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What's new in pulmonary and critical care medicine
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What's new in pulmonary and critical care medicine

Disclosures: Helen Hollingsworth, MD Nothing to disclose. April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)]. Geraldine Finlay, MD Nothing to disclose.

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.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2015. | This topic last updated: Jul 24, 2015.

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.

ASTHMA

Soy isoflavone supplementation does not improve asthma control (June 2015)

Patients with asthma often request guidance on dietary alterations that might improve asthma control. Preliminary studies suggested that soy isoflavone supplementation might fill this role, possibly by a reduction in eosinophil leukotriene synthesis. However, in a 24-week multicenter trial that included 386 adults and children age 12 or older with poorly controlled asthma, isoflavone supplementation did not significantly improve pulmonary function, symptom scores, episodes of poor asthma control, or exhaled nitric oxide [1]. High-quality studies are essential to determining the efficacy of dietary adjustments; this study demonstrates that soy isoflavone supplements are not useful in poorly controlled asthma. (See "Alternative and experimental agents for the treatment of asthma", section on 'Dietary alterations'.)

Investigational agent shows promise in asthma (June 2015)

GATA3 is a transcription factor that is essential for Th2 lymphocyte differentiation and activation. An investigational synthetic DNA molecule (SB010) has been developed that uniquely binds to GATA3 messenger RNA and cleaves it. The effect of SB010 was assessed in 43 patients with mild allergic asthma who were randomly assigned to inhalation of SB010 or placebo once daily for 28 days [2]. The early and late asthmatic responses to allergen bronchoprovocation were significantly attenuated by SB010. The degree of suppression of the late response was similar to that of inhaled glucocorticoids. This study supports a potential role for disruption of GATA3 (and thus Th2 cytokines) in asthma. (See "Alternative and experimental agents for the treatment of asthma", section on 'GATA3-specific DNAzyme'.)

Warning about use of non-prescription asthma treatments (April 2015)

The US Food and Drug Administration (FDA) released a consumer warning about the potential health risks of over-the-counter (OTC) homeopathic products for asthma [3]. The efficacy and safety of OTC products are not evaluated by the FDA. In addition, there is evidence that some non-prescription therapies, such as racemic epinephrine inhaler (sold as Asthmanefrin) and systemic ephedrine (sold as Bronkaid and Primatene tablets), are less effective than standard therapies for asthma and have a higher rate of side effects. Thus, OTC products are not recommended for the routine care of asthma, particularly acute asthma symptoms. These warnings are an important reminder for clinicians to ask their patients about use of OTC products. (See "Asthma in children younger than 12 years: Rescue treatment for acute symptoms", section on 'Nonstandard therapies' and "Alternative and experimental agents for the treatment of asthma", section on 'Risks associated with inhaled epinephrine' and "Alternative and experimental agents for the treatment of asthma", section on 'Homeopathic agents' and "Homeopathy", section on 'Specific diseases'.)

Safety of inhaled long-acting beta agonist/glucocorticoid for asthma during pregnancy (February 2015)

An important clinical question for pregnant women with asthma is whether using a combination long-acting beta-agonist (LABA) plus inhaled glucocorticoid confers an increased risk for adverse fetal outcomes, compared with monotherapy using a higher dose of the inhaled glucocorticoid. In a study of 1302 pregnant women with asthma, the risk for a major congenital malformation was not increased when a LABA plus low dose inhaled glucocorticoid was compared with a medium dose inhaled glucocorticoid, or when a LABA plus medium-dose inhaled glucocorticoid was compared with a high-dose inhaled glucocorticoid [4]. (See "Management of asthma during pregnancy", section on 'Long-acting beta-adrenergic agents'.)

Safety of omalizumab for asthma during pregnancy (February 2015)

The safety of omalizumab exposure during pregnancy in humans has not been formally evaluated, but outcomes from an omalizumab registry have been published [5]. There were 169 pregnancies with known outcomes: 156 live births (160 infants), 1 fetal death/stillborn, and 11 spontaneous abortions. The rate of preterm birth was 14 percent, and 11 percent of infants were small for gestational age. Congenital anomalies were present in 13 percent, and 4 percent had a major anomaly. While the sample size is small, these results are similar to findings from other studies of pregnant women with asthma. Further data are needed to more fully characterize outcomes of omalizumab use in pregnancy. (See "Management of asthma during pregnancy", section on 'Anti-immunoglobulin E'.)

