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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
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2016. | This topic last updated: Sep 22, 2016.

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

Safety of inhaled glucocorticoid-LABA combination therapy in asthma (September 2016)

In early studies, a small increase in asthma-related deaths associated with salmeterol led the US Food and Drug Administration to place a boxed warning on the use of long-acting beta agonists (LABAs) in asthma. While concerning, the number of events was small, and it could not be determined if the potential risk of salmeterol could be mitigated by combining LABAs with inhaled glucocorticoids. Three large randomized trials including 30,000 children and adults found no increase in asthma-related adverse events or deaths among patients who used combination inhalers with salmeterol or formoterol plus an inhaled glucocorticoid versus glucocorticoid monotherapy [1-3]. These studies support the safety of these fixed-dose combination inhalers in patients with moderate-to-severe asthma. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)

Farm animals, asthma, and the innate immune response (September 2016)

Exposure to farm animals, particularly early in life, is negatively associated with the development of allergic disease. A recent study compared 60 children from Amish and Hutterite communities, two genetically similar, reproductively isolated farming populations in the United States [4]. The Amish have traditional, single-family farms with exposure to horses and dairy cows, whereas the Hutterites live and work on large farms that are highly industrialized. Amish children have significantly lower rates of asthma and allergic sensitization than their Hutterite counterparts. Endotoxin levels were significantly higher in the Amish homes, and dust extracts from the Amish homes, but not the Hutterite homes, significantly blocked airway hyperresponsiveness and eosinophilia in a mouse model. In addition, in vitro studies showed an enhanced innate immune response in Amish, but not Hutterite, children. These findings suggest that the closer contact with farm animals in the Amish lifestyle may help prevent the development of asthma by altering the innate immune response. (See "Increasing prevalence of asthma and allergic rhinitis and the role of environmental factors", section on 'Farms, villages, worms, and other parasites'.)

Lack of association between acetaminophen and asthma in children (September 2016)

More frequent use of acetaminophen was associated with increased asthma-related complications in children in observational studies, leading to the recommendation by some for children with asthma to avoid acetaminophen. However, these findings were not replicated in a prospective, randomized trial comparing acetaminophen and ibuprofen use [5]. In this trial, 300 children with mild persistent asthma were randomly assigned to as-needed treatment with acetaminophen or ibuprofen for fever or pain over a 48-week period. All children received standard controller therapy for asthma. There was no significant difference between the two groups in the number of asthma exacerbations requiring treatment with systemic glucocorticoids or in the number of asthma exacerbations. Thus, we do not advise restricting the use of acetaminophen in children with asthma. (See "Virus-induced wheezing and asthma: An overview", section on 'Acetaminophen use for febrile illnesses'.)

Evaluation of recurrent wheezing in children <2 years of age (August 2016)

The American Thoracic Society has developed guidelines for evaluation of children <2 years of age who have recurrent wheezing that is unresponsive to bronchodilators or inhaled or systemic glucocorticoids [6]. Suggested evaluation includes one or more of the following: videofluoroscopic swallowing study (modified barium swallow) for possible swallowing dysfunction; 24-hour esophageal pH monitoring for assessment of gastroesophageal reflux; and/or flexible fiberoptic bronchoscopy bronchoalveolar lavage (BAL) to assess for lower airway bacterial infection. Our approach is consistent with these guidelines. (See "Approach to wheezing in infants and children", section on 'Radiography' and "Approach to wheezing in infants and children", section on 'Endoscopy' and "Approach to wheezing in infants and children", section on 'Evaluation for gastroesophageal reflux'.)

Omalizumab for allergic asthma in children 6 to 11 years of age (July 2016)

Omalizumab, a monoclonal antibody to immunoglobulin E (IgE), is an option for patients with moderate to severe persistent asthma and sensitization to perennial aeroallergens who are inadequately controlled on inhaled glucocorticoids. The US Food and Drug Administration (FDA) has now lowered the approved age range from 12 to 6 years of age, expanding the therapeutic options in step 5 asthma management in children [7]. (See "Asthma in children younger than 12 years: Treatment of persistent asthma with controller medications", section on 'Step-up therapy' and "Asthma in children younger than 12 years: Treatment of persistent asthma with controller medications", section on 'Anti-IgE therapy' and "Anti-IgE therapy", section on 'Omalizumab therapy in asthma'.)

