Groin Hernias in Adults

Posted by Carla Rothaus • February 20th, 2015

Watchful waiting is safe for men with asymptomatic inguinal hernias, but data from randomized trials suggest that most men will ultimately undergo surgery, primarily because of pain. Watchful waiting is not recommended in women, given their higher prevalence of femoral hernias. Read the new Clinical Practice review on this topic.

The lifetime risk of development of a groin hernia has been estimated at 27% for men and 3% for women.

Clinical Pearls

- Describe the epidemiology of and risk factors for groin hernia.

Inguinal hernias are more common on the right side than on the left and are 10 times more common in men than in women. Among adults, the annual frequency of groin hernia repair was found to increase consistently with age, from 0.25% at 18 years of age to 4.2% at 75 to 80 years of age. Femoral hernias account for fewer than 5% of groin hernias; however, 35 to 40% of femoral hernias are not diagnosed until the patient presents with strangulation or bowel obstruction, and mortality is higher in association with emergency repair than with elective repair. Femoral hernias are more common in women than in men, but a woman with a groin mass is still 5 times more likely to have an inguinal hernia than a femoral hernia. A major risk factor for a groin hernia is a family history of groin hernias, which is associated with up to eight times the risk.

Figure 1. Types of Hernia and Hernia Anatomy from an Anterior Perspective.

- How are hernias diagnosed?

Inguinal hernias are diagnosed by means of a physical examination disclosing a visible bulge or an easily palpable mass on straining with an examining finger in the external ring. Differentiating an indirect from a direct inguinal hernia is unnecessary, because it does not affect treatment. It is not always possible to differentiate an inguinal hernia from a more worrisome femoral hernia during physical examination.
Imaging studies are required only in cases in which there are typical symptoms in the absence of physical findings, to rule out an occult hernia or other condition. Ultrasonography is relatively inexpensive and avoids the use of radiation, but its accuracy is operator-dependent. Computed tomography and magnetic resonance imaging (MRI) are alternatives; MRI provides the best anatomic detail and has the highest sensitivity and specificity.

Morning Report Questions

Q: How should an asymptomatic or minimally symptomatic groin hernia be managed?

A: Regardless of the type of hernia, symptomatic patients should be offered repair to improve quality of life. However, the results of two randomized trials comparing prompt repair with a strategy of watchful waiting for asymptomatic or minimally symptomatic inguinal hernias have argued against routine repair. One of these, a single-center randomized trial from the United Kingdom involving 160 patients, showed no significant difference between groups in pain scores and a minimal difference in scores on the 36-Item Short Form Health Survey at 1 year. In a larger multicenter trial from North
America, there was no significant difference at 2 years in pain or quality of life between the group that underwent surgery and the group that did not. In both studies, approximately one quarter of patients assigned to watchful waiting crossed over to surgery, primarily because of increasing pain; the delay did not affect the frequency of operative complications. Both studies have recently been updated with longer-term follow-up data. The estimated frequency of crossover to surgery from the watchful-waiting group was 72% by 7.5 years in the U.K. trial and 68% by 10 years in the North American trial; most crossovers to surgery were a result of increasing pain.
The logical conclusion is that watchful waiting is safe but only delays the inevitable surgery. Because the patients in both studies had presented to their physicians with concerns about their hernias, the results may not be generalizable to the larger group of patients with asymptomatic hernias and no concerns. Another important caveat is that these results apply only to inguinal hernias and not to femoral hernias, because of the higher risks of serious complications with the latter.

Q: How do laparoscopic herniorrhaphy and open surgical repair compare?

A: Laparoscopic herniorrhaphy results in less pain initially, an earlier return to normal activities, and easier repair of recurrent hernias that have previously undergone open repair, and it allows treatment of bilateral hernias through the same skin incisions. The risks of common surgical complications are similar for laparoscopic and open repair; complications include wound seroma or hematoma (approximately
7 to 8% risk), wound infection (approximately 1% risk), testicular complications (approximately 0.7% risk), and complications related to the mesh — for example, contraction, erosion, and infection.
However, laparoscopic repair is associated with a small risk life-threatening vascular or visceral injury (0.9 and 1.8 per 1000 procedures, respectively). Whereas laparoscopic repair requires general anesthesia, open repair can be performed under local anesthesia; the possibility of using local anesthesia is a particular advantage in older patients who require repair and have serious coexisting medical conditions. Laparoscopic herniorrhaphy is more expensive, but the costs of the procedure may be offset by an earlier return to daily function and work.

Figure 3. Laparoscopic Totally Extraperitoneal Herniorrhaphy.