Novel glucocorticoid receptor agonist for asthma (February 2015)

The investigational agent AZD5423 is a nonsteroidal compound that binds to the glucocorticoid receptor in a different manner from that of traditional glucocorticoids. It suppresses production of proinflammatory proteins (like traditional glucocorticoids), but with reduced adverse effects in animal models. An inhaled dry powder formulation of AZD5423 was assessed in a trial that randomly assigned 20 subjects with mild allergic asthma to pretreatment with AZD5423, budesonide, or placebo for seven days followed by allergen-bronchoprovocation [6]. AZD5423 attenuated the fall in forced expiratory volume in one second (FEV1) during the late phase asthmatic response compared with budesonide or placebo, but did not affect the early decrease in FEV1. AZD5423 also decreased allergen-induced sputum eosinophilia and allergen-induced airway hyperresponsiveness at 24 hours and was well-tolerated. Additional studies are needed to determine the safety and efficacy of AZD5423 compared with inhaled glucocorticoids. (See "Alternative and experimental agents for the treatment of asthma", section on 'Novel glucocorticoid receptor agonist'.)

COPD

Augmentation therapy in alpha-1 antitrypsin deficiency (June 2015)

“Augmentation therapy” consisting of regular infusions of alpha-1 antiprotease obtained from pooled human plasma is an accepted therapy for alpha-1 antitrypsin (AAT) deficiency, although high-quality studies demonstrating efficacy have been lacking. In the RAPID trial, patients with AAT deficiency were randomly assigned to weekly intravenous augmentation therapy (93 patients) or placebo (87 patients) for 24 months [7]. The rate of loss of lung density, as measured by computed tomography (CT) at full inspiration, was lower among augmentation recipients than placebo recipients. No significant differences were observed in other measures of lung function, quality of life, or exacerbation frequency. The effect on lung density suggests that augmentation therapy for AAT deficiency may slow progression of emphysema. (See "Treatment of alpha-1 antitrypsin deficiency", section on 'Clinical efficacy'.)

Roflumilast reduces exacerbations in severe COPD (April 2015)

Roflumilast is an oral medication that is occasionally used in severe chronic obstructive pulmonary disease (COPD). In a multicenter trial, nearly 2000 patients with COPD, severe airflow obstruction, and at least two exacerbations in the prior year were randomly assigned to oral roflumilast or placebo for one year [8]. All patients used a combination inhaled glucocorticoid and long acting beta-agonist inhaler in addition to study medication. Tiotropium was also allowed. Moderate-to-severe COPD exacerbations were 14 percent lower among those taking roflumilast compared with those taking placebo. Severe exacerbations requiring hospital admission were decreased by 24 percent, although confidence intervals approached no effect. Roflumilast may help to reduce COPD exacerbations when added to other respiratory medications, although the effect appears to be modest. (See "Management of stable chronic obstructive pulmonary disease", section on 'PDE-4 inhibitors'.)

CRITICAL CARE

Investigational dabigatran reversal agent (June 2015)

Dabigatran is a direct oral anticoagulant used in patients with atrial fibrillation or venous thromboembolism. However, lack of a specific reversal agent has been a persistent concern. Idarucizumab, an experimental monoclonal antibody-based therapy, has now been demonstrated to reverse the effects of dabigatran. In a cohort of 90 elderly patients who had clinically significant bleeding or the need for an urgent invasive procedure while taking dabigatran for atrial fibrillation, idarucizumab caused rapid normalization of clotting times and/or surgical hemostasis [9]. There were five thrombotic events and 18 deaths; without a control group it is unclear how these would compare with outcomes in similar patients who did not receive idarucizumab. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Antidotes under development'.)

Oxygen not helpful in normoxic STEMI patients (June 2015)

Small studies have raised the possibility of harm from supplemental oxygen in patients with ST-elevation myocardial infarction (STEMI). In the AVOID study, 441 normoxic patients with confirmed STEMI were randomly assigned to either supplemental oxygen (8 L/min) or no oxygen [10]. The trial showed no improvement in the primary end point of a diminution in infarct size with oxygen and perhaps evidence of a larger infarct. For STEMI patients who are not hypoxic, we suggest not administering supplemental oxygen. (See "Overview of the acute management of ST elevation myocardial infarction", section on 'Oxygen'.)

