C-Diff Which type of Clostridium difficile infection (CDI) is the most common? A) Health care facility (HCF)onset B) Community-onset, HCFassociated C) Community-associated D) Indeterminate origin Answer • B) Community-onset, HCF-associated Historical background • Clostridium difficile first described in 1935 • emergence of clindamycin-associated colitis (condition due to toxin-producing clostridia) seen in 1970s • for many years thereafter, C difficile infection (CDI) thought easily treatable with metronidazole • however, outbreaks of virulent epidemic strain associated with high morbidity and mortality reported in last decade Types of • CDI: health care facility (HCF)-onset—develops >48 hr after admission to HCF • community-onset but HCF-associated— constitutes majority of cases; symptom onset occurs briefly after discharge from HCF • community-associated—rare; no history of discharge from HCF in preceding 12 wk (if discharge within 4-12 wk • CDI categorized as of indeterminate origin All the following antimicrobial agents are frequent inducers of CDI, except: A) Ampicillin B) Clindamycin C) Macrolides D) Third-generation cephalosporins Answer • C) Macrolides Prevalence • has risen dramatically since 1990s; highest in patients 65 yr of age (800 cases per 100,000, vs 140 cases per 100,000 in overall population) • infection emerging in populations previously thought to be at low risk • Factors contributing to resurgence of C difficile–associated diarrhea (CDAD): virulence of C difficile strains • Resistance to antimicrobial agents • increasing numbers of elderly and immunocompromised people • possibly, increased use of alcoholbased handrubs for hygiene in HCFs Proportion of population with positive toxin assay for C difficile • healthy neonates — vast majority (but generally asymptomatic colonization); healthy adults — only 1% to 2% • hospitalized patients— 8% to 18%; patients with antibioticassociated diarrhea (AAD)—10% to 25%; • patients with pseudomembranous colitis (PMC)—95% to 100 Risk factors for CDAD • • • • • • • • • • • • • • • >65 yr of age antimicrobial exposure gastrointestinal (GI) surgery tube feeding use of proton pump inhibitors and histamine-2 receptor antagonists Comorbidities (especially organ transplantation and renal failure) use of cancer chemotherapeutic agents length of stay in hospital single greatest risk factor for exposure to C difficile Antimicrobial agents that induce CDI: frequent inducers— ampicillin third-generation cephalosporin Clindamycin Fluoroquinolones infrequent inducers—macrolides and sulfonamides rare inducers —consider switching to this category in cases in which anti-infective agent cannot be entirely eliminate C difficile colonization is associated with an increased risk for recurrent C difficileassociated diarrhea (CDAD). A) True B) False Answer • B) False • • • • • • • • • • • • Pathogenesis of CDAD disruption of normal enteric flora acquisition of toxigenic C difficile once infection acquired, 50% of patients mount protective serum antibody response (which results in asymptomatic colonization [carrier state]), and 50% unable to mount protective antibody response (develop CDAD) 60% to 90% of patients with CDAD recover without recurrence recurrence may occur when comorbidity or trigger responsible for infection persists Risk for CDAD after colonization: C difficile colonization paradoxically associated with reduced risk IgG levels and CDAD: patients colonized with C difficile who have high levels of IgG antibody against toxin A less likely to develop mild or severe CDAD Mechanism of CDAD: presence of toxin in intestine induces array of inflammatory cascade reactions that result in multiple disruptions of epithelial barrier, neutrophil infiltration, and, subsequently, PMC New epidemic strain (B1/NAP1) of C difficile: contains additional toxin (“binary toxin”) deletions in negative regulatory genes allow increased production of toxins A and B (produces 16-23 times more toxin than nonepidemic strain) has greater propensity for resistance to fluoroquinolones associated with higher incidence of sepsis, leukemoid reactions, colectomies, and death Which of the following agents should not be used to treat CDAD? A) Metronidazole B) Vancomycin C) Probiotics D) Atropine Answer • D) Atropine • • • • • • • Treatment of CDAD 25% of patients improve without need for further therapy after change in or complete discontinuation (if possible) of triggering antibiotic older randomized trial showed similar treatment success and relapse rates with metronidazole and oral vancomycin more recent study showed that vancomycin appears to be more effective than metronidazole against B1/NAP1 strain (for moderate to severe CDI) atropine and similar antimotility agents should be avoided probiotics —trials of many probiotics showed high efficacy for prevention of AAD, but most effective probiotic undetermined due to high heterogeneity Fulminant colitis: x-ray of abdomen recommended in patients with moderate to severe CDI to rule out impending or present toxic megacolon positive finding indicates need for immediate subtotal colectom Approximately _______ of patients with CDAD relapse within 30 days after cessation of therapy. A) 20% B) 33% C) 40% D) 50% Answer • A) 20% • • • • • • • • • • Recurrent CDAD 20% of patients relapse within 30 days after cessation of therapy (>50% experience further relapses) Underlying mechanism lack of host immune response to toxin A Prophylactic metronidazole or oral vancomycin for patients with ongoing antibiotic use not currently recommended treatment—age, comorbidities, and immune status need to be considered use vancomycin for initial recurrence (use metronidazole only for mild cases) for subsequent recurrences, treat with tapered or pulsed vancomycin for 6 wk (consider use of rifaximin after completion of vancomycin and intravenous immunoglobulin [IVIG]) Saccharomyces boulardii as probiotic: has little effect on initial episode of CDI treated with vancomycin or metronidazole, but appears to reduce rate of recurrence not approved by Food and Drug Administration (FDA) for this purpose Lactobacillus casei as probiotic: recent randomized trial showed lower incidence of AAD and 0% C difficile toxin in patients who consumed probiotic drink containing L casei (DanActive) than in placebo group L casei only probiotic proven effective in primary prevention of CD New treatments for C difficile • in development—monoclonal antibodies to toxins A and B • fidaxomycin (currently in phase III trials) • currently available for other indications— IVIG for cases of severe refractory recurrent CDI (efficacy unclear) • Fecal transplantation: emerging body of literature suggests efficacy in treatment of recurrent C difficile colitis • donor stool must be tested for viral and other enteric pathogens and parasites • best donor close family member • efficacy in treating or preventing CDI not yet studied in randomized trials • Animals as source of C difficile: strains in animals generally different from those in humans, but potential for transmission exists Questions and Answers • • • • • • • • • • Outpatient management of patient with relapse of C difficile enteritis shortly after course of oral metronidazole if recurrence mild, second course of metronidazole reasonable oral vancomycin recommended in most cases Dosing of vancomycin for outpatient treatment of CDI: 2010 guidelines from Infectious Diseases Society of America (IDSA) recommend 125 mg oral vancomycin qid (however, most practitioners use 250 mg qid) Number of stool samples needed to diagnose CDI: depends on diagnostic test used polymerase chain reaction extremely sensitive for C difficile (requires only one sample) if enzyme immunoassay negative but result questionable, retest (speaker recommends different test rather than second sample with same test) Test of cure: almost never required because patients carry toxigenic C difficile well after symptoms resolve retesting recommended in patients with recurrence, because episode may be caused by antibiotic and not by C difficile Helping patients tolerate metronidazole: probiotics may help mitigate nausea and other adverse effects limit duration of therapy (10-14 days recommended Questions and Answers • • • • • • • • • Once-daily metronidazole for treatment of CDI: not recommended on basis of current data, but speaker suspects it would be appropriate In-hospital testing for colonization of C difficile Current guidelines do not recommend routine testing in patients, mainly because identification and isolation of asymptomatic carriers not shown to reduce transmission Test for specific type of C difficile in colonized patients: most tests confined to semiformed, loose, or watery stools, so laboratory often automatically rejects samples from patients with asymptomatic colonization (because they have formed stool) instrument that distinguishes between epidemic and nonepidemic strains exists, but used only in research (not clinically available) Dose of clindamycin and risk of developing CDI: no dose-dependent effect lowest dose possible (150 or 300 mg) recommended for treating skin and soft tissue infections; if higher dose indicated, IV rather than oral route advised avoid use of clindamycin in patients with history of CDI Ground or tap water as source of community-associated CDI: anti-infectives ubiquitous in ground and tap water Rates of community-associated CDI low because both anti-infective agent and exposure to C difficile required for infection Fidaxomicin for treatment of CDI • recent trial found lower rates of relapse in patients without B1/NAP1 strain to be main advantage of oral fidaxomicin (vs vancomycin) for treatment of CDI • first in new class of macrocyclic antibiotics that inhibit RNA polymerase • has narrow spectrum of activity • achieves high stool levels • approval by FDA expected soon Ceftaroline fosamil is the only βlactam antibiotic active against: A) Extended-spectrum βlactamase-producing gramnegative bacteria B) Pseudomonas aeruginosa C) Acinetobacter baumannii D) Methicillinresistant Staphylococcus aureus Answer • D) Methicillin-resistant Staphylococcus aureus Ceftaroline fosamil • • • • fosamil part of prodrug (converted to active form of ceftaroline in vivo) like other Beta-lactam antibiotics, binds to penicillin-binding proteins (PBPs) in cell membrane (unlike other Beta-lactam antibiotics, binds to and inhibits modified PBP 2a found in methicillin-resistant Staphylococcus aureus) • not active against extended-spectrum beta-lactamaseproducing gram-negative bacteria and some other resistant organisms, such as Pseudomonas aeruginosa and Acinetobacter baumannii • approved by FDA for skin and soft tissue infections and community-acquired pneumonia • recent article found drug to be fairly effective against resistant S aureus organisms in vitro The presence and degree of pyuria cannot be used to diagnose a catheter-associated urinary tract infection. A) True B) False Answer • A) True • • • • • • • Catheter-associated urinary tract infection (CAUTI) defined as 10 3 colony-forming units/mL in urine specimen from catheterized patient, plus compatible symptoms and no other identified source presence and degree of pyuria cannot be used to diagnose UTI, although its absence in symptomatic patients suggests alternative source of symptoms lack of alternative source key to diagnosis (if source not identified, initiation of treatment reasonable antibiotic should be discontinued and patient reevaluated if no response seen within 72 hr) Condom catheterization possible alternative to reduce catheter-associated bacteriuria (but data about effects on risk for UTI insufficient) decreased recurrent bacteriuria and faster resolution of symptoms associated with replacement of catheters in place for 2 wk at time of treatment data suggest 7 days of antimicrobial therapy sufficient for most patients; guidelines for management of CAUTI available on IDSA website Which of the following statements about the use of spinosad for treating head lice is incorrect? A) More effective than permethrin B) Combing of nits not required C) Two or more applications required for full efficacy D) Approved in January 2011 for individuals ≥4 yr of age Answer • C) Two or more applications required for full efficacy Head lice • • • • • • • difficult to eliminate 6 to 12 million infestations annually in US combined annual direct and indirect costs $1 billion many lice resistant to permethrin (not ovicidal) spinosad —produced by soil bacterium appears nontoxic to mammals more effective than permethrin in 2 combined phase III trials (85% lice-free [vs 44%] after treatment) • combing out nits not required • one application usually sufficient • approved by FDA in January 2011 for individuals 4 yr of age In the United States, 60 cases of Cryptococcus _______ were reported in humans between 2004 and July 1, 2010. A) neoformans B) laurentii C) albidus D) gattii Answer • D) gattii Cryptococcus gattii • before 1999, thought to cause disease only in immunocompetent hosts in tropics and subtropics • identified in animals and humans on Vancouver Island in 1999 and on mainland of British Columbia in 2004 (several hundred cases) • 60 cases reported in humans (immunocompromised and nonimmunocompromised) from 2004 to July 1, 2010, in US • causes respiratory and central nervous system disease • consider in patient with symptoms consistent with chronic meningitis or respiratory syndrome and those without known immunocompromis Prevention of SSIs in nasal carriers of S aureus • 800 patients undergoing surgery randomized to receive intranasal mupirocin plus chlorhexidine soap or placebo • results — rate of S aureus infection 3.4% in treatment group vs 7.7% in placebo group (relative risk, 0.42) Treatment of influenza with oseltamivir is recommended in all the following groups, except: A) Patients <5 yr or ≥65 yr of age B) Healthy adolescents C) Individuals with chronic disease D) Pregnant or postpartum women Answer • B) Healthy adolescents Groups for whom treatment of influenza with oseltamivir recommended: • • • • • • • children 5 yr of age (especially 2 yr) elderly (65 yr of age) persons with chronic diseases