Exercise-Induced Bronchoconstriction

Posted by Carla Rothaus • February 13th, 2015

Asthma or asthma-like conditions can limit the ability of athletes to perform. This article reviews the diagnosis and treatment of asthma and exercise-induced bronchoconstriction in athletes.

The term exercise-induced bronchoconstriction describes the transient narrowing of the airways after exercise, a phenomenon that occurs frequently among athletes who may not have a diagnosis of asthma or even have any respiratory symptoms.

Clinical Pearls

- Describe a key factor in the pathogenesis of exercise-induced bronchoconstriction.

The mechanism of exercise-induced bronchoconstriction has not been established with certainty; both airway cooling resulting from conditioning of inspired air and postexercise rewarming of airways have been proposed as mechanisms. However, the key stimulus is probably airway dehydration as a result of increased ventilation, resulting in augmented osmolarity of the airway-lining fluid. This is thought to trigger the release of mediators — such as histamine, cysteinyl leukotrienes, and prostaglandins — from airway inflammatory cells, which leads to airway smooth-muscle contraction and airway edema.

- How is asthma or exercise-induced bronchoconstriction in athletes diagnosed?

The demonstration of more than 10% diurnal variability in peak expiratory flows measured twice daily over a period of 2 weeks, or more than 12% (and >200 ml) variability in forced expiratory volume in 1 second (FEV1) over time or after 4 weeks of treatment, is consistent with a diagnosis of asthma or exercise-induced bronchoconstriction. The likelihood of airways to narrow can also be demonstrated, if airflow limitation is present, by a more than 12% (and >200 ml) change in the FEV1 after inhalation of an aerosolized beta2-agonist; if the baseline airway caliber is normal, this likelihood can be assessed as the presence of airway hyperresponsiveness documented with the use of bronchoprovocation testing. These tests include direct challenges (e.g., with inhaled methacholine), which act on airway smooth muscle to cause bronchoconstriction, and indirect challenges, such as eucapnic voluntary hyperpnea (particularly recommended for athletes), hyperosmolar tests with saline or mannitol, and laboratory or field exercise tests. However, athletes may have a positive response to only one of these types of tests, and airway responsiveness can normalize a few weeks after they stop intense training. Therefore, more than one type of test may be needed, and ideally the testing should be performed during a period of intense training.

Figure 1. Diagnosis of Asthma and Exercise-Induced in Athletes.

Morning Report Questions

Q: What general measures are recommended for the management of exercise-induced bronchoconstriction?

A: As for all patients with asthma, education about asthma self-management is essential; this should include advice about environmental measures, inhaler-use technique, and the use of an asthma action plan for the management of exacerbations, in addition to regular follow-up. Mechanical barriers such as face masks, although they are not always well tolerated, can help reduce the effects of cold air exposure in winter-sports athletes or the inhalation of particulate air pollutants. A pre-exercise warm-up
(i.e., low-intensity or variable-intensity precompetitive exercise) can result in a reduction in exercise-induced bronchoconstriction in more than half of persons. However, whenever possible, it is preferable for sensitized athletes not to exercise close to busy roads or during periods of high allergen exposure. Measures to reduce chloramine formation in chlorinated pools, improve ventilation of pool environments, and reduce exposure to other indoor and outdoor pollutants, including ozone, particulate matter, and nitrogen oxides, should also be promoted.

Q: What pharmacologic therapies are commonly used?

A: The most common management strategy for athletes with asthma or exercise-induced bronchoconstriction who are exercising daily is daily treatment with inhaled glucocorticoids, with short-acting inhaled beta2-agonists used occasionally before exercise. Inhaled glucocorticoids are the mainstay of asthma therapy in athletes, as they are in nonathletes; these agents are allowed by sports authorities. Apart from helping to control asthma and improve pulmonary function, an additional benefit of treatment with inhaled glucocorticoids is a progressive reduction, with regular use, in airway responses to various stimuli, including exercise. If low doses of inhaled glucocorticoids do not achieve asthma control, the addition of another controller drug should be considered, preferably a long-acting inhaled beta2-agonist. Leukotriene-receptor antagonists are also an option for maintenance treatment, and the combination of inhaled glucocorticoids and leukotriene-receptor antagonists may provide additional protection.

Table 1. Specific Issues in the Management of Asthma in Athletes.

Table 2. Treatment of Asthma and Exercise-Induced Bronchoconstriction in Athletes.

Table 3. Current Antidoping Status of Asthma Medications.

Smoking and Mortality

Posted by Carla Rothaus • February 13th, 2015

Using data from five U.S. cohort studies, the authors of a new report estimate that 17% of excess mortality among smokers is due to diseases not already established as caused by smoking; for example, renal failure, infections, and intestinal ischemia could potentially be linked to smoking.

Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases (12 types of cancer, 6 categories of cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and pneumonia including influenza) that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States.

Clinical Pearls

- Are current estimates of smoking-related mortality rates in the United States accurate?

The 2014 Surgeon General’s report estimates that cigarette smoking causes more than 480,000 deaths each year in the United States. This widely cited estimate of the mortality burden of smoking may be an underestimate, because it considers deaths only from the 21 diseases (mentioned above) that have been formally established as caused by smoking. Associations between smoking and the 30 most common causes of death in the United Kingdom in the Million Women Study suggest that the excess mortality observed among current smokers cannot be fully explained by these 21 diseases.

- Are there additional diseases that contribute to the excess mortality among current smokers in the United States?

In a prospective analysis, data were pooled from five contemporary U.S. cohort studies and included 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 to 2011.
During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking.
These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), and various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4).

Table 2. Relative Risks of Death from Specific Causes among Persons 55 Years of Age or Older, According to Sex and Smoking Status.

Morning Report Questions

Q: Is there an association between smoking and death from breast and prostate cancer?

A: In the analysis published in this week’s issue of the Journal, smoking remained significantly associated with death from breast cancer among women who were not current drinkers. However, associations between smoking and death from breast cancer may also be biased by differences in screening or treatment patterns among smokers, and information on these variables was not available in this study. Additional studies with detailed information on these factors may be useful in clarifying whether smoking is causally associated with death from breast cancer. Mortality from prostate cancer in this population was 43% higher among current smokers than among those who had never smoked, a finding that is consistent with most previous analyses of prostate-cancer mortality. The Surgeon General concluded that although there was insufficient evidence that smoking increases the incidence of prostate cancer, the available evidence suggested that current or recent smoking increases the risk of advanced-stage disease and of death from prostate cancer. Higher mortality from prostate cancer among smokers could be caused by delayed diagnosis owing to less intense medical surveillance or by a promoting effect of smoking on later stages of carcinogenesis and progression.

Table 3. Mortality and Excess Mortality, According to Sex and Smoking Status.

Q: To what extent does the 2014 Surgeon General’s report underestimate yearly deaths from smoking?

A: Results of this study suggest that the Surgeon General’s recent estimate of smoking-attributable mortality may have been an underestimate. The Surgeon General’s estimate, which took into account only the 21 diseases formally established as caused by smoking, was that approximately 437,000 deaths among adults are caused each year by active smoking (not including secondhand smoke).
However, the Surgeon General’s report presents an alternative estimate of 556,000 deaths among adults on the basis of the excess mortality from all causes. The difference between these two estimates is nearly 120,000 deaths. If, as suggested by the results in the cohort used in this study, at least half of this difference is due to associations of smoking with diseases that are causal but are not yet formally established as such, then at least 60,000 additional deaths each year among U.S. men and women may be caused by cigarette smoking.

Gastrointestinal Bleeding

Posted by Carla Rothaus • February 6th, 2015

In the latest Clinical Problem-Solving article, a 66-year-old man with ischemic cardiomyopathy presented to the hospital with a 2-day history of fatigue, dizziness on standing, and bright red blood from the rectum that transitioned to black, tarry stools. Angioectasias are increasingly recognized in patients with either pulsatile or nonpulsatile left ventricular assist devices (LVADs).

Clinical Pearls

What are angioectasias?

Angioectasias are thin-walled, dilated, ectatic blood vessels with or without an endothelial lining. Their pathogenesis is uncertain but may be associated with aging-related chronic obstruction of submucosal veins that extends to venules, capillaries, and arteries and ultimately results in loss of precapillary-sphincter competency and development of arteriovenous communications. Angioectasias occur most commonly in elderly patients, especially in those with renal failure or aortic stenosis. Multiple angioectasias may occur in patients with LVADs and other systemic processes and may involve any portion of the bowel, especially the small bowel.

- What is the connection between left ventricular assist devices and angioectasia formation and bleeding?

Angioectasias are increasingly recognized in patients with either pulsatile or nonpulsatile LVADs. Risk factors for angioectasia formation and bleeding are thought to be similar to those for aortic stenosis. In patients with either aortic stenosis or an LVAD, a narrow pulse pressure may result in hypoxia of intestinal tissue with subsequent vascular dilation and angioectasia formation. The mechanical pump in nonpulsatile LVADs creates high shear stress, causing consumption of high-molecular-weight von Willebrand factor multimers and acquired von Willebrand factor deficiency, thus conferring a predisposition to bleeding. High-molecular-weight von Willebrand factor levels have been reported to be reduced in patients with nonpulsatile LVADs and to normalize after removal of the device. According to one report, gastrointestinal bleeding is more common among patients with nonpulsatile LVADs than among patients with pulsatile LVADs (20% vs. 10%).