House dust mite sublingual immunotherapy for allergic asthma (May 2016)

Injection allergen immunotherapy with house dust mite extract has demonstrated benefit in patients with asthma and house dust mite allergy, but is inconvenient and carries a small risk of serious allergic reactions. Sublingual immunotherapy tablets (SLIT-tablets) are a safer form of allergen immunotherapy with proven efficacy in allergic rhinoconjunctivitis, but studies in patients with allergic asthma are limited. In a randomized trial of over 800 house dust mite-sensitive adults with asthma not controlled by inhaled budesonide and short-acting beta-agonists, subjects were treated with house dust mite SLIT-tablets or placebo for 7 to 12 months, after which inhaled budesonide was gradually withdrawn and then stopped [8]. House dust mite SLIT significantly prolonged the time to first moderate or severe asthma exacerbation, reducing the absolute risk of an exacerbation during budesonide withdrawal from 32 to 25 percent with placebo and SLIT, respectively. However, clinically meaningful improvements in other measures of asthma symptoms were not clearly demonstrated. Thus, further study is needed to assess the effectiveness of SLIT-tablets in patients with allergic asthma. HDM SLIT-tablets are not yet available in the United States, but are available in Australia, Japan, and parts of Europe. (See "Sublingual immunotherapy for allergic rhinoconjunctivitis and asthma", section on 'Moderate-persistent asthma'.)

New guidelines regarding the endocrine effects of long-term inhaled glucocorticoids in children (April 2016)

The Pediatric Endocrine Society Drugs and Therapeutics Committee released guidelines regarding adrenal insufficiency in children on long-term inhaled corticosteroids (ICS) [9]. The guidelines recommend testing for adrenal insufficiency in children and adolescents who are taking long-term ICS (eg, >6 months) and have symptoms suggesting adrenal insufficiency (hypoglycemia, altered mental status, fatigue, weakness, anorexia, Cushingoid features, growth failure, or weight loss). The guidelines also suggest screening asymptomatic children and adolescents who are taking high-dose ICS. However, because of the rarity of clinically significant adrenal insufficiency, we prefer to follow an individualized determination of the need for screening, based on the presence of the following risk factors: >6 months' use of ICS at doses exceeding those considered "high," combined use of high-dose ICS and intranasal glucocorticoids or intermittent use of systemic glucocorticoids, and low body mass index (BMI) (eg, <15th percentile for age). The first step in screening for adrenal insufficiency is measurement of an 8 AM serum cortisol, followed by additional testing based on the result. (See "Major side effects of inhaled glucocorticoids", section on 'Children and adolescents'.)

A second monoclonal antibody against interleukin-5 approved for severe eosinophilic asthma (April 2016)

Reslizumab, a monoclonal antibody to interleukin (IL)-5, has been approved by the US Food and Drug Administration (FDA) for add-on maintenance therapy of severe asthma in patients who are age 18 or older and have an eosinophilic phenotype [10]. It is similar to mepolizumab, which was approved in late 2015. In clinical trials of reslizumab, an eosinophilic phenotype was defined as a peripheral blood absolute eosinophil count ≥400/microL. Studies in patients with severe eosinophilic asthma have shown that reslizumab reduces the rate of exacerbations by approximately 50 percent compared with placebo [11,12]. Reslizumab is administered intravenously at four-week intervals. The US FDA has added a boxed warning because anaphylaxis occurred in 0.3 percent of treated patients. (See "Treatment of severe asthma in adolescents and adults", section on 'Reslizumab'.)

COPD

Glycopyrronium-indacaterol versus fluticasone-salmeterol for moderate-to-severe COPD (June 2016)

Current guidelines suggest use of an inhaled glucocorticoid (ICS)-long-acting beta agonist (LABA) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who are at increased risk of exacerbations. New data suggest that long-acting anticholinergic (LAMA)-LABA combinations, which improve pulmonary function and variably reduce symptoms in patients with COPD at low risk of exacerbations, may also benefit patients at increased risk of exacerbation. In a multicenter trial, glycopyrronium-indacaterol once daily was compared with fluticasone-salmeterol twice daily in over 3000 patients with moderate-to-severe COPD and at least one moderate-severe exacerbation in the previous year [13]. Over the 52-week trial, glycopyrronium-indacaterol reduced exacerbations by 11 percent and was associated with slightly fewer episodes of pneumonia compared with fluticasone-salmeterol. The use of LAMA-LABA combinations in these patients, in preference to an ICS-LABA combination, requires further study to determine the generalizability and durability of these findings. (See "Management of stable chronic obstructive pulmonary disease", section on 'Comparison with LAMA-LABA'.)

