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CHEST publishes select peer-reviewed, accepted manuscripts Online First each week. The media embargo is lifted on the date of Online First publication. Final, edited versions will appear in a numbered issue of CHEST and may contain substantive changes. We encourage readers to check back for the final article. Online First papers are indexed in PubMed and by search engines, but the information, including the final title and author list, may be updated on final publication.

original research 
Martin B. Brodsky, PhD, ScM; Debra M. Suiter, PhD; Marlís González-Fernández, MD, PhD; Henry J. Michtalik, MD, MPH, MHS; Tobi B. Frymark, MA; Rebecca Venediktov, MS; Tracy Schooling, MA
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Background  Hospitalizations for aspiration pneumonia have doubled among the elderly. Using a bedside water swallow test (WST) to screen for swallowing-related aspiration can be efficient and cost-effective for preventing additional comorbidities and mortality. We evaluated screening accuracy of bedside WSTs used to identify patients at risk for dysphagia-associated aspiration.

Methods  Sixteen online databases, Google Scholar, and known content experts through May 2015 were searched. Only prospective studies with patients ≥18 years old given WST screenings validated against nasoendoscopy or videofluoroscopy were included. Data extraction used dual masked extraction and quality assessment following MOOSE guidelines.

Results  Airway response (e.g., coughing/choking) with or without voice changes (e.g., wet/gurgly voice quality) was used to identify aspiration during 3 different bedside WSTs. Pooled estimates for single sip volumes (1-5 ml) were 71% sensitive (95%CI, 63%-78%) and 90% specific (95%CI, 86%-93%). Consecutive sips of 90-100 ml trials were 91% sensitive (95%CI, 89%-93%) and 53% specific (95%CI, 51%-55%). Trials of progressively increasing volumes of water were 86% sensitive (95%CI, 76%-93%) and 65% specific (95%CI, 57%-73%). Airway response with voice change improved overall accuracy in identifying aspiration.

Conclusion  Currently used bedside WSTs offer sufficient, although not ideal, utility in screening for aspiration. Consecutive sips with large volumes in patients who did not present with overt airway responses or voice changes appropriately ruled out risk of aspiration. Small volumes with single sips appropriately ruled in aspiration when clinical signs were present. Combining these bedside approaches may offer improved screening accuracy, but further research is warranted.

original research 
Leah Jayes; Patricia L. Haslam; Christina G. Gratziou; Pippa Powell; John Britton; Constantine Vardavas; Carlos Jimenez-Ruiz; Jo Leonardi-Bee

Background  Smoking tobacco increases the risk of respiratory disease in adults and children, but communicating the magnitude of these effects in a scientific manner that is accessible and usable by public and policymakers presents a challenge. We have therefore summarised scientific data on the impact of smoking on respiratory diseases to provide the content for a unique resource, SmokeHaz.

Methods  We conducted systematic reviews and meta-analyses of longitudinal studies (published to 2013) identified from electronic databases, grey literature, and experts. Random effect meta-analyses were used to pool the findings.

Results  We included 216 papers. Among adult smokers, we confirmed substantially increased risks of lung cancer (Risk Ratio (RR) 10.92, 95% CI 8.28-14.40; 34 studies), COPD (RR 4.01, 95% CI 3.18-5.05; 22 studies) and asthma (RR 1.61, 95% CI 1.07-2.42; 8 studies). Exposure to passive smoke significantly increased the risk of lung cancer in adult non-smokers; and increased the risks of asthma, wheeze, lower respiratory infections, and reduced lung function in children. Smoking significantly increased the risk of sleep apnoea, and asthma exacerbations in adult and pregnant populations; and active and passive smoking increased the risk of tuberculosis.

Conclusions  These findings have been translated into easily digestible content and published on the SmokeHaz website (www.smokehaz.eu).

original research 
Shuoyan Ning, MD; Rebecca Barty, MSc; Yang Liu, MMath; Nancy M. Heddle, MSc; Bram Rochwerg, MD; Donald M. Arnold, MD
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Background  Platelet transfusions are commonly used in critically ill patients, but transfusion thresholds, count increments, and predictors of ineffectual transfusions remain unclear.