Morning Report Questions

Q: How are angioectasias treated?

A: Treatment of angioectasias is difficult, no matter what causes them, and randomized, controlled trials are lacking to guide therapy. Management involves supportive care, with iron supplementation, blood transfusion when indicated, and endoscopic therapy when feasible. Patients who require blood transfusions commonly undergo aggressive endoscopy in an attempt to identify and treat lesions. Although endoscopic therapy for angioectasias has been reported to reduce the rates of rebleeding, data are lacking with respect to the effects of this treatment in patients with LVADs. Endoscopic therapy includes argon plasma coagulation, placement of endoscopic hemoclips, contact thermal therapy (bipolar electrocautery or heater probe), or a combination of these techniques. In addition, an injection of normal saline or epinephrine may be used as an adjunct to one of these therapies. Patients with active clinical bleeding and hemodynamic instability should be treated with angiographic therapy, such as embolization or vasopressin infusion.

Q: Are there any effective medical therapies?

A: Medical therapies such as estrogen and octreotide have been ineffective in the treatment of bleeding angioectasias and thus are no longer recommended. In one randomized, controlled trial, thalidomide (which appears to have properties that are antiangiogenic, prothrombotic, or both) reduced bleeding from gastrointestinal angioectasias. However, the use of thalidomide is limited in patients with LVADs because it is associated with an increased risk of thrombosis.

Diabetic Ketoacidosis

Posted by Carla Rothaus • February 6th, 2015

The latest review in the Fluids and Electrolytes series focuses on the safe removal of excess hydrogen ions, the administration of sodium bicarbonate, and the possible contribution of intracellular acidosis to the development of cerebral edema in patients with diabetic ketoacidosis. Several of the issues facing clinicians who care for patients with diabetic ketoacidosis are related to acid-base disorders.

Clinical Pearls

- How do changes in extracellular fluid volume affect assessment of the severity of diabetic ketoacidosis?

Because of hyperglycemia-induced osmotic diuresis and natriuresis, patients with diabetic ketoacidosis usually present with a marked contraction of the extracellular fluid volume. This factor affects the assessment of their acid-base status and in some cases their therapy. Determination of the severity of metabolic acidemia is usually based on the extent of the decrease in the plasma bicarbonate concentration. Nevertheless, as shown in the equation below, the plasma bicarbonate concentration may be only moderately reduced when there is both a large deficit of bicarbonate in the extracellular fluid and a severe contraction of the volume of extracellular fluid.

Extracellular fluid bicarbonate concentration [HCO3−] = extracellular fluid HCO3− content (divided by) extracellular fluid volume.

It is important to adjust for changes in the volume of extracellular fluid when using the ratio of the increase in the plasma anion gap to the decrease in the plasma bicarbonate concentration to gauge the magnitude of the acid load.

- What subgroups of patients with diabetic ketoacidosis may benefit from treatment with sodium bicarbonate?

Most patients with diabetic ketoacidosis do not require the administration of sodium bicarbonate, since infused insulin will slow the rate of ketoacid production, and bicarbonate ions will be produced when ketoacid anions are oxidized. Although the current consensus opinion is that sodium bicarbonate should not be administered in patients with diabetic ketoacidosis unless the arterial plasma pH falls below 6.90, the authors of this review suggest that this decision in adult patients with diabetic ketoacidosis should be individualized and not based solely on an arbitrary blood pH value. Therapy with sodium bicarbonate may be required in patients in whom a large component of the acidemia is due to hyperchloremic metabolic acidosis, since they may have insufficient circulating anions to metabolize and produce bicarbonate ions, and acidemia may worsen quickly with a rapid infusion of saline. Therapy with sodium bicarbonate may also be considered in the initial treatment of a subgroup of patients who are expected to have a low rate of ketoacid removal (i.e., patients who have marked decrease in their level of consciousness or those with preexisting advanced renal dysfunction [estimated glomerular filtration rate,

Morning Report Questions

Q: How might the sodium-hydrogen ion exchanger in brain-cell membranes contribute to cerebral edema in diabetic ketoacidosis?

A: Brain cells swell when there is a large osmotic force favoring an intracellular shift of water, owing to a higher effective osmolality in brain cells than the effective osmolality in plasma in capillaries near the blood-brain barrier. An increased number of intracellular brain osmoles may occur with an increased influx of sodium ion into brain cells. A high concentration of hydrogen ions in brain cells may activate mechanisms of sodium ion transport in cell membranes, primarily the sodium-hydrogen exchanger 1. The concentration of hydrogen ions in brain cells could increase when beta-hydroxybutyric acid enters cells on the monocarboxylic acid cotransporter. This cation exchanger is also activated by a high insulin concentration in interstitial fluid. If cation exchange through this sodium-hydrogen ion exchanger 1 increases further when the pH in the extracellular fluid increases, that could explain, at least in part, the increased risk of cerebral edema among children with diabetic ketoacidosis when sodium bicarbonate is administered.

