Disclosures: Helen Hollingsworth, MD Employee of UpToDate, Inc. April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)]. Employment: Employee of UpToDate, Inc. Geraldine Finlay, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
Aspirin therapy for aspirin-exacerbated respiratory disease (October 2014)
Aspirin desensitization followed by daily aspirin therapy is used in the treatment of aspirin-exacerbated respiratory disease (AERD). The utility of aspirin therapy in patients who have asthma and chronic polypoid rhinosinusitis but who tolerate aspirin has been unclear. In a small trial, 20 patients with AERD and 14 patients with asthma and CRS with nasal polyposis, but without aspirin intolerance, were randomized to receive aspirin therapy or placebo . Aspirin therapy improved several asthma and rhinitis outcomes and led to lower maintenance doses of inhaled glucocorticoids in patients with aspirin intolerance, but was not beneficial in patients without aspirin intolerance. Although small, the findings of this trial support the clinical impression that aspirin's benefits are limited to patients with intolerance. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Efficacy of aspirin therapy in AERD'.)
Mepolizumab for severe asthma associated with peripheral blood eosinophilia (October 2014)
The anti-interleukin-5 monoclonal antibody mepolizumab has previously been shown to reduce exacerbations in patients with severe asthma and eosinophilic airway inflammation. Two additional trials validate using peripheral blood eosinophil counts to select patients with severe asthma who are likely to respond to mepolizumab, demonstrate comparable effects of intravenous and subcutaneous preparations, and show a glucocorticoid-sparing effect.
●The larger multicenter trial (MEpolizumab as adjunctive therapy iN patients with Severe Asthma, MENSA) evaluated mepolizumab (given either intravenously or subcutaneously every four weeks) in patients with severe asthma and eosinophilic airway inflammation despite high-dose inhaled glucocorticoids . At 32 weeks, exacerbations were reduced by approximately 50 percent for the groups using mepolizumab given by either route, compared with placebo.
●In a group of patients with severe asthma requiring systemic glucocorticoids, the SteroId ReductIon with mepolizUmab Study (SIRIUS) compared subcutaneous mepolizumab, given every four weeks, with placebo . At 20 weeks, mepolizumab allowed a median reduction in the systemic glucocorticoid dose of 50 percent, decreased the number of asthma exacerbations, and improved control of asthma symptoms.
Mepolizumab is not commercially available at present, although it is under review by regulatory agencies. (See "Alternative and experimental agents for the treatment of asthma", section on 'Anti-IL-5 antibodies'.)
Intermittent montelukast for acute wheezing episodes in young children (September 2014)
Several randomized trials have examined the intermittent use of leukotriene receptor antagonists (LTRAs) in preschool children with recurrent wheezing, with mixed results. The most recent trial adds to the data that do not favor this approach in most children, although specific subgroups based upon genotype may benefit. In this trial, over 1300 children aged 10 months to 5 years with a history of two or more wheezing episodes were randomly assigned to intermittent montelukast or placebo at the onset of any subsequent wheezing episode over a 12 month period . No difference between the groups was seen in the frequency of unscheduled medical visits for wheezing episodes, although subgroup analysis suggested the response to montelukast was modified by arachidonate 5-lipoxygenase (ALOX5) genotype. Further study is needed to define and confirm these subpopulations. (See "Treatment of recurrent virus-induced wheezing in young children", section on 'Intermittent leukotriene-receptor antagonists'.)
Combination of varenicline and nicotine patch improves smoking cessation rates (October 2014)
In a randomized trial, 435 smokers were assigned to treatment with varenicline combined with either a nicotine or a placebo patch . Nicotine or placebo patches were started two weeks before the quit day and varenicline was started one week before the quit day. Both patches and varenicline were continued for 12 weeks. Treatment with varenicline and the nicotine patch resulted in a higher rate of continuous abstinence compared with varenicline and the placebo patch (49 versus 33 percent) at six months after the end of drug treatment. Prior studies have also shown higher rates of abstinence with the combination of nicotine replacement therapy (NRT) and bupropion, and with the combination of varenicline and bupropion. We continue to suggest initiating therapy with medication from a single class (eg, varenicline, bupropion, or NRT), given the increased cost and additional side effects with combining therapies, but combining medication classes is a reasonable option for patients who have failed initial therapy. (See "Pharmacotherapy for smoking cessation in adults", section on 'Patients who fail to quit'.)
