A Man with Somnolence after Surgery

Posted by • July 28th, 2016

7-28 article 2 figure 1Although several theories have been postulated to explain the pathogenesis of the fat embolism syndrome, the end result is the embolization and agglutination of lipids, a process that causes obstruction of local blood flow in end organs (such as the lungs, brain, and skin) and leads to symptoms.

A 46-year-old man had worsening somnolence 1 day after replacement surgery with a femoral endoprosthetic implant. Fever, tachycardia, hypertension, and tachypnea developed, and examination revealed somnolence, gaze deviation, rigidity, and hyperreflexia. A diagnosis was made in a new Case Record.

Clinical Pearl

• What clinical findings are associated with malignant hyperthermia?

Malignant hyperthermia occurs in susceptible persons who have been exposed to halogenated volatile anesthetic agents or depolarizing muscle relaxants. It usually occurs between 30 minutes and 24 hours after such an exposure. Malignant hyperthermia is manifested by marked (sometimes extreme) temperature elevation, tachycardia, profound rigidity, agitation, hypercarbia, and acidosis.

Clinical Pearl

• When would you expect the symptoms of the neuroleptic malignant syndrome to appear in an affected patient?

Neuroleptic agents are sometimes administered in patients who have postoperative delirium, and postoperative use of antiemetic agents is common. Medications from each of these therapeutic classes can be associated with the development of the neuroleptic malignant syndrome. The symptoms typically evolve over a period of 1 to 3 days and include mental-status changes, profound rigidity, bradykinesia, hyperthermia, and autonomic instability, which is manifested by hypertension, tachycardia, and tachypnea.

Morning Report Questions

Q: What are some of the features of the fat embolism syndrome? 

A: The classic triad of findings includes respiratory insufficiency (most commonly manifested by hypoxemia), neurologic abnormalities (usually somnolence), and a petechial rash, which typically appears on the head, neck, thorax, and axillae. The fat embolism syndrome has an incidence of 1 to 3% after a single long-bone fracture (most commonly the femur) and a higher incidence after multiple fractures. It is more common among younger patients and those with closed fractures. The syndrome most commonly occurs between 24 and 72 hours after the precipitating injury, but onset between 12 and 24 hours after the inciting event is not uncommon. Eighty-five to 95% of patients with cerebral fat embolism who receive the appropriate supportive care survive.

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Q: Is the presence of a petechial rash required for diagnosis of the fat embolism syndrome? 

A: Early clinical descriptions of the fat embolism syndrome included the major criteria of respiratory insufficiency, cerebral involvement, and petechial rash; fever and tachycardia, were two minor criteria. However, in a later study involving persons with the fat embolism syndrome, 34% had somnolence as the earliest clinical sign or symptom; 75% had respiratory manifestations, and in 20%, the respiratory manifestations were initially dyspnea or tachypnea rather than hypoxemia. A petechial rash was a sign at presentation in only 17% of patients. Thus, it appears that the absence of hypoxemia and rash at the time of medical consultation does not rule out this diagnosis.

Liraglutide in Type 2 Diabetes

Posted by • July 28th, 2016

Liraglutide in Type 2 Diabetes graphTo assess the long-term effects of liraglutide on cardiovascular outcomes and other clinically important events, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was initiated in 2010. Patients with type 2 diabetes who had a glycated hemoglobin level of 7.0% or more were eligible if they either had not received drugs for this condition previously or had been treated with one or more oral antihyperglycemic agents or insulin (human neutral protamine Hagedorn, long-acting analogue, or premixed) or a combination of these agents.

Patients with type 2 diabetes and high cardiovascular risk were assigned to receive either the glucagonlike peptide 1 analogue liraglutide or placebo. In this new Original Article, the rate of first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was lower with liraglutide.

Clinical Pearl

• What is the mechanism of action of liraglutide?

Liraglutide, an analogue of human glucagon-like peptide 1 (GLP-1), has been approved for the treatment of type 2 diabetes. Its efficacy in lowering glucose levels has been established, and it has been associated with slight reductions in weight and blood pressure.

Clinical Pearl

• Is liraglutide associated with cardiovascular benefit in patients with type 2 diabetes who are at high risk for cardiovascular disease?

In the LEADER trial, patients in the liraglutide group had a lower risk of the primary composite outcome — first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis — and lower risks of death from cardiovascular causes, death from any cause, and microvascular events than did those in the placebo group. The frequencies of nonfatal myocardial infarction and nonfatal stroke were lower in the liraglutide group than in the placebo group, although the differences were not significant.