Figure 3. Increased Flux through the Sodium-Hydrogen Exchanger 1Leading to an Increase in the Number of Effective Osmoles in Brain Cells.

Q: What measures can be taken to reduce the risk of cerebral edema during treatment?

A: A number of focused measures might be considered in the treatment of patients with diabetic ketoacidosis to reduce their risk of cerebral edema. The effective osmolality in plasma must not be permitted to decrease during the first 15 hours of treatment. When potassium ions are needed, this goal can be achieved if potassium chloride is added to 0.9% saline, at a concentration of 30 to 40 mmol per liter. This solution has an effective osmolality that is reasonably close to that of the urine in these patients at that time. If glucose is to be administered to prevent neuroglycopenia when the plasma glucose concentration decreases, it seems prudent to administer it in a solution that has the smallest possible volume of electrolyte-free water. The clinician should take a detailed history of fluid ingestion and look for signs that indicate recent gastric emptying, with its attendant risk of intestinal absorption of electrolyte-free water. A large bolus of saline should be administered only if there is a hemodynamic emergency.

Preexposure Prophylaxis for HIV-1 Infection

Posted by Chana Sacks • February 4th, 2015

In December 2007, Elizabeth Mataka, the United Nations Special Envoy for HIV/AIDS in Africa, highlighted one of many stark realities of the HIV epidemic: “61% of all those living with HIV in Africa are women,” she wrote. “And 26 years into the epidemic, we know that underpinning this terrible statistic is gender inequality.”

Condoms work. But in light of the tremendous and persistent burden of HIV infection, researchers have worked to develop alternative approaches to reduce HIV transmission, particularly methods that might allow women increased options, and with that, more control over their own health. Whether or not pre-exposure prophylaxis (PrEP)– a daily anti-viral regimen to prevent HIV infection – is an important tool in the HIV-prevention armamentarium has been hotly debated, both in the scientific literature and in the popular press.  Prior trials have yielded equivocal results, with the 2012 FEM-PrEP trial failing to show efficacy in reducing HIV acquisition among women.

To better evaluate PrEP’s potential for women, researchers designed the VOICE trial, published in NEJM this week, to assess the efficacy of 3 different PrEP regimens. 5,000 sexually-active women 18 to 45 years of age from South Africa, Uganda, and Zimbabwe were randomized to one of 5 treatment arms: oral tenofovir disoproxil fumarate (TDF), oral TDF plus emtricitabine (TDF-FTC), oral placebo, tenofovir (TFV) vaginal gel, or placebo vaginal gel.

Study participants were counseled to use study products daily and were provided HIV risk-reduction counseling, condoms, and hepatitis B immunizations. The mean age of participants was 25.3 years; 21% of women were unmarried, and 71% were using an injectable hormonal contraception.  HIV-1 testing was performed monthly and plasma tenofovir levels checked quarterly.

The results were disappointing:  during the trial period, 312 incident HIV-1 infections occurred, with no difference in the rates of seroconversions between treatment arms. 52 occurred in the TDF arm (HR 1.49), 61 in TDF-FTC (HR 1.04), 61 in TFV gel (HR 0.85), 60 in oral placebo, and 70 in gel placebo. In fact, the Data Safety Monitoring Board stopped both the oral TDF and TFV gel arms early for futility.

Importantly, adherence to study drugs was low, and the discordance between participant self-reporting and measured plasma tenofovir levels is striking:  in interviews, participants across treatment arms reported mean adherence of 90%. However, in a random sample, tenofovir was detected on average in no more than 30% of quarterly plasma samples in any treatment arm.  This finding underscores the importance of objective markers of adherence in clinical trials.

In terms of adverse events: more serum creatinine elevations were seen in participants randomized to oral TDF-FTC relative to oral placebo (1.3% vs. 0.2%; P=0.004). There were no significant differences in other adverse events between treatment arms.

NEJM Deputy Editor Dr. Lindsey Baden describes where we go from here: “Developing effective, deployable HIV prevention strategies remains a high global priority. These strategies must account for human behavior and limit potential toxicity in otherwise healthy persons to be successful.”

So, is PrEP a promising strategy to reduce rates of HIV-1 infection among women in sub-Saharan Africa? Not as demonstrated in this trial. Perhaps the low adherence tells the whole story, but for now, this study adds to the disappointing data regarding PrEP and the effort to prevent HIV in women.