Methods  This retrospective study included consecutive adult non-oncology patients who received platelet transfusions in intensive care units (ICU) in 3 Canadian academic hospitals between 2006 and 2015. Data were collected from a validated transfusion database. We determined independent predictors of ineffectual platelet transfusions, defined as transfusions that raised platelet counts by < 5 x109/L. Reasons for transfusion were adjudicated in a subgroup of patients who were transfused despite normal platelet counts.

Results  We identified 7,320 ICU admissions (n=7,073 patients) during which 15,879 platelet transfusions were administered. Most admissions (78.7%) were for cardiac surgery. Based on 5,700 analyzable transfusions, median pre-transfusion platelet count was 87 x109/L [interquartile range (IQR) 57-130]. For 79.6% and 17.8% of transfusions, pre-transfusion platelet count was ≥50 x109/L and ≥150 x109/L, respectively. Reasons for transfusion despite normal platelet count were active bleeding or surgery in patients receiving anti-platelet agents or anticoagulants. Median platelet count increment was 23 x109/L (IQR 7-44); and 21.8% of transfusions were ineffectual. ABO incompatibility, sepsis, liver disease, red cell and cryoprecipitate transfusion were associated with poor count increment.

Conclusions  Platelet transfusions were commonly used in ICU when platelet counts were ≥50 x109/L. One platelet transfusion increased platelet count by 23 x109/L. One in 5 transfusions was ineffectual and ABO incompatibility was identified as a modifiable risk factor. These data can help direct efforts to reduce platelet overuse and improve transfusion quality.

original research 
Béla Nagy, Jr., MD, PhD; Béla Nagy, MD, PhD; Libor Fila, MD; Luka A. Clarke, PhD; Ferenc Gönczy, MD; Olga Bede, MD, PhD; Dóra Nagy, MD; Rita Újhelyi, MD, PhD; Ágnes Szabó, MD; Andrea Anghelyi, MD; Miklós Major, MD; Zsolt Bene, MD; Zsolt Fejes, MSc; Péter Antal-Szalmás, MD, PhD; Harjit Pal Bhattoa, MD, PhD; György Balla, MD, PhD; János Kappelmayer, MD, PhD; Margarida D. Amaral, PhD; Milan Macek, Jr., MD, PhD; István Balogh, PhD
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Background  Increased expression of the human epididymis protein 4 (HE4) was previously described in lung biopsy samples from cystic fibrosis (CF) patients, but it has remained unknown whether serum HE4 concentrations are elevated in CF.

Methods  Seventy-seven children with CF from six Hungarian CF centers and 57 adult CF patients from a Czech center were enrolled. In addition, 94 individuals with non-CF lung diseases, and 117 normal controls without pulmonary disorders were analyzed. Serum HE4 was measured by an immunoassay and its expression was further investigated via the quantification of HE4 mRNA using RT-qPCR in CF versus non-CF respiratory epithelium biopsies. The expression of the potential regulator miR-140-5p was analyzed using an UPL-based RT-qPCR assay. HE4 was measured in the supernatants from unpolarized and polarized cystic fibrosis bronchial epithelial (CFBE) cells expressing wt- or F508del-CFTR.

Results  Serum HE4 levels were significantly elevated in children with CF (99.5 [73.1-128.9] pmol/L) compared to controls (36.3 [31.1-43.4] pmol/L; P<0.0001). This observation was replicated in CF adults (115.7 [77.8-148.7] pmol/L; P<0.0001). In contrast, abnormal but lower HE4 concentrations were found in cases of severe bronchitis, asthma, pneumonia or bronchiectasis. In CF patients, the concentrations of HE4 were positively correlated with overall disease severity and C-reactive protein concentrations, while a significant inverse relationship was found between HE4 and the spirometric FEV1 value. Relative HE4 mRNA levels were significantly upregulated (P=0.011) with a decreased miR-140-5p expression (P=0.020) in the CF versus non-CF airway biopsies. There were 2-fold higher HE4 concentrations in the supernatant of polarized F508del-CFTR CFBE cells compared to wt cells.