Combination inhaled glucocorticoid/long-acting beta agonists in patients with COPD and cardiovascular risk factors or disease (May 2016)

While the evidence has been generally reassuring about the safety of combination inhaled glucocorticoid plus long-acting beta agonist (ICS-LABA) inhalers in patients with chronic obstructive pulmonary disease (COPD), patients with known cardiovascular disease (CVD) were excluded from previous clinical trials. In the three-year randomized trial, Study to Understand Mortality and MorbidITy (SUMMIT), the effect of the fluticasone furoate-vilanterol combination inhaler was compared with the individual components and placebo in almost 17,000 patients with moderate COPD (FEV1 between 50 and 70 percent of predicted) and known or increased risk of CVD [14]. Relative to placebo, the combination inhaler did not affect all-cause mortality or composite cardiovascular events. Thus, the presence of CVD should not affect the role of ICS-LABA inhalers in COPD. (See "Management of the patient with severe COPD and cardiovascular disease", section on 'Combination inhaled bronchodilator plus glucocorticoid'.)

CRITICAL CARE

IDSA/ATS guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia (August 2016)

The Infectious Diseases Society of America and the American Thoracic Society have released updated guidelines for the management of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) [15]. Empiric therapy for HAP and VAP should include agents with activity against Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacilli. Choice of a specific regimen for empiric therapy should be based upon knowledge of the prevailing pathogens (and susceptibility patterns) within the healthcare setting as well as risk factors for multidrug resistance in the individual patient. The guidelines emphasize that a seven-day course of antimicrobial therapy is appropriate for most patients rather than a longer duration. (See "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Treatment'.)

Palliative care consultation for families of patients in the intensive care unit (August 2016)

Post-intensive care syndrome-family (PICS-F) is a term given to family members who have been affected physically and psychologically during the intensive care unit (ICU) stay of critically ill patients. Therapeutic measures for PICS-F are poorly studied. One multicenter randomized trial examined the impact of a palliative care-led consultation for surrogate decision-makers of critically ill patients in the ICU who were unlikely to wean from mechanical ventilation [16]. Compared with routine family meetings conducted by the ICU team, palliative care-led consultation did not reduce symptoms of anxiety or depression of family members and may have increased symptoms of posttraumatic stress disorder. However, limitations of this study include possible inadequate "dosing" of the intervention (on average, 1.4 encounters per family and physician presence at only 9 percent of meetings), leaving the possibility that more aggressive and supportive interventions may have different outcomes. (See "Post-intensive care syndrome (PICS)", section on 'Post-intensive care syndrome-family'.)

Interventions for post-intensive care syndrome lack benefit (July 2016)

Several interventions (eg, early and aggressive physical therapy regimens and multidisciplinary post-intensive care unit syndrome clinics) have been used to prevent or treat long-term mental and physical sequelae during recovery from critical illness, although their effectiveness has been poorly studied. Two recent randomized trials address such interventions.

A single-center trial of 300 critically ill ventilated patients reported no benefit for an intensive daily physical rehabilitation regimen initiated in the intensive care unit (ICU) and continued until hospital discharge, when compared with usual care (ie, intervention as needed when requested by the health care team) [17]. (See "Post-intensive care syndrome (PICS)", section on 'Prevention'.)

A multicenter randomized trial of 291 survivors of septic shock reported that a multidisciplinary team-based intervention that included primary care physician contact, case management, education, subspecialist referral, and medications did not improve mental health parameters six months after ICU discharge [18]. (See "Post-intensive care syndrome (PICS)", section on 'PICS clinics'.)

Although discouraging, methodological flaws to these trials may have limited the detection of a potential benefit from the treatment strategies, and further studies are warranted.