Patients with immunosuppression pregnant or postpartum women people with morbid obesity Extensively drug-resistant tuberculosis (TB): defined as resistance to isoniazid plus rifampin plus fluoroquinolone plus injectable drug • automated molecular assay (Xpert MTB/RIF)—rapidly tests for Mycobacterium tuberculosis and resistance to rifampin in sputum samples • developed in public-private partnership; both sensitive and rapid Choose the incorrect statement about stroke. A) Focal neurologic deficit with presumed vascular onset B) Duration >24 hr C) Typically diagnosed by computed tomography (CT) D) Transesophageal echocardiography helpful in identifying cause Answer • C) Typically diagnosed by computed tomography (CT) Stroke • defined as focal neurologic deficit with presumed vascular onset • duration >24 hr • if less than 24 hr, called transient ischemic attack (TIA) • however, most TIAs last 15 min) • computed tomography (CT) not very useful but diffusionweighted magnetic resonance imaging (MRI) extremely helpful in establishing diagnosis It is estimated that control of hypertension in patients would reduce the incidence of stroke in the United States by: A) 50% B) 40% C) 33% D) 20% Answer • A) 50% • • • • • • • • • • • • • • • • • • • • Indistinct symptoms that may suggest stroke: loss of consciousness headache; march of symptoms from one body part to another positive neurologic findings Transesophageal echocardiography (TEE) superior to transthoracic echocardiography (TTE) in identifying causes of stroke (eg, left ventricular thrombus; valvular disease; patent foramen ovale plaque in aortic arch) Ischemic penumbra (IP): relatively hypoperfused area of brain (between normal tissue and tissue of infarct) at risk for infarction but not irreversibly damaged target for acute intervention (salvaging IP one of goals of treatment) Resurgence in stroke mortality rate: annual death rate declined over last 20 yr, but expected to double over next 30 yr Risk factors for stroke: controllable—hypertension (HTN) Hyperlipidemia diabetes mellitus (DM) smoking noncontrollable — ethnicitysex nationality Guidelines for stroke prevention: treat HTN, cholesterol, and DM; smoking cessation discontinue heavy alcohol use weight reduction moderate-intensity exercise for 30 min most days of week estimated that control of HTN in patients would reduce incidence of stroke in United States by 50 Aggressive statin therapy should be avoided in patients after a stroke or transient ischemic attach (TIA). A) True B) False Answer • B) False • Stroke Prevention by Aggressive Reduction in Cholesterol • Levels (SPARCL) study: 5000 patients with recent history of stroke or TIA and hyperlipidemia randomized to 80 mg atorvastatin vs placebo • results — aggressive antihyperlipidemic therapy reduced incidence of fatal or nonfatal stroke by 16% and need for revascularization surgery in heart and neck by almost 50% • implications — aggressive statin therapy should be strongly considered in patients after stroke or TIA • most effective agent and dosage unclear • Management of DM and stroke prevention: results of several recent trials suggest more aggressive control of type 1 and type 2 DM does not reduce risk for stroke • Stroke risk in smokers: smoking 2 packs of cigarettes daily associated with 2-fold risk for stroke • if smoking stopped, risk reverts to baseline within 5 yr • Screening asymptomatic patients for carotid disease: in United States, 66% of adults >40 yr of age have some carotid plaque (and 10% of men >65 yr of age have moderate to high-grade asymptomatic stenosis) • presence of plaque clear marker of risk for stroke • consider noninvasive screening for all patients at increased risk All the following antiplatelet agents are approved for use in the prevention of recurrent stroke, except: A) Aspirin (ASA) B) Clopidogrel C) Ticlopidine D) Cilostazol Answer • D) Cilostazol Antiplatelet therapy • • • • • • • • • antiplatelet agents approved for use in prevention of recurrent stroke include aspirin (ASA), clopidogrel, ASA plus dipyridamole, and ticlopidine no good evidence antiplatelet therapy reduces risk for stroke in asymptomatic patients possibly small benefit in older women and men with substantial atherosclerotic risk (however, substantial increase in risk for hemorrhagic stroke) in symptomatic patients, antiplatelet agents reduce risk for stroke by 25% ASA good for almost all patients little reason to use dipyridamole clopidogrel probably no better than ASA, except in patients with gastrointestinal (GI) intolerance, allergy to ASA, stents, or history of TIA or stroke while on ASA combination of clopidogrel and ASA may be beneficial in patients with atrial fibrillation (AF) who cannot tolerate warfarin (consider dabigatran) many new anticoagulant agents in development or have just become available for clinical use Intravenous tissue plasminogen activator (IV tPA) is the only acute treatment available for stroke. A) True B) False Answer • A) True Acute treatment of stroke • when patient with possible stroke or TIA presents at emergency department (ED), questions that must be answered include whether patient should be admitted, whether he or she requires treatment with intravenous tissue plasminogen activator (IV tPA), and whether carotid endarterectomy (CEA) or carotid artery stenting (CAS) should be considered Assessing risk for stroke following TIA • Age/BP/Clinical Features/Duration/DM (ABCD2) scoring system—assesses risk for stroke within first 2 day after TIA • higher score correlates with higher risk based on clinical data collected in ED diffusion MRI gives information on whether patient has had stroke or at risk for stroke and about carotid stenosis • suggestions —if patient presents >1 wk after TIA, admission probably unnec essary, but evaluation indicated; if ABCD 2 • score high, admission and careful observation necessary • even low-risk patients with established TIA should be admitted if possible because other high-risk factors may be discovered in hospital over time, eg, carotid stenosis ASCD2 • Age ≥ 60? Yes +1 • BP ≥ 140/90 mmHg at initia evaluation? Yes +1 • Clinical Features of the TIA: Unilateral Weakness +2 Speech Disturbance without Weakness +1 • Duration of Symptoms? 