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A. Administer dexamethasone 10 mg intravenously.

B. Consult neurosurgery for emergent spinal decompression.
С Consult radiation oncology for emergent spinal radiation.

D. Perform MRI of the brain.

E. Perform MRI of the entire spinal cord.

1-167. A 21-year-old man is treated with induction chemotherapy for acute lymphoblastic leukemia. His initial white blood cell count before treatment was 15 6,000/uL. All of the following are expected complications during his treatment EXCEPT:

A. Acute kidney injury

B. Hypercalcemia
С Hyperkalemia

D. Hyperphosphatemia

E. Hyperuricemia

1-168. All of the following would be important for prevention of these complications EXCEPT:

A. Administration of allopurinol 300 mg/m² daily

B. Administration of intravenous fluids at a minimum of3000mL/m² daily

C. Alkalinization of the urine to a pH of greater than 7.0 by administration of sodium bicarbonate

D. Frequent monitoring of serum chemistries every 4 hours

E. Prophylactic hemodialysis before initiating chemotherapy

ANSWER

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:

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%.

Posttest probability = (0.10)(0.66)/[((UO)(0.66) + (0.90)(0.16)] = 0.31

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 ТРЦТР + HV). The specificity is TN/(TN + №). 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 [48/(48 + 190)] x 100 = 20.2%, and the negative predictive value would be L?60/(760 + 2)J x 100 = 99.7%.

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 10% - 2%= 8%. 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 1/8% = 12.5 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.

Date: 2016-04-22; view: 525