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 Morning Report Questions

Q: What are some of the adverse events that were associated with liraglutide in the LEADER trial?

A: In the LEADER trial, adverse events leading to the permanent discontinuation of the trial regimen were more common with liraglutide than with placebo. This result appears to have been driven by gastrointestinal disorders in the liraglutide group. There were more episodes of gallstone disease with liraglutide, a finding that has been reported previously. Acute pancreatitis occurred in 18 patients in the liraglutide group and in 23 in the placebo group. There has been considerable interest in a potential association between the use of GLP-1–receptor agonists and pancreatitis and pancreatic cancer, although there is no consistent preclinical, pharmacovigilance, or epidemiologic evidence to date. Among rodents receiving liraglutide, higher rates of thyroid C-cell tumors and hyperplasia have been observed than were observed among control animals. In the LEADER trial, no episodes of C-cell hyperplasia or medullary thyroid carcinoma were observed in patients in the liraglutide group. Randomized trials of this type, despite their size, are not powered to determine the effect of drugs on cancer risk and can therefore neither confirm nor exclude such a possibility.

7-28 article 1 table 2

Q: How do the results of the LEADER trial compare with those of other trials assessing the cardiovascular safety of newer anti-hyperglycemic therapies?

A: The pattern of cardiovascular benefits that were associated with liraglutide in the LEADER trial appears to differ from that with the sodium–glucose cotransporter 2 inhibitor empagliflozin in the previously reported EMPA-REG OUTCOME trial. The time to benefit emerged earlier in that trial than in the LEADER trial, and the heterogeneity of the direction and magnitude of the effects on the components of the primary composite outcome in that trial contrasts with the consistency of the effect in the LEADER trial. It should be noted that in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, the GLP-1–receptor agonist lixisenatide, which is shorter-acting than and structurally dissimilar to liraglutide, did not show any cardiovascular benefit in patients with diabetes and a recent acute coronary syndrome. There are a number of other trials regarding cardiovascular outcomes in high-risk cohorts of patients with type 2 diabetes in which similar magnitude effects on glycemic control have been shown but without significant benefits with respect to rates of cardiovascular events or death. These include trials with insulin, thiazolidinediones, and DPP-4 inhibitors. The LEADER trial had greater statistical power and included patients with a higher baseline glycated hemoglobin level than did most previous studies. However, no obvious single explanation in terms of either the study designs or the included populations is apparent to explain the divergent findings across this body of medical literature.

Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage

Posted by • July 27th, 2016

blood pressure figure 1 What is the ideal blood pressure goal for spontaneous cerebral hemorrhage? Results of the ATACH-2 trial are discussed.

As a surgery resident, one of the first concepts I learned was that high blood pressure was bad in a patient who was actively bleeding.  This meant that for a trauma patient with a large liver or splenic laceration, systolic blood pressure should be kept around 90 mm Hg.  Similarly, for a ruptured abdominal aortic aneurysm, one of our first steps in management is to place the patient on an esmolol drip to get the blood pressure down.  Intuitively, this makes sense — high pressure increases the rate of bleeding, likely leading to worse clinical outcomes and even death.  This concept might also apply to spontaneous cerebral hemorrhage, however, here there is also good reason to be concerned that lowering blood pressure could be harmful. In stroke, rapid blood pressure lowering is thought to adversely affect neurological outcomes.   The INTERACT-2 trial published in NEJM in 2013, did not show a significant difference in rate of death or severe disability with intensive systolic blood pressure lowering (to <140 mm Hg) within 6 hours of symptom onset as compared with standard blood pressure goals of <180 mm Hg.

While INTERACT-2 was a negative trial, there were findings that suggested that earlier intensive blood pressure lowering might have benefits. Recently published Online First in NEJM, Qureshi et al. investigate whether earlier intensive blood pressure lowering may improve outcomes in spontaneous cerebral hemorrhage in the ATACH-2 trial.

This multicenter, randomized, unblinded, open-label trial compared intensive systolic blood pressure lowering (goal systolic blood pressure 110-139 mm Hg) to standard anti-hypertensive treatment  (goal systolic blood pressure 140-179 mm Hg) initiated within 4.5 hours of symptom onset in patients with spontaneous supratentorial intracerebral hemorrhage and at least one systolic blood pressure reading of 180 mm Hg or more.  Patients were required to have a Glasgow Coma Scale (GSC) of 5 or more and a hematoma of less than 60cm3.  Assigned blood pressure control was continued for 24 hours.  Intravenous nicardipine was the first line anti-hypertensive followed by intravenous labetolol (or diltiazem or urapidil if labetolol unavailable).  The primary outcome was the proportion of patients who had moderately severe or severe disability (based on the Rankin score) or death at 3 months.  Secondary outcomes included quality of life (measured by the EQ-5D questionnaire or the proportion of patients with 33% expansion of the hematoma on repeat CT scan after 24 hours.