Permissive underfeeding in critically ill adults (May 2015)

Meeting the complete caloric needs of critically ill patients is potentially associated with harm due to overfeeding, so standard feeding regimens in this population are typically designed to meet 70 percent of their caloric requirements. However, the optimal caloric goal for critically ill adults remains unclear. In a randomized trial of 894 critically ill patients (medical, surgical, trauma; PermiT), standard enteral feeding (70 to 100 percent of caloric requirements) was compared with 14 days of permissive underfeeding (40 to 60 percent of caloric requirements), while keeping the protein content the same in both groups [11]. There were no significant differences in mortality, gastrointestinal intolerance, infectious complications, or length of hospital stay between the two groups. This trial supports the continued practice of underfeeding in critically ill adults. Further trials are needed to confirm the optimal balance of protein and nonprotein calories in this population. (See "Nutrition support in critically ill patients: An overview", section on 'Calories'.)

High-flow oxygen therapy by nasal cannula for acute hypoxemic respiratory failure in adults (May 2015)

In adults with acute hypoxemic respiratory failure without hypercapnia, high-flow oxygen therapy by nasal cannula is a reasonable alternative to standard oxygen therapy or noninvasive positive pressure ventilation. Such patients should be managed in settings with appropriate monitoring (eg, emergency departments or intensive care units). In a multicenter trial of 310 adults with hypoxemic respiratory failure without hypercapnia that compared high-flow oxygen therapy by nasal cannula with standard oxygen therapy by face mask or noninvasive positive pressure ventilation (NPPV), the intubation rate was not significantly different for patients receiving high-flow oxygen compared with standard therapy or NPPV [12]. Patients who received high-flow oxygen therapy had significantly lower 90-day mortality and fewer days of mechanical ventilation than the other two groups, although patients receiving NPPV might have had a greater degree of baseline lung injury. (See "Continuous oxygen delivery systems for infants, children, and adults", section on 'High flow'.)

Use of high-flow nasal oxygen in postoperative care (May 2015)

Oxygen delivered via high-flow nasal cannula (HFNC) can oxygenate patients as well as provide small amounts of positive airway pressure. It is unknown whether HFNC is an effective therapy for the treatment of postoperative acute hypoxemic respiratory failure. One study of 830 patients who were at risk of or who developed acute respiratory failure following cardiothoracic surgery were randomly assigned to receive either continuous HFNC or noninvasive ventilation (NIV) with bilevel positive airway pressure (delivered for at least four hours per day) [13]. HFNC and NIV had similar rates of treatment failure (eg, reintubation) and mortality but skin breakdown was more commonly encountered with NIV. Although this study suggested that HFNC and NIV were comparable, methodologic flaws in study design may have affected the outcome, and additional randomized studies will be necessary before HFNC can be routinely used as first-line therapy for the treatment or prevention of postoperative respiratory failure. However, it may be an alternative to NIV, particularly for those in whom NIV is not tolerated. HFNC is not routinely available in all institutions for adult use and it should only be administered by staff educated in its application. (See "Overview of the management of postoperative pulmonary complications", section on 'Postoperative respiratory failure'.)

PTSD experienced by survivors of critical care (April 2015)

Patients who survive critical care in an intensive care unit (ICU) are known to experience significant rates of posttraumatic stress disorder (PTSD). Less has been known about risk factors for PTSD in these patients or their symptom course over time. A recent meta-analysis found that 24 percent of patients who received critical care experienced clinically important PTSD symptoms one to six months after ICU discharge [14]. Only a small drop in the prevalence, to 22 percent, was seen 7 to 12 months post-discharge. Risk factors for PTSD symptoms included benzodiazepine use during critical care, early memories of frightening ICU experiences, and pre-ICU psychopathology. Neither the severity of critical illness nor length of ICU stay was predictive. PTSD symptoms were associated with poorer quality of life. Among several interventions that aim to reduce PTSD symptoms in this population, keeping an ICU diary has shown the most robust evidence of efficacy. (See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, and diagnosis", section on 'ICU hospitalization'.)

