamine, epinephrine, phenytoin, and external ventricular tachyarrhythmia; cardiac pacing for bradydysrhythmias and mag- ventricular tachyarrhythmias. nesium, lidocaine, or phenytoin for ventricular Hyperkalemia in acute poison- tachydysrhythmias. Internal cardiac pacing and ing. Toxicity occurs at lower cardioversion can increase ventricular irritability drug levels in chronic poison- and should be reserved for refractory cases. ing than in acute poisoning. (continued ) 171 172 TABLE 32-3 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Depressed Cyclic antidepres- Amitriptyline, doxepin, Inhibition of α-adrenergic Physiologic depression Hypertonic sodium bicarbonate (or hypertonic sants imipramine dopaminergic, GABA- (HPIM-18 Table e50-2), saline) and lidocaine for ventricular tachydys- ergic, histaminergic, seizures, tachycardia, cardiac rhythmias associated with QRS prolongation. muscarinic, and seroto- conduction delays (increased Use of phenytoin is controversial. Avoid class IA, nergic receptors; inhibi- PR, QRS, JT, and QT inter- IC, and III antiarrhythmics. tion of sodium channels vals; terminal QRS right axis (see membrane-active deviation) with aberrancy agents); inhibition of nor- and ventricular tachydys- epinephrine and serotonin rhythmias. Anticholinergic reuptake. toxidrome (see above). Cholinergics Acetylcholinesterase Carbamate insecti- Inhibition of acetylcho- Physiologic depression Atropine for muscarinic signs and symptoms. inhibitors cides (aldicarb, car- linesterase leading to (HPIM-18 Table e50-2). Pralidoxime (2-PAM), a cholinesterase reactivator, baryl, propoxur) and increased synaptic ace- Muscarinic signs and symp- for nicotinic signs and symptoms due to medicinals (neostig- tylcholine at muscarinic toms: seizures, excessive organophosphates, nerve gases, or an unknown mine, physostigmine, and nicotinic cholinergic secretions (lacrimation, anticholinesterase. tacrine); nerve gases receptor sites salivation, bronchorrhea and (sarin, soman, tabun, wheezing, diaphoresis), and VX) organophosphate increased bowel and bladder insecticides (diazinon, activity with nausea, vomit- chlorpyrifos-ethyl, ing, diarrhea, abdominal malathion) cramps, and incontinence  Muscarinic agonists Bethanecol, mush- Stimulation of CNS and of feces and urine. Nicotinic rooms (Boletus, postganglionic para- signs and symptoms: Clitocybe, Inocybe sympathetic cholinergic hypertension, tachycardia, spp.), pilocarpine (muscarinic) receptors muscle cramps, fas- ciculations, weakness, and Nicotinic agonists Lobeline, nicotine Stimulation of pregan- paralysis. Death is usually (tobacco) glionic sympathetic and due to respiratory failure. parasympathetic and Cholinesterase activity in striated muscle (neu- plasma and red cells 30%, symptomatic thetics, nitrates, to ferric (Fe3+) state pre- logic stimulation and subse- hypoxia, or ischemia (contraindicated in G6PD nitrites, nitrogen vents oxygen binding, quent depression (HPIM-18 deficiency). Exchange transfusion and hyperbaric oxides, nitro- and transport, and tissue Table e50-2), gray-brown oxygen for severe or refractory cases. nitroso hydrocarbons, uptake (methemoglo- cyanosis unresponsive to phenazopyridine, pri- binemia shifts oxygen oxygen at methemoglobin maquine-type antima- dissociation curve to the fractions >15–20%, head- larials, sulfonamides. left). Oxidation of hemo- ache, lactic acidosis (at globin protein causes methemoglobin fractions hemoglobin precipitation >45%), normal PO2 and and hemolytic anemia calculated oxygen satura- (manifest as Heinz bod- tion but decreased oxygen ies and “bite cells” on saturation and increased peripheral blood smear). methemoglobin fraction by co-oximetry (oxygen saturation by pulse oximetry may be falsely increased or decreased but is less than normal and less than the calculated value). (continued ) 177 178 TABLE 32-3 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Discordant AGMA inducers Ethylene glycol Ethylene glycol causes Initial ethanol-like intoxi-Gastric aspiration for recent ingestions. Sodium CNS depression and cation, nausea, vomiting, bicarbonate to correct acidemia. Thiamine, folinic increased serum increased osmolar gap, acid, magnesium, and high-dose pyridoxine to osmolality. Metabolites facilitate metabolism. Ethanol or fomepizole for calcium oxalate crystalluria. (primarily