I-1. The answer is D. (Chap. 1) Evidence-based medicine (EBM) is an important cornerstone to the effective and efficient practice of internal medicine. EBM refers to the concept that clinical decisions should be supported by data with the strongest evidence gleaned from randomized controlled clinical trials. Clearly, in some situations, it is impossible or unethical to perform randomized controlled trials, and data from observational studies such as cohort or case-control studies supply important information regarding disease associations. Professional organizations and government agencies use EBM to develop clinical practice guidelines. These guidelines combine the best available evidence from clinical and observational studies with expert opinion to develop clinical-decision support tools (option C). The purpose of clinical guidelines is to provide a framework for diagnosis and treatment of a specific clinical problem in a cost-effective and efficient manner. When multiple clinical trials have been published, accumulated data can be summarized in a systematic review (option A). In a systematic review, the researchers carefully scrutinize the methods of published trials for inclusion into the review and use statistical analysis to attempt to provide additional strength to clinical findings. A new branch of research called comparative effectiveness research (option B) attempts to compare different approaches to treating disease to determine effectiveness from both a clinical and cost-effectiveness standpoint. A variety of methods can be used, and systematic reviews are an important tool in comparative effectiveness research. The weakest type of evidence is anecdotal evidence (option E), which is one individual’s clinical experience in treating a disease and can be biased by prior experiences.
I-2. The answer is D. (Chap. 1) Before performing any procedure, a physician has the ethical duty to discuss the details of the procedure with the patient and ensuring that he or she understands before proceeding. This process includes ensuring that the patient has the mental capacity to provide consent, outlining the risks and benefits of the procedure, and discussing alternatives and potential consequences of these alternatives. Informed consent does not require that a patient outline his or her wishes if he or she becomes incompetent to make decisions. This is accomplished in an advanced directive, which can outline the goals of care and also appoint someone to make medical decisions.
I-3. The answer is A. (Chap. 2) Disability-adjusted life years (DALYs) is the standard measure for determining global burden of disease by the World Health Organization. This measure takes into account both absolute years of life lost because of disease (premature death) as well as productive years lost because of disability. DALYs is believed to more accurately reflect the true effects of disease within a population because individuals who become disabled cannot contribute fully to society. Life expectancy, years of life lost because of disease, standardized mortality ratios, and infant mortality do provide important information about the general health of a population but do not capture the true burden of disease.
I-4. The answer is E. (Chap. 2) The causes of morbidity and burden of disease in a population differ from the absolute causes of mortality in a population. Unipolar depressive disorder accounts for 10.0 million disability-adjusted life years lost (DALYs) in high-income countries. Depression is quite common in the general population of developed countries. However, the death rate from depression is low and is mainly reflected in suicides. Thus, depression creates disability and lost productivity without a significant impact on years of life lost. Depression often presents at young ages and persists or recurs throughout a lifetime, leading to significant morbidity over time. After unipolar depressive disorder, the leading causes of DALYs lost in high-income countries are ischemic heart disease, cerebrovascular disease, Alzheimer’s disease and other dementia, and alcohol use disorders. However, worldwide, the leading cause of DALYs is lower respiratory infections caused by the high burden of disease in low-income countries with an estimated 76.9 million DALYs lost because of lower respiratory infections in low-income countries. Additionally, in low-income countries, the top five causes of DALYs are related to infectious diseases (diarrheal diseases, HIV, malaria) and prematurity.
I-5. The answer is D. (Chap. 2) Although ischemic heart disease is the leading cause of death worldwide, low-income countries have a disproportionate number of deaths caused by lower respiratory tract infections. This primarily reflects the large numbers of individuals in low-income countries who die of tuberculosis and other infectious pneumonias. Ischemic heart disease is the second leading cause of death in low-income countries.
I-6. The answer is B. (Chap. 2) Global health experts have developed priorities for improving global health in conjunction with the World Health Organization (WHO). Many of these efforts are focused on the prevention, early recognition, and treatment of infectious diseases in developing countries and the developing world. Among infectious causes of disease, malaria ranks as the third most deadly. In 2001, the WHO Roll Back Malaria campaign was endorsed by heads of state in Africa in an effort to develop a coordinated plan for malaria prevention and treatment. A major goal of the Roll Back Malaria campaign was to prevent gains in disease prevention in one country from being lost because of lack of a coordinated effort in neighboring countries. This effort involves a multifaceted approach that includes vector control, prevention of transmission, and early recognition and treatment. Insecticide-treated bed nets are a simple and cost-effective method of reducing malaria transmission with a 50% decreased incidence of malaria in individuals who sleep under these bed nets. Indoor residual spraying is also an important factor in decreasing malaria transmission as outdoor vector control alone is ineffective in controlling transmission. It has been found that 80% of structures in a community must be treated to decrease disease transmission. Another important part of decreasing disease transmission is to give at least two doses of effective antimalarial drugs during pregnancy to decrease placental transmission of disease. If disease is unable to be prevented, it is important to recognize and treat the disease early. Chloroquine resistance has emerged in many areas around the world, particularly in sub-Saharan Africa, the Middle East, India, Southeast Asia, and parts of South America. Given the widespread chloroquine resistance, the WHO now recommends only artemisinin-based combination therapy for falciparum malaria infection.
I-7. The answer is A. (Chap. 3) Bayes’ theorem is a statistical model based on conditional probabilities that is useful in medical decision making. The three components of Bayes’ theorem as it relates to medical decision making are the pretest probability of disease, the sensitivity of the test, and the specificity of the test. These factors are combined into the following formula:
In most occasions, the pretest probability is an estimate based on the prevalence of disease in the population and the clinical situation. The false-positive rate is 1 – specificity. In this clinical scenario, the pretest probability of disease was estimated at 10%, and the treadmill ECG stress test has an average sensitivity of 66% and a specificity of 84%. Based on the formula above, the posttest probability would be low at only 31%.
I-8 and I-9. The answers are C and C, respectively. (Chap. 3) In evaluating the usefulness of a test, it is imperative to understand the clinical implications of the sensitivity and specificity of that test. Simply, the sensitivity is the proportion of people with disease that are correctly identified by the test—the true-positive rate. Alternatively, the specificity can be viewed as the true-negative rate and is the proportion of individuals without disease who would have a negative test result. The perfect test would have a sensitivity of 100% and a specificity of 100%, but this is unachievable in clinical practice. Sensitivity and specificity are inherent properties of the test and are not affected by the disease prevalence. However, by obtaining information about the prevalence of the disease in the population, one can generate a two-by-two table, as shown below. This table is used to generate the total number of patients in each group of the population. The sensitivity of the test is . The specificity is . In this case, the disease prevalence is 10%. In a population of 1000 individuals, 100 would truly have latent tuberculosis, and the table is filled in as follows:
I-10. The answer is D. (Chap. 3) A receiver operating characteristic (ROC) curve plots sensitivity (or true-positive rate) on the y-axis and 1 − specificity (or false-positive rate) on the x-axis. Each point on the curve represents a cutoff point of sensitivity and 1 − specificity, and these cutoff points are used to select the threshold value for a diagnostic test that yields the best trade-off between true-positive and false-positive tests. The area under the curve can be used as a quantitative measure of the information content of a test. Values range from 0.5 (a 45-degree line) representing no diagnostic information to 1.0 for an ideal test. In the medical literature, ROC curves are often used to compare alternative diagnostic tests, but the interpretation of a specific test and ROC curve is not as simple in clinical practice. One criticism of the ROC curve is that it only evaluates only one test parameter with exclusion of other potentially relevant clinical data. Also, one must consider the underlying population in which the ROC curve was validated and how general-izable this is the entire population with disease.
I-11. The answer is C. (Chap. 3) The positive and negative predictive values of a test are strongly influenced by the prevalence of disease in a population. The positive predictive value is calculated as the number of true-positive test results divided by the number of all positive test values. Alternatively, the negative predictive value is calculated as the number of true-negative test results divided by the number of all negative test results. For example, in a population of 1000 with a disease prevalence of 5%, a specific test has a sensitivity of 95% and a specificity of 80%. In this setting, the two-by-two table would be completed as follows:
Thus, the positive predictive value of the test would be , and the negative predictive value would be .
The sensitivity and specificity of the test, however, are properties of the test and are not affected by disease prevalence. Positive and negative likelihood ratios are calculated from the sensitivity and specificity and are defined as the ratio of the probability of a given test result (positive or negative) in an individual with disease to the probability of that test result in a patient without disease. For a positive likelihood ratio, a higher ratio indicates that a test performs better at identifying a patient with disease. For the negative likelihood ratio, a smaller ratio performs better at ruling out disease. The number needed to treat is a measure of the effectiveness of an intervention. It is simply calculated as 1 divided by the absolute reduction in risk related to the intervention.
I-12 and I-13. The answers are B and C, respectively. (Chap. 3) The goal of a meta-analysis is to summarize the treatment benefit conferred by an intervention by combining and summarizing data available from multiple clinical trials. Meta-analyses often focus on summary measures of relative risk reductions expressed by the relative risk or odds ratios; however, clinicians should also understand the absolute risk reduction (ARR) related to an intervention. This is the difference in mortality (or another endpoint) between the treatment and the placebo arms. In this case, the absolute risk reduction is . From this number, one can calculate the number needed to treat (NNT), which is 1/ARR. The NNT is the number of patients who must receive the intervention to prevent one death (or another outcome assessed in the study). In this case, the NNT is patients.
I-14. The answer is E. (Chap. 4) Within a population, it is certainly impractical to perform all possible screening procedures for the variety of diseases that exist in that population. This approach would be overwhelming to the medical community and would not be cost effective. Indeed, the amount of monetary and psychological stress that would occur from pursuing false-positive test results would add an additional burden on the population. When determining which procedures should be considered as screening tests, a variety of endpoints can be used. One of these is to determine how many individuals would need to be screened in the population to prevent or alter the outcome in one individual with disease. Although this can be statistically determined, there are no recommendations for what the threshold value should be and may change based on the invasiveness or cost of the test and the potential outcome avoided. Additionally, one should consider both the absolute and relative impact of screening on disease outcome. Another measure used in considering the utility of screening tests is the cost per life year saved. Most measures are considered cost effective if they cost less than $30,000 to $50,000 per year of life saved. This measure is also sometimes adjusted for the quality of life as well and presented as quality-adjusted life years saved. A final measure that is used in determining the effectiveness of a screening test is the effect of the screening test on life expectancy of the entire population. When applying the test across the entire population, this number is surprisingly small, and a goal of about 1 month is desirable for a population-based screening strategy.
I-15. The answer is C. (Chap. 4) Evaluating the utility of screening tests requires also understanding the potential biases that can exist when interpreting data from screening trials. One of the most difficult to ascertain but potentially the most confounding is lead time bias. Simply, lead time bias refers to the bias that occurs when one finds a tumor at an earlier clinical stage than would be expected from usual care but ultimately does not lead to an overall change in the outcome. In this case, the apparent difference in time to diagnosis and death likely represents lead time bias. To fully determine this, one would need to know outcome data for the entire trial. In the case of lead time bias, one would find that although the number of tumors diagnosed at early stages was increased, the overall mortality would be the same. The recently published Lung Cancer Screening Trial (N Engl J Med, August 4, 2011) showed that low-dose helical CT scan in high-risk patients was associated 20% reduction in risk of dying from lung cancer compared with chest x-ray. Although this was the first clinical trial to show a radiologic intervention reducing mortality from lung cancer, how these results will translate into clinical practice and cost effectiveness is still uncertain.
I-16. The answer is E. (Chap. 4) The U.S. Preventive Services Task Force (USPSTF) is an independent panel of experts selected by the federal government to provide evidence-based guidelines for prevention and screening for disease. The panel typically consists of primary care providers from internal medicine, family medicine, pediatrics, and obstetrics and gynecology. The USPSTF provides guidelines on a variety of measures, including blood pressure, height, weight, cholesterol, Pap smears, mammography, colorectal cancer screening, and adult immunizations. However, the most recent review of the evidence by the USPSTF concluded that there was insufficient evidence to recommend screening for thyroid disease in adults. Notably, the USPSTF also recommends against screening for prostate cancer in men older than 75 years and states that there is insufficient evidence for screening among younger men.
I-17. The answer is B. (Chap. 4) Predicted increases in life expectancy are average numbers that apply to populations, not individuals. Because we often do not understand the true nature of risk of disease, screening and lifestyle interventions usually benefit a small proportion of the total population. For screening tests, false-positive test results may also increase the risk of diagnostic tests. Although Pap smears increase life expectancy overall by only 2–3 months, for an individual at risk of cervical cancer, Pap smear screening may add many years to life. The average life expectancy increases resulting from mammography (1 month), PSA (2 weeks), and exercise (1–2 years) are less than from quitting smoking (3–5 years).
I-18. The answer is B. (Chaps. 4 and 235) Current guidelines from the National Cholesterol Education Project Adult Treatment Panel III recommend screening in all adults older than 20 years old. The testing should include fasting total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. The screening should be repeated every 5 years. All patients with type 1 diabetes should have lipids followed closely to decrease cardiovascular risk by combining the results of lipid screening with other risk factors to determine risk category and intensity of recommended treatment.
I-19. The answer is B. (Chap. 5) Bioavailability is the amount of the drug that is available to the systemic circulation when administered by routes other than the intravenous route. In this setting, bioavailability may be much less than 100%. The primary factors affecting bioavailability are the amount of drug that is absorbed and metabolism of the drug before entering the systemic circulation (the first-pass effect). Oral itraconazole is the recommended treatment for mild blastomycosis, but a problem with use of this drug is its bioavailability, which is estimated at about 55%. Although oral itraconazole does not experience a significant first-pass effect, its absorption from the stomach can be quite variable under different conditions. A first important consideration is the drug preparation. Whereas the liquid formulation should be taken on an empty stomach, the capsule should be taken after a meal. Furthermore, having an acid pH improves bioavailability, and use of gastric acid suppressors such as H2 blockers or proton pump inhibitors should be avoided with itraconazole use. When acid suppressors cannot be withheld, it is recommended to coadminister itraconazole with a cola beverage, which has been shown to enhance absorption in some clinical trials. Oral contraceptive pills will not affect the bioavailability of itraconazole; however, azole antifungals (including itraconazole) inhibit CYP450 3A4 and may increase the serum levels of estrogens and progestins.
I-20. The answer is D. (Chap. 5) Aminoglycoside antibiotics (tobramycin, gentamicin, amikacin) are active against Pseudomonas aeruginosa and are recommended for treatment of exacerbations of cystic fibrosis in combination with a beta-lactam antibiotic. The volume of distribution is increased in cystic fibrosis, altering drug metabolism and often necessitating higher doses than are normally given. To ensure therapeutic concentrations of tobramycin, a peak level should be check about 30 minutes after completion of an infusion. To reduce the risk of nephrotoxicity, a trough level should be checked immediately before the administration of a dose to ensure that the drug has been adequately metabolized. To ensure that steady-state concentration has been achieved, it is recommended that these levels be checked after three to five doses.
I-21. The answer is A. (Chap. 5) Digitalis is a cardiac glycoside that exerts its effect via reversible inhibition of the sodium–potassium–ATPase pump. The cellular effect of this inhibition is to increase intracellular sodium and decrease extracellular potassium. The increase in intracellular sodium leads to a change in the membrane potential of the cell and an influx of calcium. This influx of calcium improves inotropy of the heart and leads to increased vagal tone with resultant decrease in heart rate through action at the sinoatrial and atrioventricular nodes. Digoxin is a drug with a narrow therapeutic window, meaning that the effective dose and the toxic dose are close to one another. Digoxin is a substrate for P-glycoprotein, which is an efflux pump that excretes drugs into the proximal tubule of the kidney. Caution must be taken when introducing a new medication that is an inhibitor of P-glycoprotein because these drugs can increase the serum concentration of digoxin. Examples of inhibitors of P-glycoprotein include amiodarone, clarithromycin, verapamil, and diltiazem. In this patient, initiation of an oral amiodarone load in the face of the patient’s known renal insufficiency was sufficient to cause digoxin toxicity. The typical manifestations of digoxin toxicity in this patient with a subacute onset include lethargy, generalized weakness, and delirium. Gastrointestinal manifestations may be seen but are less pronounced that in acute overdoses. The cardiac manifestations of digoxin toxicity are of the greatest concern, and the electrocardiogram can demonstrate a wide range of abnormalities, including bradycardia, atrial tachyarrhythmias, atrioventricular block, and ventricular tachycardia or fibrillation. The ECG can evolve over time, so continuous cardiac monitoring is warranted. Electrolyte abnormalities are common, especially hyperkalemia caused by the effects on the sodium–potassium–ATPase pump. However, in chronic toxicity, hypokalemia can also be seen. Worsening renal function is also a frequent manifestation and is often the cause for the rise in digoxin levels. The therapeutic range of digoxin is between 0.8 and 2 ng/mL. However, the level may not correlate well with the development of toxicity. Levels greater than 10 ng/mL often require treatment with digoxin-specific antibody fragments (Fab). This patient has other indications for use of Fab fragments as well given the complete heart block on ECG. Thus, observation alone is not an appropriate choice in this patient. Fab fragments are highly effective in the management of cardiac arrhythmias and are given as a single intravenous dose. Given the large molecular weight of digoxin and large volume of distribution, neither hemodialysis nor hemoperfusion is effective in elimination of digoxin. There are case reports of combined use of Fab fragments and plasmapheresis in individuals with profound renal failure, but this is not a standard option.
I-22. The answer is C. (Chap. 5) Some medications circulate in the plasma partially bound to plasma proteins. In this setting, only unbound (or free) drug can distribute to the sites of action to exert pharmacologic effects. Examples of medications that are bound to plasma proteins include phenytoin, warfarin, valproic acid, and amiodarone. Hypoalbuminemia can lead to increased free levels of drugs that are more highly protein bound and can lead to drug toxicity at total drug levels that are not typically considered toxic. In this case, the patient has evidence of worsening liver disease with a low albumin level that has lead to signs and symptoms of phenytoin toxicity. A free drug level should be checked to confirm this. Although phenytoin can be used safely in those with mild liver disease, it should be discontinued in individuals with evidence of cirrhosis, which this patient clearly exhibits. Signs and symptoms of phenytoin toxicity include slurred speech, horizontal nystagmus, and altered mental status that can progress to obtundation and coma. Typically, severe phenytoin toxicity is not encountered unless the total phenytoin level is greater than 30 μg/mL. However, in the case of hypoalbuminemia, the total level can substantially misrepresent the free level of drug. When the free phenytoin level was checked in this case, it was elevated at 5 μg/mL (therapeutic range, 1.0–2.5 μg/mL). Other less likely possibilities in the differential diagnosis of this patient include nonconvulsive status epilepticus and hepatic encephalopathy, but the presence of horizontal nystagmus is more suggestive of phenytoin toxicity. Infection is also a common cause of altered mental status in individuals with cirrhosis. However, the ascitic fluid does not support a diagnosis of spontaneous bacterial peritonitis that may be associated with a positive Gram stain of the ascites fluid. The history and physical examination are not consistent with a diagnosis of bacterial meningitis, and a head CT is not likely to provide additional information in this clinical setting.
I-23. The answer is D. (Chap. 5; VD Cataldo et al: N Engl J Med 364:947, 2011.) In the past decades, increasing interest and research has occurred in the area of genetic variability with respect to drug effects, particularly in the area of cancer chemotherapy. Each individual tumor contains multiple mutations that exhibit different biologic advantages that promote proliferation of tumor cells and escape from immune attack by the host. As investigators have learned more about the function of these mutations, drug development has concurrently allowed specific therapies directed against a particular mutation. Some specific examples of chemotherapeutic successes with targeted chemotherapy include use of imatinib in chronic myelogenous leukemia and gastrointestinal stroma tumors. In non–small cell lung cancer (NSCLC; adenocarcinoma and squamous cell carcinoma), targeted chemotherapeutic agents have included small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, a monoclonal antibody against vascular endothelial growth factor, and a monoclonal antibody that binds to EGFR. Current research is continuing to define the most appropriate role of these agents in the treatment of NSCLC. Recently, the National Comprehensive Cancer Network recognized the EGFR tyrosine kinase inhibitor erlotinib as second- and third-line therapy in individuals who have advanced stage NSCLC with good performance status. However, in individuals with activating mutations of the EGFR, erlotinib monotherapy is recommended. The two most common mutations are deletions of exon 19 and an arginine for leucine substitution at position 858 in exon 21. In clinical trials, individuals with these mutations, treatment with erlotinib or gefitinib is associated with an initial response rate of 55–90%. Moreover, those with activating mutations of EGFR have improved progression-free survival when treated with erlotinib or gefitinib. On the other hand, those without these mutations have been shown to do worse with these medications. Therefore, it is important to perform testing for mutations of EGFR before using either of these medications. Other clinical predictors of response to the EGFR tyrosine kinase inhibitors are female sex, lack of tobacco use, adenocarcinoma by pathology, and individuals of East Asian descent.
I-24. The answer is D. (Chap. 5) Calcineurin inhibitors such as tacrolimus and cyclosporine are immunosuppressive agents that are used after solid organ transplants as well as for treatment of graft-versus-host disease (GVHD) in bone marrow transplant patients. These drugs are primarily metabolized via the cytochrome P450 pathway and excreted into bile. Many drugs and foods can be inhibitors or inducers of this pathway, and thoughtful consideration of possible drug interactions must be considered when starting any patient on a new medication while on tacrolimus or cyclosporine. In this case, voriconazole inhibits metabolism of tacrolimus, leading to increased serum concentrations of the drug. The clinical signs and symptoms of tacrolimus toxicity include hypertension, edema, headaches, insomnia, and tremor. In addition, elevated levels of tacrolimus can lead to worsening renal function and electrolyte abnormalities, including hyperkalemia, hypomagnesemia, hypophosphatemia, and hyperglycemia. It is recommended that the tacrolimus dose be decreased to one-third of the original dose when it is necessary to co-administer tacrolimus and voriconazole. Aspergillus meningitis is a rare infection that typically results from direct invasion from a rhinosinusitis. Congestive heart failure is unlikely in the clinical scenario because this is a young woman with no known heart disease and the neurologic symptoms are not consistent with that diagnosis. GVHD occurs when transplanted immune cells recognizes the host cells as foreign and initiates an immune response. GVHD occurs after allogeneic hematopoietic stem cell transplants, and there is increased risk of GVHD in those with a greater disparity of human leukocyte antigens between the graft and the host. GVHD presents acutely with a diffuse maculopapular rash, fever, elevations in bilirubin and alkaline phosphatase, and diarrhea with abdominal cramping. There are case reports of nephritic syndrome related to GVHD, but renal involvement is not common. Also unlikely are neurologic symptoms, headache, hypertension, and tremor. Thrombotic thrombocytopenic purpura (TTP) could be considered in an individual with renal disease, altered mental status, and hypertension if there was concurrent evidence of an intravascular hemolytic process. However, TTP has not been associated with administration of voriconazole.
I-25. The answer is E. (Chap. 5) Adverse drug reactions create significant morbidity in the treatment of disease. The most common classes of drugs that cause adverse events are antimicrobials, nonsteroidal anti-inflammatory drugs and aspirin, analgesics, anticoagulants, glucocorticoids, antineoplastics, diuretics, digoxin, and hypoglycemic agents. These drugs account for about 90% of all adverse drug events. Adverse drug events can be broadly classified as related or unrelated to the intended pharmacologic action. In this case, the patient has developed serum sickness (option E) after administration of benzathine penicillin. Serum sickness is an immunologic reaction to penicillin that is not a part of the intended pharmacologic action of the drug. Serum sickness is a type III immune complex mediated reaction that occurs when complex of drug and the appropriate antibody are deposited on endothelial cells. After the first exposure to the drug, it takes about 1–2 weeks for the immune reaction to occur, although with subsequent exposures, this would occur more quickly. Deposition of the immune complexes leads to complement activation with neutrophilic inflammation. Clinically, serum sickness presents as fever, urticarial rash, lymphadenopathy, inflammatory arthritis, and glomerulonephritis. Clinical recovery typically occurs in 7–28 days. Common pharmacologic causes of serum sickness are antibiotics and foreign proteins, including streptokinase, vaccines, and therapeutic antibodies. Secondary syphilis typically does not present until 4–10 weeks after primary infection. The rash typically is an erythematous maculopapular eruption that affects the palms and soles. Secondary syphilis should be adequately treated by the patient’s single dose of benzathine penicillin as long as the primary infection occurred with the past year. A Jarisch-Herxheimer reaction occurs when there is a systemic reaction to the killing of syphilis organisms. It begins in the first 24 hours after treatment and is associated with fevers, myalgias, headaches, and tachycardia. Disseminated gonococcal infection presents as an asymmetric migratory polyarthritis with fever and a papular or pustular rash. Septic arthritis may occur. A negative urethral swab result does not rule out this possibility, but the clinical presentation is not consistent with disseminated gonococcal infection. Approximately 10–20% of patients with rheumatoid arthritis have a negative rheumatoid factor. Although the disease most often presents with a symmetric inflammatory arthritis of the larger joints, the acute presentation of this patient makes this diagnosis less likely.