In this analysis with 500 patients in each arm, the mean systolic blood pressure in the intensive-treatment group was about 130 mm Hg versus about 140 mm Hg in the standard-treatment group.  Failure to achieve target blood pressure control within 2 hours occurred in about 12% in the intensive- treatment group compared to less than 1% in the standard-treatment group.

The rate of the primary outcome of death or disability was similar between the two groups, both close to 38%.    There was also no difference in quality of life, percentage of patients with hematoma expansion, rates of death at 3 months or in neurologic deterioration at 24 hours after randomization.  While there was no difference in immediate adverse events, there was a higher risk of adverse events in the intensive-treatment group in the 3 months after randomization compared to the standard group (~25% vs 20% p=0.05).  Specifically, there were more renal adverse events in the intensive-treatment group (9% vs 4%, p=0.002).

Overall, the results of the study are similar to those in the INTERACT-2 trial; there was no significant difference in death or disability with intensive blood pressure lowering compared with standard blood control.  These findings do not support intensive blood pressure lowering in spontaneous intracerebral hemorrhage.

Immunogenicity of a Meningococcal B Vaccine

Posted by • July 21st, 2016

7-21 article 2 In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitides B at a U.S. university. Data suggested that vaccination would control the university outbreak because it isolates expressed antigens that were closely related to the vaccine antigens.

The development of an effective meningococcal serotype B vaccine has been a challenge. In this new Original Article, estimates of potential seroprotection are determined during a vaccine campaign at a U.S. university in response to an outbreak of Neisseria meningitidis.

Clinical Pearl

• What has been an obstacle to the development of an effective vaccine against serotype B meningococcal disease?

Although the incidence of meningococcal disease has been declining, in part because of the routine administration of meningococcal A, C, W, and Y vaccines in adolescents, the prevention of serogroup B disease has presented particular challenges; it is not possible to use the meningococcal B polysaccharide as a vaccine antigen owing to its similarity to human glycoproteins, the presence of which could lead to an autoimmune response. Meningococcal B vaccines that are derived from the outer-membrane vesicles of specific outbreak strains have been developed, but these vaccines have not provided broad protection beyond the outbreak strain.

Clinical Pearl

• What does the Meningococcal Antigen Typing System predict regarding the protection afforded by 4CMenB against meningococcal B strains in the United States?

The Meningococcal Antigen Typing System predicts that 4CMenB will protect against 91% of U.S. meningococcal B strains. Although the system is designed to quantify the expression of antigen-using polyclonal antibodies against the fHbp, NHBA, and NadA components of 4CMenB and to determine whether bacterial expression is sufficient to elicit a vaccine response, the system cannot determine the degree to which heterogeneity in vaccine-induced immunity can be expected within populations. In addition, the results of the typing system cannot be generalized to patients of other ages or to different schedules of administration because the results are based on pooled serum specimens from infants who received four doses of 4CMenB. Serum bactericidal antibody (SBA) testing of individual serum specimens is the reference standard for quantifying immune responses and is thought to be more informative with regard to protection against disease. There is little indication of how broadly 4CMenB protects people against the diverse strains of meningococcal B. No large-scale assessment of the breadth of individual vaccine-induced immunity has been conducted.

Morning Report Questions

Q: In the study by Basta et al., what level of protective immunity against an outbreak strain was observed among university students who received the 4CMenB vaccine?

A: Data from the study by Basta et al. indicate that only 66.1% of U.S. university students who were fully vaccinated with 4CMenB had putatively protective immunity against a meningococcal B outbreak strain. This level of seropositivity was lower than expected, given the antigenic similarity between the outbreak strain and the components of the vaccine and given that the Meningococcal Antigen Typing System predicted that 4CMenB would induce responses against the outbreak strain. The authors also analyzed immune responses to two of the 4CMenB vaccine reference strains and found that for the 44/76-SL and 5/99 reference strains, 86.9 to 100% and 96.7 to 100% of students, respectively, who were vaccinated with two doses had putatively protective hSBA titers. The results indicate that knowledge of hSBA immunity against the vaccine reference strains is not sufficient to predict individual-level immunity against an outbreak strain, even when the strain expresses one or more antigens that are closely related to the vaccine antigens.

