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What's new in pulmonary and critical care medicine

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2014. | This topic last updated: Oct 29, 2014.

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

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 [1]. 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 [2]. 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 [3]. 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 [4]. 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'.)

Interplay between allergen and bacterial exposures in the development of asthma (June 2014)

Data have been conflicting about the role of allergen exposure in the development of asthma and recurrent wheeze in children. The Urban Environment and Childhood Asthma (URECA) study assessed allergen exposure in a large birth cohort at high risk for asthma, and also bacterial content of house dust in a nested study of 104 children [5]. Accumulated allergen exposure over the first three years of life was associated with increased allergic sensitization and with recurrent wheeze at age three, but exposure in the first year was negatively associated with recurrent wheeze. Moreover, the combination of early-life exposure to these allergens with high-level exposure to bacteria in house dust was associated with a further reduction in risk of recurrent wheeze by age three. These observations suggest that the effects of early life allergen exposure may differ from those of cumulative exposure and that the combination of high-level allergen and bacterial exposure in early-life may be protective against allergen sensitization and recurrent wheeze. (See "Risk factors for asthma", section on 'Influence of bacterial exposure'.)

An anti-thymic stromal lymphopoietin monoclonal antibody shows promise in allergic asthma (June 2014)

Thymic stromal lymphopoietin (TSLP) is an epithelial-cell-derived cytokine that may play a role in allergic inflammation. In a proof-of-concept study, 31 patients with allergic asthma were randomly assigned to receive the anti-TSLP monoclonal antibody (AMG 157) or placebo intravenously, once a month for three doses [6]. On day 84, patients who received AMG 157 demonstrated significant blunting in their response to inhaled allergen, when compared with those who received placebo. This study provides support for anti-TSLP as a novel therapy for allergic asthma; further studies are planned. (See "Alternative and experimental agents for the treatment of asthma", section on 'Anti-thymic stromal lymphopoietin'.)

Breastfeeding and development of asthma (May 2014)

Studies of breastfeeding are invariably subject to confounding, and data regarding the effects of breastfeeding on the prevention of asthma have been conflicting. In a systematic review and meta-analysis, the strongest protective effect of breastfeeding was seen in the birth to two years age group, in which rates for both "recent asthma" and "asthma ever" were consistently reduced, regardless of duration or exclusivity of breastfeeding [7]. This protective effect decreased with age, which is consistent with findings from individual studies that followed children until adolescence and found that breastfeeding was ultimately not protective against asthma in the highest risk children. The early reduction in asthma-type symptoms is probably due in part to the decreased number of clinically significant respiratory tract infections seen in breastfed infants. (See "The impact of breastfeeding on the development of allergic disease", section on 'Breastfeeding and asthma'.)

COPD

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 [8]. Similar results were seen in a separate pair of trials that included a total of 1266 subjects and lasted 48 weeks [9]. 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'.)

Statin therapy does not reduce COPD exacerbations (June 2014)

In observational studies of chronic obstructive pulmonary disease (COPD), statins have been associated with a reduced rate and severity of exacerbations, rate of hospitalizations, and mortality. However, these beneficial effects were not supported in a trial that randomly assigned 885 participants with COPD, but without other indications or contraindications for statin therapy, to simvastatin or placebo for up to 36 months [10]. Simvastatin did not reduce the rate of exacerbations or the time to first exacerbation. (See "Management of exacerbations of chronic obstructive pulmonary disease", section on 'Ineffective interventions'.)

CRITICAL CARE

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) [11]. 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 [12]. 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'.)

Early goal-directed therapy for sepsis and septic shock (April 2014, MODIFIED October 2014)

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 optimal targets and impact on mortality are unclear. In two multicenter randomized trials involving 1300 patients (ProCESS) [13] and 1600 patients (ARISE) [14], EGDT, compared with usual care, did not improve mortality at 60 days or 90 days. These trials suggest that strict adherence to an aggressive EGDT protocol is not required in patients with severe sepsis. However, the early administration of fluids and antibiotics prior to randomization likely biased the results. A third randomized trial is underway to identify optimal EGDT targets and specific subpopulations of patients who may benefit from more aggressive protocols. (See "Evaluation and management of severe sepsis and septic shock in adults", section on 'Protocol-directed therapy'.)

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) [15]. 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'.)

