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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: Jul 2014. | This topic last updated: Aug 25, 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.


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 [1]. 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 [2]. 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 [3]. 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'.)


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 [4]. Similar results were seen in a separate pair of trials that included a total of 1266 subjects and lasted 48 weeks [5]. 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 [6]. 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'.)


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” [7,8]. Practical preparatory procedures to ensure patient comfort and dignity before withdrawal of life support are also available [7]. (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 [9]. 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 [10]. 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 [11]. 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'.)

Early goal-directed therapy for sepsis and septic shock (April 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 have not been determined. A multicenter trial (ProCESS) randomly assigned over 1300 patients with septic shock to one of three arms: the EGDT-based protocol using targets from an earlier trial; a less aggressive EGDT protocol; or usual care [12]. There was no difference in 60-day mortality between the groups, suggesting that strict adherence to the aggressive EGDT protocol is not required in patients with severe sepsis. There are several potential explanations for these results, and further randomized trials are 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'.)

Lower infectious risk with restrictive blood transfusion strategy (April 2014)

A restrictive blood transfusion strategy (eg, transfusion at a hemoglobin level of 7 to 8 g/dL) is associated with a trend towards lower mortality compared with a liberal strategy (transfusion for a hemoglobin level <10 g/dL) in many medical and surgical settings. A new meta-analysis of randomized trials found that a restrictive, compared with a liberal, strategy was associated with a lower risk of serious infections (12 versus 17 percent, respectively) in hospitalized patients [13]. The greatest benefit was seen in patients undergoing orthopedic surgery and those who presented with sepsis. The safety of restrictive transfusion in patients with acute coronary syndromes (eg, myocardial infarction) has not been evaluated adequately, and higher thresholds may be needed in this population. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Overview of our approach'.)

Decreased mortality from sepsis (March 2014)

Several studies have suggested that mortality from sepsis is decreasing, although most have been limited by size or other factors and did not constitute high-quality evidence. Using an internationally-accepted, standardized definition of sepsis, a 12-year multicenter study of over 100,000 patients in Australia and New Zealand with severe sepsis and septic shock reported a 50 percent risk reduction (35 to 18 percent) in in-hospital mortality between 2000 and 2012 [14]. This study, together with reports of improved compliance with treatment guidelines, suggests that the reduction in mortality is authentic and possibly due to improved therapeutic strategies for sepsis recognition and management. (See "Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis", section on 'Mortality and prognosis'.)

FDA warning about doripenem for ventilator-associated pneumonia (March 2014)

In 2014, the US Food and Drug Administration (FDA) approved revisions to the doripenem label warning clinicians about increased mortality rates in patients who received doripenem rather than imipenem for ventilator-associated bacterial pneumonia, based on results of a randomized trial that was stopped early due to safety concerns [15]. In the intention-to-treat population of the trial, 28-day all-cause mortality was higher and clinical response rates were lower among patients receiving doripenem than in those receiving imipenem, although different dosing regimens and use of adjunctive aminoglycosides may have influenced these results [16]. Doripenem is not approved by the FDA for the treatment of pneumonia. (See "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on 'Gram-negative pathogens'.)


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 [17,18]. 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 [19]. 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 [20]. 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'.)


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 [21]. 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'.)


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) [22]. 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) [23]. 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'.)

Thrombolytic therapy for acute pulmonary embolus and right ventricular dysfunction (April 2014)

The administration of thrombolytic therapy to patients with acute pulmonary embolus (PE) and right ventricular (RV) dysfunction is controversial. One multicenter trial (PEITHO) randomized 1005 patients with acute PE and RV dysfunction to receive intravenous thrombolytic therapy (tenecteplase) plus heparin or placebo plus heparin [24]. Compared with heparin alone, tenecteplase resulted in a reduction in death or hemodynamic decompensation at seven days following randomization (6 versus 3 percent). Subgroup analysis suggested that the benefits were largely driven by preventing decompensation and not by mortality. However, the addition of tenecteplase was associated with statistically-significant increases in hemorrhagic stroke (2.0 versus 0.2 percent), extracranial bleeding, and major bleeding. This trial suggests that while thrombolytic therapy prevents further hemodynamic collapse in patients with acute PE and RV dysfunction, the high risk of hemorrhage will prevent its routine administration. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Right ventricle dysfunction'.)