glycolic acid) Delayed AGMA, back pain, AGMA, crystalluria or renal dysfunction, ethylene cause AGMA, CNS renal failure. Coma, sei- glycol level >3 mmol/L (>20 mg/dL), and for depression, and renal zures, hypotension, ARDS in ethanol-like intoxication or increased osmolal failure. Precipitation of severe cases. gap if level not readily obtainable. Hemodialysis oxalic acid metabolite for persistent AGMA, lack of clinical improvement, as calcium salt in tis- and renal dysfunction. Hemodialysis also useful sues and urine results for enhancing ethylene glycol elimination and in hypocalcemia, tissue shortening duration of treatment when ethylene edema, and crystalluria. glycol level >8 mmol/L (>50 mg/dL). AGMA inducers Iron Hydration of ferric (Fe3+) Initial nausea, vomiting, Whole-bowel irrigation for large ingestions. ion generates H+. Non- abdominal pain, diarrhea. Endoscopy and gastrostomy if clinical toxicity transferrin-bound iron AGMA, cardiovascular and and large number of tablets still visible on x-ray. catalyzes formation CNS depression, hepatitis, IV hydration. Sodium bicarbonate for acidemia. of free radicals that coagulopathy, and seizures IV deferoxamine for systemic toxicity, iron level cause mitochondrial in severe cases. Radiopaque >90 μmol/L (>500 g/dL). injury, lipid peroxidation, iron tablets may be seen on increased capillary per- abdominal x-ray. meability, vasodilation, and organ toxicity.  Methanol Methanol causes Initial ethanol-like intoxi- Gastric aspiration for recent ingestions. Sodium ethanol-like CNS cation, nausea, vomiting, bicarbonate to correct acidemia. High-dose depression and increased osmolar gap. folinic acid or folate to facilitate metabolism. increased serum Delayed AGMA, visual Ethanol or fomepizole for AGMA, visual symp- osmolality. Formic acid (clouding, spots, blindness) toms, methanol level >6 mmol/L (>20 mg/dL), metabolite causes AGMA and retinal (edema, hyper- and for ethanol-like intoxication or increased and retinal toxicity. emia) abnormalities. Coma, osmolal gap if level not readily obtainable. seizures, cardiovascular Hemodialysis for persistent AGMA, lack of depression in severe cases. clinical improvement, and renal dysfunction. Possible pancreatitis. Hemodialysis also useful for enhancing methanol elimination and shortening duration of treatment when methanol level >15 mmol/L (>50 mg/dL). Salicylate Increased sensitivity of Initial nausea, vomiting, IV hydration and supplemental glucose. Sodium CNS respiratory center hyperventilation, alkalemia, bicarbonate to correct acidemia. Alkaline diure- to changes in PO2 and alkaluria. Subsequent alka- sis for systemic toxicity. Hemodialysis for coma, Pco2 stimulates respira- lemia with both respiratory cerebral edema, seizures, pulmonary edema, tion. Uncoupling of oxi- alkalosis and AGMA, and renal failure, progressive acid-base disturbances dative phosphorylation, paradoxical aciduria. Late or clinical toxicity, salicylate level >7 mmol/L inhibition of Krebs cycle acidemia with CNS and (>100 mg/dL) following acute overdose. enzymes, and stimula- respiratory depression. tion of carbohydrate Cerebral and pulmonary and lipid metabolism edema in severe cases. generate unmeasured Hypoglycemia, hypocal- endogenous anions and cemia, hypokalemia, and cause AGMA. seizures can occur. 179 (continued ) 180 TABLE 32-3 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Discordant CNS syndromes Extrapyramidal Antipsychotics (see Decreased CNS dopa- Akathisia, dystonia, Oral or parenteral anticholinergic agent such as reactions above), some cyclic minergic activity with parkinsonism benztropine or diphenhydramine. antidepressants and relative excess of antihistamines. cholinergic activity. Isoniazid Interference with acti- Nausea, vomiting, agitation, High-dose IV pyridoxine (vitamin B6) for agitation, vation and supply of confusion; coma, respiratory confusion, coma, and seizures. Diazepam or pyridoxal-5-phosphate, depression, seizures, lactic barbiturates for seizures. a cofactor for glutamic and ketoacidosis in severe acid decarboxylase, cases. which converts glutamic acid to GABA, results in decreased levels of this inhibitory CNS neu- rotransmitter; complex- ation with and depletion of pyridoxine itself; inhibition of nicotine- adenine dinucleotide dependent lactate and  hydroxybutyrate