Control of Hypertension in Pregnancy

Posted by Carla Rothaus • January 30th, 2015

In a trial comparing less-tight control of hypertension (target diastolic blood pressure, 100 mm Hg) with tight control (85 mm Hg) among pregnant women, rates of pregnancy loss, high-level neonatal care, and serious maternal complications were similar between groups.

Blood-pressure targets for women with nonsevere hypertension during pregnancy are much debated. Relevant randomized, controlled trials have been small and of moderate or poor quality; tight control (the use of antihypertensive therapy to normalize blood pressure) has been associated with maternal benefits (e.g., a decrease in the frequency of severe hypertension and possibly in the rate of antenatal hospitalization) but sometimes, though not consistently, with perinatal risks (e.g., poor fetal growth and well-being). The Control of Hypertension in Pregnancy Study (CHIPS) was designed to compare less-tight control with tight control of nonproteinuric, nonsevere hypertension in pregnancy with respect to perinatal and maternal outcomes.

Clinical Pearls

- How common is hypertension among pregnant women?

Almost 10% of pregnant women have hypertension; hypertension is preexisting in 1% have preexisting hypertension, gestational hypertension without proteinuria develops in 5 to 6%, and preeclampsia develops in 2%. Preexisting hypertension and gestational hypertension before 34 weeks are associated with an increased risk of perinatal and maternal complications.

- How does tight control as compared to less-tight control of nonsevere, nonproteinuric hypertension in pregnant women affect perinatal outcomes?

In the study by Magee et al., the frequency of the primary outcome – pregnancy loss or high-level neonatal care for more than 48 hours – did not differ significantly between the groups. The primary-outcome rates were similar among 493 women assigned to less-tight control and 488 women assigned to tight control (31.4% and 30.7%, respectively; adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.77 to 1.35). Most high-level neonatal care for more than 48 hours was related to complications of prematurity. There were no significant between-group differences with respect to other perinatal outcomes, including the proportion of newborns who were small for gestational age and the frequency of respiratory complications and treatment.

Table 2. Primary and Other Perinatal Outcomes.

Morning Report Questions

Q: How does tight control as compared to less-tight control of nonsevere, nonproteinuric hypertension in pregnant women affect serious maternal complications and other outcomes?

A: The frequency of the secondary outcome — serious complications (including death) — was also similar in the two groups. There were no maternal deaths. The most common maternal complication was the receipt of blood products. The frequency of abruption did not differ significantly between the groups. The gestational age at delivery and the frequency of cesarean delivery did not differ significantly between the groups.

Table 3. Secondary and Other Maternal Outcomes.

Q: Were there any significant between-group differences in this study?

A: Severe hypertension (equal to or greater than 160/110 mm Hg) developed in 40.6% of the women in the less-tight-control group and 27.5% of the women in the tight-control group (P<0.001).

Figure 2. Blood-Pressure Values among Women with Severe Hypertension.

Allergic Rhinitis

Posted by Carla Rothaus • January 30th, 2015

Allergic rhinitis is common and is often associated with asthma. Treatment includes intranasal glucocorticoids, oral and nasal antihistamines, leukotriene-receptor antagonists, and, when pharmacotherapy is not effective or produces unacceptable side effects, allergen immunotherapy. Read the latest Clinical Practice review on this topic.

The frequency of sensitization to inhalant allergens is increasing and is now more than 40% in many populations in the United States and Europe. Allergic rhinitis contributes to missed or unproductive time at work and school, sleep problems, and among affected children, decreased involvement in outdoor activities.

Clinical Pearls

- What is the relation between allergic rhinitis and other atopic

The presence of allergic rhinitis (seasonal or perennial) significantly increases the probability of asthma: up to 40% of people with allergic rhinitis have or will have asthma. Atopic eczema frequently precedes allergic rhinitis. Patients with allergic rhinitis usually have allergic conjunctivitis as well. The factors determining which atopic disease will develop in an individual person and the reasons why some people have only rhinitis and others have rhinitis after eczema or with asthma remain unclear.

- What is included in the differential diagnosis for rhinitis, and how is allergic rhinitis diagnosed?

The differential diagnosis includes forms of rhinitis that are nonallergic in origin such as a noninflammatory rhinopathy (also known as vasomotor rhinitis) and nonallergic chronic rhinosinusitis. Seasonal symptoms can be caused by viral infections, especially if the patient is a child or lives with children; rhinovirus has a marked peak in incidence in September and a smaller peak in the spring. The diagnosis of allergic rhinitis is often made clinically on the basis of characteristic symptoms and a good response to empirical treatment with an antihistamine or nasal glucocorticoid. Formal diagnosis is based on evidence of sensitization, measured either by the presence of allergen-specific IgE in the serum or by positive epicutaneous skin tests (i.e., wheal and flare responses to allergen extracts) and a history of symptoms that correspond with exposure to the sensitizing allergen. Epicutaneous skin testing and testing for allergen-specific IgE have similar sensitivity, although they do not identify sensitization in an entirely overlapping group of patients.