Q: How conclusive are the immunogenicity data in the study by Basta et al. regarding the efficacy of the 4CMenB vaccine?

A: Further evaluation of 4CMenB efficacy is needed because of the limitations in drawing inferences about protection from immunogenicity data alone. It is possible that vaccinees who had no detectable SBA titer against the outbreak strain but who had an immune response to the meningococcal antigens that were used to develop the vaccine may benefit from some degree of protection. The findings of Basta et al. also raise questions about whether a third dose of 4CMenB might increase the proportion of seropositive responses against strains that were not perfectly matched to the vaccine.

Extending Aromatase-Inhibitor Therapy

Posted by • July 21st, 2016

Goss OA 07.21.16The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely. The MA.17R trial, conducted by Goss et al., examined the effects of treatment with an aromatase inhibitor for 10 years rather than 5 years after any duration of prior treatment with tamoxifen, in postmenopausal women with hormone-receptor–positive early breast cancer.

An additional 5 years of adjuvant aromatase-inhibitor therapy in women with early hormone-receptor–positive breast cancer resulted in longer disease-free survival and a lower incidence of contralateral breast cancer than placebo, but not in longer overall survival. An Original Article explains.

Clinical Pearl

• What are current strategies to reduce the risk of recurrence in postmenopausal women who receive treatment for hormone-receptor–positive early breast cancer?

Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety of adjuvant regimens, including tamoxifen for 10 years, tamoxifen for up to 5 years followed by an aromatase inhibitor for 5 years, or an initial aromatase inhibitor for 5 years. Extrapolating from these results, many patients have chosen to continue taking an aromatase inhibitor for more than 5 years (if they do not have unacceptable side effects), despite the lack of specific data on its value and pending the results of clinical trials.

Clinical Pearl

• Does extending aromatase-inhibitor therapy for an additional 5 years prolong disease-free survival in postmenopausal women with hormone-receptor–positive early breast cancer?

The MA.17R trial showed that treatment with an aromatase inhibitor for an additional 5 years after initial treatment for 4.5 to 6 years was beneficial in preventing disease recurrence, independently of nodal status, prior adjuvant chemotherapy, time since the last dose of aromatase inhibitor, and duration of prior therapy with tamoxifen or an aromatase inhibitor. The rate of 5-year disease-free survival was 95% (95% confidence interval [CI], 93 to 96) in the letrozole group and 91% (95% CI, 89 to 93) in the placebo group. The hazard ratio involving disease recurrence or the occurrence of contralateral breast cancer with letrozole versus placebo was 0.66 (95% CI, 0.48 to 0.91; P=0.01). The annual incidence rate of contralateral breast cancer was 0.21% (95% CI, 0.10 to 0.32) in the letrozole group and 0.49% (95% CI, 0.32 to 0.67) in the placebo group (P=0.007), with a hazard ratio of 0.42 (95% CI, 0.22 to 0.81).

Table 2: Recurrence of Breast Cancer or Occurrence of Contralateral Breast Cancer

Morning Report Questions

Q: What is the effect of extended aromatase-inhibitor therapy on overall survival in postmenopausal women with hormone-receptor–positive early breast cancer? 

A: In the MA.17R trial, a total of 200 participants had died by the time of data cutoff (100 in each study group). The major causes of death in the letrozole and placebo groups were breast cancer (31 and 34 deaths, respectively), other primary cancers (26 and 25), and cardiovascular events (14 and 11). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) in the letrozole group and 94% (95% CI, 92 to 95) in the placebo group, with a hazard ratio for death of 0.97 (95% CI, 0.73 to 1.28; P=0.83). No significant difference in overall survival between letrozole and placebo was found in any of the prespecified subgroups.

Figure 1: Kaplan–Meier Curves for Disease-free and Overall Survival

Q: What safety issues were associated with extended aromatase-inhibitor therapy in the MA.17R trial?

A: In the MA.17R trial, bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. Only a minority of the fractures in both groups were located in the hip, spine, pelvis, or femur, and no significant change in physical health was recorded in either group, perhaps because most of the women in both groups took bone-protecting supplements or medications during the study. Overall, the low incidence of reported toxic effects is probably due to self-selection on the part of study participants who had had few unacceptable side effects through the first 5 years of aromatase-inhibitor therapy and were thus willing to undergo another 5 years of treatment.