Palliative care of patients in the intensive care unit (July 2014)

The traditional goals of intensive care unit (ICU) care are to reduce the morbidity and mortality associated with critical illness, maintain organ function, and restore health. When the acute illness or accompanying organ dysfunction is refractory to treatment, these goals of care can no longer be met. When aggressive care is likely to result in outcomes that are not congruent with patient values and preferences, ICU clinicians must ensure that patients die with dignity. A paradigm to assist in the delivery of palliative care to patients dying in the ICU has been developed that is termed the “ABCDs (attitudes, behaviors, compassion, and dialogue) of dignity-conserving care” [16,17]. Practical preparatory procedures to ensure patient comfort and dignity before withdrawal of life support are also available [16]. (See "Palliative care: The last hours and days of life", section on 'Patients dying in the ICU'.)

Intraoperative PEEP (June 2014)

The optimal level of intraoperative positive end-expiratory pressure (PEEP) for mechanically ventilated patients undergoing surgery is unknown. In the PROVHILO trial, 900 patients undergoing abdominal surgery and at moderate risk of pulmonary complications were randomly assigned to receive either high levels (12 cm H2O) or low levels (≤2 cm H2O) of PEEP, administered at a constant tidal volume of 8 mL/kg [18]. The rate of postoperative complications, length of ICU stay, and mortality were no different between the groups. However, patients on high levels of PEEP were more likely to become hypotensive (46 versus 36 percent) and require vasopressor support (62 versus 52 percent). High levels of PEEP intraoperatively do not appear to be of benefit and may be harmful in patients undergoing abdominal surgery, although the level of PEEP used in this study (12 cm H2O) was unusually high, which may have mitigated any potential benefit. Further studies are needed before an optimal level of PEEP can be recommended in this population. (See "Positive end-expiratory pressure (PEEP)", section on 'Intraoperative patients'.)

Heparin-induced thrombocytopenia-like syndrome in the absence of heparin exposure (spontaneous HIT) (June 2014)

Heparin-induced thrombocytopenia (HIT) is a rare, potentially life-threatening condition in which exposure to heparin induces an autoantibody to a platelet protein (platelet factor 4), which can cause catastrophic arterial and venous thrombosis along with thrombocytopenia. Reports have emerged of a HIT-like syndrome in the absence of heparin exposure, often in patients with a preceding infection or surgery. Criteria for this syndrome, termed “spontaneous HIT,” include clinical features of HIT without prior heparin exposure, a strongly positive immunoassay for HIT antibodies, and a positive functional assay for platelet activation by patient serum in the absence of heparin [19]. Patients with any form of HIT require immediate administration of a non-heparin anticoagulant. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'No prior heparin exposure (spontaneous HIT)'.)

Video laryngoscopy for tracheal intubation of the critically ill (June 2014)

While the use of video laryngoscopes for emergency airway management continues to grow, evidence of their effectiveness in critically ill patients has been limited. However, according to a recent meta-analysis of nine trials involving 2133 patients requiring tracheal intubation in the intensive care unit, video laryngoscopy reduced the rate of difficult intubation (odds ratio [OR] 0.29) and increased the rate of first-attempt success (OR 2.07), a factor associated with reduced complication rates [20]. This meta-analysis supports the use of video laryngoscopes for intubating critically ill patients in the intensive care unit and emergency department. (See "Devices for difficult emergency airway management in adults", section on 'Video laryngoscopes'.)

INTERSTITIAL LUNG DISEASE

N-Acetylcysteine not helpful in idiopathic pulmonary fibrosis (June 2014)

Excess production of oxidants is thought to contribute to lung injury in idiopathic pulmonary fibrosis (IPF), and the antioxidant agent N-Acetylcysteine (NAC) showed promise in previous studies of IPF. However, in the PANTHER trial, monotherapy with NAC did not slow the decline in forced vital capacity (FVC) over 60 weeks compared with placebo [21,22]. Furthermore, NAC did not reduce deaths or acute exacerbations, but appeared to increase the rate of serious cardiac adverse events. We have consequently revised our prior suggestion in favor of oral NAC and no longer advise use of NAC for these patients. (See "Treatment of idiopathic pulmonary fibrosis", section on 'N-Acetylcysteine'.)

Nintedanib slows decline in lung function in idiopathic pulmonary fibrosis (June 2014)

Nintedanib is a tyrosine kinase inhibitor with activity against multiple growth factors that have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In two trials (INPULSIS-1 and INPULSIS-2), over 1000 patients with IPF were randomly assigned to nintedanib or placebo for 52 weeks [23]. The rate of decline in forced vital capacity (FVC) was significantly lower in the nintedanib group than the placebo group in both trials. In one of the trials (INPULSIS-2), the time to first exacerbation was also decreased with nintedanib. Nintedanib is not commercially available at present, although it is under review by regulatory agencies. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib'.)