Morning Report Questions

Q: What pharmacologic treatment is available for allergic rhinitis?

A: Pharmacologic treatment options include H1-antihistamines, intranasal glucocorticoids, and leukotriene-receptor antagonists. Therapy usually starts with oral antihistamines, frequently initiated by the patient. H1-antihistamines are also available as nasal sprays by prescription. The intranasal preparations appear to be similar to oral preparations in efficacy but may be less acceptable to patients owing to a bitter taste. The effect of antihistamines on symptoms, especially nasal congestion, is modest. They can be combined with oral decongestants, and the combination can improve nasal airflow in the short term (on the basis of data from trials lasting 2 to 6 weeks), at the cost of some side effects. Topical nasal decongestants are more effective than oral agents, but there are reports of rebound congestion (rhinitis medicamentosa) or reduced effectiveness beginning as early as 3 days after treatment, and only short-term use is recommended. In one study, adding an intranasal glucocorticoid reversed the reduced effectiveness of a topical decongestant. Intranasal glucocorticoids are the most effective pharmacotherapy for seasonal allergic rhinitis, yet the overall efficacy is moderate. Although the clinical effects appear within a day, the peak effect in cases of perennial rhinitis is not reached for several weeks. The superiority of intranasal glucocorticoids over antihistamines in the treatment of perennial allergic rhinitis is uncertain. The effect of leukotriene-receptor antagonists on the symptoms of allergic rhinitis is similar to or slightly less than that of oral antihistamines, and some randomized trials have shown a benefit of adding the leukotriene-receptor antagonist montelukast to an antihistamine. Although the majority of trials have favored intranasal glucocorticoids over this combination, data are inconsistent; this combination should be considered for patients whose symptoms are inadequately controlled with an antihistamine and who do not wish to
use a glucocorticoid nasal spray. There is no significant benefit of adding an oral antihistamine or montelukast to a nasal glucocorticoid. However, in randomized trials, the combination of an intranasal antihistamine plus an intranasal glucocorticoid has been shown to be superior to either agent alone.

Q: What types of immunotherapy are available in the United States?

A: Although allergen immunotherapy has traditionally been administered subcutaneously in the United States, rapidly dissolving tablets for sublingual administration were recently approved by the Food and Drug Administration for treatment of grass and ragweed allergy. With immunotherapy, unlike pharmacotherapy, the effect persists after the discontinuation of therapy. If there is improvement in the first year, injections are generally continued for at least 3 years. Data from randomized trials are lacking to guide decisions about the duration of therapy. Subcutaneous immunotherapy carries a risk of systemic reactions, which occur in 0.1% of injection visits, in rare cases leading to life-threatening anaphylaxis (1 reaction per 1 million injection visits). Although subcutaneous immunotherapy has not been compared with sublingual immunotherapy in large head-to-head trials, indirect comparisons suggest that subcutaneous immunotherapy is more effective for symptom relief. However, sublingual immunotherapy has a clear advantage in terms of safety, with very few reports of anaphylactic reactions.

Table 1. Pharmacotherapy and Immunotherapy for Allergic Rhinitis.

Abdominal Pain, Dyspnea, and Diplopia

Posted by Carla Rothaus • January 27th, 2015

Peripheral causes of acute generalized weakness include motor neuronopathies, acute acquired polyneuropathies, myopathies, and presynaptic and postsynaptic neuromuscular-transmission disorders.

Clinical Pearls

- Is botulism a presynaptic or postsynaptic neuromuscular-transmission disorder?

Botulism is a toxin-mediated disease that results in the presynaptic blockade of acetylcholine transmission across the neuromuscular junction. 

- What is adult intestinal toxemia?

Adult intestinal toxemia is a rare form of botulism that is caused by colonization of the gut by toxigenic clostridium bacteria. In adult intestinal toxemia, C. baratii is more frequently the pathogen than C. botulinum.

Morning Report Questions

Q: What are the clinical features of botulism? 

A: Patients typically present with blurred vision, ptosis, and diplopia. Impaired bulbar function is manifested as facial weakness, dysarthria, and dysphagia. Descending muscle weakness affects head control and subsequently arm, respiratory, and leg musculature. The weakness typically has a proximal-to-distal pattern and is bilateral. Autonomic symptoms, including nausea, vomiting, ileus, poor pupil reactivity, and alterations in blood pressure and heart rate, are common; the gastrointestinal symptoms may precede the neurologic symptoms. Intact sensorium, preserved sensation, and absence of fever are typical. Results of cerebrospinal fluid, blood, and urine tests and imaging studies are usually normal.