Diagnostic criteria for hepatorenal syndrome (April 2015)

The International Club of Ascites has altered their diagnostic criteria for hepatorenal syndrome [15]. The new criteria recognize that, in such patients, acute kidney injury can sometimes be characterized by small absolute increases in serum creatinine. (See "Hepatorenal syndrome", section on 'Diagnosis'.)

Mortality is unchanged in severe sepsis with early goal-directed therapy (April 2015)

Early goal-directed therapy (EGDT) is the administration of intravenous fluids to patients with severe sepsis or septic shock within the first six hours of presentation using physiologic targets to guide fluid management. Although EGDT is widely accepted, the impact on mortality is unclear. In three multicenter randomized trials involving 1300 patients (ProCESS) [16], 1600 patients (ARISE) [17], and 2160 patients (ProMISe) [18], EGDT, compared with usual care, did not improve mortality at 60 days or 90 days. The early administration of fluids and antibiotics prior to randomization in these trials likely biased the results. However, they suggest that strict adherence to an aggressive EGDT protocol is not required in every patient with severe sepsis. (See "Evaluation and management of severe sepsis and septic shock in adults", section on 'Protocol-directed therapy'.)

Increased mortality with delayed treatment for spontaneous bacterial peritonitis (April 2015)

Patients with spontaneous bacterial peritonitis (SBP) who develop septic shock have high mortality rates, but early initiation of antimicrobial therapy may result in improved outcomes. In a retrospective study of patients with cirrhosis and SBP-associated septic shock, the risk of mortality nearly doubled (1.9-fold increase) with every hour delay in administering antimicrobial therapy [19]. In patients with suspected SBP-associated sepsis, ascitic fluid cultures should be obtained immediately and empiric antimicrobial therapy initiated to maximize the patient's chance of survival. (See "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis", section on 'Prognosis'.)

No effect of blood storage duration on transfusion outcomes (April 2015)

Observational studies have come to differing conclusions regarding the effect of red blood cell (RBC) storage duration on transfusion outcomes. Two new randomized trials addressing this question now demonstrate that blood storage duration does not affect clinical outcomes. The Age of BLood Evaluation (ABLE) trial evaluated critically ill adults requiring an RBC transfusion, and the REd CEll Storage duration Study (RECESS) evaluated patients undergoing complex cardiac surgery [20,21]. Neither trial found a difference in primary outcome (90-day mortality or change in multi-organ dysfunction score [MODS], respectively), or in a variety of secondary outcomes or adverse events. These data, along with a previously published randomized trial in premature infants, provide strong evidence in support of current transfusion practice that does not take into account RBC storage duration. (See "Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters", section on 'Clinical relevance of storage time'.)

Transfusion threshold for patients who have undergone cardiac surgery (March 2015)

For patients undergoing cardiac surgery, significant postoperative anemia is associated with worse outcomes. However, transfusion of red blood cells carries with it significant risks and burdens. In the TITRe2 trial, 2007 patients who underwent cardiac surgery were randomly assigned to a restrictive transfusion threshold (hemoglobin <7.5 g/dL) or a liberal threshold (<9 g/dL) [22]. There was no difference in the rate of the primary combined outcome of serious infection or an ischemic event. We suggest a transfusion threshold of 7.5 to 8 g/dL for these patients. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Blood transfusion'.)

Ketamine for intubation in patients with elevated intracranial pressure (February 2015)

The use of ketamine as an induction agent for rapid sequence intubation (RSI) in patients with head trauma has been debated because some observational studies suggest it elevates intracranial pressure (ICP). However, a systematic review of 10 trials involving 953 critically ill patients, all managed with intubation and mechanical ventilation, concluded that the use of intravenous ketamine did not adversely affect patient outcomes, including mortality [23]. Most studies included in the review had methodological limitations, but two randomized, double-blinded controlled trials comparing the effects of prolonged ketamine and sufentanil infusions in patients with traumatic brain injury found no differences in mean daily ICP and cerebral perfusion pressures. The findings of this systematic review support our view that ketamine is an appropriate induction agent for RSI in patients with suspected ICP elevation and normal blood pressure or hypotension. (See "Sedation or induction agents for rapid sequence intubation in adults", section on 'Elevated intracranial pressure'.)