Table 3: Adverse Events

 

Initiation Strategies for Renal-Replacement Therapy

Posted by • July 14th, 2016

2016-07-08_11-02-36Renal-replacement therapy is the cornerstone of the management of severe acute kidney injury. Gaudry et al. compared a strategy of early initiation of renal-replacement therapy with a strategy of delayed initiation in patients in the intensive care unit who had acute kidney injury of Kidney Disease: Improving Global Outcomes (KDIGO) classification stage 3.

This multicenter randomized trial compared strategies of early and delayed renal-replacement therapy in patients with severe acute kidney injury. There was no significant difference in mortality, the primary outcome, between the study groups. A new Original Article summarizes.

Clinical Pearl

• What evidence is available from randomized trials regarding the optimal timing for the initiation of renal-replacement therapy in critically ill patients with severe acute kidney injury?

Many studies have focused on methods of renal-replacement therapy, but the issue of when to initiate the therapy in the absence of a potentially life-threatening complication directly related to renal failure remains a subject of debate. The available knowledge about the initiation of renal-replacement therapy during acute kidney injury derives predominantly from observational studies. Indirect evidence has suggested that early renal-replacement therapy could confer a survival benefit. However, two observational studies reported high survival rates among patients who did not receive renal-replacement therapy, and one study reported adverse outcomes in association with very early renal-replacement therapy in patients with sepsis.

Clinical Pearl

• What potential advantages do early initiation and delayed initiation of renal-replacement therapy each offer?

Early initiation of renal-replacement therapy may allow for better control of fluid and electrolyte status, removal of uremic toxins, and prevention of complications such as gastric hemorrhage and metabolic encephalopathy. Delaying renal-replacement therapy initiation is intuitively unlikely to have any immediate benefit per se. However, a delay may allow time for the stabilization of a patient’s condition before renal-replacement therapy is initiated and may avoid the need for such support, which is not devoid of risk.

Morning Report Questions

Q: Is there a survival or other benefit associated with a delayed strategy of renal-replacement therapy in critically ill patients with severe acute kidney injury? 

A: In the study by Gaudry et al., contrary to the authors’ hypothesis, no survival benefit was observed with the delayed strategy of renal-replacement therapy. Mortality did not differ significantly between the two study groups: 48.5% (95% CI, 42.6 to 53.8) in the early-strategy group and 49.7% (95% CI, 43.8 to 55.0) in the delayed-strategy group (P=0.79). In this trial, however, a strategy of delayed initiation of renal-replacement therapy in critically ill patients with severe acute kidney injury obviated the need for renal-replacement therapy in almost 50% of cases (resulting in a considerable difference in the total number of renal-replacement therapy sessions). The lengths of stay in the intensive care unit and in the hospital were similar in the two groups, which indicates that allowing time for renal function recovery did not lead to prolongation of the stay in the intensive care unit.

Q: Do the results of the study by Gaudry et al. suggest that a “wait and see” approach should be favored for all critically ill patients with severe acute kidney injury?

A: The authors of the Gaudry study state that their study should not be interpreted as suggesting that a “wait and see” approach is safe for all patients. Indeed, careful surveillance is mandatory when deciding to delay renal-replacement therapy in patients with severe acute kidney injury so that any complication will be detected and renal-replacement therapy initiated without delay.

Figure 1. Probability of Survival and Timing of Renal-Replacement Therapy.

Table 2.  Primary and Secondary Outcomes and Adverse Events.

A Man in an Unresponsive State

Posted by • July 14th, 2016

2016-07-08_11-07-57Clinical care for patients with acute liver failure should focus on preventing and treating associated complications, identifying the cause so that targeted therapy (if available) can be initiated, and determining the patient’s transplant eligibility.

A 32-year-old man was admitted to this hospital after being found in an unresponsive state in his jail cell. He had jaundice and encephalopathy; results of liver-function tests were abnormal, and CT revealed cerebral edema. Diagnostic tests were performed. A new Case Records of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What factors are associated with an increased risk for acetaminophen-induced hepatotoxicity?

Even therapeutic doses of acetaminophen can occasionally result in acute liver failure under certain circumstances. This phenomenon has been referred to as therapeutic misadventure and has been reported in patients who have chronic alcoholism and limited food intake that results in malnutrition and glutathione deficiency. This combination of factors leads to hepatic glutathione deficiency, which results in an inability of the liver to detoxify acetaminophen metabolites and causes oxidative injury to hepatocytes. In addition, the concomitant administration of opioids, such as oxycodone, can slow intestinal motility and enhance acetaminophen toxicity.

Clinical Pearl

• What are some of the therapies for hepatic encephalopathy in patients with acute liver failure?