Aspirin does not prevent acute respiratory distress syndrome in adults (July 2016)

Preclinical and clinical observational studies have suggested a potential role for aspirin in the prevention of acute respiratory distress syndrome (ARDS). The ability of aspirin to prevent ARDS was tested in a randomized trial of 390 patients who were assessed upon presentation to an emergency department to be at risk of developing ARDS [19]. Aspirin, administered at 325 mg orally followed by 81 mg daily for seven days, had no effect on the incidence of ARDS at one week (approximately 10 percent in each group). However, the lower than expected rate of ARDS in this study may have limited the potential to detect a study drug effect. (See "Acute respiratory distress syndrome: Novel therapies in adults", section on 'Aspirin'.)

Outbreak of Burkholderia cepacia infection associated with contaminated oral liquid docusate (June 2016)

In June 2016, a multistate outbreak of Burkholderia cepacia infection was reported in the United States [20]. B. cepacia typically causes lung colonization and infection in patients with cystic fibrosis (CF), but most cases in this outbreak have involved mechanically ventilated intensive care unit patients without CF. The types of infections involved have not yet been reported. Because cases in one state have been associated with contaminated oral liquid docusate, the United States Centers for Disease Control and Prevention (CDC) recommends that facilities not use liquid docusate products for any patient. PharmaTech LLC, the manufacturer of the contaminated product, Diocto Liquid, has voluntarily recalled all non-expired lots [21]. Updated information about the outbreak and public health reporting can be found on the CDC’s website. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Outbreak of Burkholderia cepacia infection'.)

Apneic oxygenation in adults undergoing rapid sequence intubation in the emergency department (June 2016)

A number of techniques are used to prevent oxygen desaturation during rapid sequence intubation (RSI). One such technique involves giving oxygen passively via nasal cannula during the apneic phase of RSI. The results of a recent observational study of 635 patients being intubated in the emergency department suggest that this technique may have benefits beyond simply preventing hypoxia [22]. According to this study, the rate of first pass successful intubation without hypoxia was greater in patients managed with apneic oxygenation (82 percent) compared with patients managed without this intervention (69 percent). The improvement was due to both an increase in the rate of first pass successful intubation and a decrease in the incidence of hypoxia. While further studies are needed to confirm this finding, apneic oxygenation is a simple, beneficial intervention that should be used whenever RSI is performed in the emergency department. (See "Rapid sequence intubation for adults outside the operating room", section on 'Preoxygenation'.)

Dosing of direct oral anticoagulants in obese patients (June 2016)

Limited data are available to guide dosing of direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, rivaroxaban) in patients with obesity. The International Society of Thrombosis and Hemostasis (ISTH) has issued guidance on this subject [23]. The major recommendations include use of DOACs at standard doses for those with a body mass index (BMI) ≤40 kg/m2 or weight <120 kg, and avoidance of DOACs in individuals with a BMI >40 kg/m2 or weight ≥120 kg. (See "Direct oral anticoagulants: Dosing and adverse effects".)

Early initiation of renal replacement therapy (June 2016)

It is unclear if the early initiation of renal replacement therapy (RRT) (ie, without an obvious indication such as severe hyperkalemia, metabolic acidosis, pulmonary edema or advanced uremic symptoms) provides any benefit to critically ill patients with acute kidney injury (AKI) compared with later initiations of RRT. Two new randomized trials have evaluated this in somewhat different patient populations. In the larger trial, 620 critically ill patients with severe AKI were randomized to early or delayed RRT [24]. There was no difference in 60-day mortality, and nearly one-half of patients in the delayed RRT group recovered without requiring RRT. In contrast, a second trial of 231 critically ill patients with more moderate AKI showed reduced 90-day mortality with earlier RRT [25]. In the delayed initiation group, only 11 patients ended up not requiring RRT, and early RRT reduced the duration of AKI and length of stay. However, we have lower confidence in the results of the smaller trial, because it is possible that the relatively small size of the trial resulted in an overestimate of the treatment benefit. It is otherwise difficult to understand how minor differences in the protocols and patient populations could achieve such dramatically different outcomes. Until further data are available, UpToDate suggests that RRT not be initiated in the absence of obvious clinical indications. (See "Renal replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Timing of elective initiation'.)