Driving pressure in acute respiratory distress syndrome predicts survival (February 2015)

Limiting pressure and over distension of mechanically ventilated lung improves survival in patients with acute respiratory distress syndrome (ARDS). Lung protective ventilation strategies traditionally use low tidal volume (VT) and plateau pressure (pPlat) with or without high positive end expiratory pressure (PEEP) to achieve this goal. One retrospective statistical analysis of nine trials compared driving pressure (ΔP; ie, difference between pPlat and applied PEEP) with the standard variables, VT, pPlat, and PEEP to predict survival in  3562 patients mechanically ventilated for ARDS [24]. Among ventilator variables, ΔP was the best predictor of survival. Even in patients who were ventilated using a lung protective strategy, small increases in ΔP resulted in a 30 to 40 percent increase in mortality. However, because ΔP is largely determined by VT, pPlat, and PEEP, we suggest the continued use of these standard variables rather than ΔP to manage ventilator settings in patients with ARDS. Use of ΔP will need to be tested in a large randomized trial before it can be routinely used in this population. (See "Mechanical ventilation of adults in acute respiratory distress syndrome", section on 'Driving pressure'.)

Adjunctive glucocorticoids for hospitalized patients with community-acquired pneumonia (January 2015)

There has been interest in using glucocorticoids as adjunctive therapy to antibiotics in hospitalized patients with community-acquired pneumonia (CAP) in an attempt to reduce the inflammatory response, which is likely to contribute to the morbidity of the disease. There are conflicting data on this approach, but the largest randomized trial suggests a modest benefit. In the trial, which included 785 hospitalized adults with CAP, prednisone 50 mg daily for seven days shortened the time to clinical stability by approximately one day compared with placebo, without an increase in complications [25]. In another randomized trial that included 120 patients in Spain with severe CAP and a high inflammatory response, there was less treatment failure among patients who received methylprednisolone 0.5 mg/kg every 12 hours for five days than in those who received placebo, but no difference in the rate of in-hospital mortality [26]. Pending the results of a larger trial evaluating mortality rates in severe CAP, we do not favor the routine use of adjunctive glucocorticoids in adults with CAP. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Glucocorticoids'.)

INTERSTITIAL LUNG DISEASE

Sirolimus approved for use in pulmonary lymphangioleiomyomatosis (June 2015)

Pulmonary lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung disease associated with mutations in proteins of the mechanistic target of rapamycin (mTOR) complex. Sirolimus (also known as rapamycin) has been approved by the US Food and Drug Administration for the treatment of moderate-to-severe pulmonary LAM [27]. Approval was based on an earlier trial in which sirolimus slowed the decline in pulmonary function, quality of life, and functional performance compared with placebo. (See "Pulmonary lymphangioleiomyomatosis", section on 'mTOR inhibition'.)

Novel variants in telomerase pathway associated with familial interstitial pneumonia (March 2015)

Several genes that maintain chromosome telomeres have been associated with idiopathic pulmonary fibrosis (IPF). In a study of 25 kindreds of familial interstitial pneumonia (FIP), the familial form of IPF, nine rare loss-of-function variants were identified in the gene that encodes the regulator of telomere elongation helicase 1 (RTEL1), which helps regulate telomere replication and stability [28]. The rare variants identified in this study segregate with FIP in genetic studies and are associated with very short telomeres in peripheral blood mononuclear cells. In 163 additional FIP kindreds, heterozygous variants of RTEL1 were found in eight families (approximately 5 percent). These observations further support the role of genes affecting telomeres in FIP. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)

LUNG CANCER

Stereotactic body radiation therapy for stage I non-small cell lung cancer (May 2015)

Stereotactic body radiation therapy (SBRT) was compared with surgery in two randomized trials but both were prematurely closed because of poor patient accrual. A combined analysis of these trials found that overall survival was superior with SBRT at three years, although there were no differences in rates of locoregional recurrence or distant metastasis [29]. SBRT is an alternative that has growing evidence to support comparable outcomes in selected stage I patients. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Stereotactic body radiation therapy'.)