Conclusions  HE4 serum levels positively correlate with the overall severity of CF and the degree of pulmonary dysfunction. HE4 may thus be utilized as novel inflammatory biomarker and possibly also as measure of treatment efficacy in CF lung disease.

recent advances in chest medicine 
Julie Morisset, M.D.; Cheilonda Johnson, M.D.; Eric Rich, M.D.; Harold R. Collard, M.D., FCCP; Joyce S. Lee, M.D.
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Interstitial lung disease (ILD) is a frequent pulmonary manifestation and an important cause of morbidity and mortality in patients with idiopathic inflammatory myopathy. Myositis related ILD presents a therapeutic challenge for clinicians, as there are no available guidelines to help with management decisions. This review covers the existing evidence on the pharmacologic and non-pharmacologic management of myositis related ILD, highlighting the lack of randomized controlled data to guide treatment. Given the absence of existing guidelines to inform treatment decisions, we provide a comprehensive summary, including dosing, side effects, and suggested monitoring, of the commonly used immunosuppressive agents and a proposed treatment algorithm, based on the existing literature.

original research 
Scott T. Micek, PharmD; Bethany Chew; Nicholas Hampton, PharmD; Marin H. Kollef, MD
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Background  Non-ventilated hospital-acquired pneumonia (NVHAP) is a serious nosocomial infection increasingly attributed to antibiotic-resistant bacteria.

Methods  A retrospective case-control study comparing patients with and without NVHAP from 1 January 2014 to 31 December 2014 at Barnes-Jewish Hospital, a 1300-bed urban academic medical center in St. Louis, Missouri.

Results  174 consecutive patients with NVHAP were enrolled. A random sample of 696 control patients matched on age, gender, race, and hospital admission date were selected from a total of 5322 potential matched controls. NVHAP was pathogen-negative in 98 cases (56.3%). Respiratory viruses were identified in 42 (24.1%) patients, Gram-negative bacteria in 25 (14.4%) patients, and Gram-positive bacteria in 20 (11.5%) patients. Individuals developing NVHAP were more likely to die (15.5% versus 1.6%; P < 0.01), require intensive care (56.3% versus 22.8%; P < 0.01), mechanical ventilation (19.0% versus 3.9%; P < 0.01), and to have longer hospital length of stay (15.9 days [9.8 days, 26.3 days] versus 4.4 days [2.9 days, 7.3 days]; P < 0.01). The case-control study identified a strong association between hospital mortality and NVHAP, with NVHAP patients having an 8.4 times greater odds of death (95% CI, 5.6 – 12.5).

Conclusions  The occurrence of NVHAP was associated with significant increases in mortality, the use of intensive care, mechanical ventilation, and hospital length of stay. We also found that respiratory viruses were an important etiology of NVHAP. These findings suggest that efforts aimed at the successful prevention of NVHAP could improve patient outcomes and reduce health care costs.

original research 
Wesley H. Self, MD, MPH; Carlos G. Grijalva, MD, MPH; Derek J. Williams, MD, MPH; Alison Woodworth, PhD; Robert A. Balk, MD; Sherene Fakhran, MD; Yuwei Zhu, MD, MS; D. Mark Courtney, MD, MSCI; James Chappell, MD, PhD; Evan J. Anderson, MD; Chao Qi, PhD; Grant W. Waterer, MD, PhD; Christopher Trabue, MD; Anna M. Bramley, MPH; Seema Jain, MD; Kathryn M. Edwards, MD; Richard G. Wunderink, MD
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Background  Predicting intensive care need among adults with community-acquired pneumonia (CAP) remains challenging.

Methods  Using a multicenter prospective cohort study of adults hospitalized with CAP, we evaluated the association of serum procalcitonin concentration at hospital presentation with the need for invasive respiratory and/or vasopressor support (IRVS) within 72 hours. Logistic regression was used to model this association, with results reported as the estimated risk of IRVS for a given procalcitonin concentration. We also assessed whether the addition of procalcitonin changed the performance of established pneumonia severity scores, including the pneumonia severity index and American Thoracic Society minor criteria, for prediction of IRVS.