10-59 minutes +1 ≥ 60 minutes +2 • Diabetes Mellitus in Patient's History? Yes +1 • • • • ScienceDaily (June 6, 2011) —CMAJ(Canadian Medical Association Journal). The ABCD2 score (Age, Blood pressure, Clinical features, Duration of symptoms and Diabetes) is commonly used as a tool for physicians to identify people at high-risk of stroke after transient ischemic attacks, although it has not been widely applied clinically by physicians at the bedside. The study, designed to assess the effectiveness of the ABCD2 score, included 2056 patients aged 18 or older who experienced a transient ischemic attack or minor stroke at eight Canadian emergency departments between 2007 and 2010. The mean age of the patients was 68 years, and half were female. For most patients, this was their first transient ischemic attack; about half experienced motor weakness, one-third reported speech irregularities and most had symptoms for at least 10 minutes. Thirty-eight (1.8%) of patients had a stroke within 7 days of the first visit and 65 (3.2%) within 90 days. An additional 201 patients (9.8%) had a second transient ischemic attack between 7 and 90 days. "We found that an ABCD2 score of more than five had low sensitivity for predicting subsequent stroke at 7 or 90 days," states Dr. Jeffrey Perry, University of Ottawa and Ottawa Hospital Research Institute, with coauthors. "We believe that the sensitivities we found are too low to be clinically acceptable." "The ABCD2 score can be credited for increasing awareness of transient ischemic attack as a medical emergency that carries with it a substantial and modifiable risk for subsequent stroke," write the authors. "This study determined that the criteria used to calculate the score are not sensitive enough to classify patients as being at low risk. We also determined that the 2009 recommendation by the American Heart Association of using an ABCD2 score of more than two to determine high risk has a very low specificity, classifying almost all patients as requiring immediate imaging and perhaps admission to hospital." • Importance of diffusion-weighted MRI in assessment of patient with presumed TIA: when patient presents, 33% chance of abnormality on diffusion-weighted imaging; at 12 hr after presentation, 66% chance of abnormality (unequivocal indication of stroke) • Thrombolysis (IV tPA): only acute treatment available; 4.5-hr time window (but treat as quickly as possible for best outcome) • benefit—10% to 15% of patients recover who would not otherwise improve • however, associated with 6% risk for ICH • patient must have measurable focal neurologic deficit which is not improving • many contraindications to treatment Choose the incorrect statement about carotid endarterectomy (CEA) and carotid artery stenting (CAS) in symptomatic patients. A) CEA of no benefit for patients with carotid stenoses <50% B) CAS is a good alternative to CEA in highrisk patients C) No need to avoid CEA in older patients and those with comorbidities D) Younger patients appear to have better outcomes with CAS, while older patients do better with CEA Answer • D) Younger patients appear to have better outcomes with CAS, while older patients do better with CEA • • • • • • • • • • Standard work-up for suspected TIA or stroke includes MRI, MR or CT angiography, TEE or TTE, electrocardiography (ECG) monitoring, and other tests MR angiography (MRA) almost as good as CT angiography (CTA) in head and neck (safer; easy to use); carotid ultrasonography also good but more technician dependent than CTA or MRA also, cannot see base ofskull or intracranially with carotid ultrasonography Carotid endarterectomy (CEA): no benefit for symptomatic patient with stenosis <50%, modest benefit for stenosis 50% to 70%, and substantial benefit for stenosis >70% (data apply only if performing vascular surgeon has 3%-5% mortality and morbidity rate) do not need to avoid procedure in older patients and those with comorbidities be cautious about symptomatic women with moderate stenosis (more risk and less benefit than men) perform surgery promptly (unless stroke large) Carotid artery stenting (CAS): studies show CAS equivalent to CEA for efficacy and possibly slightly better for complications good alternative in high-risk patients (may be safer for asymptomatic patients) some data suggest younger patients have better outcomes with CAS, while older patients do better with CE Atrial fibrillation (AF) • warfarin reduces incidence of stroke in setting of AF by 66% (no combination of antiplatelet agents • can match results); risk for bleeding small; may also consider • dabigatran (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY] trial compared warfarin to 2 different doses of dabigatran bid for treatment of AF • results show dabigatran not inferior to warfarin in preventing stroke and systemic emboli, and has fewer side effects) • Patent foramen ovale (PFO): associated with stroke, particularly in young patients • data from recent randomized study do not support use of mechanical closure over medical therapy • second study under way The most common type of delirium is: A) Hypoactive B) Hyperactive C) Mixed Answer • C) Mixed Features of delirium • • • • • • • • • • • • • • • • • • • disturbance in consciousness global cognitive disturbance (particularly attention and vigilance) Relatively abrupt in onset and fluctuating in course due to underlying physiologic disturbances other common features include sleepwake cycle disturbances, emotional lability, hallucinations (oneiroid), illusions, and delusional beliefs motor changes Syndromes included under term “delirium”: acute mental status change subacute befuddlement Encephalopathy intensive care unit (ICU) delirium sundowning Subtypes of delirium: hypoactive—prevalence 35% in ICU features include lethargy, confusion, and sedation easy to miss (often attributed to primary psychiatric disorder, eg, depression) hyperactive —features include agitation and hyperarousal, (yelling, screaming) pulling out IV lines, endotracheal tubes, and catheters much harder to miss, but relatively rare mixed—characterized by periods of hyperactive and hypoactive symptoms most common type of delirium Only _______ of patients fully recover cognitively from an episode of delirium. A) 15% B) 20% C) 30% D) 50% Answer • B) 20% Associated outcomes • patients who develop delirium in hospital • have much higher mortality rate for 1 yr after occurrence (hazard ratio 2 to 3, even when controlling for variables) • Delirium nonspecific warning sign that something wrong physiologically • (eg, fever or hypotension) that requires further definition • associated with increased—functional decline • nursing home placement • persistent cognitive decline (only 20% of patients fully recover from episode of delirium Which of the following classes of drugs are associated with delirium? A) Psychoactive drugs B) Narcotics C) Anticholinergic agents D) A, B, and C Which of the following classes of drugs are associated with delirium? A) Psychoactive drugs B) Narcotics C) Anticholinergic agents D) A, B, and C Answer • D) A, B, and C Drug classes associated with delirium • psychoactive medications (eg, BZDs); narcotics; anticholinergic medications • polypharmacy increases overall likelihood of developing delirium • study by Lu and Tune found long-term exposure to anticholinergic drugs seems to predict development of delirium over time (important to get assistance from pharmacists in determining patients’ anticholinergic load from their medications Benzodiazepines (BZDs) for the management of hyperactive delirium: A) Are absolutely contraindicated B) Can be safe and effective at low doses and are the drug of choice when medical therapy is necessary C) Should be avoided unless the precipitating cause of delirium is withdrawal from BZDs or alcohol Answer • C) Should be avoided unless the precipitating cause of delirium is withdrawal from BZDs or alcohol Treatment of delirium • • • • • • • • • • • • • • • • • identify and address underlying cause review of medications, neurologic and mental status examination, taking of vital signs, and general medical work-up all helpful in determining underlying etiology management requires interdisciplinary effort (physicians; nurses; physical and occupational therapists; pharmacists; family members and loved ones) early physical therapy shown to decrease length of delirium getting patient mentally active also helpful Nonpharmacologic management: facilitate constant presence of family member (or, if not possible, sitter) to provide interpersonal contact and reorientation provide visual and hearing aids if needed wrap IV lines in gauze so patient cannot see them mobilize patient early and often good sleep hygiene important (keep patient awake during day if possible, provide uninterrupted sleep at night) Management of hyperactive delirium: avoid restraints if absolutely necessary, can use antipsychotics to calm patient (not approved by Food and Drug Administration [FDA]); however, recent studies have shown haloperidol (Haldol) and quetiapine (Seroquel) helpful treatments for agitated delirium watch for QT interval prolongation on ECG avoid BZDs unless precipitating cause of delirium is BZD or alcohol withdrawal Choose the correct statement(s) about estradiol andmigraines. A) Estradiol levels decrease in perimenopause B) Fluctuations in estradiol levels affect hyperexcitability in brain C) Estrogen receptors decrease in number, eg, in the brain stem and periaqueductal gray, during perimenopause D) A, B, and C Answer • B) Fluctuations in estradiol levels affect hyperexcitability in brain A study of migraine in menopause found that migraines tend to improve after _______ menopause and worsen after _______ menopause. A) Physiologic; surgical B) Surgical; physiologic Answer • A) Physiologic; surgical The fraction of women whose migraines improve after starting oral contraceptives is approximately _____. A) 13% B) 21% C) 33% D) 66% Answer • C) 33% Improvement in migraines as women age may result from the loss of serotonergic cells in the dorsal raphe. A) True B) False Answer • A) True Choose the correct statement(s) about the risks and benefits of HRT for the treatment of migraines. A) A meta-analysis suggests that the use of HRT for ≈5 yr during perimenopause does not increase the risk for thromboembolic events B) A study showed use of low-dose (<50 mg) estrogen patches in younger women who did not smoke did not increase the risk for stroke C) For women with menstrual migraine, maintenance of estrogen between 50 to 70 pg/mL is most effective D) A, B, and C Answer • D) A, B, and C Choose the correct statement(s) about the use of medications by patients with migraines.Polypharmacy occurs in ≈80% of migraine sufferers More than 95% take medication, mostly over-thecounter (OTC) Approximately 40% use prescribed medications Patients with mild headaches are more likely to take OTC drugs than prescribed medications Most patients have not consulted a physician about their headaches Answer • B) 1,2,3,5 Study data show which of the following OTC formulations to be superior to 50 mg sumatriptan as determined by a score comprising the sum of pain intensity differences at 4 hr? A) Acetaminophen, aspirin, and caffeine B) Ibuprofen C) A combination of aspirin and magnesium D) Butterbur Answer • A) Acetaminophen, aspirin, and caffeine Which of the following drugs or drug classes may produce interactions of concern with triptans? A) Ergotamines B) Metoclopramide C) Monoamine oxidase inhibitors D) A, B, and C Answer • D) A, B, and C Serotonin syndrome occurs more often with high-dose monotherapy with SSRIs (0.9 to 0.9 cases per 1,000 patientmonths) than with SSRIs combined with triptans A) True B) False Answer • A) True Which of the following combinations of triptans and βblockers requires changes in the recommended dose of triptan? A) Sumatriptan and propranolol B) Sumatriptan and metoprolol C) Zolmitriptan and propranolol D) Rizatriptan and propranolol Answer • D) Rizatriptan and propranolol What is the treatment of Aphthous ulcers of the mouth? • • • • • • Aphthous ulcers, commonly referred to as canker sores, are a common problem with young adults. There are 3 types of aphthous ulcers: minor, major and herpetiform. Minor aphthae are small and shallow, major aphthae are larger with deeper ulceration and herpetiform aphthae are more numerous and vesicular. Aphthous ulcers may be located on the tongue, labial or buccal mucosa, the soft palate or the floor of the mouth. They are rarely associated with fevers, adenopathy or other systemic symptoms. The common course of aphthae is 10-14 days, although the course of major lesions may be longer. Herpetiform ulcers usually have a course of 7-10 days. The etiology of aphthous ulcers is uncertain but may be due to a combination of stress, physical or chemical trauma, food sensitivity or infection. Sodium lauryl sulfate, an ingredient in toothpaste, has also been implicated. Another risk factor may be a family history of aphthous ulcers. An autoimmune etiology is the current prevailing hypothesis. Smoking is not a risk factor and actually provides a protective effect against recurrent aphthae. Major aphthae can have an association with human immunodeficiency virus (HIV) infection. Recurrent aphthae are associated with celiac disease and inflammatory bowel disease. Treatment of aphthous ulcers is largely empiric due to the uncertainty of the etiology. There are 5 categories of treatment: antibiotic, anti-inflammatory, immune modulatory, symptomatic and alternative. If used, antibiotics are given topically or systemically. Tetracycline and minocycline are the most common agents used and have been shown to decrease pain and duration of ulcerations. A 250 mg tetracycline capsule can be dissolved in 180 mL of water and used (swish and swallow or swish and spit) 4 times daily, or 100 mg minocycline can be dissolved in 180 mL of water twice daily the same way. These agents should not be used by pregnant women or children. Anti-inflammatory effects can be achieved with local-acting steroids. Triamcinolone paste (Kenalog in Orabase) and dexamethasone elixir are commonly used and have been shown to speed healing with recurrent minor aphthous ulcers. Systemic or intralesional steroids are reserved for severe disease. Immune modulators, such as oral thalidomide and topical amlexanox (Aphthasol), have improved healing times with aphthous ulcers. Studies on thalidomide are primarily in HIV-infected patients. Symptomatic agents that provide effective pain relief include 2% viscous lidocaine, benzocaine preparations and a combination of over-the-counter magnesium hydroxide antacid and diphenhydramine hydrochloride (SOR C; Ref. 3). Systemic analgesics may be required for pain that is refractory to local agents. Improved healing times have been reported with alternative agents although there are no controlled trials. These include zinc gluconate lozenges, vitamin C, vitamin B, lysine, sage and chamomile mouthwash, and Echinacea. A 45-year-old