Meta-analysis of adjuvant chemotherapy for non-small cell lung cancer (April 2015)

Multiple randomized trials found that adjuvant chemotherapy improves overall survival in patients undergoing a complete resection for non-small cell lung cancer (NSCLC) compared with surgery alone. In an individual patient data meta-analysis conducted by the Non-Small Cell Lung Cancer Collaborative Group, the five-year survival rate was significantly improved compared with surgery alone (64 versus 60 percent) [30]. Adjuvant chemotherapy is recommended following surgical resection of II and IIIA NSCLC. Adjuvant chemotherapy is also suggested for patients with resected stage IB NSCLC, although these patients may reasonably choose to not have adjuvant chemotherapy. (See "Adjuvant systemic therapy in resectable non-small cell lung cancer", section on 'Meta-analyses'.)

LUNG TRANSPLANTATION

Promising outcomes after lung transplantation for advanced hypersensitivity pneumonitis (July 2015)

Lung transplantation may be a reasonable option for patients with advanced chronic hypersensitivity pneumonitis (HP) that is refractory to avoidance of known allergens and immunosuppressive medications. In a case series of 31 such patients, lung transplantation was associated with 96 and 89 percent survival at one and five years, respectively [31]. The inciting allergen was identifiable in 12 patients (birds, mold, wood bark), but not in the remaining nine. Two patients with known culprit allergens experienced a recurrence of HP in the allograft due to repeat exposure, but improved after more meticulous allergen avoidance. (See "Treatment and prognosis of hypersensitivity pneumonitis (extrinsic allergic alveolitis)", section on 'Lung transplantation'.)

PULMONARY VASCULAR DISEASE

Extended anticoagulation for pulmonary embolism (July 2015)

Patients with unprovoked pulmonary embolism (PE) are at high risk of recurrence once anticoagulation is discontinued. Whether anticoagulation beyond a conventional course is beneficial was investigated in a randomized trial of 371 adult patients with a first episode of symptomatic unprovoked PE who had completed six months of warfarin therapy [32]. Rates of recurrent thrombosis were seven times higher in patients treated with placebo compared with those who continued anticoagulant therapy. However, rates of major bleeding were higher with extended anticoagulation, and once discontinued, the benefit of reduced recurrence was not maintained. These results reflect similar data derived from patients with deep venous thrombosis treated with extended anticoagulant therapy. Clinicians should continue to evaluate patients with unprovoked venous thromboembolism on an individual basis and weigh the benefits of extended anticoagulation against the risk of major bleeding. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Recurrence with and without anticoagulation'.)

Limited occult cancer screening for venous thromboembolism (June 2015)

Occult cancer is associated with venous thromboembolism (VTE). However, evidence to support a specific evaluation strategy is limited. In a randomized trial of 854 patients with a first unprovoked episode of VTE, a limited strategy for the evaluation of cancer (basic laboratory testing, chest radiography, and breast, cervical, and prostate cancer screening) was compared with a more comprehensive strategy (the limited strategy plus CT of the abdomen and pelvis) [33]. Both strategies identified a low incidence of cancer (approximately 4 percent) and cancer-related mortality at one year was low (1 percent) in both groups. Thus, the addition of CT of the abdomen and pelvis did not improve cancer detection, and the study supports our practice of adopting a limited approach to evaluation in patients with a first episode of unprovoked VTE. (See "Evaluating patients with established venous thromboembolism for acquired and inherited risk factors", section on 'First episode of uncomplicated unprovoked VTE'.)

Inferior vena cava filter as adjunct to anticoagulation does not improve outcomes (May 2015)

In patients with significant pulmonary embolism (PE), it is unknown whether the routine insertion of an inferior vena cava (IVC) filter as an adjunct to anticoagulation provides additional protection against recurrent PE. In an open-label randomized trial (PREPIC2), 399 patients with "severe" PE (included patients with a diagnosis of PE plus at least one of the following: age >75 years, active cancer, signs of right ventricle dysfunction, chronic respiratory insufficiency, or other high-risk characters) received either standard anticoagulation alone or anticoagulation plus a retrievable IVC filter [34]. Adjunctive therapy with an IVC filter did not alter the rate of PE recurrence, deep vein thrombosis recurrence, or mortality at three or six months. This study suggests that the routine insertion of an IVC filter in patients with severe PE is not warranted. The main indication for filter insertion should continue to be a contraindication to anticoagulation, and any additional indications should be considered on a case-by-case basis. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena cava filter'.)