Helmet-delivered noninvasive ventilation in acute respiratory distress syndrome (May 2016)

In patients with acute respiratory distress syndrome (ARDS), noninvasive ventilation (NIV) delivered with a face mask is often not sufficient to prevent intubation. Problems include patient discomfort and air leaks. Delivery of NIV using a helmet (ie, a transparent hood that covers the entire head, sealed with a rubber collar at the neck) may circumvent some of these issues. A preliminary trial compared the two approaches by randomly assigning patients with ARDS who required NIV to continue face mask NIV or switch to helmet–delivered NIV [26]. Helmet-delivered NIV reduced the need for intubation (18 versus 62 percent) and increased ventilator-free days. It also reduced length of stay and 90-day mortality without additional adverse effects. While encouraging, early trial termination may have exaggerated the efficacy. In addition, general concerns regarding limited physician experience and unclear guidelines regarding patient selection, optimal ventilator settings, and monitoring need to be addressed before helmet-delivered NIV can be applied as a therapy for patients with ARDS. (See "Mechanical ventilation of adults in acute respiratory distress syndrome", section on 'Invasive versus noninvasive'.)

Simplified approach to acetylcysteine infusion for acetaminophen poisoning (April 2016)

The treatment of acetaminophen poisoning with acetylcysteine is sometimes complicated by nonallergic anaphylactic reactions (NAARs). The results of a large retrospective study, in addition to recent clinical experience, suggest that these reactions can be reduced by using a two-bag regimen instead of the traditional three-bag regimen described in the manufacturer’s package insert and most dosing references. In the study, NAARs occurred in 10 percent of the 389 patients treated with the standard regimen versus 4.3 percent of the 210 patients treated with a modified two-bag regimen [27]. In both regimens, acetylcysteine was infused over 20 hours. While further study is needed to ensure the safety and effectiveness of this regimen, we believe this is a reasonable approach to treatment in adults and older adolescents with acetaminophen poisoning. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Simplified 20 hour IV protocol'.)

Noninvasive ventilation for postoperative respiratory failure (April 2016)

Patient selection is critical for the success of noninvasive ventilation (NIV). The indications for NIV in medical patients with respiratory failure are well defined. However, the indications in patients with postoperative respiratory failure are less clear. The role of NIV was studied in a trial of nearly 300 spontaneously breathing patients who developed acute hypoxemic respiratory failure following abdominal surgery [28]. Compared with patients treated with oxygen only, patients who received NIV had fewer reintubations, more ventilator-free days, and fewer healthcare-associated infections. The exclusion of patients requiring immediate reintubation and lower than expected rates of reintubation in general limits interpretation of this study. Although encouraging, these results do not support the routine administration of NIV for the treatment of respiratory failure in surgical patients. Clinicians should continue to individualize NIV and utilize it on a trial basis in this population. (See "Overview of the management of postoperative pulmonary complications", section on 'Postoperative respiratory failure'.)

High-flow oxygen following extubation (March 2016)

High-flow oxygen delivered via nasal cannula (HFNC) is being increasingly used in intensive care and high-dependency units since it can deliver high amounts of supplemental oxygen and a small amount of positive expiratory pressure. The efficacy of HFNC following extubation was studied in over 500 patients (mostly postoperative or neurologic) who had been mechanically ventilated for an average of only one to two days and considered at low risk of reintubation [29]. Patients were randomly assigned to conventional low-flow oxygen or HFNC immediately following extubation. HFNC led to a reduction in the rate of reintubation and respiratory failure at 72 hours. These findings suggest that HFNC may be useful in patients who are at low risk for reintubation. However, the results may not apply to other patient populations, since critically ill medical patients and patients at high risk of reintubation were excluded from this study. (See "Extubation management", section on 'Oxygen'.)