I-26. The answer is A. (Chap. 5) In population surveys of noninstitutionalized elderly adults, up to 10% had at least one adverse drug reaction in the prior year. Adverse drug reactions are common in elderly adults and are related to altered drug sensitivity, impaired renal or hepatic clearance, impaired homeostatic mechanisms, and drug interactions. Long half-life benzodiazepines are linked to the increased occurrence of hip fractures in elderly adults. The association may be caused by the increased risk of falling (related to sedation) in a population with a high prevalence of osteoporosis. This association may also be true for other drugs with sedative properties such as opioids or antipsychotics. Exaggerated responses to cardiovascular drugs such as angiotensin-converting enzyme inhibitors may occur because of a blunted vasoconstrictor or chronotropic response to reduced blood pressure. Conversely, elderly patients often display decreased sensitivity to beta-blockers.
I-27. The answer is C. (Chap. 5) Grapefruit juice inhibits CYP3A4 in the liver, particularly at high doses. This can cause decreased drug elimination via hepatic metabolism and increase potential drug toxicities. Atorvastatin is metabolized via this pathway. Drugs that may enhance atorvastatin toxicity via this mechanism include phenytoin, ritonavir, clarithromycin, and azole antifungals. Aspirin is cleared via renal mechanisms. Prevacid can cause impaired absorption of other drugs via its effect on gastric pH. Sildenafil is a phosphodiesterase inhibitor that may enhance the effect of nitrate medications and cause hypotension.
I-28. The answer is E. (Chap. 6) The top two causes of death for men and women are the same—heart disease and cancer. These two broad categories of disease account for more than 50% of all deaths in men and 47% of deaths in women. Likewise, the number one cause of cancer death (lung cancer) is the same in men and women. After this, there are significant differences in the major causes of death between the sexes. Cerebrovascular disease is the third most common cause of death in women responsible for 6.7% of death, but in men, it is only the fifth most common cause of death with only 4.5% of all deaths. Although chronic lower respiratory disease is the fourth most common cause of death in both men and women, the percentage of deaths from chronic lower respiratory disease in women is 5.3% compared with 4.9% in men. Other diseases that are responsible for a greater percentage of deaths in women are Alzheimer’s disease, sepsis, pneumonia, and hypertension.
I-29. The answer is C. (Chap. 6) Coronary heart disease (CHD) is the most common cause of death in men and women, but important sex differences exist in the presentation and treatment of CHD. At the time of presentation of CHD, women are about 10–15 years older than men with CHD. In addition, women have a greater number of medical comorbidities at the time of diagnosis, including hypertension, heart failure, and diabetes mellitus. Angina is the most common presenting symptom of CHD in women and may have atypical features, including nausea, indigestion, and upper back pain. Women who present with a myocardial infarction (MI) more often present with cardiogenic shock or cardiac arrest, but men have a greater risk of ventricular tachycardia on presentation with MI. In the past, women had a greater risk of death from MI when presenting at younger ages, but this gap has decreased in recent years. However, women are still referred less often by physicians for diagnostic and therapeutic cardiovascular procedures, and there are more false-positive and false-negative diagnostic test results in women. Women are also less likely to receive angioplasty, thrombolysis, coronary artery bypass grafting, aspirin, and beta-blockers. Despite this, the 5- and 10-year survival rates after coronary artery bypass grafting are the same for men and women.
I-30. The answer is A. (Chap. 6) In general, the risk factors for coronary heart disease (CHD) are similar in men and women. However, an elevated total triglyceride level has been demonstrated to be an independent risk factor in women but not men. Low high-density lipoprotein and diabetes mellitus are also stronger risk factors in women, but they also influence CHD in men. Other shared risk factors include elevated total cholesterol, hypertension, obesity, smoking, and lack of physical activity.
I-31. The answer is E. (Chap. 6) Sex differences exist in the prevalence of many common diseases. Hypertension is more common in women, particularly in those older than 60 years. In addition, most autoimmune diseases are more common in women, including rheumatoid arthritis, systemic lupus erythematosus, and autoimmune thyroid disease. Major depression is twice as common in women than men, and this is true even in developing countries. Other psychological disorders that are more common in women are eating disorders and anxiety. Endocrine disorders, including obesity and osteoporosis, are more common in women, and 80% of patients referred for bariatric surgery are women. However, the prevalence of both type 1 and type 2 diabetes mellitus is the same between men and women.
I-32. The answer is C. (Chap. 6) Alzheimer’s disease (AD) affects women twice as commonly as men. This sex difference cannot fully be explained by the difference in life expectancy between men and women. The brains of women differ from men in terms of size, structure, and functional organization. In addition, it is thought that estrogen may play a role in the development of AD. Women with AD have lower levels of circulating estrogen than age-controlled women without disease. Although observational studies suggested a protective effect of estrogen replacement therapy on the development of AD, this was not borne out in randomized and blinded placebo-controlled trials. Indeed, the largest trial to date demonstrated an increase in dementia and mild cognitive impairment in individuals receiving either estrogen or combined hormone replacement therapy.
I-33. The answer is E. (Chap. 7) The cardiovascular system undergoes many changes in a pregnant woman to accommodate the needs of the developing fetus. Plasma volume begins to expand early in pregnancy and ultimately is increased by about 40–50% at term. Coincident with the increased plasma volume, cardiac output increases as well by about 40%. Although this is primarily attributable to increases in stroke volume, heart rate also increases in pregnancy by about 10 beats/min. In the second trimester, systemic vascular resistance falls, and subsequently blood pressure decreases as well. Thus, a blood pressure greater than 140/90 mmHg is considered abnormal and is associated with increased maternal and fetal morbidity and mortality.
I-34. The answer is D. (Chap. 7) Chronic essential hypertension occurs in up to 5% of all pregnancies. Although hypertension is not a contraindication to pregnancy, the condition is associated with an increased risk of intrauterine growth restriction, preeclampsia, placental abruption, and perinatal mortality. The cardiovascular changes of pregnancy typically do lead to a fall in systemic vascular resistance and a fall in blood pressure in the second trimester, but it is not safe to discontinue medications in those with a prior diagnosis of hypertension if the blood pressure in the first trimester is greater than 120/80 mmHg. When choosing an antihypertensive medication in pregnancy, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be strictly avoided because they are known to cause birth defects, including congenital malformations and intrauterine death, particularly in the second and third trimesters. The most common medications used in pregnancy are α-methyldopa, labetalol, and nifedipine. Although these medications have limited data from randomized controlled trials, there is a long history of safety with use of these medications. Diuretics such as hydrochlorothiazide appear also to be safe in pregnancy, although there are concerns that use of diuretics would impair the volume expansion that occurs during pregnancy.
I-35. The answer is B. (Chaps. 7 and 150) Most cardiovascular conditions can be managed safely in pregnancy, although these pregnancies are often considered high risk. The conditions that are considered to be contraindications to pregnancy are idiopathic pulmonary arterial hypertension and Eisenmenger syndrome (congenital heart disease resulting in pulmonary hypertension with right-to-left shunting). In these cases, it is typically recommended to terminate the pregnancy because there is a high risk of maternal and fetal death. Peripartum cardiomyopathy can recur in subsequent pregnancies, and it is recommended that individuals with an abnormal ejection fraction avoid further pregnancies. Approximately 15% of individuals with Marfan syndrome will have a major cardiovascular complication in pregnancy, although the condition is not considered a contraindication to pregnancy. An aortic root diameter of less than 40 mm is generally associated with the best outcomes in pregnancy. The valvular heart disease with the greatest risk in pregnancy is mitral stenosis. There is an increased risk of pulmonary edema, and pulmonary hypertension is a common long-term consequence of mitral stenosis. However, aortic stenosis, aortic regurgitation, and mitral regurgitation are typically well tolerated. Congenital heart disease in the mother is associated with an increased risk of congenital heart disease in the offspring, but atrial and ventricular septal defects are usually well tolerated in pregnancy as long as there is no evidence of Eisenmenger syndrome.
I-36. The answer is D. (Chap. 7) This patient has severe eclampsia, and delivery should be performed as rapidly as possible. Mild eclampsia is the presence of new-onset hypertension and proteinuria in a pregnant woman after 20 weeks’ gestation. Severe eclampsia is eclampsia complicated by central nervous system symptoms (including seizure), marked hypertension, severe proteinuria, renal failure, pulmonary edema, thrombocytopenia, or disseminated intravascular coagulation. Delivery in a mother with severe eclampsia before 37 weeks’ gestation decreases maternal morbidity but increases fetal risks of complications of prematurity. Aggressive management of blood pressure, usually with labetalol or hydralazine intravenously, decreases the maternal risk of stroke. However, similar to any hypertensive crisis, the decrease in blood pressure should be achieved slowly to avoid hypotension and risk of decreased blood flow to the fetus. Eclamptic seizures should be controlled with magnesium sulfate; it has been shown to be superior to phenytoin and diazepam in large randomized clinical trials.
I-37. The answer is C. (Chap. 7) Pregnancy causes a hypercoagulable state, and deep venous thrombosis (DVT) occurs in about 1 in 2000 pregnancies. DVT occurs more commonly in the left leg than the right leg during pregnancy because of compression of the left iliac vein by the gravid uterus. In addition, pregnancy represents a procoagulant states with increases in factors V and VII and decreases in proteins C and S. Approximately 25% of pregnant women with DVT have a factor V Leiden mutation, which also predisposes to preeclampsia. Warfarin is strictly contraindicated because of a risk of fetal abnormality. Low-molecular-weight heparin (LMWH) is appropriate therapy at this point in pregnancy but is typically switched to unfractionated heparin 4 weeks before anticipated delivery because LMWH may be associated with an increased risk of epidural hematoma. Ambulation, rather than bedrest, should be encouraged as with all DVTs. There is no proven role for local thrombolytics or an inferior vena cava filter in pregnancy. The latter would be considered only when anticoagulation is not possible.
I-38. The answer is E. (Chap. 7) Pregnancy complicated by diabetes is associated with greater maternal and perinatal morbidity and mortality rates and occurs in 4% of all pregnancies. Women with gestational diabetes are at increased risk of preeclampsia, delivering infants large for gestational age, and birth lacerations. Their infants are at risk of hypoglycemia and birth injury. Appropriate therapy can reduce these risks. All women should be screened for gestational diabetes unless they fall into a low-risk group. Low-risk groups include age younger than 25 years, body mass index less than 25 kg/m2, no maternal history of macrosomia or gestational diabetes, no diabetes in any first-degree relative, and those who are not members of a high-risk ethnic group (African American, Hispanic, or Native American).
I-39. The answer is B. (Chap. 8) Medical providers are often asked to provide guidance regarding the postoperative risk of complications after a variety of noncardiac surgical procedures. When evaluating risk of complications, it is useful to categorize the surgical procedures into a low, intermediate, or higher risk category. Individuals who are at the highest risk of complications include those undergoing an emergent major operation, especially in elderly adults. Other higher risk procedures include aortic and other noncarotid major vascular surgery and surgeries with a prolonged operative time and large anticipated blood loss or fluid shifts (e.g., pancreaticoduodenectomy or Whipple procedure). Surgeries that are believed to be an intermediate risk include major thoracic surgery, major abdominal surgery, carotid endarterectomy, head and neck surgery, orthopedic surgery, and prostate surgery. Lower risk procedures include eye, skin, and superficial surgery as well as endoscopy.
I-40. The answer is E. (Chap. 8) Poor exercise tolerance is an important predictor of postoperative complications. To standardize the determination of functional status, general guidelines are available that attempt to categorize the risk of complications according to functional status (Table I-40). The risk of postoperative complications increases when an individual cannot meet a metabolic equivalent (MET) level of 4. General activities that require a MET level of 4 include carrying 15–20 lb, playing golf, and playing doubles tennis. In addition, individuals experience increased risk of postoperative complications if they are unable to walk four blocks or climb two flights of stairs when walking at a normal pace. Individuals at highest risk of postoperative complications in relation to exercise capacity are those who have difficulty performing activities of daily living because of dyspnea, angina, or excessive fatigue.
TABLE I-40 Functional Status
I-41. The answer is D. (Chap. 8) Cardiovascular events continue to be a major source of morbidity and mortality after surgical interventions, and preoperative prediction of those individuals at the highest risk of cardiovascular events has been an area of much research. Over the years, a variety of risk stratification tools have been developed to assist clinicians in determining which patients may benefit from preoperative noninvasive cardiac testing or initiation of preoperative preventive medical management. One of the simplest and most widely used is the revised cardiac risk index (RCRI), which scores patients on a scale from 0–6. The six factors that comprise the RCRI (Table I-41) are high-risk surgical procedures, known ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes mellitus requiring insulin, and chronic kidney disease with a creatinine greater than 2 mg/dL. An individual would be considered as having ischemic heart disease if he or she had a history of angina, myocardial infarction, or prior angioplasty or bypass surgery. In addition, ischemic heart disease would be considered present if a patient was requiring sublingual nitroglycerin, had a positive exercise test result, or had pathologic Q waves on the electrocardiogram (ECG). Therefore, the patient has a RCRI score of 3 (high-risk surgery, ischemic heart disease by ECG, and diabetes mellitus requiring insulin).
TABLE I-41 Revised Cardiac Risk Index Clinical Markers
High-Risk Surgical Procedures
Major intraperitoneal or intrathoracic procedures
Ischemic Heart Disease
History of myocardial infarction
Current angina considered to be ischemic
Requiring sublingual nitroglycerin
Positive exercise test
Pathological Q waves on ECG
History of PTCA or CABG with current angina considered to be ischemic
Congestive Heart Failure
Left ventricular failure by physical examination
History of paroxysmal nocturnal dyspnea
History of pulmonary edema
S3 gallop on cardiac auscultation
Bilateral rales on pulmonary auscultation
Pulmonary edema on chest radiograph
History of transient ischemic attack
History of cerebrovascular accident
Treatment with insulin
Chronic Renal Insufficiency
Serum creatinine >2 mg/dL
Abbreviations: CABG, coronary artery bypass grafting; ECG, electrocardiogram; PTCA, percutaneous transluminal coronary angioplasty.
Source: Adapted from Lee TH et al: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 100:1043, 1999, with permission.
Individuals with scores of 3 or higher fall in the highest risk category of the RCRI. These individuals have an estimated postoperative risk of major cardiovascular events between 9 and 11%. If an individual has a risk score of 2, the risk of postoperative cardiovascular events is 4–6.6%. There is a 1% risk of postoperative events with a risk score of 1 and a 0.5% risk with a risk score of 0. No group has a risk score as high as 20% using this methodology.
I-42. The answer is B. (Chap. 8) Pulmonary and cardiovascular complications are a major source of morbidity and mortality after surgery. Primary care physicians are often asked to determine a patient’s postoperative risk of pulmonary complications. Factors identified by the American College of Physicians as conferring an increased risk of pulmonary complications are shown in Table I-42. Although many of these factors are directly related to pulmonary function, some of these are not. Notably, the presence of congestive heart failure and a serum albumin level of less than 3.5 g/dL predict postoperative pulmonary complications. Asthma is not a predictor of pulmonary complications as long as the disease is under sufficient control. Factors listed in the table that are useful determinants of asthma control include peak expiratory flow rate greater than 100 L or 50% predicted and forced expiratory volume in 1 second of less than 2 L.
TABLE I-42 Predisposing Risk Factors for Pulmonary Complications
1. Upper respiratory tract infection: cough, dyspnea
2. Age greater than 60 years
4. American Society of Anesthesiologists Class ≥2
5. Functionally dependent
6. Congestive heart failure
7. Serum albumin <3.5 g/dL
8. FEV1 <2 L
9. MVV <50% of predicted
10. PEF <100 L or 50% predicted value
11. PCO2 ≥45 mmHg
12. PO2 ≤50 mmHg
Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; MVV, maximum voluntary ventilation; PEF, peak expiratory flow rate; PCO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen.
Source: Modified from Smetana GW et al: Preoperative pulmonary risk stratification for noncardiothoracic surgery: Systematic review for the American College of Physicians. Ann Intern Med 144:581, 2006 and Mohr DN et al: Postgrad Med 100:247, 1996, with permission.
I-43. The answer is E. (Chap. 9) Communication of bad news is an inherent component of the physician–patient relationship, and these conversations often occur in a hospital setting where the treating provider is not the primary care provider for the patient. Many physicians struggle with providing clear and effective communication to patients who are seriously ill and their family members. In the scenario presented in this case, it is necessary to have a discussion about the patient’s poor prognosis and determine the goals of care without the input of the patient because her mental status remains altered. Failure to provide clear communication in the appropriate environment can lead to tension in the relationship between the physician and patient and may lead to overly aggressive treatment. The P-SPIKES approach (Table I-43) has been advocated as a simple framework to assist physicians in effectively communicating bad news to patients. The components of this communication tool are:
• Preparation—Review what information needs to be communicated and plan how emotional support will be provided.
• Setting of interaction—This step is often the most neglected. Ensure a quiet and private environment and attempt to minimize any interruptions.
• Patient (or family) perceptions and preparation—Assess what the patient and family know about the current condition. Use open-ended questions.
• Invitation and information needs—Ask the patient or family what they would like to know and also what limits they want regarding bad information
• Knowledge of the condition—Provide the patient and family with the bad news and assess understanding.
• Empathy and exploration—Empathize with the patient and family’s feelings and offer emotional support. Allow plenty of time for questions and exploration of their feelings.
• Summary and planning—Outline the next steps for the patient and family. Recommend a timeline to achieve the goals of care.
TABLE I-43 Elements of Communicating Bad News—The P-SPIKES Approach
Setting a follow-up meeting is not a primary component of the P-SPIKES framework but may be necessary when a family or patient is not emotionally ready to discuss the next steps in the care plan.
I-44. The answer is C. (Chap. 9) Advance care planning documentation is an increasing component of medical practice. As of 2006, 48 states and the District of Columbia had enacted legislation regarding advance care planning. The two broad types of advance care planning documentation are living wills and designation of a health care proxy (option C). Although these two documents are often combined into a single document, designation of a health care proxy is not one of the primary components of a living will. The living will (or instructional directive) delineates the patient’s preferences (option A) regarding treatment under different scenarios (e.g., whether condition is perceived as terminal). These documents can be very specific to a condition such as cancer but may also be very broad in the case of elderly individuals who do not currently have a terminal condition but want to outline their wishes for care in the event of an unexpected health crisis. Examples of what this might include general statements regarding the receipt of life-sustaining therapies (option D) and the values that should guide the decisions regarding terminal care (option B).
I-45. The answer is D. (Chap. 9) Depression is difficult to diagnose in individuals with terminal illness and is often an overlooked symptom by physicians because many individual believe it a normal component of terminal illness. Furthermore, symptoms commonly associated with depression such as insomnia and anorexia are also frequently seen in serious illness or occur as a side effect of treatment. Although about 75% of terminally ill patients express some depressive symptoms, only 25% or less have major depression. When assessing depression in terminally ill individuals, one should focus on symptoms pertaining to the dysphoric mood, including helplessness, hopelessness, and anhedonia. It is inappropriate to do nothing in when one believes major depression is occurring (option A). The approach to treatment should include nonpharmacologic and pharmacologic therapies. The pharmacologic approach to depression should be the same in terminally ill individuals as in non–terminally ill individuals. If an individual has a prognosis of several months or longer, selective serotonin reuptake inhibitors (fluoxetine, paroxetine) or serotonin–noradrenaline reuptake inhibitors (venlafaxine) are the preferred treatment because of their efficacy and side effect profile. However, these medications take several weeks to become effective. Thus, starting fluoxetine alone (option C) is not preferred. In patients with major depression and fatigue or opioid-induced somnolence, combining a traditional antidepressant with a psychostimulant is appropriate (option D). Psychostimulants are also indicated in individuals with a poor prognosis who are not expected to live long enough to experience the benefits of treatment with a traditional antidepressant. A variety of psychostimulant medications are available, including methylphenidate, modafinil, dextroamphetamine, and pemoline. Because this patient has a prognosis of several months or longer, methylphenidate alone is not recommended (option E). Because of their side effect profile, tricyclic antidepressants (option A) are not used in the treatment of depression in terminally ill patients unless they are used as adjunctive treatment for chronic pain.
I-46. The answer is C. (Chap. 9) A primary goal of palliative care medicine is to control pain in patients who are terminally ill. Surveys have found that 36–90% of individuals with advanced cancer have substantial pain, and an individualized treatment plan is necessary for each patient. For individuals with continuous pain, opioid analgesics should be administered on a scheduled basis around the clock at an interval based on the half-life of the medication chosen. Extended-release preparations are frequently used because of their longer half-lives. However, it is inappropriate to start immediately with an extended-release preparation. In this scenario, the patient was treated with a continuous intravenous infusion via patient-controlled analgesia for 48 hours to determine her baseline opioid needs. The average daily dose of morphine required was 90 mg. This total dose should be administered in divided doses two or three times daily (either 45 mg twice daily or 30 mg three times daily). In addition, an immediate-release preparation should be available for administration for breakthrough pain. The recommended dose of the immediate-release preparation is 20% of the baseline dose. In this case, the dose would be 18 mg and could be given as either 15 or 20 mg four times daily as needed.
I-47. The answer is E. (Chap. 9) Withdrawal of care is a common occurrence in intensive care units. More than 90%of Americans die without performance of cardiopulmonary resuscitation. When a family decides to withdraw care, the treating care team of doctors, nurses, and respiratory therapists must work together to ensure that the dying process will be comfortable for both the patient and the family. Commonly, patients receive a combination of anxiolytics and opioid analgesics. These medications also provide relief of dyspnea in the dying patient. However, they have little effect on oropharyngeal secretions (option A). The accumulation of secretions in the oropharynx can produce agitation, labored breathing, and noisy breathing that has been labeled the “death rattle.” This can be quite distressing to the family. Treatments for excessive oropharyngeal secretions are primarily anticholinergic medications, including scopolamine delivered transdermally (option E) or intravenously, atropine, and glycopyrrolate. Although placement of a nasal trumpet or oral airway (option D) may allow better access for suctioning of secretions, these can be uncomfortable or even painful interventions that are typically discouraged in a palliative care situation. N-acetylcysteine (option B) can be used as a mucolytic agent to thin lower respiratory secretions. Pilocarpine (option C) is a cholinergic stimulant and increases salivary production.
I-48. The answer is A. (Chap. 10) In recent years, there has been increasing focus on both the safety and quality of health care provided throughout the world. An Institute of Medicine report identified safety as an essential component of quality in health care. Improving safety and quality in health care relies on understanding the frequency and type of adverse events that occur in the health care system. An adverse event is defined as an injury caused by medical management rather than the underlying disease of the patient. One of the largest studies that has attempted to quantify adverse events in hospitalized patients was the Harvard Medical Practice Study. In this study, the most common adverse event was an adverse drug event, which occurred in 19% of hospitalizations. Other common adverse events included wound infections (14%), technical complications of a procedure (13%), diagnostic mishaps (15%), and falls (5%).
I-49. The answer is A. (Chap. e2) Since 1993, numerous population studies have shown that 30–40% of American adults seek and or use at least one complementary and alternative medicine (CAM) approach. The most prevalent are nonmineral nonvitamin dietary supplements, relaxation, medication, massage, and chiropractic care. Approximately 1% of Americans use acupuncture. The most common reasons are for back or musculoskeletal pain and control of symptoms not adequately addressed by conventional therapy. CAM expenses are estimated to be $34 billion per year, representing 1.5% of total health care expenditures and 11% of out-of-pocket expenses.
I-50. The answer is E. (Chap. e4) Minority patients have poorer health outcomes from many preventable and treatable conditions such as cardiovascular disease, asthma, diabetes, cancer, and others. The causes of these differences are multifactorial and include social determinants (education, socioeconomic status, environment) and access to care (which often leads to more serious illness before seeking care). However, there are also clearly described racial differences in quality of care when patients enter the health care system. These differences have been found in cardiovascular, oncologic, renal, diabetic, and palliative care. Eliminating these differences will require systematic changes in health system factors, provider-level factors, and patient-level factors.
I-51. The answer is A. (Chap. e6) Breast cancer in pregnant women is defined as cancer diagnosed during pregnancy or up to 1 year after delivery. Only about 5% of all breast cancers occur in women younger than 40 years of age, and of those, approximately 25% are pregnancy-associated cancer. Needle biopsy of breast masses in pregnant women is often nondiagnostic, and false-positive test results may occur. Breast cancers diagnosed during pregnancy have a worse outcome than other breast cancers. The cancers tend to be diagnosed at a later stage (often the signs are thought to be related to pregnancy) and tend to have a more aggressive behavior. Approximately 30% of breast cancers found in pregnancy are estrogen receptor positive in contrast to 60–70% being estrogen receptor positive overall. Larger tumor size, positive axillary nodes, Her-2 positivity, and higher stage are all more common in pregnant women.