dehy- drogenases resulting in substrate accumulation. Lithium Interference with cell Nausea, vomiting, diarrhea, Whole-bowel irrigation for large inges- membrane ion transport, ataxia, choreoathetosis, tions. IV hydration. Hemodialysis for coma, adenylate cyclase and encephalopathy, hyper- seizures, severe, progressive, or persistent Na+, K+-ATPase activity, reflexia, myoclonus, encephalopathy or neuromuscular dysfunction, and neurotransmitter nystagmus, nephrogenic peak lithium level >8 meq/L following acute release. diabetes insipidus, falsely overdose. elevated serum chloride with low anion gap, tachy- cardia. Coma, seizures, arrhythmias, hyperthermia, and prolonged or permanent encephalopathy and move- ment disorders in severe cases. Delayed onset after acute overdose, particularly with delayed-release for- mations. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. (continued ) 181 182 TABLE 32-3 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Discordant Serotonin syndrome Amphetamines, Promotion of serotonin Altered mental status (agi- Serotonin receptor antagonists such as cyprohep- cocaine, dextrometho- release, inhibition of tation, confusion, mutism, tadine, discontinue offending agent(s). rphan, meperidine, serotonin reuptake, or coma, seizures), neuromus- MAO inhibitors, selec- direct stimulation of cular hyperactivity (hyper- tive serotonin (5HT) CNS and peripheral reflexia, myoclonus, rigidity, reuptake inhibitors, tri- serotonin receptors tremors), and autonomic cyclic antidepressants, (primarily 5HT-1a and dysfunction (abdominal pain, tramadol, triptans, 5HT-2), alone or in diarrhea, diaphoresis, fever, tryptophan. combination. flushing, labile hyperten- sion, mydriasis, tearing, salivation, tachycardia). Complications include hyperthermia, lactic acido- sis, rhabdomyolysis, and multisystem organ failure. Membrane-active Amantadine, antiar- Blockade of fast sodium QRS and JT prolongation (or Hypertonic sodium bicarbonate (or hypertonic agents rhythmics (class I and membrane channels both) with hypotension, ven- saline) for cardiac conduction delays and mono- III agents; some β prolongs phase 0 (depo- tricular tachyarrhythmias, morphic ventricular tachycardia. Lidocaine blockers), antipsychot- larization) of the cardiac CNS depression, seizures. for monomorphic ventricular tachycardia ics (see above), anti- action potential, which Anti-cholinergic effects with (except when due to class Ib antiarrhythmics). histamines (particularly prolongs the QRS duration amantadine, antihistamines, Magnesium, isoproterenol, and overdrive pacing  diphenhydramine), and promotes reentrant carbamazepine, disopyramide, for polymorphic ventricular tachycardia. carbamazepine, local (monomorphic) ventricu- antipsychotics, and cyclic Physostigmine for anticholinergic effects (see anesthetics (including lar tachycardia. Class Ia, antidepressants (see above). above). Naloxone for opioid effects (see HPIM- cocaine), opioids Ic, and III antiarrhythmics Opioid effects with meperi- 18 Chap. 393). Extracorporeal removal for some (meperidine, propoxy- also block potassium dine and propoxy phene agents (see text). phene), orphenadrine, channels during phases (see HPIM-18 Chap. 393). quinoline antimalarials 2 and 3 (repolarization) Cinchonism (hearing loss, (chloroquine, hydroxy- of the action potential, tinnitus, nausea, vomiting, chloroquine, quinine), prolonging the JT inter- vertigo, ataxia, headache, cyclic antidepressants val and promoting early flushing, diaphoresis) and (see above). after-depolarizations and blindness with quinoline polymorphic (torsades des antimalarials. pointes) ventricular tachy- cardia. Similar effects on neuronal membrane channels cause CNS dysfunction. Some agents also block α-adrenergic and cholinergic receptors or have opioid effects (see above and HPIM-18 Chap. 393). Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; ATPase, adenosine triphosphatase, CNS, central nervous system; 5-HT, 5-hydroxytrypta- mine (serotonin); GABA, γ-aminobutyric acid; G6PD, glucose-6-phosphate dehydrogenase; MAO, monoamine oxidase; SIADH, syndrome of inappropriate antidiuretic hormone secretion, VX, extremely toxic persistent nerve agent (no common chemical name). 