Age-adjusted D-dimer for the diagnosis of pulmonary embolism (April 2014)

D-dimer levels are frequently used in diagnostic algorithms for pulmonary embolism (PE). However, levels rise with age, resulting in limited specificity in older populations (>50 years). In a prospective multicenter trial (ADJUST-PE) of over 3000 patients with suspected PE, age-adjusted D-dimer cutoffs were used in conjunction with clinical probability to stratify patients for observation or for diagnostic imaging [25]. In patients with a low pretest probability for PE, use of an age-adjusted D-dimer, compared with a fixed D-dimer cutoff level of <500 mg/mL, was associated with a similar low rate of subsequent symptomatic thromboembolic events at three months, and an increased proportion of patents in whom the diagnosis could be excluded without imaging (40 versus 20 percent). While use of age-adjusted D-dimer levels is promising, further validation is warranted before they can be routinely applied in clinical practice for the diagnostic evaluation of PE. (See "Diagnosis of acute pulmonary embolism", section on 'CT pulmonary angiography-based algorithms'.)

Thrombotic risk postpartum (February 2014)

In postpartum women, the risk of venous thrombosis is highest during the first six weeks, but less is known about when the risk returns to baseline. A five-year retrospective analysis of almost 1.7 million women examined rates of thrombosis during the first year following delivery, comparing various postpartum time periods to a six-week period one year later [26]. Risk of a thrombotic event was 11 times higher in the first six weeks postpartum (25 per 100,000 deliveries) and abruptly declined by 7 to 12 weeks (6 per 100,000 deliveries), returning to baseline by 13 to 18 weeks (2 per 100,000). Thus, the risk of thrombosis postpartum persisted beyond six weeks but absolute rates were low in weeks 7 to 18. These results support current practice of postpartum thromboembolism prophylaxis in select populations for a minimum of six weeks with extended prophylaxis for longer periods in those at higher risk. (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis", section on 'Timing during pregnancy'.)


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 [27]. 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 [28,29]. 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 [30]. 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'.)

Pregabalin versus pramipexole for the treatment of restless legs syndrome (February 2014)

Two major classes of drugs are used to treat restless legs syndrome (RLS) in adults: dopamine agonists and alpha-2-delta calcium channel ligands. Both classes have been shown to be effective compared with placebo, but the classes have not been compared head-to-head. In a randomized trial that included over 700 adults with RLS, both pregabalin and pramipexole reduced the symptom burden of RLS more than placebo but augmentation, a complication of dopaminergic therapy that can limit long-term effectiveness, occurred less frequently with pregabalin [31]. Overall, however, pregabalin was less well tolerated than pramipexole, leading to a higher rate of treatment discontinuation due to side effects. More comparative trials are needed to better understand the long-term safety and tolerability profile of treatment options for RLS. (See "Treatment of restless legs syndrome in adults", section on 'Pregabalin'.)


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 [32]. 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 [33]. 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'.)

Acid suppression and pneumonia (March 2014)

Previous observational studies reported an association between proton pump inhibitor (PPI) use and community acquired pneumonia (CAP), but a new meta-analysis suggests the observation might have been due to confounding. The meta-analysis included eight cohort studies with over 4 million new users of nonsteroidal antiinflammatory drugs (NSAIDs), of which nearly 100,000 were treated prophylactically with PPIs and about 50,000 were treated with histamine 2 receptor antagonists (H2RAs) [34]. On adjusted analysis, neither the use of PPIs nor H2RAs was associated with an increased risk of hospitalization for CAP during the six months following initiation of NSAIDs. (See "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders", section on 'Pneumonia'.)

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