man complains of "bumps" located over the extensor elbow and knee areas, the buttocks near the gluteal crease and episodes of clustered lesions elsewhere (e.g., his trunk). The bumps have been present for 6 months and are intensely pruritic. (See photographs.) His past medical history includes hypertension for which he has taken hydrochlorothiazide and lisinopril (generic, Zestril) for more than 1 year. He works in an industry where he is exposed to brake fluid. During several short vacations from work, he notes no change in the eruption. An avid outdoorsman, he sleeps in cabins while on outdoor adventures. He is specifically concerned about "MRSA." Further review of systems reveals mild diarrhea and abdominal cramping over the same time period. He has a family history of lactose intolerance but hadn’t had symptoms prior to development of the rash. On examination, numerous excoriated papular lesions are found over the olecranon, prepatellar, intergluteal and surrounding areas. A few vesicles are also visible. Further workup is done, including a skin biopsy with direct immunofluorescence, that shows deposits of IgA in the papillary dermis. Which of the following options is expected to improve the dermatitis the MOST? • Dermatitis Herpetiformis • This patient likely has dermatitis herpetiformis (DH), a blistering autoimmune dysfunction often seen in conjunction with gluten-sensitive enteropathy (GSE). The diagnosis is supported by the presence of grouped erythematous urticarial plaques and vesicles. Lesions are most often noted on extensor surfaces of the elbows and knees, back, as well as the buttocks. The rash is intensely pruritic; making the diagnosis is complicated by the fact that patients scratch until the lesions are excoriated. Incidence of DH is 10 to 39 in 100,000. Onset usually occurs between 20 and 40 years of age but may occur at any age, including childhood. Males are more often affected (2:1). DH principally affects whites, occurring only rarely in African Americans or Asians. Diagnosis is made by skin biopsy and direct immunofluorescence. Specimens showing a granular pattern of immunoglobulin A (IgA) deposited in the upper papillary dermis suggest DH. Two biopsy specimens are usually recommended. The first is taken from an edge of a lesion (hematoxylin and eosin [H&E] staining) and a second from normal-appearing skin. A vigorous immune response in skin with lesions may degrade IgA antibodies, causing falsenegative directed immunofluorescence (DIF). Therefore, DIF is best done in normal-appearing skin. While the majority of patients with DH have no gastrointestinal complaints, >90% show some degree of GSE when endoscopy is performed. Villous atrophy, elevated intraepithelial lymphocyte counts and increased T-cell lymphocytes are noted on intestinal biopsy. Ten percent of patients with DH have symptoms of malabsorption, bloating or diarrhea. In patients without GSE symptoms, increasing the amount of dietary gluten intake may promote symptoms. Initial treatment of DH involves a gluten-free diet. Gluten is a protein found in grasses including rye, wheat and barley (species Triticeae). Strict compliance with a gluten-free diet resolves small bowel mucosal abnormalities and improves cutaneous manifestations of DH in most patients. Rice and oats do not contain gluten and are alternatives for patients who must avoid gluten. DH resolves with complete avoidance of gluten, although improvement usually takes several months. A gluten-free diet is often difficult to achieve, because tiny amounts are found in nearly all restaurant and prepared foods. The variety of gluten-free foods has increased significantly over the past decade. Diaminodiphenyl sulfone (Dapsone) and sulfapyridine are the primary therapies for DH. Diaminodiphenyl sulfone given in a dose of 25-400 mg daily is first-line therapy after dietary changes. The usual dose is 50 mg twice daily. Side effects include nausea, vomiting and headache, with hemolytic anemia a less common problem. The mechanism of action of dapsone in DH is poorly understood. Symptomatic improvement of DH often begins within hours of dapsone therapy, although it does not improve intestinal mucosal abnormalities. Less effective therapies for DH include colchicine, prednisone, azathioprine (Imuran) and cyclosporine. Persons who have DH should be counseled regarding the increased incidence of intestinal lymphoma with their condition. A lactose-free diet does not improve symptoms of DH. • • • • • • A 45-year-old male consults you because he tested positive for hepatitis B at a recent blood donation drive. He is concerned about his test results and wants to know if he truly has hepatitis B. Which one of the following statements is TRUE regarding hepatitis B? Detection of hepatitis B surface antigen (HBsAg) is confirmatory for recent hepatitis B infection. Presence of hepatitis B e antigen (HBeAg) is unrelated to the levels of hepatitis B virus (HBV) DNA. In acute hepatitis B, conversion to HBsAg negative status does not occur until 9-12 months after symptom onset in 95% of adults. Patients who are HBsAg negative, anti-HBc negative but antiHBs positive require vaccination. Patients who are HBsAg negative, anti-HBc positive and antiHBs negative have most likely recovered from an acute HBV infection. You see a 32-year-old gravida 1 para 1 who is trying to become pregnant again. Her first pregnancy was complicated by severe nausea and vomiting during the first trimester. She wants to know whether she can prevent these symptoms from recurring. You tell her which ONE of the following? Preconception exercise and low-fat diet can prevent nausea in early pregnancy. There is nothing she can do. Taking a multivitamin at the time of conception may help decrease nausea and vomiting during the pregnancy. Spacing her pregnancies at least 18 months apart may help decrease her symptoms. Drinking green tea may prevent the development of nausea. • Nausea and Vomiting in Pregnancy • Nausea and vomiting complicate up to 80% of pregnancies. Although the pathophysiology of nausea during pregnancy is not well understood, it is associated with improved pregnancy outcomes. Levels of human chorionic gonadotropin (hCG) may be related to severity of nausea and vomiting during pregnancy, as women with molar pregnancies and twin pregnancies (both of which cause higher levels of hCG) tend to have more severe symptoms. Women have increased symptoms with an empty stomach. Symptoms can occur at any time during the day. For most women, nausea and vomiting are self-limited, resolving soon after the 1st trimester. Severe nausea and vomiting, referred to as hyperemesis gravidarum, is less common, affecting only 1% of pregnancies. Hyperemesis is characterized by persistent vomiting. The three criteria used to make a diagnosis of hyperemesis are loss of > 5% of prepregnancy body weight, ketonuria and hypokalemia. Many women with hyperemesis require intravenous fluids to maintain hydration, and some may need parenteral hyperalimentation. A common-sense approach to treating nausea and vomiting of pregnancy