I-52. The answer is C. (Chap. 34) Chronic cough is one of the most common causes of referral to pulmonary, allergy, and otolaryngology practices and is frequently encountered in primary care. A cough is classified as chronic when it persists for longer than 8 weeks and has a wide range of differential diagnoses, including cardiac, pulmonary, upper airway, and gastrointestinal diseases. The initial history and physical examination is important in providing clues to the potential etiology, particularly in the setting of a normal chest radiograph and examination. The most common causes of chronic cough in an otherwise normal individual are cough-variant asthma, gastroesophageal reflux disease, postnasal drip, and medications. In this patient, there are clues that should lead one to suspect cough-variant asthma as a potential cause. Asthma can present only with cough. Although this presentation is more common in children, it can present this way in adults as well. This patient does have triggers that include cold air and exercise, both of which can lead to increased bronchoconstriction. In addition, the parasympathetic–sympathetic balance favors bronchoconstriction that is worse in the early morning hours with cough late at night. Although spirometry demonstrating reversible airflow obstruction is typically seen in asthma, asthma has significant clinical variability, and lung function varies over time. In this patient, the spirometry results are normal, and the bronchodilator response is insufficient to diagnose reversibility, which requires a response of at least 12% and an increase of at least 200 mL in either the forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC). To establish the diagnosis more definitively, demonstration of a fall in FEV1 of at least 20% during a bronchoprovocation test with methacholine would be sufficient in this clinical scenario to diagnose asthma and would be safe to perform in this patient with normal pulmonary function at baseline. An alternative approach would be to treat empirically with low-dose inhaled corticosteroids given the clinical history.
In many cases, the cause of chronic cough is multifactorial. This patient has minor symptoms of allergic rhinitis, which may be a contributing factor. Nasal corticosteroids may also be required, but given the reported triggers, would not be sole treatment. The patient gives no history to suggest GERD, which may be clinically silent. If the cough failed to improve with treatment for asthma, antacid medications may be indicated. Finally, increasing numbers of adults are becoming infected with Bordetella pertussis because individual immunity wanes in adulthood, and more parents are electing to forego childhood immunizations. In this scenario, the patient typically gives a history of an upper respiratory infection with a strong cough at the onset of the illness. When the illness has progresses to the recovery phase, diagnosis is typically made by serology, and culture is not useful.
I-53. The answer is A. (Chap. 34) Hemoptysis is a relatively common symptom that causes a significant degree of distress in the patient. In most individuals, the hemoptysis is mild and self-limited despite the anxiety that it causes. Worldwide, tuberculosis remains the most common cause of hemoptysis. However, in the United States, the most common cause of hemoptysis is acute bronchitis of viral or bacterial etiology. Given the acute nature of the illness and mild degree of hemoptysis, this patient’s presentation would be most consistent with the diagnosis of acute bronchitis. Antiplatelet or anticoagulant agents may increase the risk of bleeding but are not sufficient in the absence of an underlying cause to initiate hemoptysis. Moreover, these agents are typically associated with underlying alveolar rather than airway damage. Most patients who experience hemoptysis fear lung cancer, which can present with acute hemoptysis, but this patient’s report of primarily blood-streaked sputum would make this less likely, especially in the face of a normal chest radiograph. Lung abscesses rarely present with hemoptysis, and the typical presentation is one of a prolonged illness.
I-54. The answer is E. (Chap. 34) Life-threatening hemoptysis is a medical emergency. Defining massive hemoptysis can be difficult but generally should be viewed as any amount of hemoptysis that can lead to airway obstruction because most patients who die of hemoptysis die from asphyxiation and airway obstruction. The immediate management of hemoptysis is to establish a patent airway and establish the site of bleeding. The initial step is to place the patient with the bleeding side in a dependent position. In this patient with a known lesion of the right upper lobe, he should be placed with the right side (not left) in a dependent position. The patient should be intubated with the largest possible endotracheal tube to allow for adequate suctioning. When immediately available, placement of a dual-lumen endotracheal tube can allow selective ventilation of the nonbleeding lung while providing access to continue suctioning from the affected side. Certainly, correction of any underlying coagulopathy would be important in the management of this patient. If conservative measures fail to stop the bleeding, the first step is to attempt embolization of the bleeding artery, but in rare instances, urgent surgical intervention may be required.
I-55. The answer is D. (Chap. 221) Microbial agents have been used as bioweapons as far back as the sixth century BC when water supplies were poisoned with Claviceps purpurea by the Assyrians. In modern times, science that has been often sponsored by governmental agencies has lead to new ways to enhance and spread microbial bioweapons. Bioterrorism should be delineated from biowarfare. Although bioterrorism has the potential to lead to thousands of deaths if used in a large-scale manner, the primary impact is the fear and terror generated by the attack. However, biowarfare specifically targets mass casualties and seeks to weaken the enemy. The Working Group for Civilian Biodefense has outlined key features that characterize agents that are the most effective bioweapons. These 10 features are:
1. High morbidity and mortality rates
2. Potential for person-to-person spread
3. Low infective dose and highly infectious by the aerosol route
4. Lack of rapid diagnostic capability
5. Lack of a universally available effective vaccine
6. Potential to cause anxiety
7. Availability of pathogen and feasibility of production
8. Environmental stability
9. Database of prior research and development
10. Potential to be weaponized
A lack of effective and available treatment is not one of the characteristics of an effective bioweapon. Bacillus anthracis is the causative organism of anthrax, one of the most prototypical microbial bioweapons, but many antibiotics have efficacy against anthrax and can be lifesaving if initiated early.
I-56. The answer is B. (Chap. 221) Yersinia pestis is a gram-negative rod that causes the plague and has been one of the most widely used bioweapons over the centuries. Although Y. pestis lacks environmental stability, it is highly contagious and has a high mortality rate, making it an effective agent of bioterrorism. There are two major syndromes caused by Y. pestis that reflect the mode of infection. These patients presented with symptoms typical of bubonic plague, which still exists widely in nature. In the United States, the area with the greatest number of naturally occurring cases of bubonic plague is in the Southwest with transmission occurring via contact with infected animals or fleas. In this case, infected animals or fleas were present in the concentrated population of an immigrant camp that had poor sanitation. After an individual is bitten by an infected vector, the bacteria travel through the lymphatics to regional lymph nodes, where they are phagocytized but not destroyed. The organisms can then multiply with the cells, leading to inflammation, painful and markedly enlarged lymph nodes, and fever. The affected lymph nodes can develop necrosis and are characteristically called buboes. Infection can progress to severe sepsis and death. The mortality rate for treated bubonic plague is 1–15% and 40–60% in untreated cases. When Y. pestis is used as an agent of bioterrorism, it is aerosolized to a large area, and the affected cases present primarily with pneumonic plague. Pneumonic plague presents with fever, cough, hemoptysis, and gastrointestinal symptoms that occur 1–6 days after exposure. Without treatment, pneumonic plague has an 85% morality rate with death occurring rapidly within 2–6 days. The treatment for Y. pestis could include aminoglycosides or doxycycline.
I-57. The answer is D. (Chap. 221) In the event of a bioterrorism attack, botulinum toxin would be most likely delivered by either aerosol or contamination of the food supply. Contamination of the water supply is possible, but it is not an optimal route for bioterrorism. Botulinum toxin is inactivated by chlorine, which is used in many water supplies for purification. In addition, heating any food or water to greater than 85°C for longer than 5 minutes will inactivate the toxin. Finally, there is an environmental decay rate of 1% per minute. So the time interval between release and ingestion would need to be very short, which would be difficult with an entire city water supply.
I-58. The answer is B. (Chap. 221) Anthrax is caused by the gram-positive spore-forming rod Bacillus anthrax. Anthrax spores may be the prototypical disease of bioterrorism. Although not spread person to person, inhalational anthrax has a high mortality and a low infective dose (five spores) and may be spread widely with aerosols after bioengineering. It is well documented that anthrax spores were produced and stored as potential bio-weapons. In 2001, the United States was exposed to anthrax spores delivered as a powder in letters. Of 11 patients with inhalation anthrax, five died. All 11 patients with cutaneous anthrax survived. Because anthrax spores can remain dormant in the respiratory tract for 6 weeks, the incubation period can be quite long, and postexposure antibiotics are recommended for 60 days. Trials of a recombinant vaccine are underway.
I-59. The answer is D. (Chap. 221) The three major clinical forms of anthrax are gastrointestinal (GI), cutaneous, and inhalational. GI anthrax results from eating contaminated meat and is an unlikely bioweapon. Cutaneous anthrax results from contact with the spores and results in a black eschar lesion. Cutaneous anthrax had a 20% mortality before antibiotics became available. Inhalational anthrax typically presents with the most deadly form and is the most likely bioweapon. The spores are phagocytosed by alveolar macrophages and transported to the mediastinum. Subsequent germination, toxin elaboration, and hematogenous spread cause septic shock. A characteristic radiographic finding is mediastinal widening and pleural effusion. Prompt initiation of antibiotics is essential because the mortality rate is likely 100% without specific treatment. Inhalational anthrax is not known to be contagious. Provided that there is no concern for release of another highly infectious agent such as smallpox, only routine precautions are warranted.
I-60. The answer is C. (Chap. 221) Using the characteristics listed in the question, the Centers for Disease Control and Prevention developed classifications of biologic agents that are based on their potential to be used as bioweapons. Six types of agents have been designated as category A: Bacillus anthracis, botulinum toxin, Yersinia pestis, smallpox, tularemia, and the many viruses that cause viral hemorrhagic fever. Those viruses include Lassa virus, Rift Valley fever virus, Ebola virus, and yellow fever virus.
I-61. The answer is C. (Chap. 222) Chemical agents were first used in modern warfare during World War I when 1.3 million died as a result of chemical agents. Since then, chemical agents have been used during warfare and bioterrorism, but most agents have a fairly low associated mortality rate. The chemical agents generally fall into one of five categories: nerve agents, asphyxiants, pulmonary damaging, vesicants, and behavior altering or incapacitating. Nerve agents include cyclohexyl sarin, sarin, soman, tabun, and VX and largely exert their effects through acetylcholinesterase inhibition. The most common asphyxiant is cyanide, which is liberated through cyanogen chloride or hydrogen cyanide. Chlorine gas, hydrogen chloride, nitrogen oxide, and phosgene are common agents that primarily cause pulmonary damage and adult respiratory distress syndrome. Vesicants include mustard gas and phosgene oxime, and agent 15/BZ is the primary chemical causing alterations in behavior or incapacitation.
I-62. The answer is D. (Chap. 222) Sulfur mustard was first used as a chemical warfare agent in World War I. This agent is considered a vesicant and has a characteristic odor of burning garlic or horseradish. It is a threat to all exposed epithelial surfaces, and the most commonly affected organs are the eyes, skin, and airways. Large exposures can lead to bone marrow suppression. Erythema resembling a sunburn is one of the earliest manifestations of sulfur mustard exposure and begins within 2 hours to 2 days of exposure. The timing of exposure can be delayed as long as 2 days depending on the severity of exposure, ambient temperature, and humidity. The most sensitive body areas are warm, moist locations, including the axillae, perineum, external genitalia, neck, and antecubital fossae. Blistering of the skin is frequent and may be anything from small vesicles to large bullae. The bullae are dome shaped and flaccid. Filled with clear or straw-colored fluid, these bullae are not hazardous because the fluid does not contain any vesicant substances. The respiratory passages are also affected. With mild exposure, the only manifestation may be a complaint of irritation and congestion. Laryngospasm may occur. In severe cases, there is necrosis of the airways with pseudomembrane formation. The damage that occurs after sulfur mustard exposure is airway predominant, and alveolar damage is very rare. The eyes are particularly sensitive to sulfur mustard and have a shorter latency period than the skin injury. Almost all exposed individuals develop redness of the eyes. With higher exposure, there is a greater severity of conjunctivitis and corneal damage. The cause of death after mustard gas exposure is sepsis or respiratory failure, but the mortality rate is typically low. Even during World War I, when antibiotics and endotracheal intubation were not available, the mortality rate was only 1.9%. There is no antidote to sulfur mustard. Complete decontamination in 2 minutes stops clinical injury, and decontamination within 5 minutes can decrease skin injury by half. Treatment is largely supportive.
I-63. The answer is A. (Chap. 222) Chlorine gas exposure primarily causes pulmonary damage and edema with respiratory distress syndrome. The initial decontamination of a victim exposed to chlorine gas should include removal of all clothing if no frostbite is present. The victim should gently wash the skin with soap and water with care to avoid aggressive bathing that may lead to serious abrasion of the skin. The eyes are flushed with water or normal saline. Supportive care should include forced rest, fresh air, and maintenance of a semiupright position. Oxygen is not required because the patient is not hypoxemic or in any respiratory distress. Delayed pulmonary edema can occur even if the patient is initially asymptomatic. Thus, observation for a period of time after exposure is required.
I-64 and I-65. The answers are D and D, respectively. (Chap. 222) This patient has symptoms of an acute cholinergic crisis as seen in cases of organophosphate poisoning. Organophosphates are the “classic” nerve agents, and several different compounds may act in this manner, including sarin, tabun, soman, and cyclosarin. Except for agent VX, all of the organophosphates are liquid at standard room temperature and pressure and are highly volatile, with the onset of symptoms occurring within minutes to hours after exposure. VX is an oily liquid with a low vapor pressure; therefore, it does not acutely cause symptoms. However, it is an environmental hazard because it can persist in the environment for a longer period. Organophosphates act by inhibiting tissue synaptic acetylcholinesterase. Symptoms differ between vapor exposure and liquid exposure because the organophosphate acts in the tissue upon contact. The first organ exposed with vapor exposure is the eyes, causing rapid and persistent pupillary constriction. After the sarin gas attacks in the Tokyo subway in 1994 and 1995, survivors frequently complained that their “world went black” as the first symptom of exposure. This is rapidly followed by rhinorrhea, excessive salivation, and lacrimation. In the airways, organophosphates cause bronchorrhea and bronchospasm. It is in the alveoli that organophosphates gain the greatest extent of entry into the blood. As organophosphates circulate, other symptoms appear, including nausea, vomiting, diarrhea, and muscle fasciculations. Death occurs with central nervous system penetration causing central apnea and status epilepticus. The effects on the heart rate and blood pressure are unpredictable.
Treatment requires a multifocal approach. Initially, decontamination of clothing and wounds is important for both the patient and the caregiver. Clothing should be removed before contact with the health care provider. In Tokyo, 10% of emergency personnel developed miosis related to contact with patients’ clothing. Three classes of medication are important in treating organophosphate poisoning, anticholinergics, oximes, and anti-convulsant agents. Initially, atropine at doses of 2–6 mg should be given intravenously or intramuscularly to reverse the effects of organophosphates at muscarinic receptors; it has no effect on nicotinic receptors. Thus, atropine rapidly treats life-threatening respiratory depression but does not affect neuromuscular or sympathetic effects. This should be followed by the administration of an oxime, which is a nucleophile compound that reactivates the cholinesterase whose active site has been bound to a nerve agent. Depending on the nerve agent used, oxime may not be helpful because it is unable to bind to “aged” complexes that have undergone degradation of a side chain of the nerve agent, making it negatively charged. Soman undergoes aging within 2 minutes, thus rendering oxime therapy useless. The currently approved oxime in the United States is 2-pralidoxime. Finally, the only anticonvulsant class of drugs that is effective in seizures caused by organophosphate poisoning is the benzodiazepines. The dose required is frequently higher than that used for epileptic seizures, requiring the equivalent of 40 mg of diazepam given in frequent doses. All other classes of anticonvulsant medications, including phenytoin, barbiturates, carbamazepine, and valproic acid, will not improve seizures related to organophosphate poisoning.
I-66. The answer is D. (Chap. 223) Detonation of a nuclear device is the most likely scenario of radiation bioterror. The initial blast will cause acute mortality caused by the shock wave and thermal damage. Subsequent mortality would be caused by acute radiation exposure and fallout to more distant populations that largely depend on weather patterns. The initial detonation releases mostly highly damaging gamma particles and neutrons. Alpha and beta particles are not highly toxic in this situation. Alpha particles are large, have limiting penetrating power, and are stopped by cloth and human skin. Beta particles, although small, travel only a short distance (a few millimeters) in tissue and cause mostly burn-type injuries. Radioactive iodine is a beta particle emitter. Acute radiation syndrome causes death by hematopoietic bone marrow suppression and aplasia; gastrointestinal tract damage with malabsorption and translocation of bacteria; and in severe cases, neurologic damage. Appropriate medical supportive therapy can reduce mortality and allow patient with more severe exposure to survive. Radiation causes dose-dependent bone marrow suppression that is irreversible at high doses. Bone marrow transplantation is controversial in cases of non-recovery of bone marrow. The acute exposure symptoms, predominantly thermal injury, respiratory distress, and GI symptoms, make resolve within days. However, subsequent bone marrow dysfunction typically develops within 2 weeks but may take as long as 6 weeks to manifest.
I-67. The answer is D. (Chap. 223) Much of the initial damage related to a “dirty” bomb is related to the power of the blast rather than the radiation. After a terrorist attack, it is important to identify all individuals who might have been exposed to radiation. The initial treatment of these individuals should be to stabilize and treat the most severely injured ones. Those with severe injuries should have contaminated clothing removed before transportation to the emergency department, but further care should not be withheld for additional decontamination because the risk of exposure to health care workers is low. Individuals with minor injuries who can be safely decontaminated without increasing the risk of medical complications should be transported to a centralized area for decontamination. A further consideration regarding treatment after radiation exposure is the total dose of radiation that an individual was exposed to. At a dose less than 2 Gy, there are usually no significant adverse outcomes, and no specific treatment is recommended unless symptoms develop. Many individuals will develop flulike symptoms. However, a complete blood count should be obtained every 6 hours for the first 24 hours because bone marrow suppression can develop with radiation exposure as low as 0.7 Gy. The earliest sign of this is a fall in the lymphocyte count of greater than 50%. Potential treatments of radiation exposure include use of colony-stimulating factors and supportive transfusions. Stem cell transfusion and bone marrow transplantation can be considered in the case of severe pancytopenia that does not recover. However, this is controversial, given the lack of experience with the procedure for this indication. After the Chernobyl nuclear reactor accident, none of the bone marrow transplants were successful.
I-68. The answer is B. (Chap. 16) The patient has a classic presentation of malignant hyper-thermia likely caused by succinylcholine or inhalational anesthetic administration as part of her anesthetic regimen. This syndrome occurs in individuals with inherited abnormality of skeletal muscle sarcoplasmic reticulum that causes a rise in intracellular calcium content after inhalational anesthetic or succinylcholine administration. The syndrome presents with hyperthermia, or an uncontrolled increase in body temperature that exceeds the ability of the body to lose heat; muscular rigidity; and acidosis, cardiovascular instability, and rhabdomyolysis. Because the temperature dysregulation is not attributable to alteration in hypothalamic set point, antipyretics such as acetaminophen, ibuprofen, and corticosteroids are ineffective at treating the condition. Haloperidol is associated with neuroleptic malignant syndrome and should not be used to treat this condition. Physical cooling in addition to dantrolene are the treatments of choice. Dantrolene disrupts excitation–contraction coupling in skeletal muscle, thereby diminishing thermogenesis. Dantrolene may also be used in neuroleptic malignant syndrome and occasionally the serotonin syndrome.
I-69. The answer is C. (Chap. 16) Hyperthermia occurs when exogenous heat exposure or an endogenous heat-producing process, such as neuroleptic malignant syndrome or malignant hyperthermia, leads to high internal temperatures despite a normal hypothalamic temperature set point. Fever occurs when a pyrogen such as a microbial toxin, microbe particle, or cytokine resets the hypothalamus to a higher temperature. A particular temperature cutoff point does not define hyperthermia. Rigidity and autonomic dysregulation are characteristic of malignant hyperthermia, a subset of hyperthermia. Fever, not hyperthermia, responds to antipyretics.
I-70. The answer is E. (Chap. 17) Elderly adults and young children are at highest risk of nonexertional heat stroke. Environmental stress (heat wave) is the most common precipitating factor, particularly in bedridden individuals and individuals living in poorly ventilated or non–air-conditioned conditions. Medications such as antiparkinson treatment, diuretics, and anticholinergics increase the risk of heat stroke.
I-71. The answer is A. (Chap. 17) Based on the characteristic rash and Koplik’s spots, this patient has measles. A rare but feared complication of measles is subacute sclerosing panencephalitis. His examination does not support epiglottitis because he has no drooling or dysphagia. His rash is not characteristic of acute HIV infection, and he lacks the pharyngitis and arthralgias commonly seen with this diagnosis. The rash is not consistent with herpes zoster, and he is quite young to have this condition. Splenic rupture occasionally occurs with infectious mononucleosis, but this patient has no pharyngitis, lymphadenopathy, or splenomegaly to suggest this diagnosis. Because of mandatory vaccination, measles is very uncommon in the United States (as well as central and south America); almost all cases are imported. However, countries with lower rates of vaccination still have endemic measles.
I-72. The answer is C. (Chap. 17) This case is likely toxic shock syndrome, given the clinical appearance of septic shock with no positive blood cultures. The characteristic diffuse rash, as well as the lack of a primary infected site, make Staphylococcus the most likely inciting agent. Streptococcal toxic shock usually has a prominent primary site of infection, but the diffuse rash is usually much more subtle than in this case. Staphylococcal toxic shock can be associated with immunosuppression, surgical wounds, or retained tampons. Mere Staphylococcus aureus colonization (with an appropriate toxigenic strain) can incite toxic shock. Centers for Disease Control and Prevention guidelines state that measles, Rocky Mountain spotted fever, and leptospirosis need to be ruled out serologically to confirm the diagnosis. However, this patient is at very low risk for these diagnoses based on vaccination and travel history. Juvenile rheumatoid arthritis would become a consideration only if the fevers were more prolonged and there was documented evidence of organomegaly and enlarged lymph nodes.
I-73. The answer is C. (Chap. 17) Although he never underwent joint fluid sampling, the presentation of monoarticular arthritis of the great toe in the context of a patient taking diuretics makes gout very likely. Allopurinol, although effective at controlling hyperuricemia, is a frequent culprit in drug-induced hypersensitivity syndromes. This syndrome generally presents with evidence of systemic hypersensitivity, including rash, eosinophilia, and often renal or hepatic dysfunction. Desquamative erythroderma and toxic epidermal necrolysis have been described additionally with allopurinol, but the absence of mucous membrane involvement makes TEN less likely. The absence of preexisting septic arthritis makes toxic shock less likely. Angioedema is not known to be associated with diffuse erythroderma. Diffuse erythema is not a feature of bacterial endocarditis, which frequently has associated focal skin lesions such as Osler lesions or Janeway nodes. Finally, in the absence of a focal area of infection, MRSA cellulitis would not explain the findings.
I-74. The answer is C. (Chap. 18) Fever of unknown origin (FUO) is defined as the presence of fevers to greater than 38.3°C (101.0°F) on several occasions occurring for more than 3 weeks without a defined cause after appropriate investigation into potential causes have failed to yield a diagnosis. Initial laboratory investigation into an FUO should include a complete blood count with differential, peripheral blood smear, ESR, C-reactive protein, electrolytes, creatinine, calcium, liver function tests, urinalysis, and muscle enzymes. In addition, specific testing for a variety of infections should be performed, including VDRL for syphilis, HIV, CMV, EBV, PPD testing, and blood, sputum, and urine cultures if appropriate. Finally, the workup should include evaluation for inflammatory disorders. These tests include antinuclear antibodies, rheumatoid factor, ferritin, iron, and transferrin. This patient has had a significant workup that has demonstrated primarily nonspecific findings, including elevation in the erythrocyte sedimentation rate and ferritin as well as borderline enlargement of multiple lymph nodes. The only finding that may help define further workup is the elevation in calcium levels. When combined with the clinical symptoms and prominent lymph nodes, this could suggest granulomatous diseases, including disseminated tuberculosis, fungal infections, or sarcoidosis. The next step in the work up of this patient would be to obtain a sample from an enlarged lymph node for cultures and pathology to confirm granulomatous inflammation and provide additional samples for microbiology. In recent studies, up to 30% of individuals will not have an identified cause of FUO, and infectious etiologies continue to comprise 25% of all FUO. The most common infection causing FUO is extrapulmonary tuberculosis, which may be difficult to diagnose because PPD is often negative in these individuals. However, one would not consider empirical therapy if the possibility to obtain definitive diagnosis exists through a procedure such as a needle biopsy because it is prudent to have not only the diagnosis but also the sensitivity profile of the organism to ensure appropriate therapy. Even in the presence of granulomatous infection, sarcoidosis would be considered a diagnosis of exclusion and would require definitive negative mycobacterial cultures before considering therapy with corticosteroids. Serum angiotensin-converting enzyme levels are neither appropriately sensitive nor specific for diagnosis of sarcoidosis and should not be used to determine if therapy is needed. PET-CT imaging would be unlikely to be helpful in this situation because the presence of granulomatous inflammation can lead to false-positive results or will confirm the presence of already characterized abnormal lymph nodes.
I-75. The answer is D. (Chap. 19) When evaluating a patient with hypothermia, it is important to consider all the possible factors that could contribute to hypothermia because treatment of hypothermia alone without treating the underlying cause could lead to delayed diagnosis and poor outcomes. In some instances, it is clear that the cause of hypothermia is simply prolonged exposure to cold without proper clothing. However, in patients such as this one, the clinician will need to look for findings that would be unexpected in a patient with hypothermia. This patient has a moderate degree of hypothermia (between 28.0°C and 32.2°C). At this range of hypothermia, the expected clinical presentation would be one of a global slowing of metabolism. Clinically, this would include a depressed level of consciousness with papillary dilatation. Often, these individuals experience a paradoxical instinct to take off their clothes. In addition, the heart rate, blood pressure, and respiratory rate would be expected to decrease. Carbon dioxide production by tissues typically decreases by 50% for each 8°C drop in body temperature. A common error in the treatment of individuals with hypothermia is overly aggressive hyperventilation in the face of this known decrease in carbon dioxide production.