Bronchoscopic lung volume reduction with nitinol coils in severe emphysema (October 2014)
Bronchoscopic placement of nitinol coils is an experimental method to treat emphysema. When the coils are deployed in areas of emphysema, they resume their coiled shape, collecting and collapsing the surrounding lung tissue and thereby reducing hyperinflation. In a multicenter, observational study, 60 patients with severe heterogeneous emphysema underwent bronchoscopic placement of nitinol coils (55 bilateral, 5 unilateral) with a median of 10 coils per lobe . Serious adverse events included seven COPD exacerbations, four pneumothoraces, and one episode of hemoptysis. The remaining patients experienced modest but sustained improvements in quality of life and lung function at six and 12 months. Randomized trials with a longer duration of follow-up are needed to confirm these findings. (See "Emerging therapies for COPD: Bronchoscopic treatment of emphysema", section on 'Coils'.)
Long-acting beta agonist olodaterol for use in COPD (August 2014)
Olodaterol, a once-daily, long-acting beta agonist (LABA), is approved for the treatment of COPD in the United States, Canada, Russia, Denmark, and several other countries; it is not approved for use in asthma. In two trials that included a total of 1838 subjects with moderate-to-severe COPD, 24 weeks of olodaterol resulted in significant improvement in airflow limitation and quality of life, compared with placebo . Similar results were seen in a separate pair of trials that included a total of 1266 subjects and lasted 48 weeks . In all reports, adverse events with olodaterol were comparable to those of placebo. (See "Management of stable chronic obstructive pulmonary disease", section on 'Beta agonists'.)
Prophylactic antibiotics do not benefit patients with acute liver failure (October 2014)
The role of prophylactic antibiotics in the treatment of patients with acute liver failure is controversial. In a retrospective study of 1551 patients with acute liver failure, antimicrobial prophylaxis did not reduce the incidence of bloodstream infection or mortality . Our approach to antibiotic prophylaxis is to not give patients prophylactic antibiotics, but instead give antibiotics only if there is evidence of active infection, positive surveillance culture results, or clinical deterioration. (See "Acute liver failure in adults: Management and prognosis", section on 'Infection surveillance and prevention'.)
Antibiotic decontamination of the digestive tract in the ICU and antimicrobial resistance (October 2014)
The use of prophylactic antibiotics to decontaminate the oropharyngeal and/or digestive tracts of critically ill patients and reduce the risk of infection confers a modest mortality benefit but is not widely used, in part, because of concern that it can promote antimicrobial resistance. A large multicenter cluster-randomized trial in intensive care units in the Netherlands compared resistance rates with selective oropharyngeal decontamination (SOD; antibiotics applied to the oropharynx only) and selective digestive decontamination (SDD; antibiotics applied to the oropharynx and through a nasogastric tube plus a different intravenous antibiotic) . Rates of rectal colonization with highly resistant bacteria were overall lower with SDD than SOD, but colonization with aminoglycoside-resistant gram-negative bacilli increased more over time with SDD than SOD. Given the very low baseline rate of antimicrobial resistance in the Netherlands and the absence of a control group that received no prophylactic antibiotics, these findings do not sufficiently allay concerns about long-term antimicrobial resistance with antibiotic use for decontamination of the gastrointestinal tract. (See "Epidemiology and prevention of infections and antimicrobial resistance in the intensive care unit", section on 'Decontamination of the digestive tract'.)
Restrictive transfusion threshold safe in septic shock (October 2014)
Blood transfusion using a lower (restrictive) hemoglobin threshold has been adopted in a variety of settings, including hemodynamically stable patients in the intensive care unit. However, debate has remained regarding the safety of this approach in patients with septic shock. A new randomized trial has shown that a restrictive hemoglobin threshold of 7 g/dL can be used in this setting. The Transfusion Requirements in Septic Shock (TRISS) trial randomly assigned 998 patients with septic shock to a restrictive or a liberal transfusion strategy (hemoglobin threshold of 7 or 9 g/dL) . All outcomes were similar between the two groups at 90 days, including mortality, cardiac ischemia, and transfusion reactions. We and other experts agree that for most patients with septic shock, red blood cell transfusion should be reserved for those with a hemoglobin of ≤7 g/dL. (See "Evaluation and management of severe sepsis and septic shock in adults", section on 'Red blood cell transfusions' and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Intensive care unit/septic shock'.)
Enteral versus parenteral nutrition in critically ill patients (October 2014)
In critically ill patients, the benefits of enteral nutrition compared with parenteral nutrition are unclear, with small randomized trials suggesting marginal benefit to enteral nutrition in surgical patients. One large multicenter randomized trial compared enteral nutrition with parenteral nutrition in 2400 critically ill patients, most of whom had medical rather than surgical illnesses . There was no difference in mortality or rates of infections between the groups. These findings support the continued use of enteral nutrition in both medical and surgical patients who are critically ill, when feasible. (See "Nutrition support in critically ill patients: An overview", section on 'Enteral versus parenteral'.)