Therapies for hepatic encephalopathy in patients with acute liver failure target elevated intracranial pressure; such therapies include hyperosmotic therapies such as mannitol and hypertonic saline, hyperventilation, and the induction of hypothermia. In contrast, lactulose is not indicated for the treatment of hepatic encephalopathy due to acute liver failure, because it may worsen electrolyte abnormalities and dehydration and does not address the underlying defect, the loss of ammonia detoxification.

Morning Report Questions

Q: How can a patient with remote hepatitis B virus (HBV) serologic test results that included a positive test for HBV surface antibodies be susceptible to acute HBV infection?

A: There are several possibilities to consider. First, a test result for HBV surface antibodies years earlier might have been a false positive; however, analytical false positives are uncommon with this assay. Second, patients with a positive test for HBV surface antibodies because of an HBV infection in the past can, on rare occasion, be infected with HBV again because of incomplete protection afforded by these antibodies against another HBV serotype. Third, a breakthrough infection in a vaccinated person is possible; however, of patients who have an antibody response to the HBV vaccine, even those who have a waning serum level of HBV surface antibodies, the majority retain immunologic memory and would be expected to have a protective HBV surface antibody response on reexposure to HBV. When such breakthrough infections have been documented in apparently immunocompetent persons, they have typically been transient and asymptomatic.

Q: What serologic findings characterize the inactive-carrier phase of chronic HBV infection?

A: In patients in whom acute HBV infection does not resolve but rather progresses to chronic infection, the disease can evolve through several phases — including immunotolerant, immunoactive, and inactive-carrier phases — that are influenced by the infected patient’s immunologic response. During the inactive-carrier phase, serum HBV DNA levels are low or even undetectable, serum aminotransferase levels are typically normal, HBV surface antigen can be lost, and seroconversion of HBV surface antibodies can occur. The HBV genome persists in a stable form in the nuclei of infected hepatocytes, even in the absence of detectable circulating HBV surface antigen, and infection can reactivate at a later time, at which point both HBV surface antigen and HBV core IgM antibodies may become detectable in the serum. Reactivation is sometimes seen in patients who are immunosuppressed (e.g., owing to the administration of glucocorticoids or cancer chemotherapy agents or to progressive HIV infection), but reactivation can also occur spontaneously.

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Posted by • July 13th, 2016

2016-07-08_11-11-05Patients are fearful of nausea and vomiting during the course of cancer treatment, as it is an expected side effect of chemotherapy. Senior oncology physicians describe the early days of cancer treatment when large bowls lined the ward, positioned close to each patient. In the present age, we are still concerned about chemotherapy-induced nausea and vomiting (CINV). New agents such as 5-hydroxytryptamine-3 (5HT3) receptor antagonists, neurokinin-1 (NK-1) receptor antagonists, and long-established drugs such as dexamethasone are within the oncologist’s armamentarium. Despite a combination of these agents, patients can still suffer from severe nausea and vomiting, which may lead to hospital admissions, delays in treatment and plenty of misery.

Olanzapine, an antipsychotic drug that blocks several neurotransmitters, is not licensed for use in CINV. However, small single center studies have suggested that this drug is a useful treatment in cases of poorly controlled emesis. Olanzapine received approval for use in 1996, and since 2011 it has been available in a generic formulation. In a double-blind phase III study published in this week’s NEJM, Navari and colleagues investigated the role of olanzapine in CINV. All eligible patients were administered highly emetogenic chemotherapy regimens that included cisplatin (>70mg/m2), or doxorubicin (60mg/m2) and cyclophosphamide (600mg/m2). Patients who were chemotherapy naïve were randomly assigned to receive olanzapine (10mg/day, oral) or placebo over the first four days of one treatment cycle. All patients were also treated with 5-HT3 receptor antagonists, NK-1 receptor antagonists, and dexamethasone in accordance with international anti-emetic guidelines.

The primary endpoint compared the number of patients with no nausea in the acute (0-24 hours post chemotherapy), delayed (24-120 hours post-chemotherapy) and the overall (0-120 hours post-chemotherapy) periods among those receiving highly emetogenic chemotherapy.

The trial participants were from 46 academic or community practice institutions within the United States. The final analysis included 186 patients in the olanzapine arm and 183 patients in the placebo group. The proportion of patients with no nausea was significantly higher in the olanzapine arm compared to placebo arm in the acute (74% vs. 45% p=0.0015), delayed (42% vs. 25%, p=0.0015) and overall periods (37% vs. 22%, p=0.0015). Complete responses, which measured the absence of emesis and no use of rescue anti-emetics, were also significantly higher among patients treated with olanzapine in all three time periods. Among adverse events, patients receiving olanzapine reported more undesired sedation on day 2 post-chemotherapy; however, patients did not discontinue treatment and these side effects resolved.