In this patient, despite the hypothermia there is an increased respiratory rate in the setting of a metabolic acidosis. This finding suggests a lesion in the central nervous system or ingestion of an alcohol that would lead to a metabolic acidosis. Ingestion is confirmed by the presence of a very high anion gap (28) as well as an osmolar gap. The osmolar gap can be calculated as (Sodium × 2) + (BUN/2.8) + (Glucose/18) + (Ethanol/4.6). In this patient, the calculated osmolarity would be 301.6. Thus, the osmolar gap is 26, indicating the presence of some other osmotically active compound. In this case, it is prudent to measure toxic alcohol levels such as methanol and ethylene glycol.
In the management of the patient’s hypothermia, warmed intravenous fluids may be indicated. However, lactated Ringer’s solution should be avoided because the liver may be unable to metabolize lactate and lead to worsening metabolic acidosis. The cardiac complications of hypothermia may lead to bradyarrhythmias, but cardiac pacing is rarely indicated. If required, the transthoracic route is preferred because placement of any leads into the heart may lead to refractory ventricular arrhythmias.
I-76. The answer is B. (Chap. 19) This patient presents with frostbite of the left foot. The most common presenting symptom of this disorder is sensory changes that affect pain and temperature. Physical examination can have a multitude of findings, depending on the degree of tissue damage. Mild frostbite will show erythema and anesthesia. With more extensive damage, bullae and vesicles will develop. Hemorrhagic vesicles are caused by injury to the microvasculature. The prognosis is most favorable when the presenting area is warm and has a normal color. Treatment is with rapid rewarming, which usually is accomplished with a 37–40°C (98.6–104°F) water bath. The period of rewarming can be intensely painful for the patient, and often narcotic analgesia is warranted. If the pain is intolerable, the temperature of the water bath can be dropped slightly. Compartment syndrome can develop with rewarming and should be investigated if cyanosis persists after rewarming. No medications have been shown to improve outcomes, including heparin, steroids, calcium channel blockers, and hyperbaric oxygen. In the absence of wet gangrene or another emergent surgical indication, decisions about the need for amputation or debridement should be deferred until the boundaries of the tissue injury are well demarcated. After recovery from the initial insult, these patients often have neuronal injury with abnormal sympathetic tone in the extremity. Other remote complications include cutaneous carcinomas; nail deformities; and, in children, epiphyseal damage.
I-77. The answer is D. (Chap. 20) Syncope is a common medical complaint that occurs when there is global cerebral hypoperfusion. Syncope accounts for 3% of all emergency department visits and 1% of all hospitalizations. Additionally, it is estimated that 35% of all individuals will experience at least one syncopal event in their lifetimes. The most common cause of syncope in young adults is neurally mediated syncope. The incidence of neurally mediated syncope is higher in females and has a familial predisposition. Neurally mediated syncope represents a complex reflex arc of the autonomic nervous system and inherently requires an intact autonomic nervous system to occur. The final pathway of neurally mediated syncope is a surge of parasympathetic activity with inhibition of the sympathetic nervous system. This results in hypotension with accompanying bradycardia. Syncope occurs when blood flow to the brain drops abruptly. Triggers of the reflex pathway are varied. Vasovagal syncope is one category without a clearly defined trigger but can occur with intense emotions, strong odors, or orthostatic stress. Individuals who faint at the sight of blood experience vasovagal syncope. Neurally mediated syncope can also be brought about by specific situations such as cough, micturition, swallowing, or carotid sensitivity. The primary symptoms of neurally mediated syncope include premonitory symptoms such as lightheadedness and dizziness as well as parasympathetic symptoms such as diaphoresis, pallor, hyperventilation, pallor, and palpitation. Myoclonic jerks of the extremities can occur and be difficult to distinguish from seizure activity. On rare occasions, an individual may experience urinary incontinence, but fecal incontinence does not occur. Individuals usually recover very quickly from neurally mediated syncope with a rapid return to consciousness and previous level of alertness. Reassurance and avoidance of triggers are the primary treatments. Liberal intake of fluids and salt expand plasma volume and are protective against syncopal events. In randomized controlled trials, isometric counterpres-sure maneuvers (leg crossing or handgrip) are also protective. In patients with refractory syncope, fludrocortisone, beta-blockers, or vasoconstricting agents have been used with clinical success, although there are no clinical trial data to support their use.
I-78. The answer is A. (Chap. 20) The cornerstone of the evaluation of syncope is to perform an thorough history and examination. Clues to the cause of syncope include the presence of prodromal symptoms, presence of injury, and eyewitness accounts of the event. Neurally mediated syncope is one of the most common causes of syncope and often has preceding lightheadedness or dizziness. Orthostatic hypotension is also frequently preceded by symptoms of lightheadedness and is more common in older individuals. Likewise, older individuals are at greater risk of cardiac syncope. Cardiac syncope needs to be considered as cardiac syncope caused by structural heart disease or primary arrhythmia is associated with an increased risk of sudden cardiac death. Cardiac syncope is more likely to occur without warning symptoms and is more likely to have associated serious injury. Hypoglycemia can present with syncope as well and needs to be considered in this case. Neurologic causes of syncope include seizures and vertebrobasilar insufficiency. A cerebrovascular accident does not commonly cause syncope because bihemispheric disruption of cerebral blood flow is necessary to cause loss of consciousness.
In this individual, evaluation should include fingerstick glucose measurement, orthostatic blood pressures, and an electrocardiogram. Tilt table testing can be considered, particularly because the patient has had recurrent episodes of syncope in the past. A head CT scan, however, should not be a routine part of the evaluation of syncope unless there is concern about a head injury that occurred as a result of the syncope.
I-79. The answer is D. (Chap. 21) Dizziness is a common complaint affecting approximately 20% of the population over the course of the year. Most dizziness is benign, self-limited, and must be distinguished from vertigo. Although dizziness is often described as a sensation of lightheadedness, vertigo is more often described as a sensation that the room is spinning. Vertigo is most commonly from peripheral causes affecting labyrinths of the inner ear or the vestibular nerve. However, central lesions of the brainstem and cerebellum can also lead to vertigo. Features of the history and physical examination can be useful in determining central versus peripheral causes of vertigo. By history, deafness or tinnitus is typically absent with central lesions. On physical examination, spontaneous nystagmus is most often a sign of central vertigo, although it can be seen with acute vestibular neuritis. Specific patterns of vertigo that are characteristic of lesions in the cerebellar pathways are vertical nystagmus with a downward fast phase (downbeat nystagmus) and horizontal nystagmus that changes direction with gaze (gaze-evoked nystagmus). Alternatively, in peripheral vertigo, nystagmus typically is provoked by positional maneuvers and can be inhibited by visual fixation. Visual fixation does not, however, inhibit nystagmus in central lesions. Finally, central causes of nystagmus are more likely to be associated with other symptoms that would lead one to suspect a central cause. These include hiccups, diplopia, cranial neuropathies, and dysarthria.
I-80. The answer is C. (Chap. 21) The symptoms and physical examination of this patient are typical of benign paroxysmal positional vertigo (BPPV). Episodes of BPPV are typically quite brief, lasting no more than 1 minute, and are brought about by changes in position relative to gravity. Typical movements that elicit the vertigo are lying down, rolling over in bed, rising from the supine position, and tilting the head to look upward. The labyrinth of the inner ear is responsible for process information with regards to position and movement. It consists of three semicircular canals: the superior canal, the posterior canal, and the horizontal canal. BPPV results when calcium carbonate crystals called otoconia migrate from the utricle of the inner ear into the semicircular canals. By far, the most commonly affected canal is the posterior one. When this occurs, vertigo is accompanied by nystagmus that beats upward and torsionally toward the affected ear. This can be brought about by the Dix-Hallpike maneuver, which is described in the clinical scenario. Less commonly, the horizontal canal is affected, leading to horizontal nystagmus. The primary treatment of BPPV is repositioning therapy that uses gravity to remove the otoconia from the affected canal. The Epley maneuver is the most common repositioning procedure.
The history and physical examination are not consistent with a central cause of vertigo; therefore, a brain MRI is not indicated. Methylprednisolone is the primary treatment of acute vestibular neuritis if used within the first 3 days of symptoms. Acute vestibular neuritis often presents with more prolonged symptoms that persist even when there is no movement of the head. Most patients recover spontaneously, but when used early, methylprednisolone will decrease the duration of symptoms. There is no indication for the use of antiviral therapy unless there is obvious herpes zoster infection. Likewise, the symptoms are not consistent with migrainous vertigo, which would be persistent for hours and not be affected by positional changes. Thus, the use of rizatriptan would not be helpful.
I-81. The answer is D. (Chap. 22) Complaints of weakness in a patient have a multitude of causes, and it is important to perform a thorough history and physical examination to help localize the site of weakness. Lower motor neuron diseases occur when there is destruction of the cell bodies of the lower motor neurons in the brainstem or the anterior horn of the spinal cord. Lower motor neuron diseases can also occur because of direct axonal dysfunction and demyelination. The primary presenting symptoms are those of distal muscle weakness such as tripping or decreased hand grip strength. When a motor neuron becomes diseased, it may discharge spontaneously, leading to muscle fasciculations that are not seen in disease of the upper motor neurons or myopathies. Additionally, on physical examination, lower motor neuron disease leads to decreases in muscle tone and decreased or absent deep tendon reflexes. Over time, severe muscle atrophy can occur. A Babinski sign should not be present. If there is evidence of a Babinski sign in the presence of lower motor neuron disease, this should raise the suspicion of a disorder affecting both upper and lower motor neurons such as amyotrophic lateral sclerosis.
I-82. The answer is E. (Chap. 24) Approximately 15% of individuals older than 65 years have an identifiable gait disorder. By age 80 years, 25% of individuals require a mechanical aid to assist ambulation. Proper maintenance of gait requires a complex interaction between central nervous system centers to integrate postural control and locomotion. The cerebellum, brainstem, and motor cortex simultaneously process information regarding the environment and purpose of the motion to allow for proper gait and avoidance of falls. Any disorder affecting either sensory input regarding the environment or central nervous system output has the potential to affect gait. In most case series, the most common cause of gait disorders is a sensory deficit. The causes of sensory deficits can quite broad and include peripheral sensory neuropathy from a variety of causes, including diabetes mellitus, peripheral vascular disease, and vitamin B12 deficiency, among many others. Other common causes of gait disorders include myelopathy and multiple cerebrovascular infarcts. Although Parkinson’s disease is almost inevitably marked by gait abnormalities, it occurs less commonly in the general population than the previously discussed disorders. Likewise, cerebellar degeneration is frequently associated with gait disturbance but is a less common disorder in the general population.
I-83. The answer is B. (Chap. 24) Characteristics found during the neurologic examination can assist with the localization of disease in gait disorders. In this case, the patient presents with signs of a frontal gait disorder or parkinsonism. The specific characteristics that would be seen with a frontal gait disorder are a wide-based stance with slow and short shuffling steps. The patient may have difficulty rising from a chair and has a slow, hesitating start. Likewise, there is great difficult with turning with multiple steps required to complete a turn. The patient has very significant postural instability. However, cerebellar signs are typically absent. Romberg sign may or may not be positive, and seated cerebellar testing results are normal, including heel-to-shin testing and rapid alternating movements. Additionally, there should otherwise be normal muscle bulk and tone without sensory or strength deficits. The most common cause of frontal gait disorders (sometimes known as gait apraxia) is cerebrovascular disease, especially small vessel subcortical disease. Communicating hydrocephalus also presents with a gait disorder of this type. In some individuals, the gait disorder precedes other typical symptoms such as incontinence or mental status change.
Alcoholic cerebellar degeneration and multiple system atrophy present with signs of cerebellar ataxia. Characteristics of cerebellar ataxia include a wide-based gait with variable velocity. Gait initiation is normal, but the patient is hesitant during turns. The stride is lurching and irregular. Falls are a late event. The heel-to-shin test is abnormal, and the Romberg test is variably positive.
Neurosyphilis and lumbar myelopathy are examples of sensory ataxia. Sensory ataxia presents with frequent falls. The gait with sensory ataxia, however, is narrow based. Often the patient is noted to be looking down while walking. The patient tends to walk slowly but have path deviation. Gait is initiated normal, but the patient may have some difficulty with turning. The Romberg test is typically unsteady and may result in falls.
I-84. The answer is D. (Chap. 25) Delirium is an acute confusional state that most frequently occurs in the context of an acute medical illness. Fluctuating levels of cognitive function with a particular deficit of attention are the primary clinical features of delirium. All levels of cognitive function, however, are invariably involved, including memory, language, and executive functioning. Other common associated symptoms are sleep–wake disturbances, hallucinations or delusions, affect changes, and changes in heart rate or blood pressure. Delirium remains a clinical diagnosis and is believed to affect as much as 50% of hospitalized patients. For elderly patients in intensive care, the incidence rises to between 70 and 87%. However, it has been estimated the diagnosis is missed in one-third of individuals with delirium. Once thought of as an acute but benign condition, increasing research is demonstrating delirium to have persisting effects on cognition and functioning. Delirium typically is short lived, but some episodes of delirium can last for weeks, months, or even years. When delirium persists for longer periods of time, it is thought to represent inadequate treatment of the cause of delirium or permanent neuronal damage from the episode. Delirium also has significant associated morbidity and mortality. A single episode of delirium in hospitalized patients has been associated with an in-hospital mortality rate as high as 25–33%. However, the increased mortality is not simply limited to the hospital stay. Individuals experiencing delirium in the hospital have increased mortality for the next several months to years. In addition, these individuals experience a longer hospital length of stay and are less likely to return to functional independence. Individuals who experience delirium are more likely to be discharged to nursing home care and are at increased risk of rehospitalization.
I-85. The answer is B. (Chap. 25) This patient has features of acute delirium, which can be precipitated by many causes in hospitalized patients. Broad categories of causes of delirium include toxins, medication reactions, metabolic disorders, infections, endocrine disorders, cerebrovascular disorders (especially hypertensive encephalopathy), autoimmune disorders, seizures, neoplastic disorders, and hospitalization. Although the list of causes is broad, the initial history and physical examination are important to establish potential etiologies of delirium and guide further workup. In most patients with delirium, it is difficult to obtain an accurate history; therefore, it is important to seek out a spouse of family member to outline the history further. In this case, there are features that could suggest alcohol withdrawal (hypertension, tachycardia, fevers, tremors), and one should clarify his alcohol intake with his wife. Another primary consideration in determining the etiology of a delirium episode is the time course over which it evolves and the current medications. Particularly in older hospitalized individuals, common medications used as sleep aids, such as diphenhydramine, can have a paradoxical effect with delirium and agitation. It is estimated that as many as one-third of episodes of delirium in hospitalized patients are the result of medications. Worsening infection also needs to be considered because the change in the patient’s vital signs could be indicative of an infectious source, although the elevated blood pressure is not consistent with this. Because the patient has required oxygen during his hospitalization, it is important to check an oxygen saturation or arterial blood gas because acute hypoxemia or hypercarbia can precipitate delirium. Likewise, given the patient’s history of diabetes mellitus, a fingerstick glucose is necessary because hypoglycemia could also lead to alterations in mental status with evidence of tachycardia, tremor, and diaphoresis. Other initial tests to consider in an individual with delirium are electrolytes and basic liver and kidney function. Although commonly ordered, brain imaging is most often not helpful in the evaluation of delirium.
I-86. The answer is C. (Chap. 25) Confusion is defined as a mental and behavioral state of reduced comprehension, coherence, and capacity to reason. Delirium is used to describe an acute confusional state. Delirium often goes unrecognized despite clear evidence that it is often a cognitive manifestation of many medical and neurologic illnesses. Delirium is a clinical diagnosis that may be hyperactive (e.g., alcohol withdrawal) or hypoactive (e.g., opiate intoxication). There is often dramatic fluctuation between states. Delirium is associated with a substantial mortality rate with in-hospital mortality estimates ranging from 25–33%. Overall estimates of delirium in hospitalized patients range from 15–55% with higher rates in elderly adults. Patients in the intensive care unit have especially high rates of delirium, ranging from 70–87%. The clinic setting represents the lowest risk. Postoperative patients, especially after hip surgery, have an incidence of delirium that is somewhat higher than patients admitted to the medical wards.
I-87. The answer is B. (Chap. 26) When evaluating someone who reports difficulty with language, it is important to assess speech in several different domains, which are spontaneous speech, comprehension, repetition, naming, reading, and writing. Anomia refers to the inability to name common objects and is the most common finding in patients with aphasia. Indeed, anomia is present in all types of aphasia except pure word deafness or pure alexia. Anomia can present in many fashions, including complete an inability to name, provision of a related word (“pen” for “pencil”), a description of the word (“a thing for writing”), or the wrong word. Fluency is assessed by listening to spontaneous speech. Fluency is decreased in Broca’s or global aphasia but is relatively preserved in other forms of aphasia. Comprehension is assessed by asking patients to follow conversation and provide simple answers (yes/no, pointing to appropriate objects). The most common aphasia presenting with deficits of comprehension is Wernicke’s aphasia in which fluent but nonsensical spontaneous speech (word salad) is present. Repetition asks patients to repeat a string of words, sentences, or a single word and is impaired in many types of aphasia. In addition, repetition of tongue twisters can be useful in the evaluation of dysarthria or palilalia as well. Alexia refers to the inability to read aloud or comprehend written language.
I-88. The answer is C. (Chap. 26) The parietofrontal area of the brain is responsible for spatial orientation. The major components of the network include the cingulate cortex, posterior parietal cortex, and the frontal eye fields. In addition, subcortical areas in the striatum and thalamus are also important. Together, these systems integrate information to maintain spatial cognition, and a lesion in any of these areas can lead to hemispatial neglect. In neglect syndromes, three behavioral manifestations are seen: Sensory events in the neglected hemisphere have less overall impact; there is a paucity of conscious acts directed toward the neglected hemisphere; and the patient behaves as if the neglected hemisphere is devalued. In Figure I-88, almost all of the As (the target) represented on the left half of the figure are missed. This is an example of a target detection task. Hemianopia alone is not sufficient to cause this finding because the individual can turn his or her head left and right to identify the targets.
Bilateral disorders of the parietofrontal area of the brain can lead to severe spatial disorientation known as Balint’s syndrome. In Balint’s syndrome, there is inability to orderly scan the environment (oculomotor apraxia) and inaccurate manual reaching for objects (optic apraxia). A third finding in Balint’s syndrome is simultanagnosia. Simultanagnosia is the inability to integrate information in the center of the gaze with peripheral information. An example is a target detection test in which only the A’s present in the outer portion of the figure would be indicated. Individuals with this finding also tend to miss the larger objects in a figure and would not be able to accurately identify the target when it was made much larger than the surrounding letters. Construction apraxia refers to the inability to copy a simple line drawing such as a house or star and occurs most commonly in association with parietal lesions. Object agnosia is the inability to name a generic object or describe its use in contrast to anomia when an individual should be able to describe the use of the object even if it cannot be named. The defect in the object agnosia is usually in the territory of the bilateral posterior cerebral arteries.
I-89. The answer is C. (Chap. 27) Shift work sleep disorder is a disorder of the circadian rhythm that is common in any individual who has to commonly work at night. At present, an estimated 7 million individuals in the United States work permanently at night or on rotating shifts. Increasing research devoted to sleep disorders in night shift workers has demonstrated that the circadian rhythm never fully shifts to allow one to perform at full alertness at night. The reason for this is likely multifactorial and includes the fact that most individuals who work at night try to abruptly shift their sleep schedules to a more normal pattern on days when they are not working. Consequently, night shift workers often have chronic sleep deprivation, increased length of time awake before starting work, and misalignment of their circadian phase with the intrinsic circadian phase. The results of this lead to decreased alertness and increased errors during night shifts. In an estimated 5–10% of individuals working night shifts, the excessive sleepiness during the night and insomnia during the day are deemed to be clinically significant. Strategies for treating shift work sleep disorder use a combination of behavioral and pharmacologic strategies. Caffeine does promote wakefulness, but the effects are not long lasting, and tolerance develops over time. Brief periods of exercise frequently boost alertness and can be used before starting a night shift or during the shift at times of increased sleepiness. Many sleep experts support strategic napping during shifts for no more than 20 minutes at times of circadian nadirs. Naps longer than 20 minutes can lead to sleep inertia during which an individual may feel very disoriented and groggy and experience a decline in motor skills upon abrupt awakening from sleep. Bright lights before and during night shift work may improve alertness, but one must be careful to avoid bright lights in the morning after a night shift because light entrainment is a powerful stimulus of the internal circadian clock. If an individual is exposed to bright light in the morning, it will interfere with the ability to fall asleep during the day. Night shift workers should be encouraged to wear dark sunglasses in the morning on the way home. Sleep during the day is frequently disrupted in night shift workers. Creating a quiet, dark, and comfortable environment is important, and sleep should be a priority for the individual during the day. The only pharmacologic therapy approved by the Food and Drug Administration for treatment of shift work sleep disorder is modafinil 200 mg taken 20–30 minutes before the start of a night shift. Modafinil has been demonstrated to increase sleep latency and decrease attentional failures during night shifts but does not alleviate the feelings of excessive sleepiness. Melatonin is not one of the recommended therapies for shift work sleep disorder. If used, it should be taken 2–3 hours before bedtime rather than right before bedtime to simulate the normal peaks and troughs of melatonin secretion.
I-90. The answer is C. (Chap. 27) This patient complains of symptoms that are consistent with restless legs syndrome (RLS). This disorder affects 1–5% of young to middle-aged individuals and as many as 20% of older individuals. The symptom of RLS is a nonspecific uncomfortable sensation in the legs that begins during periods of quiescence and is associated with the irresistible urge to move. Patients frequently find it difficult to describe their symptoms but usually describe the sensation as deep within the affected limb. Rarely is the sensation described as distinctly painful unless an underlying neuropathy is also present. The severity of the disorder tends to wax and wane over time and tends to worsen with sleep deprivation, caffeine intake, pregnancy, and alcohol. Renal disease, neuropathy, and iron deficiency are known secondary causes of RLS symptoms. In this patient, correcting the iron deficiency is the best choice for initial therapy because this may entirely relieve the symptoms of RLS. For individuals with primary RLS (not related to another medical condition), the dopaminergic agents are the treatment of choice. Pramipexole or ropinirole is recommended as first-line treatment. Although carbidopa/levodopa is highly effective, individuals have a high risk of developing augmented symptoms over time with increasingly higher doses needed to control the symptoms. Other options for treating RLS include narcotics, benzodiazepines, and gabapentin. Hormone replacement therapy has no role in the treatment of RLS.
I-91. The answer is A. (Chap. 27) Narcolepsy is a sleep disorder characterized by excessive sleepiness with intrusion of rapid eye movement (REM) sleep into wakefulness. Narcolepsy affects about one in 4000 individuals in the United States with a genetic predisposition. Recent research has demonstrated that narcolepsy with cataplexy is associated with low or undetectable levels of the neurotransmitter hypocretin (orexin) in the CSF. This neurotransmitter is released from a small number of neurons in the hypothalamus. Given the association of narcolepsy with the major histocompatibility antigen human leukocyte antigen DQB1*0602, it is thought that narcolepsy is an autoimmune process that leads to destruction of the hypocretin-secreting neurons in the hypothalamus. The classic symptom tetrad of narcolepsy is (1) cataplexy, (2) hypnagogic or hypnopompic hallucinations, (3) sleep paralysis, and (4) excessive daytime somnolence. Of these symptoms, cataplexy is the most specific for the diagnosis of narcolepsy. Cataplexy refers to the sudden loss of muscle tone in response to strong emotions. It most commonly occurs with laughter or surprise but may be associated with anger as well. Cataplexy can have a wide range of symptoms from mild sagging of the jaw lasting for a few seconds to a complete loss of muscle tone lasting several minutes. During this time, individuals are aware of their surroundings and are not unconscious. This symptom is present in 76% of individuals diagnosed with narcolepsy and is the most specific finding for the diagnosis. Hypnagogic and hypnopompic hallucinations and sleep paralysis can occur from any cause of chronic sleep deprivation, including sleep apnea and chronic insufficient sleep. Excessive daytime somnolence is present in 100% of individuals with narcolepsy but is not specific for the diagnosis because this symptom may be present with any sleep disorder as well as with chronic insufficient sleep. The presence of two or more REM periods occurring during a daytime multiple sleep latency test is suggestive but not diagnostic of narcolepsy. Other disorders that may lead to presence of REM during short daytime nap periods include sleep apnea, sleep phase delay syndrome, and insufficient sleep.