starts with simple lifestyle modifications. (See Table – Lifestyle Modifications to Control Nausea and Vomiting in Pregnancy.) Lifestyle Modifications to Control Nausea and Vomiting in Pregnancy Eat small, frequent meals Avoid spicy food, greasy food and caffeine Avoid strong odors Take folic acid alone (instead of entire prenatal vitamin) Keep crackers at bedside These lifestyle changes have not been rigorously studied. However, since the risk associated with these dietary changes is minimal, most experts recommend starting any discussion of the management of nausea and vomiting with these simple changes. It is important to be sure that the nausea and vomiting are from pregnancy alone and not from a secondary cause (e.g., hepatitis, gallbladder disease, appendicitis or hyperthyroidism). Several controlled trials have found that taking a multivitamin at the time of conception may decrease the amount of nausea and vomiting in pregnancy. Spacing of pregnancies, dietary intake and ingestion of green tea do not lead to decreased nausea and vomiting in pregnancy. Two controlled trials have found vitamin B6 supplementation effective in treating nausea and vomiting of pregnancy. The accepted dose is 10-25 mg given 3-4 times daily. The addition of doxylamine (20-25 mg daily) to vitamin B6 may improve effectiveness and is safe. A combination product, marketed as Bendectin, used to be available in the United States but was removed from the market due to concerns about teratogenicity that proved to be unfounded. Women can use Unisom (an over-thecounter sleep aid that contains 25 mg of doxylamine) in combination with vitamin B6. Higher doses of doxylamine (given divided during the day) may be needed for women with more severe symptoms. Most practitioners will try to treat women with nausea and vomiting early to prevent progression to hyperemesis, but this potential benefit is based on limited evidence. (See Table – First-Line Medications for Nausea in Pregnancy.) First-Line Medications for Nausea in Pregnancy Multivitamin at time of conceptionSOR A; Ref. 1Vitamin B6SOR A; Ref. 1 DoxylamineSOR A; Ref. 1Doxylamine/Vitamin B 6SOR A; Ref. 1 Ginger*SOR B; Ref. 1Antihistamines*SOR B; Ref. 1*No specific doses studied Many other treatments have been tried to treat nausea and vomiting in pregnancy. Acupressure at the P6 point of the wrist has been effective in treating nausea from chemotherapy. One prospective randomized trial of 80 women with nausea, vomiting and ketonuria did not find a reduction in vomiting with acupressure. However, acupressure confers little risk, so it may be a good option in women with milder forms of nausea and vomiting. Table – First-Line Medications for Nausea in Pregnancy.) Acupressure P6 Point Multiple other pharmacologic treatments for pregnant women are useful. Promethazine (generic, Phenergan), meclizine (generic, Antivert), ondansetron (generic, Zofran) and metoclopramide (generic, Reglan) are commonly used as second-line treatments if lifestyle modifications, vitamin B6, doxylamine and ginger have not worked. Ondansetron is now used more commonly than in the past due to its effectiveness and relative lack of side effects. It is pregnancy category B (animal studies show no adverse effect but there are no adequate or well-controlled studies in women OR animal studies have shown adverse effect but adequate studies in women have not demonstrated risk) and is very expensive. One relatively small study found no difference in the incidence of fetal malformations among groups of women (186 in each group) who took ondansetron, other antiemetic medications or no medication. Methylprednisolone (generic, Medrol) may be a last resort treatment of severe nausea and vomiting of pregnancy, but it should be reserved for refractory cases due to its potential risks. • • • • • • • • • • • • • • • Anal fissure Painful, palpable mass at the anal verge Sharp, tearing pain accompanied by rectal bleeding with defecation Sharp, spasmodic pain lasting a minute or less that reoccurs sporadically Progressive, dull perianal pain associated with fever Answer • Sharp, tearing pain accompanied by rectal bleeding with defecation Proctalgia fugax Painful, palpable mass at the anal verge Sharp, tearing pain accompanied by rectal bleeding with defecation Sharp, spasmodic pain lasting a minute or less that reoccurs sporadically Progressive, dull perianal pain associated with fever Answer • Sharp, spasmodic pain lasting a minute or less that reoccurs sporadically • Anorectal Pain • Although life-threatening conditions must be considered, anorectal pain is most commonly caused by benign conditions. Even when anorectal pain is due to a benign condition, it can be disabling to patients. Evaluation of anorectal pain begins with an inquiry about signs and symptoms, particularly those that might suggest conditions that are more serious. Slowly progressive perianal pain associated with fever suggests an anal abscess. Anal abscesses occur from infection of the anal glands located below the dentate line, an area abundant in sensory nerve fibers. Early-stage anal gland abscesses may be treated with oral antibiotics but require surgical drainage if they do not respond. Infection of the gland may spread along muscular and fascial plains in the anorectal region, resulting in perianal, ischioanal or supralevator abscesses. Fever and pain accompanied by an inability to void suggest that perianal sepsis is present. This is a medical emergency requiring intravenous antibiotics and surgical intervention. Anorectal pain associated with rectal bleeding is usually due to either an anal fissure or an external thrombosed hemorrhoid. Although rectal carcinoma rarely causes pain, all cases of rectal bleeding require evaluation. Even when a hemorrhoid or anal fissure is suspected or found, colorectal cancer screening should be considered, especially in patients ≥50 years old or patients ≥ 40 years with family history of colon cancer and in patients with other concerning symptoms (e.g., weight loss, abdominal pain). Anal fissures develop from tears in the anoderm, usually as a result of a forceful or hard bowel movement. Anal fissures cause a tearing or cutting pain occurring with defecation. Bright red bleeding may accompany the pain and is usually seen with wiping or on the surface of the stool. These fissures are most commonly found on the anterior-posterior midline. Fissures may also develop in association with syphilis, herpes infection, occult abscess or inflammatory bowel disease. These types of fissures are generally lateral to the midline. Pain from an acute anal fissure usually subsides within hours of the initial event but may reoccur with subsequent bowel movements. Treatment of acute fissures includes the use of bulk stool softeners and local steroid creams or suppositories. Fissures usually resolve in 3 months. Chronic fissures (those that persist beyond 3 months) are often accompanied by a perianal tag or sentinel pile. It is thought that chronic fissures develop due to increased anal sphincter tone. Topical calcium channel blocker