Pirfenidone slows disease progression in idiopathic pulmonary fibrosis (June 2014)

Idiopathic pulmonary fibrosis (IPF) has previously been refractory to trials of numerous medications. In the ASCEND trial, 555 patients with mild-to-moderate IPF were randomly assigned to receive the antifibrotic oral agent pirfenidone or placebo for 52 weeks [24]. Pirfenidone resulted in a significant reduction in the one-year rate of decline in forced vital capacity (FVC). In addition, pirfenidone was associated with a reduction in mortality. The efficacy of pirfenidone in more advanced disease has not been assessed. Although not commercially available in the United States, it is available elsewhere and is under review by the US Food and Drug Administration. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Pirfenidone'.)

LUNG CANCER

Combination chemotherapy for patients with a late relapse of small cell lung cancer (June 2014)

Treatment of patients with relapsed small cell lung cancer is a difficult problem that is usually managed with single agent chemotherapy. In a randomized phase III trial in patients with a sensitive relapse (ie, more than 90 days after completion of their initial combination chemotherapy), treatment with a platinum-based combination regimen significantly increased overall and progression-free survival [25]. However, severe hematologic toxicity was increased. For patients with a sensitive relapse, treatment with the original platinum-based combination or a novel platinum-based combination can be considered. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Combination chemotherapy'.)

PULMONARY VASCULAR DISEASE

Mortality benefit for thrombolysis in patients with acute pulmonary embolus (June 2014)

Thrombolytic therapy is of uncertain benefit in patients with pulmonary embolus (PE). A meta-analysis of 16 trials reported that, compared to anticoagulation alone, thrombolytic therapy was associated with a lower all-cause mortality (2.2 versus 3.9 percent) and a reduced rate of recurrent thromboembolism (1.2 versus 3.0 percent) [26]. However, it increased the risk of major hemorrhage (9.2 versus 3.4 percent) including intracranial hemorrhage (1.5 versus 0.2 percent). No mortality benefit was reported in older patients (>65 years), a population in whom the risk of hemorrhage was greatest. The data were not robust for any one specific patient population, nor was the optimal agent, dose, or method of delivery identified. Thus, the routine administration of thrombolytic therapy for patients with PE remains questionable and the decision to administer it should continue to be made on an individual patient basis. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Mortality'.)

Guidelines for pulmonary hypertension in sickle cell disease (May 2014)

The American Thoracic Society has released a clinical practice guideline regarding the diagnosis, risk stratification, and management of pulmonary hypertension (PH) associated with sickle cell disease (SCD) [27]. As symptom recognition is often delayed in PH complicating SCD, the guidelines suggest obtaining a baseline transthoracic Doppler echocardiogram in children ≥8 years old and recommend that Doppler echocardiograms be performed in adults every one to three years. A tricuspid regurgitant jet velocity (TRV) of ≥2.5 m/sec is indicative of increased morbidity in children and mortality in adults and requires further evaluation. (See "Pulmonary hypertension associated with sickle cell disease", section on 'Screening and risk stratification'.)

SLEEP MEDICINE

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 [28]. 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 [29,30]. 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'.)

Next-day impairment with insomnia drug eszopiclone (June 2014)

In 2014, the US Food and Drug Administration warned that the nonbenzodiazepine hypnotic eszopiclone in doses of 2 or 3 mg at bedtime may impair driving skills, memory, and coordination for more than 11 hours, without subjective awareness in some patients [31]. Eszopiclone has the longest half-life (6 to 9 hours) among hypnotics of this class (eg, zolpidem, zaleplon). Because of the potential for next-day impairment, a starting dose of 1 mg is now recommended in all patients. (See "Treatment of insomnia", section on 'Dosing precautions'.)

OTHER PULMONARY MEDICINE

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 [32]. 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.

(See "Cystic fibrosis: Antibiotic therapy for lung disease", section on 'Infection prevention and control'.)

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 [33]. 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'.)

Cardiovascular outcomes and azithromycin use for pneumonia (June 2014)

Large observational studies have shown conflicting results with regards to a possible increase in cardiovascular mortality associated with azithromycin use. A more recent large cohort study evaluated the association between azithromycin use and all-cause mortality and cardiovascular events in more than 60,000 United States veterans ≥65 years of age who were hospitalized with pneumonia [34]. Ninety-day mortality was significantly lower in those who were treated with an azithromycin-containing regimen versus those who received other guideline-concordant antibiotics. Compared with patients who did not receive azithromycin, those who received azithromycin were slightly more likely to have a myocardial infarction, but not arrhythmias, heart failure, or any cardiac event. An analysis of these data suggested that seven deaths were averted for each non-fatal myocardial infarction associated with azithromycin use, reflecting a net benefit of azithromycin for patients ≥65 years of age with pneumonia. (See "Azithromycin, clarithromycin, and telithromycin", section on 'QT interval prolongation and cardiovascular events'.)

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