I-92. The answer is B. (Chap. 27; http://www.sleepfoundation.org/site/c.huIXKjM0IxF/b.2417355/k.143E/2002_Sleep_in_America_Poll.htm, accessed May 12, 2011) Insomnia is the most common sleep disorder in the population. In the 2002 Sleep in America Poll, 58% of respondents reported at least one symptom of insomnia on a weekly basis, and one-third of individuals experience these symptoms on a nightly basis. Insomnia is defined clinically as the inability to fall asleep or stay asleep, which leads to daytime sleepiness or poor daytime function. These symptoms occur despite adequate time and opportunity for sleep. Insomnia can be further characterized as primary or secondary. Primary insomnia occurs in individuals with an identifiable cause of insomnia and is often a long-standing diagnosis for many years. Within the category of primary insomnia is adjustment insomnia, which is typically of short duration with a well-defined stressor. Secondary causes of insomnia include comorbid medical or psychiatric conditions and can be related to caffeine or illegal and prescribed drugs. Obstructive sleep apnea is thought to affect as many as 10–15% of the population and is currently underdiagnosed in the United States. In addition, because of the rising incidence of obesity, obstructive sleep apnea is also expected to increase in incidence over the coming years. Obstructive sleep apnea occurs when there is ongoing effort to inspire against an occluded oropharynx during sleep. It is directly related to obesity and has an increased incidence in men and in older populations. Narcolepsy affects 1 in 4000 people and is caused by deficit of hypocretin (orexin) in the brain. Symptoms of narcolepsy include a sudden loss of tone in response to emotional stimuli (cataplexy), hypersomnia, sleep paralysis, and hallucinations with sleep onset and waking. Physiologically, there is intrusion or persistence of rapid eye movement sleep during wakefulness that accounts for the classic symptoms of narcolepsy. Restless legs syndrome is estimated to affect 1–5% of young to middle-aged adults and as many as 10–20% of elderly adults. Restless legs syndrome is marked by uncomfortable sensations in the legs that are difficult to describe. The symptoms have an onset with quiescence, especially at night, and are relieved with movement. Delayed sleep phase syndrome is a circadian rhythm disorder that commonly presents with a complaint of insomnia and accounts for as much as 10% of individuals referred to the sleep clinic for evaluation of insomnia. In delayed sleep phase syndrome, the intrinsic circadian rhythm is delayed such that sleep onset occurs much later than normal. When allowed to sleep according to the intrinsic circadian rhythm, individuals with delayed sleep phase syndrome sleep normally and do not experience excessive somnolence. This disorder is most common in adolescence and young adulthood.
I-93. The answer is C. (Chap. 27) Parasomnias are abnormal behaviors or experiences that arise from slow-wave sleep. Also known as confusional arousals, the electroencephalogram during a parasomnia event frequently shows persistence of slow-wave (delta) sleep into arousal. Non–rapid eye movement (NREM) parasomnias may also include more complex behavior, including eating and sexual activity. Treatment of NREM parasomnias is usually not indicated, and a safe environment should be assured for the patient. When injury is likely to occur, treatment with a drug that decreases slow-wave sleep will treat the parasomnia. Typical treatment is a benzodiazepine. There are no typical parasomnias that arise from stage I or stage II sleep. REM parasomnias include nightmare disorder and REM-behavior disorder. REM-behavior disorder is increasingly recognized as associated with Parkinson’s disease and other parkinsonian syndromes. This disorder is characterized by the absence of decreased muscle tone in REM sleep, which leads to the acting out of dreams, sometimes resulting in violence and injury.
I-94. The answer is E. (Chap. 28) (See Figure I-94.) Bitemporal hemianopia is caused by a lesion at the optic chiasm because fibers there decusate into the contralateral optic tract. Crossed fibers are more damaged by compression than uncrossed fibers. This finding is usually caused by symmetric compression in the sellar region by a pituitary adenoma, meningioma, craniopharyngioma, glioma, or aneurysm. These lesions are often insidious and may be unnoticed by the patient. They will escape detection by the physician unless each eye is tested separately. Lesions anterior to the chiasm (retinal injury, optic nerve injury) will cause unilateral impairment and an abnormal pupillary response. Postchiasmic lesions (temporal, parietal, occipital cortex) cause homonymous lesions (similar field abnormalities in both eyes) that vary with location. Occlusion of the posterior cerebral artery supplying the occipital lobe is a common cause of total homonymous hemianopia.
I-95. The answer is E. (Chap. 28) The differential diagnosis of a red, painful eye is broad and includes corneal abrasion, subconjunctival hemorrhage, infective or allergic conjunctivitis (the most common cause of red, painful eye), keratoconjunctivitis sicca (medications, Sjogren’s syndrome, sarcoidosis), keratitis (contact lens injury, trachoma, vitamin A deficiency), herpes infection, episcleritis (autoimmune, idiopathic), scleritis (autoimmune), uveitis, endophthalmitis, or acute angle-closure glaucoma. Uveitis requires slit-lamp examination for diagnosis. Anterior uveitis involving the iris is usually idiopathic but may be associated with sarcoidosis, ankylosing spondylitis, juvenile rheumatoid arthritis, inflammatory bowel disease, psoriasis, inflammatory arthritis, Behçet’s disease, and a variety of infections. Posterior uveitis in the vitreous, retina, or choroid is more likely to be associated with a systemic disease or infection than anterior uveitis. Acute angle-closure glaucoma, although rare, is often misdiagnosed unless intraocular pressure is measured. Many physicians avoid dilating patients’ pupils for fear of provoking acute angle-closure glaucoma. The risk is remote and rarely causes permanent vision loss. The value of a complete funduscopic examination outweighs the risk of this rare event. Transient ischemic attack (TIA) caused by temporary interruption of blood flow to the retina for more than a few seconds causes transient visual abnormality (amaurosis fugax). TIA is usually associated with atherosclerosis. If flow is restored quickly vision returns to normal.
I-96. The answer is A. (Chap. 28) Age-related macular degeneration is a major cause of painless, gradual bilateral central visual loss. It occurs as nonexudative (dry) or exudative (wet) forms. Recent genetic data have shown an association with the alternative complement pathway gene for complement factor H. The mechanism link for that association is unknown. The nonexudative form is associated with retinal drusen that leads to retinal atrophy. Treatment with vitamin C, vitamin E, beta-carotene, and zinc may retard the visual loss. Exudative macular degeneration, which is less common, is caused by neovascular proliferation and leakage of choroidal blood vessels. Acute visual loss may occur because of bleeding. Exudative macular degeneration may be treated with intraocular injection of a vascular endothelial growth factor antagonist (bevacizumab or ranibizumab). Blepharitis is inflammation of the eyelids usually related to acne rosacea, seborrheic dermatitis, or staphylococcal infection. Diabetic retinopathy, now a leading cause of blindness in the United States, causes gradual bilateral visual loss in patients with longstanding diabetes. Retinal detachment is usually unilateral and causes visual loss and an afferent pupillary defect.
I-97. The answer is B. (Chap. 29) A history of severe respiratory infection, including the common cold, influenza, pneumonia, or HIV, is the most common cause of long-lasting loss of smell. The mechanism, along with cases of chronic rhinosinusitis (another common cause) is likely related to permanent damage to the olfactory epithelium. Head trauma, causing shearing and scarring of olfactory fila at the cribiform plate, may cause anosmia. Fewer than 10% of patients with posttraumatic anosmia regain normal function. The severity of disease is associated with the likelihood of olfactory abnormality in trauma and chronic rhinosinusitis. Significant decrements in smell are present in more than 50% of people older than 65 years old. This finding may explain the common finding of loss of food flavor and nutritional deficiencies in elderly adults. Confirming popular wisdom studies have shown that at any age, women have a better ability to identify odorants than men (Figure I-97).
I-98. The answer is E. (Chap. 30) Hearing loss is a common complaint, particularly in older individuals. In this age group, 33% have hearing loss to a degree that requires hearing aids. When evaluating hearing loss, the physician should attempt to determine whether the cause is conductive, sensorineural, or mixed. Sensorineural hearing loss results from injury of the cochlear apparatus or disruption of the neural pathways from the inner ear to the brain. The primary site of damage is the hair cells of the inner ear. Common causes of hair cell injury include prolonged exposure to loud noises, viral infections, ototoxic drugs, cochlear otosclerosis, Meniere’s disease, and aging. In contrast, conductive hearing loss results from impairment of the external ear and auditory canal to transmit and amplify sound through the middle ear to the cochlea. Causes of conductive hearing loss include cerumen impaction, perforations of the tympanic membrane, otosclerosis, cholesteatomas, large middle ear effusions, and tumors of the external auditory canal or middle ear among others. The initial physical examination can often differentiate between conductive or sensorineural hearing loss. Examination of the external auditory canal can identify cerumen or foreign body impaction. On otoscopic examination, it is more important to assess the topography of the tympanic membrane than to look for the presence of a light reflex. Of particular attention is the area in the upper third of the tympanic membrane known as the pars flaccida. This area can develop chronic retraction pockets that are indicative of Eustachian tube dysfunction or a cholesteatoma, a benign tumor composed of keratinized squamous epithelium. Bedside tests with a tuning fork also are useful for differentiating conductive from sensorineural hearing loss. In the Rinne’s test, air conduction is compared with bony conduction of sound. A tuning fork is placed over the mastoid process and then in front of the external ear. In conductive hearing loss, the intensity of sound is louder when placed on the bone, but in sensorineural hearing loss, the intensity is greatest at the external ear. In the Weber test, the tuning fork is placed in the midline of the head. In unilateral conductive hearing loss, the intensity of sound is loudest in the affected ear, but in unilateral sensorineural hearing loss, the intensity of sound is loudest in the unaffected ear. This patient reports left greater than right hearing loss that is suspected to be sensorineural in nature. Thus, the sound is expected to be greatest in the right ear on the Weber test. A more formal evaluation of hearing loss would include pure tone audiometry that plots hearing threshold versus frequency. Pure tone audiometry establishes the severity, type, and laterality of hearing loss. In this patient, high-frequency hearing loss would be expected based on his complaints of inability to hear the alarm tone of his digital watch.
I-99. The answer is E. (Chap. 31) Acute sinusitis is a common complication of upper respiratory tract infections and is defined as sinusitis lasting less than 4 weeks’ duration. Acute sinusitis typically presents with nasal drainage and congestion, facial pain or pressure, and headache that is worse with lying down or bending forward. The presence of purulent drainage does not differentiate bacterial from viral causes of sinusitis. The vast majority of cases of acute sinusitis are caused by viral infection. However, when patients with acute sinusitis present to a medical professional, antibiotics are prescribed more than 85% of the time. Indeed, this should not be the preferred treatment because most cases improve without antibiotic therapy. Rather, the initial approach to a patient with acute sinusitis should be symptomatic treatment with nasal decongestants and nasal saline lavage. If a patient has a history of allergic rhinitis or chronic sinusitis, nasal glucocorticoids can be prescribed as well. Antibiotic therapy is recommended in adults for symptom duration longer than 7–10 days and in children longer than 10–14 days. In addition, any patient with concerning features such as unilateral or focal facial pain or swelling should be treated with antibiotics. The initial antibiotic of choice for acute sinusitis is amoxicillin 500 mg orally three times daily or 875 mg twice daily. If a patient has had exposure to antibiotics within the past 30 days or treatment failure, a respiratory fluoroquinolone can be give. Ten percent of individuals do not respond to initial antibiotic therapy. In these cases, one can consider referral to otolaryngology for sinus aspiration and culture. Radiologic imaging of the sinuses is not recommended for evaluation of acute disease unless the sinusitis is nosocomially acquired because the procedures (CT or radiography) do not differentiate between bacterial or viral causes.
I-100. The answer is B. (Chap. 31) Approximately 5–15% of all cases of acute pharyngitis in adults are caused by Streptococcus pyogenes. Appropriate identification and treatment of S. pyogenes infection is needed because antibiotic therapy is recommended to decrease the small risk of acute rheumatic fever. In addition, treatment with antibiotics within 48 hours of onset of symptoms decreases symptom duration and, importantly, decreases transmission of streptococcal pharyngitis. In adults, the recommended diagnostic procedure by the Centers for Disease Control and Prevention and the Infectious Disease Society of America is a rapid antigen detection test for group A streptococci only. In children, however, the recommendation is to perform a throat culture for confirmation if the rapid screen result is negative to limit spread of disease and minimize potential complications. Throat culture generally is regarded as the most appropriate diagnostic method but cannot discriminate between colonization and infection. In addition, it takes 24–48 hours to get a result. Because most cases of pharyngitis at all ages are viral in origin, empiric antibiotic therapy is not recommended.
I-101. The answer is D. (Chap. 33) Shortness of breath, or dyspnea, is a common presenting complaint in primary care. However, dyspnea is a complex symptom and is defined as the subjective experience of breathing discomfort that includes components of physical as well as psychosocial factors. A significant body of research has been developed regarding the language by which a patient describes dyspnea with certain factors being more common in specific diseases. Individuals with airways diseases (asthma, chronic obstructive pulmonary disease [COPD]) often describe air hunger, increased work of breathing, and the sensation of being unable to get a deep breath because of hyperinflation. In addition, individuals with asthma often complain of a tightness in the chest. Individuals with cardiac causes of dyspnea also describe chest tightness and air hunger but do not have the same sensation of being unable to draw a deep breath or have increased work of breathing. A careful history will also lead to further clues regarding the cause of dyspnea. Nocturnal dyspnea is seen in congestive heart failure or asthma, and orthopnea is reported in heart failure, diaphragmatic weakness, and asthma that is triggered by esophageal reflux. When discussing exertional dyspnea, it is important to assess if the dyspnea is chronic and progressive or episodic. Whereas episodic dyspnea is more common in myocardial ischemia and asthma, COPD and interstitial lung diseases present with a persistent dyspnea. Platypnea is a rare presentation of dyspnea in which a patient is dyspneic in the upright position and feels improved with lying flat. On physical examination of a patient with dyspnea, the physician should observe the patient’s ability to speak and the use of accessory muscle or preference of the tripod position. As part of vital signs, a pulsus paradoxus may be measured with a value of greater than 10 mmHg common in asthma and COPD. Pulsus paradoxus greater than 10 mmHg may also occur in pericardial tamponade. Lung examination may demonstrate decreased diaphragmatic excursion, crackles, or wheezes that allow one to determine the cause of dyspnea. Further workup may include pulmonary function testing, chest radiography, chest CT, electrocardiography, echocardiography, or exercise testing, among others, to ascertain the cause of dyspnea.
I-102. The answer is B. (Chap. 34) Chronic cough should not be diagnosed until consistently present for over 2 months. The duration of cough is a clue to its etiology. Acute cough (<3 weeks) is most commonly due to a respiratory tract infection, aspiration event, or inhalation of noxious chemicals or smoke. Subacute cough (3–8 weeks duration) is frequently the residuum from a tracheobronchitis, such as in pertussis or “post-viral tussive syndrome.” Chronic cough (>8 weeks) may be caused by a wide variety of cardiopulmonary diseases, including those of inflammatory, infectious, neoplastic, and cardiovascular etiologies. In virtually all instances, evaluation of chronic cough merits a chest radiograph. The list of diseases that can cause persistent coughing without other symptoms and without detectable abnormality on physical examination is long. It includes serious illnesses such as Hodgkin’s disease in young adults and lung cancer in an older population. An abnormal chest film leads to evaluation of the radiographic abnormality to explain the symptom of cough. A normal chest image provides valuable reassurance to the patient and the patient’s family, who may have imagined the direst explanation for the cough. Chest PET-CT is often helpful in evaluation of solitary pulmonary nodules or suspected malignancy. Sinus CT should not be utilized in the initial evaluation of chronic cough without strong historical or physical examination of sinus disease or infection. While ACE-inhibitor medications are a common cause of chronic cough, measurement of ACE levels is not helpful clinically. Measurement of serum IgE may be a component of the comprehensive evaluation of patients with refractory asthma or suspected allergic bronchopulmonary aspergillosis. It is not helpful in the initial evaluation of cough in a patient without allergic history.
I-103. The answer is D. (Chap. 34) It is commonly held that medications (most notably ACE-inhibitors); post-nasal drainage; gastroesophageal reflux; and asthma, alone or in combination, account for more than 90% of patients who have chronic cough and a normal or noncontributory chest radiograph. However, clinical experience does not support this contention, and strict adherence to this concept discourages the search for alternative explanations by both clinicians and researchers. Serious pulmonary diseases, including inflammatory lung diseases, chronic infections, and neoplasms, may remain occult on plain chest imaging and require additional testing for detection. Any patient with chronic unexplained cough who is taking an ACE inhibitor should be given a trial period off the medication, regardless of the timing of the onset of cough relative to the initiation of ACE inhibitor therapy. In most instances, a safe alternative is available; angiotensin-receptor blockers do not cause cough. Post-nasal drainage of any etiology can cause cough as a response to stimulation of sensory receptors of the cough-reflex pathway in the hypopharynx or aspiration of draining secretions into the trachea. Many patients with symptomatic post-nasal drip do not develop chronic cough. Linking gastroesophageal reflux to chronic cough poses similar challenges. It is thought that reflux of gastric contents into the lower esophagus may trigger cough via reflex pathways initiated in the esophageal mucosa. Reflux to the level of the pharynx with consequent aspiration of gastric contents causes a chemical bronchitis and possible pneumonitis that can elicit cough for days after the aspiration event. Reflux may also elicit no or minimal symptoms. Assigning the cause of cough to gastroesophageal reflux must be weighed against the observation that many people with chronic reflux (such as frequently occurs during pregnancy) do not experience chronic cough. Cough due to asthma in the absence of wheezing, shortness of breath, and chest tightness is referred to as “cough-variant asthma”, and is more common in children than adults. Chronic eosinophilic bronchitis causes chronic cough with a normal chest radiograph. This condition is characterized by sputum eosinophilia in excess of 3% without airflow obstruction or bronchial hyperresponsiveness and is successfully treated with inhaled glucocorticoids. Treatment of chronic cough in a patient with a normal chest radiograph is often empiric and is targeted at the most likely cause or causes of cough as determined by history, physical examination, and possibly pulmonary-function testing. Therapy for post-nasal drainage depends on the presumed etiology (infection, allergy, or vasomotor rhinitis) and may include systemic antihistamines; antibiotics; nasal saline irrigation; and nasal pump sprays with corticosteroids, antihistamines, or anticholinergics. Antacids, histamine type-2 (H2) receptor antagonists, and proton-pump inhibitors are used to neutralize or decrease production of gastric acid in gastroesophageal reflux disease; dietary changes, elevation of the head and torso during sleep, and medications to improve gastric emptying are additional therapies. Cough-variant asthma typically responds well to inhaled glucocorticoids and intermittent use of inhaled beta-agonist bronchodilators. In this patient, the symptoms of heartburn and the timing of the cough with meals merits an empiric therapeutic trial directed toward reducing acid reflux. Empiric therapy for H. pylori eradication is not indicated at this time.
I-104. The answer is D. (Chap. 35) When a patient presents for evaluation of hypoxia, it is important to consider the underlying mechanism of hypoxia in order to determine the etiology. The primary causes of hypoxia are related to respiratory disease and include ventilation/perfusion (V/Q) mismatch, hypoventilation, and intrapulmonary right-to-left shunting. Causes of hypoxia outside of the respiratory system include intracardiac right-to-left shunting, high-altitude hypoxia, anemic hypoxia, circulatory hypoxia, and carbon monoxide poisoning. In this patient, the mechanism of hypoxia can be narrowed to two possibilities—intracardiac versus intrapulmonary right-to-left shunting—quite easily because the patient failed to correct his hypoxia in response to 100% oxygen. The history of platypnea and orthodeoxia is suggestive that the likely cause is intrapulmonary rather than intracardiac shunting. The finding of a possible lung nodule on chest radiographs in the lower lung fields also is supportive of a pulmonary cause of shunting through an arteriovenous malformation, which can appear as a lung nodule on chest x-ray. An intracardiac right-to-left shunt is caused by congenital cardiac malformations and Eisenmenger syndrome. If there was an intracardiac cause of shunt, the cardiac examination would be expected to demonstrate a murmur and/or evidence of pulmonary hypertension.
V/Q mismatch is the most common cause of hypoxia and results from perfusion of areas of the lung that receive limited ventilation. Examples of V/Q mismatch include asthma, chronic obstructive pulmonary disease, and pulmonary embolus. Hypoxia caused by V/Q mismatch can be corrected with supplemental oxygen. Hypoventilation can be caused by multiple causes, including acute respiratory depression or chronic respiratory failure with elevations in PaCO2. Hypoxia caused by hypoventilation is also correctable with oxygen but frequently has a normal alveolar–arterial oxygen gradient.
Causes of hypoxia outside the respiratory system are less common. High-altitude hypoxia becomes apparent when individuals travel to elevations greater than 3000 m. Anemic hypoxia is not associated with a decrease in PaO2, but a decrease in hemoglobin does cause decreased oxygen-carrying capacity in the blood and relative tissue hypoxia if severe. Circulatory hypoxia refers to tissue hypoxia that occurs because of a decrease cardiac output that leads to greater tissue extraction of oxygen. As a result, the venous partial pressure of oxygen is reduced, and there is an increased arterial-mixed venous oxygen gradient.
I-105. The answer is C. (Chap. 35) In the evaluation of cyanosis, the first step is to differentiate central from peripheral cyanosis. In central cyanosis, because the etiology is either reduced oxygen saturation or abnormal hemoglobin, the physical findings include bluish discoloration of both mucous membranes and skin. In contrast, peripheral cyanosis is associated with normal oxygen saturation but slowing of blood flow and an increased fraction of oxygen extraction from blood; subsequently, the physical findings are present only in the skin and extremities. Mucous membranes are spared. Peripheral cyanosis is commonly caused by cold exposure with vasoconstriction in the digits. Similar physiology is found in Raynaud’s phenomenon. Peripheral vascular disease and deep venous thrombosis result in slowed blood flow and increased oxygen extraction with subsequent cyanosis. Methemoglobinemia causes abnormal hemoglobin that circulates systemically. Consequently, the cyanosis associated with this disorder is systemic. Other common causes of central cyanosis include severe lung disease with hypoxemia, right-to-left intracardiac shunting, and pulmonary arteriovenous malformations.
I-106. The answer is C. (Chap. e13) Mitral valve prolapse is characterized by a midsystolic nonejection sound (click) followed by a late systolic murmur that crescendos and terminates with S2. A decrease in venous return induced by standing will move the click closer to S1 and increase the duration of the murmur. Squatting will increase venous return and shorten the duration of the murmur. The murmur of hypertrophic cardiomyopathy behaves in a similar fashion, but there would be no nonejection click, and left ventricular hypertrophy would be expected on electrocardiography (ECG). Aortic stenosis is best heard at the right second intercostal space radiating to the carotid and is crescendo–decrescendo in character. Congenital pulmonic stenosis is crescendo–decrescendo in character and is heard best in the second to third left intercostal space. If severe, there is a parasternal lift right ventricular overload on ECG. Tricuspid regurgitation causes a holosystolic, not midsystolic, murmur that increases with inspiration.
I-107. The answer is C. (Chap. e13) Tricuspid regurgitation and mitral regurgitation (along with ventricular septal defect) cause holosystolic murmurs. These murmurs have their onset with S1 and terminate at or with S2. Whereas tricuspid regurgitation is heard best over the left sternal border, mitral regurgitation is heard best at the apex with radiation to the base or axilla. The onset of a murmur after S1 with a nonejection sound (click) is characteristic of mitral valve prolapse. Amyl nitrate decreases the intensity of mitral regurgitation and ventricular septal defect murmurs. Tricuspid regurgitation increases with inspiration. Wide splitting of S2 is characteristic of ventricular septal defects. Inaudible A2 at the ventricular apex is characteristic of mitral regurgitation. Because of the incompetent tricuspid valve, the murmur of tricuspid regurgitation is associated with prominent c-v waves and a sharp y-descent in the jugular venous pulse.
I-108. The answer is A. (Chap. e13) Evaluating the splitting of the aortic (A2) and pulmonic (P2) components of the second heart sound (S2) during auscultation can be diagnostically useful. In normal conditions, P2 follows A2, and the splitting increases during inspiration. Reversed (or paradoxical) splitting of S2, when P2 precedes A2 during expiration (and they come closer together during inspiration), is attributable to a delay in A2 and is characteristic of severe aortic stenosis, hypertrophic obstructive cardiomyopathy, left bundle branch block, right ventricular pacing, or acute myocardial ischemia. Wide splitting of S2 is an accentuation of the physiologic pattern usually caused by delayed pulmonic valve closing (right bundle branch block, pulmonary stenosis, pulmonary hypertension) or early aortic valve closure (severe mitral regurgitation). Fixed splitting (no respiratory variation) with the murmur described is characteristic of an atrial septal defect. This is an important finding because it may be asymptomatic until the third or fourth decade of life and, if undiagnosed, may lead to severe pulmonary hypertension and Eisenmenger syndrome.
I-109. The answer is B. (Chap. 53) This patient presents with complaints of diffuse hair loss that has been associated with increased stress as well as hormonal changes after pregnancy and delivery. On physical examination, there is diffuse shedding of normal hairs without scalp lesions or scarring consistent with a diagnosis of telogen effluvium. Telogen effluvium occurs when a stressor causes the typical asynchronous hair growth pattern to become synchronous. This can occur from physical or mental stress (high fever, severe infection) or hormonal changes. When the hair growth becomes more synchronous, more hairs enter the telogen (dying) phase at the same time. The patient may present with complaints of significant hair loss, but hair density to the examiner may appear normal. Broken hairs are not observed, and gentle pulling of the hair results in more than four hairs falling out. Telogen effluvium is reversible without treatment, and this patient has identifiable stressors that are related to the cause. Reassurance and observation are all that are recommended. Some medications can cause telogen effluvium. If identified, these should be discontinued. In addition, both hyper- and hypothyroidism can lead to the condition. One should consider evaluation for these and other metabolic disorders if the condition does not reverse or the patient has additional symptoms.