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 [35]. Further exploration of this theory with larger numbers of patients is warranted. (See "Pathogenesis of pulmonary hypertension", section on 'Pathophysiology'.)

SLEEP MEDICINE

Increased cardiovascular mortality in heart failure patients treated with adaptive servo-ventilation for central sleep apnea (May 2015)

Adaptive servo-ventilation (ASV) is a type of noninvasive positive airway pressure therapy that is sometimes used in patients with symptomatic central sleep apnea (CSA) who fail or do not tolerate continuous positive airway pressure (CPAP). However, preliminary results of a randomized trial indicate that increased caution is now warranted when considering use of ASV in patients with CSA, particularly those with CSA associated with Cheyne-Stokes breathing (CSA-CSB) due to symptomatic heart failure [36]. In the SERVE-HF trial, 1325 patients with moderate to severe CSA due to symptomatic heart failure (ejection fraction ≤45 percent) were randomly assigned to ASV plus standard medical therapy or medical therapy alone [37]. While the study found no difference in the primary outcome of time to all-cause mortality or unplanned hospitalization due to heart failure, there was a 2.5 percent increase in the absolute risk of cardiovascular mortality in patients randomly assigned to ASV (10 versus 7.5 percent per year) [36]. Until further information is available, we recommend not using ASV to treat CSA-CSB due to heart failure with reduced ejection fraction; in such patients, supplemental oxygen during sleep may be the next best option to CPAP. (See "Central sleep apnea: Treatment", section on 'Adaptive servo-ventilation (ASV)'.)

Herbal products for treatment of insomnia (March 2015)

A variety of herbal products are purported to be useful for insomnia. There is little evidence from randomized controlled trials about the efficacy of many herbals, however, and for those that have been well studied (eg, valerian), there is little evidence of benefit. A meta-analysis of 14 randomized trials in over 1600 patients found no significant difference between any herbal medicine and placebo on any clinical insomnia outcome measure [38]. The majority of the trials (11 out of 14) studied valerian; chamomile, kava, and wuling were studied in one trial each. Unlike other herbals in the study, valerian was associated with a greater number of adverse events per person compared with placebo. (See "Treatment of insomnia", section on 'Over-the-counter'.)

Risk factors for neurodegeneration in REM sleep behavior disorder (March 2015)

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia in which individuals act out their dreams due to loss of REM sleep paralysis. RBD has been increasingly recognized as a prodromal symptom of alpha-synuclein neurodegeneration (eg, Parkinson disease, dementia with Lewy bodies, and multiple system atrophy). In a 10-year prospective cohort study of 89 patients with idiopathic RBD, the rate of conversion to one of these disorders was 30 percent at 3 years and 66 percent at 7.5 years [39]. The strongest risk factors for conversion were subtle motor dysfunction, abnormal color vision, olfactory dysfunction, and nonuse of antidepressants. These characteristics may prove useful for identifying candidates for novel, early-intervention neuroprotective trials in Parkinson disease and related disorders. (See "Rapid eye movement sleep behavior disorder", section on 'Prognosis and counseling'.)

OTHER PULMONARY MEDICINE

Bridging anticoagulation in patients who require warfarin interruption for surgery (July 2015)

Perioperative management of a patient receiving an anticoagulant is challenging because the risks of bleeding and thromboembolism are both increased. Not all patients require anticoagulant interruption. For those who do require interruption of their anticoagulant, the risks and benefits of bridging (use of a short-acting parenteral agent, typically a low molecular weight [LMW] heparin) have been unclear. The BRIDGE trial randomly assigned patients with atrial fibrillation to receive the LMW heparin dalteparin or placebo during warfarin interruption for surgery or an invasive procedure [40]. The risk of thromboembolism was similar in those who received dalteparin or placebo for bridging. However, patients bridged with dalteparin had a greater risk of bleeding. As a result of the BRIDGE trial, we suggest not using bridging for most individuals who require warfarin interruption. We continue to suggest bridging in certain high-risk individuals, including those with a mechanical mitral valve, thromboembolic event within the previous 12 weeks, atrial fibrillation and very high risk of stroke, recent coronary stenting, or previous thromboembolism during interruption of chronic anticoagulation. (See "Perioperative management of patients receiving anticoagulants", section on 'Whether to use bridging'.)