This placebo-controlled trial shows the benefit of olanzapine in the treatment of CINV in combination with other anti-emetics. However, the study protocol was only used in one cycle of highly emetogenic chemotherapy. Optimal dosing, safety and efficacy in multiple chemotherapy cycles have not yet been determined, and the authors suggest future clinical trials address these issues.

In an era of enormous costs of cancer care, this is a useful trial that demonstrates a new use for an available, inexpensive drug. Oncology is continuing to apply new agents with novel mechanisms of action to the treatment of cancers; however, chemotherapy is likely to remain a foundation of cancer treatment. Management of CINV will continue to be a difficult problem for patients receiving intense, multi drug chemotherapy.

A Bruising Loss

Posted by • July 7th, 2016

2016-07-01_10-18-50Whereas inherited clotting-factor deficiencies are typically clinically evident from birth, the sudden appearance of a bleeding diathesis in a previously healthy adult is suggestive of an acquired factor inhibitor. Although inhibitors to most of the major clotting factors have been described, factor VIII inhibitors are the most common; however, factor VIII inhibitors are still rare, with an estimated incidence of one to two persons per million per year.

A 32-year-old woman presented to her physician with a 3-week history of spontaneous bruising on her arms, legs, and back. The bruising began shortly after she had had sore throat, coryza, and malaise for several days, symptoms that had resolved without intervention. A new Clinical Problem-Solving summarizes.

Clinical Pearl

• What laboratory findings suggest the presence of a factor inhibitor?

A factor inhibitor should be suspected in any patient who has spontaneous bruising and an unexplained new elevation in aPTT (activated partial-thromboplastin time), particularly if the aPTT fails to be corrected after the patient’s plasma is mixed in a 1:1 ratio with normal plasma. The appearance of factor VIII inhibitors in postpartum women (usually after the first or second child), is classic. They have also been described in patients who have an underlying autoimmune disease or an underlying malignant condition, or in older patients in the absence of recognized diseases.

Clinical Pearl

• What is the Bethesda assay?

The titer of the factor VIII inhibitor is determined through the use of the Bethesda assay, in which the patient’s plasma is serially diluted with normal plasma to measure the potency of anticlotting factor activity. One Bethesda unit is defined as the inverse of the dilution of the patient’s plasma that results in 50% residual factor activity when the patient’s plasma is mixed with fixed amounts of normal plasma; any value over 5 Bethesda units is considered to be a high titer.

Morning Report Questions

Q: What is the treatment for acquired factor VIII inhibitors? 

A: Treatment of patients who have acquired factor VIII inhibitors is initially directed at controlling bleeding; longer-term therapy is also initiated to suppress inhibitor production. Whereas patients with congenital hemophilia in whom acquired inhibitors develop have a response to high doses of factor VIII, this treatment is rarely useful for acquired inhibitors that develop in patients without congenital hemophilia. Instead, treatment with recombinant factor VIIa or activated prothrombin complex concentrates should be used. Both compounds effectively negate the need for intrinsic factor VIII activity, which acts to amplify the activation of factor X; this step is not absolutely required for the generation of thrombin and can be bypassed either by adding activated factor VII plus inactive factors IX, X, and prothrombin, as in activated prothrombin complex concentrates, or by adding supraphysiologic doses of activated factor VII alone. Both agents have been associated with serious thromboembolic events, including catastrophic strokes, even in patients with severe bleeding. The rarity of these events has precluded the identification of risk factors for thrombosis, but given the risk, the agents should not be continued once the bleeding has stopped. Glucocorticoid therapy plus cyclophosphamide is the traditional first-line approach to therapy aimed at suppressing inhibitor production, but rituximab also appears to have efficacy. Patients with very high titers of inhibitors (>100 Bethesda units) may require more aggressive therapy, with all three agents simultaneously, with intravenous immunoglobulin, or with both approaches.

Figure 1. Mechanism of Factor VIII Inhibitors and Therapeutic Agents.

Q: Do factors VIII inhibitors ever clear without therapy?

A: The natural history of spontaneously acquired factor VIII inhibitors varies. A report published before the introduction of immunosuppressive therapy described rare cases in which factor VIII inhibitors acquired post partum spontaneously cleared in patients within 12 to 18 months after presentation, but the accumulated data suggest that this outcome is much more the exception than the rule.