Other causes of nonscarring alopecia include androgenic alopecia, alopecia areata, tinea capitis, and traumatic alopecia. Androgenic alopecia is the cause of male and female pattern baldness. It does not typically result from androgen excess. Rather, it is associated with an increased sensitivity of the affected hairs to the effects of androgens. Androgenic alopecia can be treated with minoxidil, finasteride, or hair transplants. Alopecia areata is a condition of focal hair loss measuring about 2–5 cm in diameter. The surrounding tissue demonstrates increased T lymphocytes, and the treatment includes intralesional glucocorticoids or topical anthralin or tazarotene. Tinea capitis is also usually a focal area of hair loss related to an underlying superficial fungal infection. However, in severe cases, large plaques and pustules can develop. Treatment with oral griseofulvin or terbinafine with topical selenium sulfide or ketoconazole is usually effective in treating the disease. Traumatic alopecia presents with multiple broken hairs at sites of increased stress related to the use of hair care products, including rubber bands, curlers, or chemicals. It can also result from trichotillomania. Discontinuation of any offending practice or agent is all that is required to return the hair to normal. Counseling is typically required for those with trichotillomania.
I-110. The answer is D. (Chap. 55) Immediate drug reactions rely on the release of mediators from mast cells or basophils, which can occur directly or through immunoglobulin E (IgE)–dependent activation of these cells. Anaphylactoid reactions that are the result of the direct mast cell degranulation do not require prior exposure to the drug or agent to cause the reaction as in this case. The major causes of anaphylactoid reactions are nonsteroidal anti-inflammatory drugs and radiocontrast media. IgE-dependent drug reactions require prior exposure to the drugs to generate the appropriate antibodies, which are expressed on the surfaces of the sensitized cells. Upon reexposure to the drug, drug protein conjugates cross-link these IgE molecules to cause activation of the cells and release of inflammatory mediators. The major drugs classes that cause IgE-dependent reactions are penicillins and muscle relaxants. The symptoms of immediate drug reactions are similar regardless of whether they are caused by direct mast cell activation or IgE mechanisms and begin within minutes of drug exposure. The symptoms include pruritus, urticaria, nausea, vomiting, diarrhea, abdominal cramping, bronchospasm, laryngeal edema, and cardiovascular collapse.
Other causes of drug reactions include deposition of immune complexes and delayed hypersensitivity T-cell reactions. Both of these types of drug reactions cause delayed reactions. The clinical scenario associated with immune complex deposition is serum sickness, which typically occurs 6 days or more after exposure to the drug. However, if the patient has had a prior exposure to the drug, the symptoms could occur at an earlier time frame. Symptoms of serum sickness include fever arthritis, nephritis, neuritis, edema, and an urticarial rash. Delayed hypersensitivity reactions are the most common causes of allergic drug eruptions and include the mild morbilliform eruptions as well as toxic epidermal necrolysis and Stevens-Johnson syndrome. Drug-cell specific T cells have been demonstrated in these reactions directed against the native drug rather than its metabolites. Hepatic metabolism into toxic intermediate compounds may occur with some drug toxicity; the prototype for this phenomenon is acetaminophen toxicity and hepatic failure.
I-111. The answer is A. (Chap. 55) Hypersensitivity syndromes can occur with many drugs, including phenytoin, carbamazepine, barbiturates, lamotrigine, minocycline, dapsone, allopurinol, and sulfonamides. This syndrome is also known as DRESS (drug reaction with eosinophilia and systemic symptoms) and presents with a diffuse purpuric and lichenoid rash associated with fever, facial and periorbital edema, generalized lymphadenopathy, leukocytosis, hepatitis, and occasionally nephritis or pneumonitis. Eosinophilia and atypical lymphocytosis can be seen. The reaction typically begins within 2–8 weeks after starting the drug but may persist for several weeks after cessation of the drug, especially if there is associated hepatitis. Mortality rates can be as high as 10% with DRESS, and it is important to recognize this as a drug reaction as immediate cessation of the offending agent is required. Mortality is highest in those with acute hepatitis. In addition to stopping the drug, treatment with systemic corticosteroids at prednisone doses of 1.5–2 mg/kg daily is recommended with a slow taper over 8–12 weeks. Topical steroids may also be helpful. Patients should be closely followed for resolution of symptoms, and the patient should be observed carefully for the late development of autoimmune thyroiditis, which can occur as long as 6 months after the initial presentation of the syndrome. Although it is important to treat the patients underlying seizure disorder, cross-reactions with other aromatic anticonvulsants can occur, and these compounds, including carbamazepine and barbiturates, can also lead to the syndrome.
I-112. The answer is E. (Chap. 56) The photosensitivity reactions of phototoxicity or photoallergy can be related to both topical or systemic administration of drugs and require the absorption of energy by the drug to create a photosensitizer that can generate reactive oxygen species. Phototoxicity is a nonimmunologic reaction that leads to erythema resembling a sunburn. Photoallergy is a less common immunologic reaction that leads to a hypersensitivity syndrome characterized severe pruritus with eczematous dermatitis. This can progress to lichenification in sun-exposed areas. Drugs that can cause both photoallergy and phototoxicity are fluoroquinolones, sulfonamides, and sulfonylureas.
I-113. The answer is B. (Chap. 57) The first step in diagnosing polycythemia vera is to document an elevated red blood cell (RBC) mass. A normal red blood cell (RBC) mass suggests spurious polycythemia. Next, serum erythropoietin (EPO) levels should be measured. If EPO levels are low, the diagnosis is polycythemia vera. Confirmatory tests include Janus kinase (JAK) 2 mutation analysis, leukocytosis, and thrombocytosis. Elevated EPO levels are seen in the normal physiologic response to hypoxia as well as in autonomous production of EPO. Further steps in the workup include evaluation for hypoxia with an arterial blood gas, consideration of smoker’s polycythemia (elevated carboxyhemoglobin levels), and disorders of increased hemoglobin affinity for oxygen. Low serum EPO levels with low oxygen saturation suggest inadequate renal production (renal failure). High RBC mass and high EPO levels with normal oxygen saturation may be seen with autonomous EPO production, such as in renal cell carcinoma.
I-114. The answer is E. (Chap. 58) von Willebrand disease (VWD) is an inherited disorder of platelet adhesion that has several types. The most common type is inherited in an auto-somal dominant fashion and is associated with low levels of qualitatively normal von Willebrand factor. As a disorder primary hemostasis associated with the development of a platelet plug, VWD is primarily associated with mucosal bleeding. General bleeding symptoms that are more common in VWD include prolonged bleeding after surgery or dental procedures, menorrhagia, postpartum hemorrhage, and large bruises. However, easy bruising and menorrhagia are common complaints and are not specific for VWD in isolation. Factors that raise concern for VWD in women with menstrual symptoms include iron-deficiency anemia, need for blood transfusion, passage of clots more than 1 inch in diameter, and need to change a pad or tampon more than hourly. Epistaxis is also a very common occurrence in the general population, but it is the most common complaint of males with VWD. Concerning features of epistaxis that may be more likely to indicate an underlying bleeding diathesis are lack of seasonal variation and bleeding that requires medical attention. Although most gastrointestinal bleeding in individuals with VWD is unrelated to the bleeding diathesis, VWD types 2 and 3 are associated with angiodysplasia of the bowel and gastrointestinal bleeding. Spontaneous hemarthroses or deep muscle hematomas are seen in clotting factor deficiencies and not seen VWD except severe VWD with associated decreased factor VIII levels less than 5%.
I-115. The answer is B. (Chap. 58) The activated partial thromboplastin time (aPTT) measures the integrity of the intrinsic and common coagulation pathways, and as such, is affected by all of the coagulation factors, except factor VII. The aPTT reagent contains phospholipids derived from animal or vegetable sources and includes an activator of the intrinsic coagulation system, such as nonparticulate ellagic acid or kaolin. The phospholipid reagent frequently varies from laboratory to laboratory. Thus, an aPTT measured in one hospital may differ from another. Isolated elevations in the aPTT can be related to factor deficiencies, heparin or direct thrombin inhibitors, lupus anticoagulant, or the presence of a specific factor inhibitor. To differentiate between the presence of factor deficiencies and inhibitors, mixing studies should be performed. Mixing studies are performed by mixing normal plasma and the patient’s plasma in a 1:1 ratio. The aPTT and prothrombin time (PT) are incubated at 37°C, and levels are measured immediately and serially thereafter for about 2 hours. If the cause is an isolated factor deficiency, the aPTT should correct to normal values and remain normal throughout the incubation period. In the presence of an acquired inhibitor, the aPTT may or may not correct immediately, but upon incubation, the inhibitor becomes more active, and the aPTT will progressively prolong. In contrast, the aPTT does not correct immediately or with incubation in the presence of lupus anticoagulants. The presence of serious bleeding in the presence of mixing studies suggesting an inhibitor should further rule out lupus anticoagulant as a cause because the lupus anticoagulant typically presents with no symptoms or as a thrombotic disorder. The mixing studies do not, however, eliminate the presence of heparin as a cause of the prolonged aPTT. If heparin were present, the thrombin time, but not the reptilase time, would be prolonged. In this scenario, both values were normal, ruling out the presence of heparin or a direct thrombin inhibitor. Likewise, disseminated intravascular coagulation can be ruled out in the presence of normal fibrinogen levels. In serious vitamin K deficiency, both the PT and aPTT should be prolonged.
I-116. The answer is E. (Chap. 59) Lymphadenopathy has many causes, including infections, immunologic diseases, and malignancy among others. In the vast majority of cases, the cause of enlarged lymph nodes is a benign process. In the primary care practice, fewer than 1% of individuals will have malignancy, and in individuals referred for lymphadenopathy, this number rises only to 16%. Some features on history and physical examination lead to an increased likelihood that the cause of lymphadenopathy is malignant in origin. Malignancy is more common in individuals older than 50 years. Fevers and chills are more commonly present in benign respiratory illness but can be present in malignancy. Thus, fever is a nonspecific symptom. Likewise, generalized versus focal lymphadenopathy is also not specific. The site of lymph node enlargement can be important and raise the risk of malignancy. The presence of supraclavicular lymphadenopathy is never normal. These lymph nodes drain the thoracic cavity and retroperitoneal space and are most commonly enlarged in malignancy. However, infectious etiologies can also cause supraclavicular lymphadenopathy. The size and texture of the lymph nodes also provide important information. Nodes less than 1.0 cm × 1.0 cm are almost always benign, but lymph nodes greater than 2.0 cm in maximum diameter or with an area of 2.25 cm2 (1.5 × 1.5 cm) are more likely to be malignant. Nodes containing metastatic cancer tend to be described as hard, fixed, and nontender. In lymphoma, however, the nodes can be tender because of rapid enlargement of the node with subsequent stretching of the capsule of the lymph nodes. Lymphomatous nodes are also frequently described as firm, rubbery, and mobile.
I-117. The answer is F. (Chap. 59) This patient’s lymphadenopathy is benign. Inguinal nodes smaller than 2 cm are common in the population at large and need no further workup provided that there is no other evidence of disseminated infection or tumor and that the nodes have qualities that do not suggest tumor (not hard or matted). A practical approach would be to measure the nodes or even photograph them if visible and follow them serially over time. Occasionally, inguinal lymph nodes can be associated with sexually transmitted diseases. However, these are usually ipsilateral and tender, and evaluation includes bimanual examination and appropriate cultures, not necessarily pelvic ultrasonography. A total-body CT scan would be indicated if other pathologic nodes suggestive of lymphoma or granulomatous disease are present in other anatomic locations. Bone marrow biopsy would be indicated only if a diagnosis of lymphoma is made first.
I-118. The answer is C. (Chap. 59) Portal hypertension causes splenomegaly via passive congestion of the spleen. It generally causes only mild enlargement of the spleen because expanded varices provide some decompression for elevated portal pressures. Myelofibrosis necessitates extramedullary hematopoiesis in the spleen, liver, and even other sites such as the peritoneum, leading to massive splenomegaly caused by myeloid hyperproduction. Autoimmune hemolytic anemia requires the spleen to dispose of massive amounts of damaged red blood cells, leading to reticuloendothelial hyperplasia and frequently an extremely large spleen. Chronic myelogenous leukemia and other leukemias and lymphomas can lead to massive splenomegaly caused by infiltration with an abnormal clone of cells. Marginal zone lymphoma typically presents with splenomegaly. If a patient with cirrhosis or right heart failure has massive splenomegaly, a cause other than passive congestion should be considered.
I-119. The answer is A. (Chap. 59) The presence of Howell-Jolly bodies (nuclear remnants), Heinz bodies (denatured hemoglobin), basophilic stippling, and nucleated red blood cells (RBCs) in the peripheral blood implies that the spleen is not properly clearing senescent or damaged RBCs from the circulation. This usually occurs because of surgical splenectomy but is also possible when there is diffuse infiltration of the spleen with malignant cells. Hemolytic anemia can have various peripheral smear findings depending on the etiology of the hemolysis. Spherocytes and bite cells are an example of damaged RBCs that might appear because of autoimmune hemolytic anemia and oxidative damage, respectively. Disseminated intravascular coagulation is characterized by schistocytes and thrombocytopenia on smear with an elevated international normalized ratio and activated partial thromboplastin time as well. However, in these conditions, damaged RBCs are still cleared effectively by the spleen. Transformation to acute leukemia does not lead to splenic damage.
I-120. The answer is A. (Chap. 59) Splenectomy leads to an increased risk of overwhelming postsplenectomy sepsis, an infection that carries an extremely high mortality rate. The most commonly implicated organisms are encapsulated. Streptococcus pneumoniae, Haemophilus influenzae, and sometime gram-negative enteric organisms are most frequently isolated. There is no known increased risk for any viral infections. Vaccination for S. pneumoniae, H. influenzae, and Neisseria meningitidis is indicated for any patient who may undergo splenectomy. The vaccines should be given at least 2 weeks before surgery. The highest risk of sepsis occurs in patients younger than 20 years of age because the spleen is responsible for first-pass immunity and younger patients are more likely to have primary exposure to implicated organisms. The risk is highest during the first 3 years after splenectomy and persists at a lower rate until death.
I-121. The answer is E. (Chap. 60) Chronic granulomatous disease (CGD) is an inherited disorder of abnormal phagocyte function. Seventy percent of cases are inherited in an X-linked fashion with the other 30% being autosomal recessive. Affected individuals are susceptible to infectious with catalase-positive organisms, especially Staphylococcus aureus. Other organisms that can be seen include Burkholderia cepacia, Aspergillus spp., and Chromobacterium violaceum. Most individuals present in childhood, and infections commonly affect the skin, ears, lungs, liver, and bone. Excessive inflammatory reaction can lead to suppuration of lymph nodes, and granulomatous inflammation can be seen on lymph node biopsy and found in the gastrointestinal and genitourinary tracts. Aphthous ulcers and eczematous skin rash can also be seen. The underlying genetic defect in CGD is the inability of neutrophils and monocytes to generate the appropriate oxidative burst in response to infectious organisms. Several mutations can lead to the disease, and these affect one of the five subunits of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase enzyme. The test of choice to diagnose chronic granulomatous disease is the nitroblue tetrazolium dye test, which demonstrates lack of superoxide and hydrogen peroxide production in the face of an appropriate stimulus.
I-122. The answer is A. (Chap. 60) Under normal or nonstress conditions, roughly 90% of the neutrophil pool is in the bone marrow, 2–3% in the circulation, and the remainder in the tissues. The circulating pool includes the freely flowing cells in the bloodstream and the others are marginated in close proximity to the endothelium. Most of the marginated pool is in the lung, which has a vascular endothelium surface area. Margination in the postcapillary venules is mediated by selectins that cause a low-affinity neutrophil–endothelial cell interaction that mediates “rolling” of the neutrophils along the endothelium. A variety of signals, including interleukin 1, tumor necrosis factor α, and other chemokines, can cause leukocytes to proliferate and leave the bone marrow and enter the circulation. Neutrophil integrins mediate the stickiness of neutrophils to endothelium and are important for chemokine-induced cell activation. Infection causes a marked increase in bone marrow production of neutrophils that marginate and enter tissue. Acute glucocorticoids increase neutrophil count by mobilizing cells from the bone marrow and marginated pool.
I-123. The answer is E. (Chap. 60) Many drugs can lead to neutropenia, most commonly via retarding neutrophil production in the bone marrow. Of the list in the answer choices, trimethoprimsulfamethoxazole is the most likely culprit. Other common causes of drug-induced neutropenia include alkylating agents such as cyclophosphamide or busulfan, antimetabolites including methotrexate and 5-flucytosine, penicillin and sulfonamide antibiotics, antithyroid drugs, antipsychotics, and anti-inflammatory agents. Prednisone, when used systemically, often causes an increase in the circulating neutrophil count because it leads to demargination of neutrophils and bone marrow stimulation. Ranitidine, an H2 blocker, is a well-described cause of thrombocytopenia but has not been implicated in neutropenia. Efavirenz is a nonnucleoside reverse transcriptase inhibitor whose main side effects include a morbilliform rash and central nervous system effects, including strange dreams and confusion. The presence of these symptoms does not require drug cessation. Darunavir is a new protease inhibitor that is well tolerated. Common side effects include a maculopapular rash and lipodystrophy, a class effect for all protease inhibitors.
I-124. The answer is E. (Chap. e49) Mercury is one of the metals that is a significant cause of health concern because of low-level exposure in environmental and occupational exposures. The toxicity of low level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on studies of the offspring of mothers who ingested mercury-contaminated fish. With respect to whether the consumption of fish by women during pregnancy is good or bad for offspring neurodevelopment, balancing the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs) in fish versus the adverse effects of mercury contamination in fish has led to some confusion and inconsistency in public health recommendations. Overall, it appears that it is best for pregnant women to either limit fish consumption to species known to be low in mercury contamination but high in omega-3-FAs (e.g., sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources. Current evidence has not supported the recent contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early childhood, has played a significant role in causing neurodevelopmental problems such as autism. Dimethylmercury, a compound only found in research labs, is “supertoxic”—a few drops of exposure via skin absorption or inhaled vapor can cause severe cerebellar degeneration and death. Acute mercury exposure can be assessed with serum levels, but chronic exposure is best assessed by assaying hair samples.
I-125. The answer is C. (Chap. 396) This patient has the typical manifestations of ciguatera poisoning from ingested snapper, grouper, or barracuda. Ciguatera poisoning is the most common nonbacterial food poisoning associated with fish in the United States; most U.S. cases occur in Florida and Hawaii. The poisoning almost exclusively involves tropical and semitropical marine coral reef fish common in the Indian Ocean, the South Pacific, and the Caribbean Sea. Among reported cases, 75% (except in Hawaii) involve the barracuda, snapper, jack, or grouper. Most, if not all, ciguatoxins are unaffected by freeze drying, heat, cold, and gastric acid. None of the toxins affects the odor, color, or taste of fish. The onset of symptoms may come within 15–30 minutes of ingestion and typically takes place within 2–6 hours. Symptoms increase in severity over the ensuing 4–6 hours. Most victims develop symptoms within 12 hours of ingestion, and virtually all are afflicted within 24 hours. More than 150 symptoms have been reported, including abdominal pain, nausea, vomiting, diarrhea, chills, paresthesias, pruritus, tongue and throat numbness or burning, odontalgia or dental dysesthesias, and an extensive variety of neurologic findings. Bradycardia, hypotension, central respiratory failure, and coma may occur. Death is rare. Symptoms may persist for 48 hours and then generally resolve. A pathognomonic symptom is the reversal of hot and cold tactile perception, which develops in some persons after 3–5 days and may last for months. More severe reactions tend to occur in persons previously stricken with the disease. Therapy is supportive and symptom directed. Consumption of fish in ciguatera-endemic regions should be avoided. All oversized fish of any predacious reef species should be suspected of harboring ciguatoxin. Neither moray eels nor the viscera of tropical marine fish should ever be eaten.
I-126. The answer is B. (Chap. e50) More than 5 million poison exposures occur in the United States each year. Most are acute, accidental (unintentional), involve a single agent, occur in the home, result in minor or no toxicity, and involve children younger than 6 years of age. Pharmaceuticals are involved in 47% of exposures and 84% of serious or fatal poisonings. Unintentional exposures can result from the improper use of chemicals at work or play; label misreading; product mislabeling; mistaken identification of unlabeled chemicals; uninformed self-medication; and dosing errors by nurses, pharmacists, physicians, parents, and elderly adults. Excluding the recreational use of ethanol, attempted suicide (deliberate self-harm) is the most common reported reason for intentional poisoning. Recreational use of prescribed and over-the-counter drugs for psychotropic or euphoric effects (abuse) or excessive self-dosing (misuse) are increasingly common and may also result in unintentional self-poisoning. About 20–25% of exposures require bedside health professional evaluation, and 5% of all exposures require hospitalization. Poisonings account for 5–10% of all ambulance transports, emergency department visits, and intensive care unit admissions. Up to 30% of psychiatric admissions are prompted by attempted suicide via overdosage. Overall, the mortality rate is low: fewer than 1% of all exposures. It is much higher (1–2%) in hospitalized patients with intentional (suicidal) overdose, who account for the majority of serious poisonings. Acetaminophen is the pharmaceutical agent most often implicated in fatal poisoning. Overall, carbon monoxide is the leading cause of death from poisoning, but this is not reflected in hospital or poison center statistics because patients with such poisoning are typically dead when discovered and are referred directly to medical examiners.
I-127. The answer is D. (Chap. e50) Sympathetic toxidromes share many features, including increased pulse, blood pressure, neuromuscular activity, tremulousness, delirium, and agitation. In many cases, these syndromes can be subclassified according to other features or relative strengths of the above symptoms. Sympathomimetics such as cocaine and amphetamines cause extreme elevations in vital signs and organ damage caused by peripheral vasoconstriction, usually in the absence of hallucinations. Benzodiazepine and alcohol withdrawal syndromes present similarly, but hallucinations and often seizures are common in these conditions. Hot, dry, flushed skin; urinary retention; and absent bowel sounds characterize anticholinergic syndromes associated with antihistamines, antipsychotics, antiparkinsonian agents, muscle relaxants, and cyclic antidepressants. Nystagmus is a unique feature of ketamine and phencyclidine overdose.
I-128. The answer is A. (Chap. e50) Lithium interferes with cell membrane ion transport, leading to nephrogenic diabetes insipidus and falsely elevated chloride. This can cause the appearance of low anion gap metabolic acidosis. Sequelae include nausea, vomiting, ataxia, encephalopathy, coma, seizures, arrhythmia, hyperthermia, permanent movement disorder, and encephalopathy. Severe cases are treated with bowel irrigation, endoscopic removal of long-acting formulations, hydration, and sometimes hemodialysis. Care should be taken because toxicity occurs at lower levels in chronic toxicity compared with acute toxicity. Salicylate toxicity leads to a normal osmolal gap as well as an elevated anion gap metabolic acidosis, respiratory alkalosis, and sometimes normal anion gap metabolic acidosis. Methanol toxicity is associated with blindness and is characterized by an increased anion gap metabolic acidosis, normal lactate and ketones, and a high osmolal gap. Propylene glycol toxicity causes an increased anion gap metabolic acidosis with elevated lactate and a high osmolal gap. The only electrolyte abnormalities associated with opiate overdose are compensatory to a primary respiratory acidosis.
I-129. The answer is B. (Chap. e50) The clinical implications of understanding the difference between therapeutic drug dosing and overdosage are critical. Drug effects begin earlier, peak later, and last longer in the context of overdose compared with commonly referenced values. Therefore, if a patient has a known ingestion of a toxic dose of a dangerous substance and symptoms have not yet begun, then aggressive gut decontamination should ensue because symptoms are apt to ensue rapidly. The late peak and longer duration of action are important as well. A common error in practice is for patients to be released or watched less carefully after reversal of toxicity associated with an opiate agonist or benzodiazepine. However, the duration of activity of the offending toxic agent often exceeds the half-life of the antagonists, naloxone or flumazenil, requiring the administration of subsequent doses several hours later to prevent further central nervous system or physiologic depression.
I-130. The answer is E. (Chap. e50) Gastric decontamination is controversial because few data are available to support or refute its use more than an hour after ingestion. It remains a very common practice in most hospitals. Syrup of ipecac is no longer endorsed for inhospital use and is controversial even for home use, although its safety profile is well documented and therefore it likely poses little harm for ingestions when the history is clear and the indication strong. Activated charcoal is generally the decontamination method of choice because it is the least aversive and least invasive option available. It is effective in decreasing systemic absorption if given within 1 hour of poison ingestion. It may be effective even later after ingestion for drugs with significant anticholinergic effect (e.g., tricyclic antidepressants). Considerations are poor visibility of the gastrointestinal tract on endoscopy after charcoal ingestion and perhaps decreased absorption of oral drugs. Gastric lavage is the most invasive option and is effective, but it is occasionally associated with tracheal intubation and bowel wall perforation. It is also the least comfortable option for the patient. Moreover, aspiration risk is highest in those undergoing gastric lavage. All three of the most common options for decontamination carry at least a 1% risk of an aspiration event, which warrants special consideration in the patient with mental status change.