Practice tool for managing direct oral anticoagulants (July 2015)

The direct oral anticoagulants ([DOACs]; dabigatran, rivaroxaban, apixaban, edoxaban) generally are used without routine laboratory monitoring of coagulation times; this lack of monitoring requirement is considered a major advantage over vitamin K antagonists. However, the DOACs have short half-lives, and one or two missed doses can be sufficient to eliminate their anticoagulant effect. A practice tool has been published to help clinicians ensure that patients are taking their DOAC correctly and are minimizing risks of thromboembolism and bleeding [41]. Counseling strategies are focused on minimizing gaps in therapy and avoiding medication interactions. Monitoring of renal function and treatment of hypertension are also emphasized. (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Comparison with heparin and warfarin'.)

Pulmonary manifestations in adults with chronic granulomatous disease (June 2015)

Pulmonary complications remain the most common manifestation of chronic granulomatous disease (CGD) in adulthood. In a series of 67 adults with CGD, two-thirds had at least one infectious or noninfectious pulmonary event, and about half had manifestations involving the gastrointestinal tract or skin [42]. Most patients with invasive pulmonary fungal infections were on itraconazole prophylaxis, although serum azole concentrations were low in the majority of the patients tested. One-third of patients with pulmonary complications, including invasive fungal infections, were asymptomatic. Serial screening for elevated inflammatory markers, such as C-reactive protein (CRP), followed by imaging of the suspected organ(s) involved if levels are elevated, are suggested to monitor for and diagnose infection. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Sites of infection' and "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Pulmonary' and "Chronic granulomatous disease: Treatment and prognosis", section on 'Antifungal prophylaxis' and "Pulmonary complications of primary immunodeficiencies", section on 'Chronic granulomatous disease' and "Chronic granulomatous disease: Treatment and prognosis", section on 'Monitoring and diagnosis'.)

Novel agent for refractory cough in adults (May 2015)

Increased sensitivity of P2X3 receptors on airway sensory nerve fibers may contribute to refractory cough. In a randomized, cross-over trial of 24 subjects with refractory cough, an investigational P2X3 antagonist (AF-219) decreased cough counts during the two-week study blocks by 75 percent compared with placebo [43]. However, taste disturbance was noted in all patients taking AF-219 and caused six subjects to withdraw from the study; nausea was also common (38 percent). These results support a role for P2X3 receptor hypersensitivity in refractory cough, but further study is needed to determine safety, efficacy, and tolerability in a larger number of patients. (See "Treatment of subacute and chronic cough in adults", section on 'Future directions'.)

Pneumococcal conjugate vaccine in adults ≥65 years of age (September 2014, MODIFIED March 2015)

The CAPiTA trial, which is the largest trial to assess the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar 13) in adults, compared PCV13 to placebo in approximately 85,000 immunocompetent adults ≥65 years of age in the Netherlands who had not received a pneumococcal vaccine previously [44]. The trial demonstrated 46 percent efficacy of PCV13 against vaccine-type pneumococcal pneumonia, 45 percent efficacy against vaccine-type nonbacteremic pneumococcal pneumonia, and 75 percent efficacy against vaccine-type invasive pneumococcal disease. Efficacy persisted for the duration of the trial (mean follow-up four years). However, some concern has been raised that since this trial began before PCV13 was used routinely in infants in the Netherlands, it might not answer the question of whether its use in adults is efficacious in countries that routinely vaccinate infants. (See "Pneumococcal vaccination in adults", section on 'Efficacy'.)

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for many years in the United States for all adults ≥65 years of age. In September 2014, the United States Advisory Committee on Immunization Practices (ACIP) began also recommending PCV13 for all adults ≥65 years of age [45]. The ACIP revision was prompted by results from the CAPiTA trial. Current recommendations for individuals ≥65 years of age who have not previously received either PCV13 or PPSV23 are to administer PCV13 followed 6 to 12 months later by PPSV23 (algorithm 1). In patients who have already received PPSV23, at least one year should elapse before they are given PCV13. (See "Pneumococcal vaccination in adults", section on 'Indications'.)

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