183 184 TABLE 32-4 HEAVY METALS Main Sources Metabolism Toxicity Diagnosis Treatment Arsenic Smelting and micro- Organic arsenic (arseno- Acute arsenic poisoning Nausea, vomiting, diarrhea, If acute ingestion, gastric electronics industries; betaine, arsenocholine) results in necrosis of intes- abdominal pain, delirium, lavage, activated charcoal wood preservatives, is ingested in seafood tinal mucosa with hemor- coma, seizures; garlicky odor with a cathartic. Supportive pesticides, herbi- and fish, but is nontoxic; rhagic gastroenteritis, fluid on breath; hyperkeratosis, care in ICU. cides, fungicides; inorganic arsenic is read- loss, hypotension, delayed hyperpigmentation, exfoliative Dimercaprol 3–5 mg/kg IM contaminant of deep- ily absorbed (lung and GI); cardiomyopathy, acute tubu- dermatitis, and Mees’ lines q4h × 2 days; q6h × 1 day, water wells; folk sequesters in liver, spleen, lar necrosis, and hemolysis. (transverse white striae of the then q12h × 10 days; alter- remedies; and coal; kidneys, lungs, and GI tract; Chronic arsenic exposure fingernails); sensory and motor native: oral succimer. incineration of these residues persist in skin, hair, causes diabetes, vasospasm, polyneuritis, distal weakness. products and nails; biomethylation peripheral vascular insuffi- Radiopaque sign on abdominal results in detoxification, but ciency and gangrene, periph- x-ray; ECG–QRS broadening, this process saturates. eral neuropathy, and cancer QT prolongation, ST depression, of skin, lung, liver (angiosar- T-wave flattening; 24-h urinary coma), bladder, and kidney. arsenic >67 μmol/d or 50 μg/d; (no seafood for 24 h); if recent Lethal dose: 120–200 mg exposure, serum arsenic (adults); 2 mg/kg >0.9 μmol/L (7 μg/dL). High (children). arsenic in hair or nails.  Cadmium Metal-plating, pig- Absorbed through inges- Acute cadmium inhalation With inhalation: pleuritic chest There is no effective treat- ment, smelting, tion or inhalation; bound by causes pneumonitis after pain, dyspnea, cyanosis, fever, ment for cadmium poison- battery, and plastics metallothionein, filtered at 4–24 h; acute ingestion tachycardia, nausea, noncardio- ing (chelation not useful; industries; tobacco; the glomerulus, but reab- causes gastroenteritis. genic pulmonary edema. With dimercaprol can exacerbate incineration of these sorbed by proximal tubules Chronic exposure causes ingestion: nausea, vomiting, nephrotoxicity). products; ingestion (thus, poorly excreted). anosmia, yellowing of cramps, diarrhea. Bone pain, frac- Avoidance of further expo- of food that con- Biologic half-life: 10–30 y. teeth, emphysema, minor tures with osteomalacia. If recent sure, supportive therapy, centrates cadmium Binds cellular sulfhydryl LFT elevations, microcytic exposure, serum cadmium >500 vitamin D for osteomalacia. (grains, cereals). groups, competes with zinc, hypochromic anemia unre- nmol/L (5 μg/dL). Urinary cadmium calcium for binding sites. sponsive to iron therapy, >100 nmol/L (10 μg/g creatinine) Concentrates in liver and proteinuria, increased urinary and/or urinary β2-microglobulin kidneys. β2-microglobulin, calciuria, >750 μg/g creatinine (but urinary leading to chronic renal β2-microglobulin also increased failure, osteomalacia, and in other renal diseases such as fractures. pyelonephritis). Lead Manufacturing of Absorbed through inges- Acute exposure with blood Abdominal pain, irritability, Identification and correction auto batteries, lead tion or inhalation; organic lead levels (BPb) of lethargy, anorexia, anemia, of exposure sources is critical. crystal, ceramics, lead (e.g., tetraethyl lead) >60–80 μg/dL can cause Fanconi’s syndrome, pyuria, In some U.S. states, screening fishing weights, etc.; absorbed dermally. In blood, impaired neurotransmis- azotemia in children with and reporting to local health demolition or sand- 95–99% sequestered in sion and neuronal cell death blood lead level (BPb) boards of children with BPb ing of lead-painted RBCs—thus, must measure (with central and peripheral >80 μg/dL; may also see >10 μg/dL and workers with houses, bridges; lead in whole blood (not nervous system effects); epiphyseal plate “lead lines” on BPb >40 μg/dL is required. In stained glass making, serum). Distributed widely in Aimpaired hematopoiesis and long bone x-rays. Convulsions, the highly exposed individual plumbing, soldering; soft tissue, with half-life renal tubular dysfunction. coma at BPb >120 μg/dL. with symptoms, chelation 185