Dexmedetomidine for agitation in ventilated patients (March 2016)

Dexmedetomidine, a centrally active alpha-2 agonist with anxiolytic, sedative, and analgesic effects but no deleterious effect on respiratory drive, is being increasingly used for treatment of agitation in mechanically ventilated patients. The randomized DahLIa trial evaluated use of dexmedetomidine in weaning patients with delirium from mechanical ventilation [30]. In a mixed population of 71 intensive care unit (ICU) patients in whom agitated delirium was prohibiting extubation, dexmedetomidine plus standard sedation (mostly propofol) resulted in an increase in ventilator-free hours and reduced time to extubation, compared with placebo plus standard sedation. However, the trial was stopped early before the target enrollment needed for adequate power was reached. Although encouraging, these results are not definitive and further studies are needed prior to recommendations for the routine use of dexmedetomidine to facilitate extubation in patients with delirium. (See "Sedative-analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects", section on 'Dexmedetomidine'.)

INTERSTITIAL LUNG DISEASE

Revised criteria for acute exacerbations of idiopathic pulmonary fibrosis (August 2016)

An international working group has published a comprehensive review of acute exacerbations of idiopathic pulmonary fibrosis (IPF) that includes a revised definition and diagnostic criteria. The report defines an acute exacerbation of IPF as, "an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality" [31]. The following diagnostic criteria are suggested: a previous or concurrent diagnosis of IPF; acute worsening or development of dyspnea typically within one month of presentation; high-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on usual interstitial pneumonia (eg, bibasilar reticular opacities associated with honeycomb changes and traction bronchiectasis); deterioration not fully explained by cardiac failure or fluid overload. Previous criteria required exclusion of other causes of acute deterioration, such as infection or pulmonary embolism. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Definition'.)

Screening for bleomycin-induced lung disease (June 2016)

There has been no consensus as to the utility of serial pulmonary function tests (PFTs, including the diffusing capacity for carbon monoxide [DLCO]) to detect early signs of bleomycin-induced lung disease, and practice is variable. Data reported from the contemporary Danish Testicular Cancer database suggest that a systematic approach to assessing PFTs before and during therapy, with early discontinuation of bleomycin for those with a drop in the DLCO of 25 percent or more, resulted in very low rates of both acute and chronic lung disease, and no adverse effect on oncologic outcomes [32]. We suggest assessment of PFTs, including DLCO, at baseline prior to treatment and at intervals during therapy for most adults receiving a bleomycin-containing chemotherapy regimen for any malignancy. The optimal frequency of testing is not established. We suggest discontinuation of bleomycin if there is a decrease in the DLCO of 25 percent or more, even if asymptomatic. (See "Bleomycin-induced lung injury", section on 'Screening for lung toxicity'.)

Danazol in telomere disorders (May 2016)

Telomeres are regions at the ends of chromosomes that maintain chromosomal integrity. Telomeres shorten with normal aging, but inherited disorders of premature telomere shortening can cause aplastic anemia (AA), pulmonary fibrosis, and certain malignancies. To date, no therapies have been developed to reverse premature telomere shortening. In the first prospective study to evaluate androgen therapy for telomere disorders, the androgen danazol was administered to 27 individuals with mutations that affect telomere length (most with AA) [33]. Danazol was associated with improved hematologic parameters in those with cytopenias, stabilization of pulmonary status in those with pulmonary fibrosis, and reduced telomere shortening in all evaluable participants. Androgens are an attractive candidate for treating telomere disorders, although further study is needed. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis", section on 'Telomerase mutations and telomere length' and "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)

Possible delayed response to pirfenidone therapy in idiopathic pulmonary fibrosis (May 2016)

In patients with idiopathic pulmonary fibrosis (IPF), serial measurement of forced vital capacity (FVC) demonstrates substantial variability over time, making it difficult to analyze treatment responses and select subsequent treatment. In a follow-up to the original trials of pirfenidone in IPF, 34 subjects on pirfenidone and 68 subjects on placebo who experienced a ≥10 percent decline in FVC in the first three or six months were reassessed six months later [34]. Fewer subjects in the pirfenidone group experienced a further ≥10 percent decline in FVC or death in the following six months compared with the placebo group (2/34 versus 19/68, respectively). While the numbers are small, this study suggests that continuing pirfenidone may be of benefit despite initial evidence of disease progression. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Pirfenidone'.)