Results  Of 1770 enrolled patients, 115 (6.5%) required IRVS. Using the logistic regression model, procalcitonin concentration had a strong association with IRVS risk. Undetectable procalcitonin (<0.05 ng/ml) was associated with a 4.0% (95% CI: 3.1%, 5.1%) risk of IRVS. For concentrations <10 ng/ml, procalcitonin had an approximate linear association with IRVS risk; for each 1 ng/ml increase in procalcitonin, there was a 1-2% absolute increase in the risk of IRVS. With a procalcitonin concentration of 10 ng/ml, the risk of IRVS was 22.4% (95% CI: 16.3%, 30.1%) and remained relatively constant for all concentrations > 10 ng/ml. When added to each pneumonia severity score, procalcitonin contributed significant additional risk information for prediction of IRVS.

Conclusions  Serum procalcitonin concentration was strongly associated with the risk of requiring IRVS among adults hospitalized with CAP and is potentially useful for guiding decisions about intensive care unit admission.

original research 
Borja G. Cosío; Hanna Shafiek; Amanda Iglesias; Aina Yanez; Rocio Cordova; Alexandre Palou; Robert Rodriguez-Roisin; German Peces-Barba; Sergi Pascual; Joaquim Gea; Oriol Sibila; Peter J. Barnes; Alvar Agusti
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Background  Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation. In vitro and ex-vivo observations suggest that this inflammatory response is partially resistant to the effect of corticosteroids, and that low-dose theophylline can restore this response via enhancement of histone deacetylase activity (HDAC). Whether or not this occurs in vivo, and what are its potential clinical consequences is unclear.

Objective  To determine if low-dose theophylline on top of inhaled long-acting beta-agonists /corticosteroids (ICS) treatment in COPD patients: (1) enhances HDAC activity and the anti-inflammatory effects of ICS in vivo; (2) reduces the concentration of inflammatory markers; and, (3) reduces exacerbation frequency.

Methods  In this prospective, double-blind, placebo-controlled clinical trial, we randomized COPD patients (FEV1<50% predicted plus at least one hospitalization due to exacerbation in the previous year) to ICS plus theophylline 100 mg bid or matched placebo. We determined at baseline and at the end of 52 weeks follow-up: (1) HDAC activity in blood monocytes and sputum macrophages; (2) the concentration of several inflammatory markers (interleukin (IL)-8, IL-6, IL-1β and tumour necrosis factor alpha (TNFα)) in serum and sputum supernatant; and, (3) the rate of exacerbations and side effects.

Results  70 patients were randomized, 36 in the theophylline and 34 in the placebo arm. HDAC activity and levels of the inflammatory markers were not different in both arms either at baseline or after 52 weeks. Likewise, the rate of exacerbations during follow-up was similar in both groups.

Conclusions  The combination of low dose oral theophylline and ICS does not enhance the anti-inflammatory properties of ICS in vivo nor influence exacerbation rate.

original research 
Roberto Carnevale, PhD; Sebastiano Sciarretta, MD; Francesco Violi, MD; Cristina Nocella, PhD; Lorenzo Loffredo, MD; Ludovica Perri, MD; Mariangela Peruzzi, MD, PhD; Antonino G.M. Marullo, MD, PhD; Elena De Falco, PhD; Isotta Chimenti, PhD; Valentina Valenti, MD; Giuseppe Biondi-Zoccai, MD, MStat; Giacomo Frati, MD, MSc
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Background  The vascular safety of electronic cigarettes still needs to be clarified. We compared the impact of electronic cigarettes versus traditional cigarettes on oxidative stress and endothelial function in healthy smokers and non-smoker adults.

Methods  We performed a cross-over single-blind study in 40 healthy subjects (20 smokers, 20 non-smokers, matched for age and sex). Firstly, all subjects smoked T-cigarettes. One week later the same subjects smoked an E-cigarette with the same nominal nicotine content. Blood samples were drawn just before and after smoking and markers of oxidative stress, nitric oxide bioavailability and vitamin E levels were measured. Flow-mediated dilatation (FMD) was also measured.