creams and glyceryl trinitrate ointments may help reduce external sphincter tone. Development of headache limits the use of the latter. In refractory cases, surgical or laser sphincterotomy of the internal anal sphincter may help to reduce reoccurrence without affecting stool continence. Botulism toxin injection into the internal anal sphincter may also help chronic anal fissures to resolve. External hemorrhoids develop in the perianal veins below the dentate line. Because they are below the dentate line, they are associated with pain. Internal hemorrhoids originate above the dentate line where only stretch nerve fibers exist and are therefore not painful. The onset of acute anorectal pain associated with a rectal lump or mass is most often indicative of a thrombosed external hemorrhoid. Evaluation reveals a visible hemorrhoid that is hard, blue to black in color and thrombosed. Treatment consists of surgical excision of the hemorrhoid and removal of the internal clot. Incision of the hemorrhoid with extraction of the clot can be performed for immediate symptom relief but is associated with a high rate of rethrombosis. Sitz baths can be recommended as a more conservative treatment for smaller thrombosed hemorrhoids, although surgical excision often provides more rapid and more effective relief. Internal hemorrhoids may prolapse to cause a palpable mass at the anal verge but generally do not cause significant pain. Internal hemorrhoids can be treated with rubber band ligation or infrared coagulation. Proctalgia fugax is a poorly understood clinical entity. Patients experience fleeting, intense, spasm-like perineal pain that lasts a few seconds to minutes at a time. Patients often experience a need to defecate but do not pass stool. Associated symptoms include sweating, tachycardia and pallor. Diagnosis is based on clinical criteria and the absence of other anorectal disease. Clinical criteria for the diagnosis of proctalgia fugax include fleeting, spasmodic anorectal pain for >12 weeks lasting no more than a few seconds to a few minutes and not due to other anorectal pathology. Because of the infrequent nature of this pain syndrome, treatment is usually not recommended. If symptoms become more frequent, small studies suggest that the inhaled beta-agonist salbutamol (generic, Serevent) reduces frequency and severity of attacks. Nighttime doses of benzodiazepines may ease nocturnal pain. Levator ani syndrome, or chronic proctalgia syndrome, is a persistent, dull anorectal ache that lasts > 20 minutes. Diagnostic criteria include absence of other pathology, presence of pain for > 12 weeks and chronic or recurrent episodes of pain lasting > 20 minutes. Patients may experience pain during palpation of the pelvic floor musculature. The likely etiology is either increased pelvic floor tone or increased visceral sensitivity. Biofeedback, sitz baths and conservative pain management are all options for treatment. • • • • • • Colorectal cancer is the second most common cause of cancer-related death in the United States. Which one of the following is TRUE concerning colorectal cancer? A second-degree relative with a colonic polyp diagnosed at age 65 years confers increased risk, prompting early screening. Most cases of colorectal cancer are found early due to effective screening techniques. Hyperplastic polyps almost never become cancerous. Polyps associated with hereditary nonpolyposis colon cancer usually become cancerous within 5 to 10 years. Asian and Hispanic people are at greatest risk. • • Hyperplastic polyps almost never become cancerous. Colon Cancer Risk • Colorectal cancer (CRC) is the 2nd most common cause of cancer-related death in the United States behind lung cancer. Due to effective screening, colorectal cancer is one of the most commonly diagnosed cancers and is the 3rd most common cancer in men and women. Colorectal cancer is usually a slowly developing process and transformation from polyp to cancer typically takes 510 years. If colorectal cancer is found early, the 5-year survival rate is 90%. It is estimated that if every person >50 years of age were screened, 60% of colorectal cancer deaths could be avoided. The Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System estimated that in 2006 the number of persons older than 50 years who had undergone a fecal occult blood test in the past year or a screening colonoscopy in the past 10 years had improved significantly from 2004, with most states reporting 50-70% screening rates. However, as a result of these relatively low screening rates, less than 40% of colorectal cancers are found early. Most colorectal cancers arise from adenomatous polyps. Hyperplastic polyps, in contrast, almost never become cancerous. Persons with a family history of colorectal adenomatous polyps and/or cancer are at higher risk. Risks related to family history are shown in Table – Estimated Relative and Absolute Risk of Developing Colorectal Cancer. A single second-degree relative with colon polyps or cancer, particularly if diagnosed after age 60 years, does not appear to confer increased risk. Estimated Relative and Absolute Risk of Developing Colorectal Cancer Family History Relative Risk for CRC Absolute Risk (%) of CRC by Age 79 No family history14One first-degree relative with colorectal cancer2.3 9More than one first-degree relative with colorectal cancer4.3 16One affected first-degree relative diagnosed with colorectal cancer before age 453.9 15One first-degree relative with colorectal adenoma2.0 8 Others at high risk include those with ulcerative colitis or with a family history of familial adenomatous polyposis or hereditary nonpolyposis colon cancer. Relative risks for these conditions are shown in Table – Relative Risk of Colorectal Cancer Related to Associated Condition. Relative Risk of Colorectal Cancer Related to Associated Condition ConditionRiskCommentsUlcerative colitis0- to 15-fold riskNo increased risk with isolated proctitis; 3-fold risk with left-sided disease (risk increases 15-20 years after diagnosis); 5- to 15-fold risk with pancolitis (risk increases 8-10 years after diagnosis)Familial adenomatous polyposis90% of untreated individuals will develop cancer by 45 years of ageAccounts for <1% of colorectal cancersHereditary nonpolyposis colorectal cancer80% risk Accounts for 3% of colorectal cancers; early diagnosis (average age 48 years) with right colon involvement predominant; associated with extracolonic cancers; polyps much more aggressive and may progress to cancer within 1- 2 years The incidence of colorectal cancer is also affected by race and ethnicity. African Americans are the group with the highest rate of colorectal cancer and also death from colorectal cancer. (See Figures – Colorectal Cancer Incidence by Race and Ethnicity and Colorectal Cancer Deaths by Race and Ethnicity from the CDC.) As a result of the increased incidence and mortality of colorectal cancer in African Americans, screening starting at age 45 years is recommended by the American College of Gastroenterology in this population (SOR C; Ref. 1). • • • • • • • • •