Immune modulatory enteral feeds in critically ill patients (August 2014)
Small retrospective studies have suggested that high-protein enteral formulas with immune modulating nutrients (IMHP), such as glutamine, selenium, and omega-3 fatty acids, may improve survival and reduce the rate of infections in critically ill patients. The effect of IMHP was examined in a multicenter, randomized, double-blind trial of 301 mechanically ventilated adult patients (MetaPlus) . There was no difference reported in the rate of infections, duration of mechanical ventilation, or length of ICU or hospital stay. Use of IMHP was associated with a higher six-month mortality rate (54 versus 35 percent) in one predefined subpopulation of medical patients, which was not seen in the surgical or trauma patients. These findings are consistent with previous large randomized trials of high-protein formulas supplemented with glutamine or omega-3 fatty acids alone, which also found lack of benefit and possible harmful effects. (See "Nutrition support in critically ill patients: Enteral nutrition", section on 'Immune modulators'.)
PULMONARY VASCULAR DISEASE
Two distinct phenotypes in patients with idiopathic pulmonary artery hypertension (January 2015)
Vasoconstriction and luminal obstruction from plexiform lesions are both thought to play a role in the pathogenesis of idiopathic pulmonary artery hypertension (IPAH). A minority of patients responds to pulmonary vasodilators (responders), suggesting vasoconstriction may be more important in the pathogenesis of the disease in these patients compared with non-responders. Functional capillary surface area (FCSA) is a measurement of the amount of available pulmonary flow (ie, pulmonary reserve) that can be recruited during vasodilatation for improved gas exchange and hemodynamics. In an observational study of 14 patients with IPAH, FSCA response to a vasodilator challenge was compared between responders and non responders. Responders had a higher FCSA which increased during vasodilator testing, supporting the hypothesis that vasoconstriction, rather than luminal obstruction, was the dominant pathogenetic process in this population . Further exploration of this theory with larger numbers of patients is warranted. (See "Pathogenesis of pulmonary hypertension", section on 'Pathophysiology'.)
Novel anticoagulant strategies with potentially lower bleeding risk (December 2014)
Anticoagulants reduce the risk of thromboembolism, but this benefit is balanced by an increased risk of bleeding. Two new strategies for anticoagulation are in development that may carry a lower risk of bleeding compared with currently available agents. The first uses an antisense oligonucleotide to reduce production of coagulation factor XI (FXI-ASO). In patients undergoing knee replacement, treatment with FXI-ASO was associated with a 3 percent risk of venous thromboembolism, compared with approximately 30 percent with low molecular weight heparin, without increasing bleeding . However, the duration of anticoagulation was long, injection site reactions were common, and no antidote is available. The second strategy targets polyphosphate, a pro-thrombotic substance released from activated platelets or microbes . In preclinical models, polyphosphate inhibitors have shown reduced arterial thrombosis without increased bleeding. Additional studies are awaited to determine the role of these new strategies in clinical practice. (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Anticoagulants in development'.)
CPAP therapy for older adults with obstructive sleep apnea (October 2014)
Continuous positive airway pressure (CPAP) is the mainstay of therapy for most adults with obstructive sleep apnea (OSA), but previous clinical trials have enrolled primarily younger adults. In a multicenter trial that included 278 adults ≥65 years of age with newly diagnosed OSA, patients randomized to receive CPAP therapy plus best supportive care had improvement in daytime sleepiness compared with those assigned to best supportive care alone . The benefits of CPAP were present at both three- and 12-month time points and were greater in those with higher CPAP usage and higher baseline sleepiness scores. Secondary endpoints, including quality of life, mobility, cognitive function, and cardiovascular events, were similar between groups. A major limitation of the trial was the lack of a sham CPAP control arm. (See "Sleep apnea and other causes of impaired sleep in older adults", section on 'Treatment'.)
Orexin receptor antagonist suvorexant for treatment of insomnia (August 2014)
The first dual orexin receptor antagonist, suvorexant (Belsomra), has been approved by the US Food and Drug Administration for the treatment of insomnia but is not yet available for clinical use . Orexin is a hypothalamic neuropeptide that plays a key role in regulating wakefulness and the sleep-wake cycle. In clinical trials for up to one year, suvorexant was associated with improved subjective total sleep time and time to sleep onset compared with placebo [19,20]. The most common adverse effect is somnolence, and next-day driving impairment has been seen in both men and women at the maximum approved dose (20 mg). The role for this novel medication, which is expected to be a C-IV controlled substance, remains to be determined, as suvorexant has not yet been compared with other pharmacologic or behavioral therapies for insomnia. (See "Treatment of insomnia", section on 'Orexin receptor antagonists'.)