I-131. The answer is E. (Chap. e51) Whereas acute mountain sickness (AMS) is the benign form of altitude illness, high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE) are life threatening. Altitude illness is likely to occur above 2500 m but has been documented even at 1500–2500 m. The acclimation to altitude includes hyper-ventilation in response to the reduced inspired PO2initially followed by increased erythropoietin and 2,3-bisphosphoglycerate. AMS is characterized by nonspecific symptoms (headache, nausea, fatigue, and dizziness) with a paucity of physical findings developing 6–12 hours after ascent to a high altitude. AMS must be distinguished from exhaustion, dehydration, hypothermia, alcoholic hangover, and hyponatremia. The most important risk factors for the development of altitude illness are the rate of ascent and a history of high-altitude illness. Exertion is a risk factor, but lack of physical fitness is not. One protective factor in AMS is high-altitude exposure during the preceding 2 months. Children and adults seem to be equally affected, but people greater than 50 years of age may be less likely to develop AMS than younger people. Most studies reveal no gender difference in AMS incidence. Sleep desaturation—a common phenomenon at high altitude—is associated with AMS. Gradual ascent is the best approach to prevent AMS. Acetazolamide or dexamethasone beginning 1 day before ascent and continuing for 2–3 days is effective if rapid ascent is necessary. A double-blind placebo-controlled trial demonstrated no benefit on AMS from gingko biloba. Mild cases of AMS can be treated with rest; more serious cases are treated with acetazolamide and oxygen. Descent is therapeutic in all serious cases, including HACE and HAPE. Patients who have recovered from mild cases of AMS may reascend carefully after recovery; patients with HACE should not.
I-132. The answer is D. (Chap. e51) High-altitude pulmonary edema (HAPE) is related to an enhanced or atypical pulmonary vascular response to hypoxia. It is not necessarily preceded by acute mountain sickness. HAPE develops within 2–4 days after arrival at high altitude; it rarely occurs after more than 4 or 5 days at the same altitude. A rapid rate of ascent, exercise, a history of HAPE, respiratory tract infections, and cold environmental temperatures are risk factors. Men are more susceptible than women. People with abnormalities of the cardiopulmonary circulation leading to pulmonary hypertension (e.g., patent foramen ovale, mitral stenosis, primary pulmonary hypertension, unilateral absence of the pulmonary artery) are at increased risk of HAPE even at moderate altitudes. Echocardiography is recommended when HAPE develops at relatively low altitudes (<3000 m) and whenever cardiopulmonary abnormalities predisposing to HAPE are suspected. The initial manifestation of HAPE may be a reduction in exercise tolerance greater than that expected at the given altitude. A dry, persistent cough may presage HAPE and may be followed by the production of blood-tinged sputum. Tachypnea and tachycardia, even at rest, are important markers as illness progresses. Crackles may be heard on auscultation but are not diagnostic. Fever and leukocytosis may occur. Descent and oxygen (to raise ) are the mainstays of therapy for HAPE. Nifedipine can be used as adjunctive therapy. Inhaled beta-agonists, which are safe and convenient to carry, are useful in the prevention of HAPE and may be effective in its treatment, although no trials have yet been carried out. Inhaled nitric oxide and expiratory positive airway pressure may also be useful therapeutic measures but may not be available in high-altitude settings. No studies have investigated phosphodiesterase-5 inhibitors in the treatment of HAPE, but reports have described their use in clinical practice. Patients with HAPE who have recovered may be able to reascend. In high-altitude cerebral edema, reascent after a few days is not advisable.
I-133. The answer is E. (Chap. e52) Untreated pneumothorax has the risk of rapidly expanding and potentially causing tension upon decompression. Patients with extensive bullae should be considered carefully because they may have a similar risk. The effect of hyperbaric oxygen in patients with chronic CO2 retention has not been studied. The other commonly quoted contraindication to hyperbaric oxygen therapy is a history of receiving bleomycin chemotherapy. Bleomycin is associated with a dose-dependent risk of pneumonitis, and this risk may be enhanced with hyperbaric oxygen exposure. There are reports of patients developing pneumonitis with high FIO2 or hyperbaric therapy even years after receiving bleomycin. Radiation proctitis and carbon monoxide poisoning are clinical conditions in which hyperbaric oxygen therapy may be warranted. The indications for hyperbaric oxygen therapy are evolving with some advocating therapy for delayed radiation injury, wound therapy, myonecrosis, thermal injuries, and other conditions in which local hypoxia may occur or impaired oxygen delivery may be present.
I-134. The answer is D. (Chap. e52) Because for every 10.1-m increase in depth of seawater, the ambient pressure (Pamb) increases by 1 standard atmosphere, at 20-m depth, a person is exposed to a Pamb of approximately 3 atmospheres absolute. Decompression sickness (DCS) is caused by the formation of bubbles from dissolved inert gas (usually nitrogen) during or after ascent (decompression) from a compressed gas dive. Deeper and longer dives increase the amount of dissolved inert gas, and more rapid ascent increases the potential for bubbles to form and affect end organs. Although variable, DCS usually does not occur unless the dive depth exceeds 7 m (1.7 atm absolute). DCS usually develops within 8–12 hours of ascent. The majority of patients present with mild symptoms, including musculoskeletal pain; fatigue; and minor neurologic manifestations, such as patchy paresthesias. A feared complication is cerebral arterial gas embolism (CAGE). To lessen the chance of gas bubbles entering the cerebral circulation, patients with DCS should remain in a horizontal posture. Initial first aid should include 100% oxygen to accelerate inert gas washout and resolution of bubbles. For patients with symptoms beyond mild DCS, recompression and hyperbaric oxygen therapy are generally recommended. If evacuated by air, the patient should be transported at low altitude by helicopter. After full recovery, diving can be restarted after at least 1 month.
I-135. The answer is B. (Chap. 268) ALI and ARDS are both characterized by diffuse lung injury, bilateral radiographic infiltrates, and hypoxemia in the absence of left atrial hypertension. ALI is considered a less severe form of diffuse lung injury that may evolve to ARDS or warrant intensive therapy to forestall the progression. The distinction between ALI and ARDS is made by the magnitude of the PaO2/FIO2ratio with ARDS defined as a ratio of 200 mmHg or below and ALI 300 mmHg or below. Many medical and surgical illnesses are associated with the development of ALI and ARDS, but most cases (>80%) are caused by a relatively small number of clinical disorders, namely, severe sepsis syndrome and bacterial pneumonia (40–50%), trauma, multiple transfusions, aspiration of gastric contents, and drug overdose. Among patients with trauma, pulmonary contusion, multiple bone fractures, and chest wall trauma or flail chest are the most frequently reported surgical conditions in ARDS, but head trauma, near drowning, toxic inhalation, and burns are rare causes. The risks of developing ARDS are increased in patients with more than one predisposing medical or surgical condition (e.g., the risk for ARDS increases from 25% in patients with severe trauma to 56% in patients with trauma and sepsis). Several other clinical variables have been associated with the development of ARDS. These include older age, chronic alcohol abuse, metabolic acidosis, and severity of critical illness.
I-136. The answer is D. (Chap. 268) To date, despite intensive investigation of multiple patho-physiologically based therapies, the only intervention that decreased mortality in patients with ARDS was a low tidal volume (6 mL/kg ideal body weight) mechanical ventilation strategy. The rationale for this intervention is that overdistension of normal alveoli in patients with ARDS promotes further lung injury. Maintaining a normal or low left atrial filling pressure is also recommended therapy for patients with ARDS. It minimizes pulmonary edema and prevents further decrements in arterial oxygenation and lung compliance, improves pulmonary mechanics, and shortens intensive care unit stay and the duration of mechanical ventilation. Numerous studies have demonstrated that placing the patient in the prone position may improve oxygenation, but there has been no consistent mortality benefit. Other “lung protective”’ strategies of mechanical ventilation (high-frequency ventilation, high positive end-expiratory pressure, pressure-volume curve measurement) are under investigation. Inflammatory mediators and leukocytes are abundant in the lungs of patients with ARDS. Many attempts have been made to treat both early and late ARDS with glucocorticoids to reduce this potentially deleterious pulmonary inflammation. Few studies have shown any benefit. Current evidence does not support the use of high-dose glucocorticoids in the care of ARDS patients. Similarly, ARDS is characterized by a surfactant deficiency, but administration of exogenous surfactant has not yielded clinical results (in contrast to the dramatic benefit in neonatal lung injury). See Table I-137.
TABLE I-137 Evidence-Based Recommendations for Acute Respiratory Distress Syndrome Therapies
I-137. The answer is E. (Chap. 268) Recent mortality estimates for ARDS range from 26–44%. The mortality rate in ARDS is largely attributable to nonpulmonary causes, with sepsis and nonpulmonary organ failure accounting for more than 80% of deaths. Mortality caused by hypoxemic respiratory failure is not typical. The degree of hypoxemia during ARDS is also not a strong predictor of outcome. The major risk factors for ARDS mortality include age, preexisting chronic medical conditions or organ dysfunction, and severity of critical illness (number of organ failures). Patients with ARDS from direct lung injury (including pneumonia, pulmonary contusion, and aspiration) have nearly twice the mortality rate of those with indirect causes of lung injury, but surgical and trauma patients with ARDS, especially those without direct lung injury, have a better survival rate than other ARDS patients. The majority of patients recover nearly normal lung function with 1 year. One year after endotracheal extubation, more than one-third of ARDS survivors have normal spirometry values and diffusion capacity, and most of the remaining patients have only mild abnormalities in their pulmonary function. Unlike the risk for mortality, recovery of lung function is strongly associated with the extent of lung injury in early ARDS. When caring for ARDS survivors, it is important to be aware of the potential for a substantial burden of emotional and respiratory symptoms. There are significant rates of depression and posttraumatic stress disorder in ARDS survivors.
I-138. The answer is D. (Chap. 269) Noninvasive ventilation (NIV) has been gaining more acceptance because it is effective in certain conditions, such as acute and chronic respiratory failure, and is associated with fewer complications, namely, pneumonia and tracheo-laryngeal trauma. The major limitation to its widespread application has been patient intolerance because the tight-fitting mask required for NIV can cause both physical and emotional discomfort. In addition, NIV has had limited success in patients with acute hypoxemic respiratory failure, for whom endotracheal intubation and conventional mechanical ventilation remain the ventilatory method of choice. The most important group of patients who benefit from a trial of NIV are those with acute exacerbations of chronic obstructive pulmonary disease (COPD) leading to respiratory acidosis . Experience from several well-conducted randomized trials has shown that in patients with ventilatory failure characterized by blood pH levels between 7.25 and 7.35, NIV is associated with low failure rates (15–20%) and good outcomes (intubation rate; length of stay in intensive care; and in some series, mortality rates). In more severely ill patients with pH below 7.25, the rate of NIV failure is inversely related to the severity of respiratory acidosis, with greater failure as the pH decreases. In patients with milder acidosis , NIV is not better than conventional therapy that includes controlled oxygen delivery and pharmacotherapy for exacerbations of COPD (systemic corticosteroids; bronchodilators; and, if needed, antibiotics). The contraindications to NIV are listed in the Table I-139.
TABLE I-139 Contraindications for Noninvasive Ventilation
Cardiac or respiratory arrest
Severe gastrointestinal bleed
Unstable angina and myocardial infarction
Facial surgery or trauma
Upper airway obstruction
High-risk aspiration or inability to protect airways
Inability to clear secretions
I-139. The answer is A. (Chap. 269) Modes of ventilation differ in how breaths are triggered, cycled, and limited. All modes allow determination of either the pressure or volume limit. Assist control and synchronized intermittent mandatory ventilation (SIMV) are volume cycled, in which a fixed volume is delivered to the patient by the machine using the necessary inspiratory pressure. Pressure control and pressure support are pressure cycled, in which a known pressure limit is imposed and volume delivered by the machine may vary. Continuous positive airway pressure does not alter pressure or deliver a fixed volume to the patient. Assist control and SIMV differ by the response to patient initiated breaths. Both will deliver a fixed volume when the patient does not initiate a breath. However, with SIMV, if the patient is breathing at a rate greater than set on the machine, each spontaneous breath is dependent completely on patient effort. On assist control, each patient initiated breath above the set rate is supported by the machine by delivering the set rate. In patients with a high respiratory rate, this can result in hyperventilation, and intrinsic PEEP because of inadequate time for exhalation of the full tidal volume. In the patient described, because each breath that is either initiated by the patient or the machine is at a set rate and a fixed volume, this is most consistent with the assist control mode of mechanical ventilation.
I-140. The answer is D. (Chap. 269) Determining when an individual is an appropriate candidate for a spontaneous breathing trial is important for the care of mechanically ventilated patients. An important initial step in determining if a patient is likely to be successfully extubated is to evaluate the mental status of the patient. This can be difficult if the patient is receiving sedation, and it is recommended that sedation be interrupted on a daily basis for a short period to allow assessment of mental status. Daily interruption of sedation has been shown to decrease the duration of mechanical ventilation. If the patient is unable to respond to any commands or is completely obtunded, the individual is at high risk for aspiration and unlikely to be successfully extubated. In addition, the patient should be hemodynamically stable and the lung injury stable or improving. If these conditions are met, the patient should be on minimal ventilatory support. This includes the ability to maintain the pH between 7.35 and an SaO2 greater than 90% while receiving an FIO2 of 0.5 or less and a PEEP of 5 cmH2) or less. The presence of rapid shallow breathing during a spontaneous breathing trial identifies patients who are less likely to be extubated successfully.
I-141. The answer is B. (Chap. 269) Patients initiated on mechanical ventilation require a variety of supportive measures. Sedation and analgesia with a combination of benzodiazepines and narcotics are commonly used to maintain patient comfort and safety while mechanically ventilated. Recent studies have shown the utility of minimizing sedation in critically ill patients. However, adequate pain control is an essential component of patient comfort. In addition, patients are immobilized and are thus at high risk for development of deep venous thrombosis and pulmonary embolus. Prophylaxis with unfractionated heparin or low-molecular-weight heparin should be administered subcutaneously. Prophylaxis against diffuse gastrointestinal mucosal injury is also indicated, particularly in individuals with neurologic insult and those with severe respiratory failure and adult respiratory distress syndrome. Gastric acid suppression can be managed with H2-receptor antagonists, proton pump inhibitors, and sucralfate. It is also recommended that individuals who are expected to be intubated for more than 72 hours receive nutritional support. Prokinetic agents are often required. Frequent positional changes and close surveillance for skin breakdown should be instituted in all intensive care units to minimize development of decubitus ulcers. In the past, frequent ventilator circuit changes had been studied as a measure for prevention of ventilator-associated pneumonia, but they were ineffective and may even have increased the risk of ventilator-associated pneumonia.
I-142. The answer is D. (Chap. 269) Mechanical ventilation is frequently used to support ventilation in individuals with both hypoxemic and hypercarbic respiratory failure. Mechanical ventilators provide warm, humidified gas to the airways in accordance with preset ventilator settings. The ventilator serves as the energy source for inspiration, but expiration is a passive process, driven by the elastic recoil of the lungs and chest wall. PEEP may be used to prevent alveolar collapse on expiration. The physiologic consequences of PEEP include decreased preload and decreased afterload. Decreased preload occurs because PEEP decreases venous return to the right atrium and may manifest as hypotension, especially in an individual who is volume depleted. In addition, PEEP is transmitted to the heart and great vessels. This complicated interaction leads to a decrease in afterload and may be beneficial to individuals with depressed cardiac function. When using mechanical ventilation, the physician should also be cognizant of other potential physiologic consequences of the ventilator settings. Initial settings chosen by the physician include mode of ventilation, respiratory rate, fraction of inspired oxygen, and tidal volume if volume-cycled ventilation is used or maximum pressure if pressure-cycled ventilation is chosen. The respiratory therapist also has the ability to alter the inspiratory flow rate and waveform for delivery of the chosen mode of ventilation. These choices can have important physiologic consequences for the patient. In individuals with obstructive lung disease, it is important to maximize the time for exhalation. This can be done by decreasing the respiratory rate or decreasing the inspiratory time (decrease the inspiration-to-expiration ratio, prolong expiration), which is accomplished by increasing the inspiratory flow rate. Care must also be taken in choosing the inspired tidal volume in volume-cycled ventilatory modes because high inspired tidal volumes can contribute to development of acute lung injury caused by overdistention of alveoli.
I-143. The answer is B. (Chap. 269) Patients intubated for respiratory failure because of obstructive lung disease (asthma or chronic obstructive pulmonary disease) are at risk for the development of intrinsic positive end-expiratory pressure (auto-PEEP). Because these conditions are characterized by expiratory flow limitation, a long expiratory time is required to allow a full exhalation. If the patient is unable to exhale fully, auto-PEEP develops. With repeated breaths, the pressure generated from auto-PEEP continues to rise and impedes venous return to the right ventricle. This results in hypotension and increases the risk for pneumothorax. Both of these conditions should be considered when evaluating this patient. However, because breath sounds are heard bilaterally, pneumothorax is less likely, and tube thoracostomy is not indicated at this time. Development of auto-PEEP has most likely occurred in this patient because the patient is currently agitated and hyperventilating as the effects of the paralytic agent wear off. In AC mode ventilation, each respiratory effort delivers the full tidal volume of 550 mL, and there is a decreased time for exhalation, allowing auto-PEEP to occur. Immediate management of this patient should include disconnecting the patient from the ventilator to allow the patient to fully exhale and decreasing the auto-PEEP. A fluid bolus may temporarily increase the blood pressure but would not eliminate the underlying cause of the hypotension. After treatment of the auto-PEEP by disconnecting the patient from the ventilator, sedation is important to prevent further occurrence of auto-PEEP by decreasing the respiratory rate to the set rate of the ventilator. Sedation can be accomplished with a combination of benzodiazepines and narcotics or propofol. Initiation of vasopressor support is not indicated unless other measures fail to treat the hypotension and it is suspected that sepsis is the cause of hypotension.
I-144. The answer is A. (Chaps. 5 and 269) To obtain a stable airway for invasive mechanical ventilation, patients must safely undergo endotracheal intubation. In most patients, paralytic agents are used in combination with sedatives to accomplish endotracheal intubation. Succinylcholine is a depolarizing neuromuscular blocking agent with a short half-life and is one of the most commonly used paralytic agents. However, because it depolarizes the neuromuscular junction, succinylcholine cannot be used in individuals with hyperkalemia because the drug may cause further increases in the potassium level and potentially fatal cardiac arrhythmias. Some conditions in which it is relatively contraindicated to use succinylcholine because of the risk of hyperkalemia include acute renal failure, crush injuries, muscular dystrophy, rhabdomyolysis, and tumor lysis syndrome. Acetaminophen overdose is not a contraindication to the use of succinylcholine unless concomitant renal failure is present.
I-145. The answers are 1-C; 2-B; 3-D; 4-A. (Chaps. 270, 271, and 272) A variety of vasopressor agents are available for hemodynamic support. The effects of these medications depend on their effects on the sympathetic nervous system to produce changes in heart rate, cardiac contractility, and peripheral vascular tone. Stimulation of α1 adrenergic receptors in the peripheral vasculature causes vasoconstriction and improves MAP by increasing systemic vascular resistance. The β1 receptors are located primarily in the heart and cause increased cardiac contractility and heart rate. The β2 receptors are found in the peripheral circulation and cause vasodilatation and bronchodilation. Phenylephrine acts solely as an α-adrenergic agonist. It is considered a second-line agent in septic shock and is often used in anesthesia to correct hypotension after induction of anesthesia. Phenylephrine is also useful for spinal shock. The action of dopamine depends on the dosage used. At high doses, dopamine has high affinity for the α receptor, but at lower doses (<5 μg/kg/min), it does not. In addition, dopamine acts at β1 receptors and dopaminergic receptors. The effect on these receptors is greatest at lower doses. Norepinephrine and epinephrine affect both α and β1 receptors to increase peripheral vascular resistance, heart rate, and contractility. Norepinephrine has less β1activity than epinephrine or dopamine and thus has less associated tachycardia. Norepinephrine and dopamine are the recommended first-line therapies for septic shock. Epinephrine is the drug of choice for anaphylactic shock. Dobutamine is primarily a β1 agonist with lesser effects at the β2 receptor. Dobutamine increases cardiac output through improving cardiac contractility and heart rate. Dobutamine may be associated with development of hypotension because of its effects at the β2 receptor causing vasodilatation and decreased systemic vascular resistance.
I-146 and I-147. The answers are B and C, respectively. (Chap. 270) Hypovolemic shock is the most common form of shock and occurs either because of hemorrhage or loss of plasma volume in the form of gastrointestinal, urinary, or insensible losses. Symptoms of hemorrhagic and nonhemorrhagic shock are indistinguishable. Mild hypovolemia is considered to be loss of less than 20% of the blood volume and usually presents with few clinical except save for mild tachycardia. Loss of 20–40% of the blood volume typically induces orthostasis. Loss of more than 40% of the blood volume leads to the classic manifestations of shock, which are marked tachycardia, hypotension, oliguria, and finally obtundation. Central nervous system perfusion is maintained until shock becomes severe. Oliguria is a very important clinical parameter that should help guide volume resuscitation. After assessing for an adequate airway and spontaneous breathing, initial resuscitation aims at reexpanding the intravascular volume and controlling ongoing losses. Volume resuscitation should be initiated with rapid IV infusion of isotonic saline or Ringer’s lactate. In head-to-head trials, colloidal solutions have not added any benefit compared with crystalloid and in fact appeared to increase mortality for trauma patients. Hemorrhagic shock with ongoing blood losses and a hemoglobin of 10 g/dL or less should be treated with transfusion of packed red blood cells (PRBCs). After hemorrhage is controlled, transfusion of PRBCs should be performed only for hemoglobin of 7 g/dL or less. Patients who remain hypotensive after volume resuscitation have a very poor prognosis. Inotropic support and intensive monitoring should be initiated in these patients. An algorithm for the resuscitation of a patient in shock is shown in Figure I-148.
I-148. The answer is D. (Chap. 270) The patient is in cardiogenic shock from an ST-elevation myocardial infarction. Shock is a clinical syndrome in which vital organs do not receive adequate perfusion. Understanding the physiology underlying shock is a crucial factor in determining appropriate management. Cardiac output is the major determinant of tissue perfusion and is the product of stroke volume and heart rate. In turn, stroke volume is determined by preload, or ventricular filling, afterload, or resistance to ventricular ejection, and contractility of the myocardium. In this patient, the hypoxic and damaged myocardium has suddenly lost much of its contractile function, and stroke volume will therefore decrease rapidly, dropping cardiac output. Systemic vascular resistance will increase in order to improve return of blood to the heart and increase stroke volume. Central venous pressure is elevated as a consequence of increased vascular resistance, decreased cardiac output and poor forward flow, and neuroendocrine-mediated vasoconstriction. The pathophysiology of other forms of shock is shown in Table I-149 as a comparison.
TABLE I-149 Physiologic Characteristics of the Various Forms of Shock
I-149. The answer is C. (Chap. 271) The annual incidence of sepsis has increased to >700,000 individuals yearly in the United States, and sepsis accounts for more than 200,000 deaths yearly. Approximately two-thirds of the cases of sepsis occur in individuals with other significant comorbidities, and the incidence of sepsis increases with age and preexisting comorbidities. In addition, the incidence of sepsis is thought to be increasing as a result of several other factors. These include increased longevity of individuals with chronic disease, including AIDS, and increased risk for sepsis in individuals with AIDS. The practice of medicine has also influenced the risk of sepsis, with an increased risk of sepsis related to the increased use of antimicrobial drugs, immunosuppressive agents, mechanical ventilation, and indwelling catheters and other hardware.
I-150. The answer is B. (Chap. 271) Sepsis is a systemic inflammatory response that develops in response to a microbial source. To diagnose the systemic inflammatory response syndrome (SIRS), a patient should have two or more of the following conditions: (1) fever or hypothermia; (2) tachypnea; (3) tachycardia; or (4) leukocytosis, leukopenia, or greater than 10% band forms. This patient fulfills the criteria for sepsis with septic shock because she meets these criteria for SIRS with the presence of organ dysfunction and ongoing hypotension despite fluid resuscitation. The patient has received 2 L of intravenous colloid and now has a central venous pressure of 18 cmH2O. Ongoing large-volume fluid administration may result in pulmonary edema as the central venous pressure is quite high. At this point, fluid administration should continue but at a lower infusion rate. In this patient, who is receiving chronic glucocorticoids for an underlying inflammatory condition, stress-dose steroids should be administered because adrenal suppression will prevent the patient from developing the normal stress response in the face of SIRS. If the patient fails to respond to glucocorticoids, she should be started on vasopressor therapy. The diagnosis of adrenal insufficiency may be very difficult in critically ill patients. Whereas a plasma cortisol level of less than 15 μg/mL indicates adrenal insufficiency (inadequate production of cortisol), many experts now feel that the adrenocorticotropic hormone stimulation test is not useful for detecting less profound degrees of corticosteroid deficiency in patients who are critically ill. A single small study has suggested that norepinephrine may be preferred over dopamine for septic shock, but these data have not been confirmed in other trials. The “Surviving Sepsis” guidelines state that either norepinephrine or dopamine should be considered as a first-line agent for the treatment of septic shock. Transfusion of red blood cells in critically ill patients has been associated with a higher risk for development of acute lung injury, sepsis, and death. A threshold hemoglobin value of 7 g/dL has been shown to be as safe as a value of 10 g/dL and is associated with fewer complications. In this patient, a blood transfusion is not currently indicated, but it may be considered if the central venous oxygen saturation is below 70% to improve oxygen delivery to tissues. An alternative to blood transfusion in this setting is the use of dobutamine to improve cardiac output.