Results  Smoking both electronic cigarettes and traditional cigarettes led to a significant increase of the levels of sNox2-dp, 8-isoPGF2α and to a significant decrease of NO bioavailability, vitamin E levels and FMD. Generalizing estimating equation analysis confirmed that all markers of oxidative stress and FMD were significantly affected by smoking and showed that the biologic effects of electronic cigarettes versus traditional cigarettes on vitamin E levels (p=0.413) and FMD (p=0.311) were not statistically different. On the other hand, electronic cigarettes appeared to have a lesser impact than traditional cigarettes on levels of sNox2-dp (p=0.001), 8-isoPGF2α (p=0.046) and NO bioavailability (p=0.001).

Conclusions  Our study demonstrates that both cigarettes have unfavorable effects on markers of oxidative stress and FMD after single use, although E-cigarette appeared to have a lesser impact. Future studies are warranted to clarify the chronic vascular effects of E-cigarette smoking.

original research 
Joaquin Sanchis, Prof.; Ignasi Gich, Dr.; Soren Pedersen, Prof.

Background  Problems with the use of inhalers by patients were noted shortly after the launch of the metered dose inhaler (MDI) and persist today. We aimed to assess the most common errors in inhaler use over the last 40 years in patients treated with MDI or dry powder inhalers (DPI).

Methods  A systematic search for articles reporting direct observation of inhaler technique by trained personnel covered the period 1975 to 2014. Outcomes were nature and frequencies of the three most common errors; the percentage of patients demonstrating correct, acceptable, or poor technique; and variations in these outcomes over these 40 years and when partitioned into years 1–20 and 21–40. Analyses were conducted in accordance with PRISMA and STROBE recommendations.

Results  Data were extracted from 144 articles reporting on a total number of 54 354 subjects performing 59 584 observed tests of technique. The most frequent MDI errors were in co-ordination (45% (95% CI 41–49%)), speed and/or depth of inspiration (44% (40–47%)), and no post-inhalation breath-hold (46% (42–49%)). Frequent DPI errors were incorrect preparation in 28% (26–33%), no full expiration before inhalation in 46% (42–50%), and no post-inhalation breath-hold in 37% (33–40%). The overall prevalence of correct technique was 31% (28–35%); of acceptable, 41% (36–47%); and of poor, 31% (27–36%). There were no significant differences between the first and second twenty-year periods of scrutiny.

Conclusions  Incorrect inhaler technique is unacceptably frequent and has not improved over the past 40 years, pointing to an urgent need for new approaches to education and drug delivery.

original research 
Catia Cillóniz, PhD; Albert Gabarrús, MSc; Miquel Ferrer, MD; Jorge Puig de la Bellacasa, MD; Mariano Rinaudo; Josep Mensa, MD; Michael S. Niederman, MD; Antoni Torres, MD
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Background  Pseudomonas aeruginosa is not a frequent pathogen in Community Acquired Pneumonia (CAP). However, in patients with severe CAP, P. aeruginosa can be the etiology in 1.8% to 8.3% of patients, with a case-fatality rate of 50% to 100%. We describe the prevalence, clinical characteristics, outcomes and risk factors associated with CAP due to multidrug and non-multidrug resistant P. aeruginosa.

Methods  Prospective observational study of 2023 consecutive adult CAP patients with definitive etiology.

Results  P. aeruginosa was found in 77 (4%) of the 2023 cases with microbial etiology. In 22 (32%) of the 68 cases of P. aeruginosa with antibiogram data, the isolates were multidrug-resistant (MDR). Inappropriate therapy was present in 49 (64%) cases of P. aeruginosa CAP, including 17/22 (77%) cases of MDR P. aeruginosa CAP. Male sex, chronic respiratory disease, C-reactive protein <12.35 mg/dL, and PSI risk class IV – V were independently associated with P. aeruginosa CAP. Prior antibiotic treatment was more frequent in MDR P. aeruginosa CAP compared with non-MDR P. aeruginosa (58% vs. 29%, p=0.029), and was the only risk factor associated with CAP due to MDR P. aeruginosa. In the multivariate analysis, age ≥65 years, CAP due to P. aeruginosa, chronic liver disease, neurologic disease, nursing-home, criteria of ARDS, acute renal failure, ICU admission, and inappropriate empiric treatment were the factors associated with 30-day mortality.