PULMONARY VASCULAR DISEASE

Updated guidelines for the treatment of venous thromboembolism (March 2016)

The American College of Chest Physicians (ACCP) has published new guidelines on antithrombotic therapy for venous thromboembolic (VTE) disease that include guidance on choice of anticoagulant, indications for extended anticoagulation, and indications for thrombolytic therapy in patients with acute pulmonary embolism (PE) [35]. In addition to a preference for direct oral anticoagulants for the treatment of VTE, the ACCP suggests extending anticoagulation beyond three months (ie, no scheduled stop date) in patients with unprovoked VTE or active cancer. For most patients with small subsegmental pulmonary embolism (SSPE), anticoagulation is suggested; however, clinical surveillance with lower extremity Doppler ultrasound may be appropriate for select patients with a low burden of SSPE who have no evidence of thrombus elsewhere and in whom the risk of recurrence is low. The guidelines suggest administration of systemic thrombolytic therapy, rather than catheter-directed thrombolysis (CDT), for patients with hemodynamically-significant PE; CDT may be appropriate for those who fail systemic thrombolysis or who are at high risk of bleeding. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Indications' and "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Patients likely to benefit' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Patients with subsegmental PE'.)

Agent selection for anticoagulation in venous thromboembolism (March 2016)

Guidelines for the treatment of acute venous thromboembolism (VTE) were issued by The American College of Chest Physicians (ACCP) [35]. Compared with earlier versions of the guidelines, the direct oral anticoagulants (DOACs) apixaban, edoxaban, rivaroxaban, or dabigatran are now the preferred agents for long-term anticoagulation in patients who are not pregnant and do not have active cancer or severe renal insufficiency. This preference was based upon randomized trials that consistently reported similar efficacy, a lower bleeding risk, and improved convenience when compared with warfarin. We agree with this preference for DOACs in patients with acute VTE, understanding that choosing among anticoagulants frequently depends upon availability and cost as well as patient comorbidities and preferences. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent'.)

SLEEP MEDICINE

CPAP in obstructive sleep apnea does not reduce cardiovascular events (August 2016)

Whether continuous positive airway pressure (CPAP) therapy can reduce the increased risk of cardiovascular morbidity and mortality associated with obstructive sleep apnea (OSA) is unknown. The largest trial to address this issue randomized 2717 patients with moderate to severe OSA and established cardiovascular disease to CPAP therapy plus usual care or usual care alone (eg, education, risk factor modification) and followed patients for 3.7 years [36]. Despite adequate control of OSA, there was no difference in cardiovascular events (eg, cardiovascular deaths, myocardial infarction, or stroke). However, the exclusion of patients who are among the most likely to benefit from CPAP (eg, patients with “sleepy” OSA) and a low adherence rate to therapy (mean was 3.3 hours per night) may have limited the potential benefit from this therapy. While the cardiovascular benefits are unproven, CPAP should be administered for the associated noncardiovascular benefits (eg, improvement in symptoms and quality of life) and should remain the mainstay of therapy for patients with moderate to severe OSA. (See "Obstructive sleep apnea and cardiovascular disease", section on 'Cardiovascular events'.)

Chronic sleep-wake disturbances after traumatic brain injury (July 2016)

Sleep-wake disturbances are very common in the weeks to months following traumatic brain injury (TBI), and a new study suggests that many of these symptoms persist long term. In a prospective case-control study in which 31 patients with TBI of any severity were evaluated at 18 months after injury, 67 percent of patients had evidence of excessive daytime sleepiness on objective testing, compared with only 19 percent of healthy controls [37]. Patients also had persistent pleiosomnia (increased need for sleep), requiring an average of one more hour of sleep per 24 hours than controls. As in earlier studies, patients tended to underestimate their symptoms, emphasizing the importance of both subjective and objective sleep testing in patients with sleep-wake complaints after TBI. (See "Sleep-wake disorders in patients with traumatic brain injury", section on 'Natural history'.)

Prevalence of central sleep apnea in the community (July 2016)

Central sleep apnea (CSA) occurs with increased frequency in patients with heart failure and other comorbid cardiovascular diseases, but the prevalence in the general population has not been well established. In a population-based study of over 5000 community-dwelling adults age 40 years and older who underwent polysomnography, the prevalence of CSA was 0.9 percent [38]. By comparison, obstructive sleep apnea was present in 48 percent of patients. Risks factors for CSA included age older than 65 years, male gender, and self-reported heart failure. Cheyne-Stokes breathing was present in approximately half of patients with CSA. (See "Central sleep apnea: Risk factors, clinical presentation, and diagnosis", section on 'Epidemiology'.)