I-151. The answer is C. (Chap. 271) Sepsis occurs as a result of the inflammatory reaction that develops in response to an infection. Microbial invasion of the bloodstream is not necessary for the development of severe sepsis. In fact, blood culture results are positive in only 20–40% of cases of severe sepsis and in only 40–70% of cases of septic shock. The systemic response to infection classically has been demonstrated by the response to lipopolysaccharide (LPS) or endotoxin. LPS binds to receptors on the surfaces of monocytes, macrophages, and neutrophils, causing activation of these cells to produce a variety of inflammatory mediators and cytokines, most notably tumor necrosis factor α (TNF-α). TNF-α stimulates leukocytes and vascular endothelial cells to release other cytokines (as well as additional TNF-α), to express cell-surface molecules that enhance neutrophil–endothelial adhesion at sites of infection, and to increase prostaglandin and leukotriene production. Whereas blood levels of TNF-α are not elevated in individuals with localized infections, they increase in most patients with severe sepsis or septic shock. Moreover, IV infusion of TNF-α can elicit the characteristic abnormalities of SIRS. Although TNF-α is a central mediator, it is only one of many proinflammatory molecules that contribute to innate host defense. Chemokines, most prominently inter-leukin-8 (IL-8) and IL-17, attract circulating neutrophils to the infection site. These and other proinflammatory cytokines probably interact synergistically with one another and with additional mediators to promote the process of complement activation and increase in procoagulant factors, cellular injury, and intravascular thrombosis. The nonlinearity and multiplicity of these interactions have made it difficult to interpret the roles played by individual mediators in both tissues and blood. This process is meant to wall off invading microorganisms to prevent infection from spreading to other tissues, but in cases of severe sepsis, this leads to tissue hypoxia and ongoing cellular injury. In addition, systemic hypotension develops as a reaction to inflammatory mediators and occurs despite increased levels of plasma catecholamines. Physiologically, this is manifested as a marked decrease in systemic vascular resistance despite evidence of increased sympathetic activation. Survival in sepsis has improved in the past decades largely because of advances in supportive care in the intensive care unit.
I-152. The answer is B. (Chap. 271) As the mortality from sepsis has increased over the past 20 years, more research has been performed to attempt to limit mortality. Antimicrobial chemotherapy should be started as soon as samples of blood and other relevant sites have been obtained for culture. A large retrospective review of patients who developed septic shock found that the interval between the onset of hypotension and the administration of appropriate antimicrobial chemotherapy was the major determinant of outcome; a delay of as little as 1 hour was associated with lower survival rates. Empiric antibiotics should have broad coverage of gram-positive and -negative organisms. In general, combination therapy has no advantage over monotherapy with broad-spectrum antibiotics. Use of inappropriate antibiotics, defined on the basis of local microbial susceptibilities and published guidelines for empirical therapy, was associated with fivefold lower survival rates even among patients with negative culture results. Specific therapies have been developed to target the inflammatory response to sepsis, particularly the effect of the inflammatory response on the coagulation system. Unfortunately, none of the pathophysiologically oriented therapies has shown consistent benefit in sepsis. Recently, activated protein C (drotrecogin-α), which had been approved by the U.S. Food and Drug Administration for the treatment of septic shock, was removed from the market by its manufacturer after the European PROWESS-SHOCK trial failed to show a survival benefit. Bicarbonate therapy is commonly used when severe metabolic acidosis is present in septic shock. However, there is no evidence that bicarbonate improves hemodynamics, response to vasopressors, or outcomes in septic shock. In patients with septic shock, plasma vasopressin levels increase transiently but then decrease dramatically. Early studies found that vasopressin infusion can reverse septic shock in some patients, reducing or eliminating the need for catecholamine vasopressors. More recently, a randomized clinical trial that compared vasopressin plus norepinephrine with norepinephrine alone in 776 patients with pressor-dependent septic shock found no difference between treatment groups in the primary study outcome, 28-day mortality. Although some patients with sepsis may benefit from red blood cell transfusion, erythropoietin is not used to treat anemia in sepsis.
I-153. The answer is A. (Chap. 272) Cardiogenic shock (CS) is characterized by systemic hypoperfusion caused by severe depression of the cardiac index (<2.2 L/min/m2) and sustained systolic arterial hypotension (<90 mmHg) despite an elevated filling pressure (pulmonary capillary wedge pressure >18 mmHg). It is associated with in-hospital mortality rates above 50%. Acute myocardial infarction (MI) with left ventricular dysfunction is the most common cause of cardiogenic shock. Other complications of acute MI such as mitral regurgitation or free wall rupture are far less common. CS is the leading cause of death of patients hospitalized with MI. Early reperfusion therapy for acute MI decreases the incidence of CS. Shock typically is associated with ST-segment elevation MI and is less common with non–ST-segment elevation MI. In patients with acute MI, older age, female sex, prior MI, diabetes, and anterior MI location are all associated with an increased risk of CS. Shock associated with a first inferior MI should prompt a search for a mechanical cause. Reinfarction soon after MI increases the risk of CS. Two-thirds of patients with CS have flow-limiting stenoses in all three major coronary arteries, and 20% have stenosis of the left main coronary artery. CS may rarely occur in the absence of significant stenosis, as seen in LV apical ballooning/Takotsubo’s cardiomyopathy.
I-154. The answer is E. (Chap. 272) In patients with acute myocardial infarction and cardiogenic shock, percutaneous coronary intervention can improve mortality rate and outcomes. Stabilizing the patient in cardiogenic shock is an important first maneuver. Initial therapy is aimed at maintaining adequate systemic and coronary perfusion by raising systemic blood pressure with vasopressors and adjusting volume status to a level that ensures optimum left ventricular filling pressure. Decreased diastolic blood pressure is detrimental because it reduces coronary blood flow. However, vasopressor and inotropic agents have the potential to exacerbate the ischemic process by raising myocardial oxygen consumption, increasing heart rate, or increasing left ventricular afterload. Norepinephrine is associated with fewer adverse events, including arrhythmias, compared with dopamine. Dobutamine has greater inotropic than chronotropic action but may cause a reduction in blood pressure due to vasodilation. Aortic counterpulsation with an intraaortic balloon pump (IABP) is helpful in rapidly stabilizing patients because it is capable of augmenting both arterial diastolic pressure and cardiac output. The balloon is automatically inflated during early diastole, augmenting coronary blood flow, and it collapses in early systole, reducing the left ventricular afterload. IABP improves hemodynamic status temporarily in most patients with cardiogenic shock. In contrast to vasopressors and inotropic agents, myocardial O2 consumption is reduced, ameliorating ischemia. IABP is contraindicated if aortic regurgitation is present or aortic dissection is suspected.
I-155. The answer is E. (Chap. 273) The most common electrical mechanism for cardiac arrest is ventricular fibrillation, which is responsible for 50–80% of cardiac arrests. Severe persistent bradyarrhythmias, asystole, and pulseless electrical activity (PEA: organized electrical activity, unusually slow, without mechanical response, formerly called electromechanical dissociation) cause another 20–30%. Pulseless sustained ventricular tachycardia (a rapid arrhythmia distinct from PEA) is a less common mechanism. Acute low cardiac output states, having a precipitous onset also may present clinically as a cardiac arrest. These hemodynamic causes include massive acute pulmonary emboli, internal blood loss from a ruptured aortic aneurysm, intense anaphylaxis, and cardiac rupture with tamponade after myocardial infarction. Sudden deaths from these causes are not typically included in the category of sudden cardiac death.
I-156. The answer is A. (Chap. 273) The probability of achieving successful resuscitation from cardiac arrest is related to the interval from onset of loss of circulation to institution of resuscitative efforts, the setting in which the event occurs, the mechanism (ventricular fibrillation, ventricular tachycardia, PEA, asystole), and the clinical status of the patient before the cardiac arrest. Return of circulation and survival rates as a result of defibrillation decrease almost linearly from the first minute to 10 minutes. After 5 minutes, survival rates are no better than 25–30% in out-of-hospital settings. Settings in which it is possible to institute prompt cardiopulmonary resuscitation (CPR) followed by prompt defibrillation provide a better chance of a successful outcome. However, the outcome in intensive care units (ICUs) and other in-hospital environments is heavily influenced by the patient’s preceding clinical status. The immediate outcome is good for cardiac arrest occurring in ICUs in the presence of an acute cardiac event or transient metabolic disturbance, but survival among patients with far-advanced chronic cardiac disease or advanced noncardiac diseases (e.g., renal failure, pneumonia, sepsis, diabetes, cancer) is low and not much better in the in-hospital than in the out-of-hospital setting. Survival from unexpected cardiac arrest in unmonitored areas in a hospital is not much better than that it is for witnessed out-of-hospital arrests. Because implementation of community response systems, survival from out-of-hospital cardiac arrest has improved, although it still remains low under most circumstances. Survival probabilities in public sites exceed those in the home environment. This may be because many patients with at home cardiac arrest have severe underlying cardiac disease. The success rate for initial resuscitation and survival to hospital discharge after an out-of-hospital cardiac arrest depends heavily on the mechanism of the event. Most cardiac arrests that are caused by ventricular fibrillation (VF) begin with a run of nonsustained or sustained ventricular tachycardia (VT), which then degenerates into VF. When the mechanism is pulseless VT, the outcome is best, VF is the next most successful, and asystole and PEA generate dismal outcome statistics. Advanced age also adversely influences the chances of successful resuscitation as well as outcomes after resuscitation.
I-157. The answer is D. (Chap. 274) Alterations in consciousness are among the most common reasons for admission to the hospital and occur frequently in seriously ill patients. When evaluating a patient with an alteration in consciousness, one must have a framework for understanding the spectrum of arousability one may encounter. Coma is a frequently misunderstood term that refers to a deep sleeplike state from which a patient cannot be aroused. A stuporous patient can be aroused briefly with noxious stimuli, and drowsiness refers to a patient who can be aroused easily with maintenance of attention for brief periods. Other conditions that alter the ability of a patient to respond appropriately to stimuli and are often confused with coma. A vegetative state is an awake but unresponsive condition that can occur in a patient who has emerged from a coma and is associated with extensive bilateral cerebral damage. A patient in a vegetative state can open the eyes spontaneously and often track objects. In addition, the patient has retention of respiratory and autonomic functions as well as spontaneous movement of extremities. However, meaningful responses to stimuli do not occur, and a vegetative state is sometimes referred to as an “awake coma.” This patient would be characterized as being in a persistent vegetative state because the duration of the vegetative state has been 1 year. At this point, the likelihood of meaningful recovery of mental faculties is almost zero. A minimally conscious state is a less severe manifestation of bilateral cerebral injury. A patient in a minimally conscious state may have rudimentary vocal or motor behaviors and minimal responses to external stimuli. Other conditions that may be misinterpreted as a coma include akinetic mutism, catatonia, abulia, and locked-in syndrome.
I-158. The answer is A. (Chap. 274) Brain death occurs when all cerebral function has ceased but the patient continues to have cardiac activity while supported by artificial means. If an individual is determined to have brain death, life-sustaining therapies are withdrawn. Although this can occur without the consent of the family, certainly it is important to have open communication with the family to allow the withdrawal of care without conflict. Most hospitals have developed specific protocols to diagnose a patient with brain death. Three essential elements should be demonstrated for the diagnosis of brain death. First, the patient should widespread cortical damage with complete absence of response to all external stimuli. Second, the patient should have no evidence of brainstem function with loss of oculovestibular and corneal reflexes and absent pupillary reaction to light. Finally, there should be no evidence of medullary activity manifested by apnea. When a brain death examination is performed, the patient should not be receiving any medications that could alter consciousness. The bedside examination will confirm absence of responsiveness to stimuli and lack of brainstem function. Apnea testing is the final examination in the performance of the brain death examination. This test is important for documenting the absence of medullary function. For an apnea test result to be accurate, the carbon dioxide must be allowed to rise to a level that would stimulate respiration. When performing the test, the patient is preoxygenated with 100% oxygen, which is sustained throughout the test. At this point, ventilator support is stopped. In the absence of any respiration, carbon dioxide rises by 2–3 mmHg/min, and it is necessary for arterial partial pressure of carbon dioxide to rise to between 50–60 mmHg. If the patient has a normal PaCO2 before beginning the apnea test, the test would typically need to continue for at least 5 minutes to be valid. The patient is observed for respiratory effort, and a PaCO2 level is often measured at the end of the test to document that the rise in carbon dioxide is adequate to stimulate respiration. Some patients may have cardiovascular instability that makes the performance of apnea testing risky because one does not wish for the apnea test to lead to cardiovascular collapse. In this setting, an electroencephalogram demonstrating absence of electrical activity is used as an adjunctive diagnostic test. Newer methods of testing, including radionuclide brain scanning, cerebral angiography, and transcranial Doppler ultrasonography, may be used, but these tests are less well validated. In most cases, clinical evidence of brain death must be sustained for 6–24 hours before withdrawal of care.
I-159. The answer is E. (Chap. 274) Foraminal herniation, which forces the cerebellar tonsils into the foramen magnum, leads to compression of the medulla and subsequent respiratory arrest. Central transtentorial herniation occurs when the medial thalamus compresses the midbrain as it moves through the tentorial opening; miotic pupils and drowsiness are the classic clinical signs. A locked-in state is usually caused by infarction or hemorrhage of the ventral pons; other causes include Guillain-Barré syndrome and use of certain neuromuscular blocking agents. Catatonia is a semi-awake state seen most frequently as a manifestation of psychotic disorders such as schizophrenia. Third-nerve palsies arise from an uncal transtentorial herniation in which the anterior medial temporal gyrus herniates into the anterior portion of the tentorial opening anterior to the adjacent midbrain. Coma may occur because of compression of the midbrain.
I-160. The answer is D. (Chap. 275) Clinicians caring for critically ill individuals are often asked to determine prognosis after events that lead to anoxic-ischemic brain injury, including prolonged cardiac arrest, shock, and carbon monoxide poisoning. Lack of cerebral circulation for longer than 3–5 minutes most often results in at least minor permanent cerebral damage, which can be difficult to predict. In the early hours after an anoxic-ischemic event, family members often ask for guidance regarding prognosis, and the clinical examination over a period of 72 hours provides important clues to whether any meaningful recovery of cerebral function may occur. However, before performing the examination, the patient must be in a stable clinical state without medications or other clinical factors that would prevent an appropriate examination. In recent years, clinical trials have supported the use of induced hypothermia to improve neurologic outcomes after cardiac arrest, and current clinical practice is to lower body temperature to 33°C for 12–24 hours. To ensure patient comfort during induced hypothermia and prevent elevation in body temperature from shivering, the patient is heavily sedated and often paralyzed for the duration of the hypothermia and through the rewarming process. Given that this patient is hypothermic, sedated, and paralyzed, the clinical examination cannot be used to provide any prognostic information to the family at the present time.
If the patient were not hypothermic, paralyzed, or sedated, the initial examination should assess for the presence of brainstem function to determine if brain death is present. If brainstem function was present, other clinical signs of poor prognosis in the first 1–3 days include the presence of status epilepticus, frequent myoclonus, lack of response on somatosensory evoked potentials, or a serum neuron specific enolase level greater than 33 μg/L. After 72 hours, the patient is often reassessed for the response to noxious stimuli and corneal or pupillary response. The absence of response or an extensor motor response only at this point in time predicts a 0–3% long-term likelihood of neurologic recovery.
I-161. The answer is C. (Chap. 275) When a patient presents to the emergency department with a severe headache, the most immediately life-threatening diagnosis is SAH. The most common cause of SAH outside of trauma is rupture of a saccular aneurysm, and some patients may experience a sentinel bleed from a small rupture, providing a window of opportunity to definitively treat the aneurysm before a more substantial bleed. The most common symptom of a SAH is a severe headache that is abrupt in onset (thunderclap headache). About 50% of individuals experience a sudden loss of consciousness caused by a rapid increase in intracranial pressure that is followed by the severe headache upon regaining consciousness. Other common characteristics associated with SAH are worsening of pain with exertion or bending forward, neck stiffness, and vomiting. In 95% of cases, blood in the subarachnoid space is visible on a noncontrasted CT scan of the head. However, if the event occurred more than 3 days previously as in this case, blood may not be seen. In this situation, the patient should undergo lumbar puncture to determine if red blood cells are present in the CSF without clearing. At this stage, the red blood cells will likely have undergone some degree of lysis with a resultant discoloration of the CSF to a characteristic yellow color called xanthochromia. The peak intensity of xanthochromia is at 48 hours, but it persists for 1–4 weeks. If the lumbar puncture demonstrates xanthochromia, then further evaluation would most likely consist of a conventional four-vessel cerebral angiography to localize the aneurysm and provide a potential method of treatment via endovascular techniques. CT angiography may be used as an alternative for localization but does not provide the opportunity for intervention. Lumbar puncture will also evaluate for meningitis and encephalitis, which are also possible in this case. Appropriate culture and polymerase chain reaction diagnostic tests should be included in the diagnostic evaluation.
I-162. The answer is A. (Chap. 275) This patient presents with an SAH caused by a ruptured anterior cerebral artery and has evidence of increased intracranial pressure with midline shift on a CT scan of the head. He has undergone aneurysm repair, and the care now should focus on the medical management of SAH. Some of the principles of the medical management of SAH include treatment of intracranial hypertension, management of blood pressure, prevention of vasospasm, and prevention of rebleeding. A patient who is unresponsive with evidence of intracranial hypertension should immediately undergo emergent ventriculostomy, which allows measurement of intracranial pressure (ICP) and can treat elevated ICP. Other strategies for treatment of elevated ICP include hyperventilation, mannitol, sedation, and hypernatremia. If a patient survives the initial aneurysmal bleed and the aneurysm is treated, the leading cause of morbidity and mortality after SAH is development of cerebral vasospasm. Vasospasms occur in about 30% of patients after SAH, typically between day 4 and 14, peaking at day 7. Efforts to prevent vasospasm include administration of nimodipine 60 mg orally every 4 hours. The mechanism of action is not clear. It may act to limit vasospasm but also likely prevents ischemia-induced cerebral injury as well. When administering the calcium channel blocker, it is important to prevent hypotension. Concurrent administration of vasopressors may be required. In addition, most patients also receive volume expansion. This therapy has commonly been known as “triple H” therapy for hypertension, hypervolemia, and hemodilution. Glucocorticoids are not used in the treatment of SAH. There is no evidence that they reduce cerebral edema or have a neuroprotective effect.
I-163. The answer is D. (Chap. 275) This patient has evidence of ICP and needs to be managed urgently. A variety of maneuvers may decrease ICP acutely. Hyperventilation causes vasoconstriction, reducing cerebral blood volume and decreasing ICP. However, this can be used only for a short period because the decrease in cerebral blood flow is of limited duration. Mannitol, an osmotic diuretic, is recommended in cases of increased ICP resulting from cytotoxic edema. Hypotonic fluids should be avoided. Instead, hypertonic saline is given to elevate sodium levels and prevent worsening of edema. A more definitive treatment to decrease ICP is to have a ventriculostomy placed by which excessive pressure can be relieved by draining CSF. Further decreases in MAP may worsen the patient’s clinical status. The patient already has had more than a 20% reduction in MAP, which is the recommended reduction in cases of hypertensive emergency. In addition, the patient is exhibiting signs of increased ICP, which indicates that cerebral perfusion pressure (MAP – ICP) has been lowered. Paradoxically, the patient may need a vasopressor agent to increase MAP and thus improve cerebral perfusion. Finally, in cases of increased ICP, nitroprusside is not a recommended intravenous antihypertensive agent because it causes arterial vasodilation and may decrease cerebral perfusion pressure and worsen neurologic function.
I-164 and I-165. The answers are E and C, respectively. (Chap. 276) This clinical scenario describes an individual with superior vena cava (SVC) syndrome, which is an oncologic emergency. Eighty-five percent of cases of SVC syndrome are caused by either small cell or squamous cell cancer of the lung. Other causes of SVC syndrome include lymphoma, aortic aneurysm, thyromegaly, fibrosing mediastinitis, thrombosis, histoplasmosis, and Behçet’s syndrome. The typical clinical presentation is dyspnea, cough, and facial and neck swelling. Symptoms are worsened by lying flat or bending forward. As the swelling progresses, it can lead to glossal and laryngeal edema with symptoms of hoarseness and dysphagia. Other symptoms can include headaches, nasal congestion, pain, dizziness, and syncope. In rare cases, seizures can occur from cerebral edema, although this is more commonly associated with brain metastases. On physical examination, dilated neck veins with collateralization on the anterior chest wall are frequently seen. There is also facial and upper extremity edema associated with cyanosis. The diagnosis of SVC syndrome is a clinical diagnosis. A pleural effusion is seen in about 25% of cases, more commonly on the right. A chest CT scan would demonstrate decreased or absent contrast in the central veins with prominent collateral circulation and would help elucidate the cause. Most commonly this would be mediastinal adenopathy or a large central tumor obstructing venous flow. The immediate treatment of SVC syndrome includes oxygen, elevation of the head of the bed, and administration of diuretics in combination with a low-sodium diet. Conservative treatment alone often provides adequate relief of symptoms and allows determination of the underlying cause of the obstruction. In this case, this would include histologic confirmation of cell type of the tumor to provide more definitive therapy. Radiation therapy is the most common treatment modality and can be used in an emergent situation if conservative treatment fails to provide relief to the patient.
I-166. The answer is A (Chap. 276) This patient presents with symptoms of spinal cord compression in the setting of known stage IV breast cancer. This represents an oncologic emergency because only 10% of patients presenting with paraplegia regain the ability to walk. Most commonly, patients develop symptoms of localized back pain and tenderness days to months before developing paraplegia. The pain is worsened by movement, cough, or sneezing. In contrast to radicular pain, the pain related to spinal cord metastases is worse with lying down. Patients presenting with back pain alone should have a careful examination to attempt to localize the lesion before development of more severe neurologic symptoms. In this patient with paraplegia, there is an definitive level at which sensation is diminished. This level is typically one to two vertebrae below the site of compression. Other findings include spasticity, weakness, and increased deep tendon reflexes. In those with autonomic dysfunction, bowel and bladder incontinence occur with decreased anal tone, absence of the anal wink and bulbocavernosus reflexes, and bladder distention. The most important initial step is the administration of high-dose intravenous corticosteroids to minimize associated swelling around the lesion and prevent paraplegia while allowing further evaluation and treatment. MRI should be performed of the entire spinal cord to evaluate for other metastatic disease that may require therapy. Although a brain MRI may be indicated in the future to evaluate for brain metastases, it is not required in the initial evaluation because the bilateral nature of the patient’s symptoms and sensory level clearly indicate the spinal cord as the site of the injury. After an MRI has been performed, a definitive treatment plan can be made. Most commonly, radiation therapy is used with or without surgical decompression.
I-167 and I-168. The answers are B and E, respectively. (Chap. 276) Tumor lysis syndrome occurs most commonly in individuals undergoing chemotherapy for rapidly proliferating malignancies, including acute leukemias and Burkitt’s lymphoma. In rare instances, it can be seen in chronic lymphoma or solid tumors. As the chemotherapeutic agents act on these cells, there is massive tumor lysis that results in release of intracellular ions and nucleic acids. This leads to a characteristic metabolic syndrome of hyperuricemia, hyper-phosphatemia, hyperkalemia, and hypocalcemia. Acute kidney injury is frequent and can lead to renal failure, requiring hemodialysis if uric acid crystallizes within the renal tubules. Lactic acidosis and dehydration increase the risk of acute kidney injury. Hyper-phosphatemia occurs because of the release of intracellular phosphate ions and causes a reciprocal reduction in serum calcium. This hypocalcemia can be profound, leading to neuromuscular irritability and tetany. Hyperkalemia can become rapidly life threatening and cause ventricular arrhythmia.
Knowing the characteristics of tumor lysis syndrome, one can attempt to prevent the known complications from occurring. It is important to monitor serum electrolytes very frequently during treatment. Laboratory studies should be obtained no less than three times daily, but more frequent monitoring is often needed. Allopurinol should be administered prophylactically at high doses. If allopurinol fails to control uric acid to less than 8 mg/dL, rasburicase, a recombinant urate oxidase, can be added at a dose of 0.2 mg/kg. Throughout this period, the patient should be well hydrated with alkalinization of the urine to a pH of greater than 7.0. This is accomplished by administration of intravenous normal or ½ normal saline at a dose of 3000 mL/m2 daily with sodium bicarbonate. Prophylactic hemodialysis is not performed unless there is underlying renal failure before starting chemotherapy.