Q: How is botulism managed?  

A: The mainstays of botulism management are rapid clinical recognition and notification of public health authorities, which enables the prompt investigation of the toxin source and possible other cases and the prompt delivery and administration of antitoxin. The effectiveness of antitoxin is greatest if it is given early after the onset of neurologic symptoms, ideally within 24 hours, and thus antitoxin should be administered, after consultation with public health authorities, on the basis of the clinical diagnosis and without awaiting the results of diagnostic testing. Antibiotic therapy has not been shown to improve neurologic recovery and is not recommended. There is no person-to-person transmission of botulism, and in the health care setting, patients can be treated with standard precautions.     

PD-1 Blockade with Nivolumab

Posted by Carla Rothaus • January 23rd, 2015

Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. An ongoing phase 1 study tests the hypothesis that nivolumab, a PD-1-blocking antibody, can inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin’s lymphoma.

Clinical Pearls

- How do tumors exploit the PD-1 [programmed death 1] pathway?

The PD-1 pathway serves as a checkpoint to limit T-cell-mediated immune responses. Both PD-1 ligands, PD-L1 and PD-L2, engage the PD-1 receptor and induce PD-1 signaling and associated T-cell “exhaustion,” a reversible inhibition of T-cell activation and proliferation. By expressing PD-1 ligands on the cell surface and engaging PD-1 receptor-positive immune effector cells, tumors can co-opt the PD-1 pathway to evade an immune response from the patient.

- Why might PD-1 blockade provide an effective therapy for Hodgkin’s lymphoma?

Classic Hodgkin’s lymphomas include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory and immune-cell infiltrate. The genes encoding the PD-1 ligands, PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively), are key targets of chromosome 9p24.1 amplification, a recurrent genetic abnormality in the nodular-sclerosis type of Hodgkin’s lymphoma. The 9p24.1 amplicon also includes JAK2, and gene dose-dependent JAK-STAT activity further induces PD-1 ligand transcription. These copy-number-dependent mechanisms and less frequent chromosomal rearrangements lead to overexpression of the PD-1 ligands on Reed-Sternberg cells in patients with Hodgkin’s lymphoma. Epstein-Barr virus (EBV) infection also increases the expression of PD-1 ligands in EBV-positive Hodgkin’s lymphomas. The complementary mechanisms of PD-1 ligand overexpression in Hodgkin’s lymphoma suggest that this disease may have genetically determined vulnerability to PD-1 blockade.

Morning Report Questions

Q: What are the adverse events that have been reported to date after nivolumab administration?

A: Adverse events that are commonly associated with PD-1-blocking antibodies include pruritus, rash, and diarrhea. Immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, and thyroiditis are
less common toxic effects of PD-1 blockade. In the study by Ansell et al., a total of 23 patients with relapsed or refractory Hodgkin’s lymphoma have been enrolled since August 2012. Results are reported through June 16, 2014. Adverse events were mainly of grade 1 or 2. Overall, drug-related adverse events were reported in 18 patients (78%). The most common were rash (in 22%) and a decreased platelet count (in 17%). Drug-related grade 3 adverse events, which were reported in 5 patients (22%), included the myelodysplastic syndrome, pancreatitis, pneumonitis, stomatitis, colitis, gastrointestinal inflammation, thrombocytopenia, an increased lipase level, a decreased lymphocyte level, and leukopenia. There were no drug-related grade 4 or 5 adverse events. There were no treatment-related deaths.

Table 2. Drug-Related Adverse Events in the 23 Patients.

Q:What is the efficacy of nivolumab in patients with relapsed or refractory Hodgkin’s lymphoma?

A: In heavily pretreated patients with relapsed or refractory Hodgkin’s lymphoma, the majority of whom had had a relapse after autologous stem-cell transplantation and brentuximab treatment, the use of nivolumab was associated with an overall response rate of 87% and a rate of progression-free survival of 86% at 24 weeks. Given the limited therapeutic options for patients with Hodgkin’s lymphoma whose disease progresses after autologous stem-cell transplantation and the relatively short-lived responses to brentuximab after relapse, nivolumab-mediated PD-1 blockade may represent a promising targeted treatment for these patients.

Table 3. Clinical Activity in Nivolumab-Treated Patients.

Figure 1. Response Characteristics and Changes in Tumor Burden in
Patients with Hodgkin’s Lymphoma Receiving Nivolumab