OTHER PULMONARY MEDICINE
Approval of the direct factor Xa inhibitor edoxaban (January 2015)
The US Food and Drug Administration has approved the oral direct factor Xa inhibitor edoxaban (Savaysa; Lixiana in Japan) for the prevention of stroke in nonvalvular atrial fibrillation and the treatment of venous thromboembolism, based upon earlier randomized trials demonstrating non-inferiority to warfarin [21-23]. Dosing is once daily at a fixed dose without monitoring. There are Boxed Warnings regarding avoidance of edoxaban in patients with atrial fibrillation who have a creatinine clearance >95 mL/minute, spinal/epidural hematoma in patients undergoing neuraxial procedures, and ischemic events following premature discontinuation. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Anticoagulation in acute pulmonary embolism" and "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Edoxaban'.)
Rituximab as maintenance therapy in ANCA-associated vasculitis (November 2014)
Azathioprine and methotrexate are conventionally considered the preferred drugs for maintenance therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial compared rituximab with azathioprine as maintenance therapy in 115 patients who had achieved remission after induction therapy with cyclophosphamide and glucocorticoids . Major relapse rates at 28 months were lower for rituximab (5 versus 29 percent). Rates of adverse events were also similar. However, the dosing of azathioprine in this trial was not consistent with the practice of many experts, and this may have contributed to the excess relapse rate. In addition, most patients had GPA, a positive PR3-ANCA, and were newly diagnosed rather than relapsed patients. It is not clear whether or not these data apply to other groups of patients with ANCA-associated vasculitis or to patients induced with rituximab rather than cyclophosphamide. Thus, either rituximab or azathioprine (or methotrexate although it was not evaluated in this trial) can be used as maintenance therapy in patients with GPA or MPA while awaiting further data to confirm these findings. (See "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis", section on 'Rituximab'.)
Lower risk of fatal bleeding with target specific oral anticoagulants versus warfarin (November 2014)
All anticoagulants carry a risk of bleeding, and the lack of an antidote for direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and the direct thrombin inhibitor dabigatran increases concerns about this risk. Reassuringly, a meta-analysis of 12 randomized trials in patients with atrial fibrillation or venous thromboembolism that compared bleeding risk with these agents versus vitamin K antagonists found lower rates of fatal bleeding, major bleeding, and intracranial bleeding with the direct factor Xa and direct thrombin inhibitors . Individual patient factors continue to play a role in anticoagulant choice and the development of reversal agents for the factor Xa and thrombin inhibitors is underway. (See "Management of bleeding in patients receiving target-specific oral anticoagulants", section on 'Risk of bleeding'.)
Investigational agent for reversal of multiple anticoagulants (November 2014)
Reversal agents for the target specific oral anticoagulants are lacking. In a study of 80 healthy volunteers given a therapeutic dose of the direct factor Xa inhibitor edoxaban, a reversal agent under development (PER977) normalized the whole blood clotting time within 10 minutes; in contrast, normalization of the clotting time took 12 to 15 hours in individuals given edoxaban followed by placebo . In addition to binding direct factor Xa inhibitors, PER977 also binds the direct thrombin inhibitor dabigatran, as well as unfractionated and low molecular weight heparins. (See "Management of bleeding in patients receiving target-specific oral anticoagulants", section on 'Antidotes under development'.)
Infection prevention measures for cystic fibrosis (October 2014)
Evidence is accumulating that a variety of respiratory pathogens can be transmitted among individuals with cystic fibrosis (CF) within the health care system. In particular, highly transmissible strains of Pseudomonas aeruginosa have been reported. Compared with sporadic strains of P. aeruginosa, infection with highly transmissible strains is associated with increased need for health care and antibiotics. To minimize risk of transmission, the CF Foundation has published updated guidelines for infection prevention and control to be applied to all individuals with CF, regardless of respiratory tract culture results . The guidelines include the following measures:
●Clinicians should use contact precautions (gown and surgical masks) at all times when caring for patients with CF.
●Patients with CF should wear surgical masks in the health care setting.
●Patients with CF should not congregate within or outside of the health care setting, should remain at least six feet away from other patients with CF, and be cared for in single-patient rooms when they require admission.
Ivacaftor for cystic fibrosis (August 2014)
Ivacaftor is a drug that restores function of the mutant ion channel in patients with cystic fibrosis (CF) due to a G551D mutation. In initial randomized trials, beneficial effects of ivacaftor significantly exceeded those of any other CF treatments. Now, a multicenter longitudinal study demonstrates improvements in pulmonary function and weight gain, reduced hospitalization, and decreased Pseudomonas aeruginosa colonization—all within six months of initiation . These findings further establish the importance of ivacaftor in the treatment of CF due to G551D or other “gating” mutations. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'CFTR modulators'.)
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