Polycystic Ovary Syndrome

Posted by • July 7th, 2016

2016-07-01_10-26-33The polycystic ovary syndrome is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries.

The polycystic ovary syndrome increases the risk of infertility, endometrial cancer, abnormal glucose metabolism, and dyslipidemia. Strategies such as lifestyle modification, hair removal, and combined oral contraceptive therapy and other pharmacotherapies are reviewed. A new Clinical Practice summarizes.

Figure 1. Basic Pathophysiology of Hyperandrogenemia in the Polycystic Ovary Syndrome.

Clinical Pearl

• How are “polycystic ovaries” defined?

Polycystic ovarian morphologic features are currently defined as 12 or more antral follicles (2 to 9 mm in diameter) in either ovary, an ovarian volume that is greater than 10 ml in either ovary, or both. A transvaginal transducer with frequencies of 8 MHz or greater commonly detects an antral follicle count in this range in asymptomatic women (in ≥50% of asymptomatic women in some series), and some experts recommend a criterion with a higher antral follicle count (≥25) for sufficient specificity. Appropriate use of either criterion requires an experienced ultrasonographer; an unqualified report of “polycystic ovaries” is inadequate for diagnostic purposes. Ovarian ultrasonography is not required for diagnosis when both hyperandrogenism and ovulatory dysfunction are present.

Clinical Pearl

• How is the polycystic ovary syndrome diagnosed?

Three sets of criteria for the polycystic ovary syndrome in women have been developed. Each set involves different combinations of hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features. The polycystic ovary syndrome is a diagnosis of exclusion. Nonclassic congenital adrenal hyperplasia can closely mimic this syndrome. An early-morning, early follicular-phase plasma level of 17-hydroxyprogesterone of less than 200 ng per deciliter effectively rules out 21-hydroxylase deficiency, which is the most common cause of nonclassic congenital adrenal hyperplasia. Androgen-secreting ovarian or adrenal tumors are rare, but they should be considered in patients with abrupt, rapidly progressive, or severe hyperandrogenism, marked hyperandrogenemia, or both.

Table 1. Diagnostic Criteria for the Polycystic Ovary Syndrome.

Morning Report Questions

Q: Name some of the conditions for which women with the polycystic ovary syndrome are at increased risk.

A: Among women with this syndrome, 50 to 80% are obese. Impaired glucose tolerance is reported in 30 to 35% of U.S. women with classic polycystic ovary syndrome, and type 2 diabetes mellitus is reported in 8 to 10%; the risk of these conditions is influenced by age, adiposity, and a family history of diabetes. Subclinical vascular disease (e.g., impaired endothelial function, increased carotid-artery intima–media thickness, and elevated coronary-artery calcium scores) has also been reported in women with the polycystic ovary syndrome and appears to be at least partly independent of adiposity. The risk of endometrial cancer is estimated to be 2.7 times as high among women with the polycystic ovary syndrome as among women without the syndrome, and the lifetime risk of endometrial cancer among women with the syndrome is 9%. Women with the polycystic ovary syndrome also have increased risks of pregnancy complications (e.g., gestational diabetes and preeclampsia), obstructive sleep apnea, and emotional distress (e.g., depression and anxiety).

Q: What are some of the general approaches to management of the polycystic ovary syndrome?

A: Treatment decisions are informed by patient priorities, the likely effectiveness and potential risks of available therapies, and whether the woman wishes to become pregnant. Typical therapeutic targets include hirsutism, irregular menses (and the risk of endometrial hyperplasia), and infertility. Mechanical hair removal (e.g., shaving and plucking) may be adequate to address hirsutism, but when pharmacologic therapy is needed, combined hormonal (estrogen–progestin) oral contraceptives are considered to be first-line agents. Other benefits of combined oral contraceptives include amelioration of acne, regular withdrawal bleeding that contributes to prevention of endometrial hyperplasia, and contraception. Oral spironolactone is an androgen-receptor antagonist that can reduce the growth of terminal hair. Spironolactone is typically used as an add-on therapy to combined oral contraceptives. Metformin reduces hyperinsulinemia and lowers serum testosterone levels by approximately 20 to 25% in women with the polycystic ovary syndrome. Metformin is recommended for women with the polycystic ovary syndrome and impaired glucose tolerance or type 2 diabetes that does not respond adequately to lifestyle modification. Clomiphene is generally considered to be the first-line agent for induction of ovulation in women with the polycystic ovary syndrome.

Table 2. Anticipated Effects of Common Therapeutic Options for the Polycystic Ovary Syndrome.