Clinical practice guideline for chronic insomnia in adults (May 2016)

The American College of Physicians has released a new clinical practice guideline for the management of chronic insomnia in adults [39]. The guideline recommends that all patients receive cognitive behavioral therapy for insomnia (CBT-I) as the initial treatment for chronic insomnia disorder. The guideline suggests that clinicians use a shared decision-making approach, including discussion of benefits, harms, and costs of short-term use of medications, to decide whether to add medication to CBT-I in patients with persistent symptoms. This approach is consistent with our preference for behavioral therapy over medication in most patients with chronic insomnia, particularly in older adults and patients with organ dysfunction, who are at increased risk for side effects from sedative-hypnotic drugs. (See "Treatment of insomnia", section on 'General approach'.)

OTHER PULMONARY MEDICINE

IDSA guidelines on the management of aspergillosis (July 2016)

The Infectious Diseases Society of America released updated guidelines for the treatment of aspergillosis [40,41]. Voriconazole remains the mainstay of therapy for invasive aspergillosis. In contrast with the previous version of the guidelines, the updated version suggests consideration of combination therapy with voriconazole plus an echinocandin for initial therapy of severe invasive aspergillosis, particularly in patients with hematologic malignancy and/or in those with profound and persistent neutropenia. We generally agree with these guidelines and suggest combination therapy with voriconazole plus an echinocandin for patients with severe, microbiologically documented invasive aspergillosis, but we also consider combination therapy for all patients with an immunocompromising condition that led to disease. (See "Treatment and prevention of invasive aspergillosis", section on 'Guidelines'.)

Restriction of fluoroquinolone use in uncomplicated infections (May 2016)

The US Food and Drug Administration (FDA) has stated that the serious adverse effects associated with fluoroquinolones generally outweigh the benefits for patients with uncomplicated acute sinusitis, acute bronchitis, and urinary tract infections who have other treatment options [42]. For patients with these infections, fluoroquinolones should be reserved for those who have no alternative treatment options. This announcement was based on an FDA safety review showing that systemic fluoroquinolone use is associated with disabling and potentially permanent serious side effects, including those involving the tendons, muscles, joints, nerves, and central nervous system. (See "Fluoroquinolones", section on 'Restriction of use for uncomplicated infections'.)

New ACCP guidelines for the treatment of unexplained chronic cough (March 2016)

The American College of Chest Physicians has published new guidelines for the treatment of unexplained chronic cough (defined as cough >8 weeks' duration that is unexplained after systematic investigation and treatment) [43]. The guidelines newly include a suggestion for a therapeutic trial of gabapentin (a central inhibitor of neurotransmitter release). Due to the known adverse effects of gabapentin (eg, somnolence, weakness, diarrhea, and nausea), the initial dose should be 300 mg daily, which can be gradually increased as tolerated to a maximum dose of 900 mg twice daily. (See "Treatment of subacute and chronic cough in adults", section on 'Gabapentin and pregabalin'.)

Treatment of unexplained chronic cough with pregabalin (March 2016)

Like gabapentin, pregabalin is thought to act centrally to inhibit neurotransmitter release. Evidence for its use in chronic cough comes from a randomized trial in which 40 adults with chronic refractory cough were assigned to take pregabalin daily or placebo combined with speech pathology treatment for 14 weeks [44]. Baseline cough frequency was 24 coughs/hour in both groups; spirometry was normal. Both groups experienced a reduction in cough severity and cough frequency, and improvements in cough-related quality of life (QOL). The pregabalin group experienced greater improvement in cough severity and QOL. Adverse effects in the pregabalin group included dizziness in 45 percent and cognitive changes in 30 percent, although these did not lead to discontinuation of the study drug. Four weeks after withdrawal of study medication, there was no deterioration in symptom control. To minimize sedation and dizziness, pregabalin is initiated at a low dose and gradually increased as tolerated over a week. Of note, the American College of Chest Physicians (ACCP) guidelines do not include pregabalin because this study was published after the guidelines were prepared. (See "Treatment of subacute and chronic cough in adults", section on 'Gabapentin and pregabalin'.)

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