Conclusions  P. aeruginosa is an individual risk factor associated with mortality in CAP. The risk factors described can help clinicians to suspect P. aeruginosa and MDR P. aeruginosa.

contemporary reviews in critical care medicine 
Mallar Bhattacharya, MD; Richard H. Kallet, MS, RRT; Lorraine B. Ware, MD; Michael A. Matthay, MD

Negative pressure pulmonary edema (NPPE) or post-obstructive pulmonary edema is a well-described cause of acute respiratory failure that occurs after intense inspiratory effort against an obstructed airway, usually from upper airway infection, tumor, or laryngospasm. Patients with NPPE generate very negative airway pressures, which augment transvascular fluid filtration and precipitate interstitial and alveolar edema. Pulmonary edema fluid collected from most patients with NPPE has a low protein concentration, suggesting hydrostatic forces as the primary mechanism for the pathogenesis of NPPE. Supportive care should be directed at relieving the upper airway obstruction with endotracheal intubation or cricothyroidotomy, institution of lung protective positive pressure ventilation, and diuresis unless the patient is in shock. Resolution of the pulmonary edema is usually rapid, in part because alveolar fluid clearance mechanisms are intact. In this review, we discuss the clinical presentation, pathophysiology, and management of negative pressure or post-obstructive pulmonary edema.

contemporary reviews in critical care medicine 
Hollis R. O'Neal, Jr., MD, MSc; Alexander S. Niven, MD; George H. Karam, MD
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The critically ill, asplenic patient presents a variety of management challenges. Historically, the focus of the care of the asplenic population has been the prevention and management of infection, including the often-fatal overwhelming post-spenectomy infection with encapsulated organisms such as Streptococcus pneumoniae. Recently, however, there has been increasing recognition of the spleen’s function in areas outside of immunity, as the asplenic state has been recognized as a risk factor for such vascular complications as thrombosis and pulmonary hypertension due to dysregulated inflammation and coagulation. Because of the relatively small size of this population and the relative infrequency with which critical illness occurs in it, there are few controlled trials which can serve as a basis for therapeutic maneuvers; thus, optimal management requires an astute clinician with an understanding of the pathogenetic mechanisms underlying the reported consequences of splenectomy. The purpose of this review is to explore the pathophysiology of the asplenic state – impairment in adaptive immunity, loss of blood filtration, endothelial dysfunction, and dysregulated coagulation – and how it leads to infection, thrombosis, and pulmonary hypertension, as well as to discuss the implications of these conditions on the management of the critically ill, splenectomized patient.

contemporary reviews in critical care medicine 
Sarah E. Jolley, MD, MSc; Aaron Bunnell, MD; Catherine L. Hough, MD, MSc
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Survivorship after critical illness is an increasingly important health care concern as intensive unit care (ICU) utilization continues to increase while ICU mortality is decreasing. Critical illness survivors experience marked disability and impairments in physical and cognitive function that persist for years after their initial ICU stay1-7. Newfound impairment is associated with increased healthcare costs and utilization, reductions in health related quality of life and prolonged unemployment5,8,9. Weakness, critical illness neuropathy and/or myopathy, and muscle atrophy are common in critically ill patients with up to 80% of patients admitted to the ICU developing some form of neuromuscular dysunction1,10,11. ICU acquired weakness (ICUAW) is associated with longer durations of mechanical ventilation and hospitalization along with greater functional impairment for survivors. Although there is increasing recognition of ICUAW as a clinical entity, significant knowledge gaps exist around identifying high risk patients for its development and understanding its role in long-term outcomes after critical illness. This review addresses the epidemiology and pathophysiology of ICUAW, highlights the diagnostic challenges associated with its diagnosis in critically ill patients and proposes a novel strategy for identifying ICUAW.

original research 
Raquel Morillo, MD; David Jiménez, PhD; Miguel Ángel Aibar, MD; Daniela Mastroiacovo, MD; Philip S. Wells, MD; Ángel Sampériz, PhD; Marta Saraiva de Sousa, MD; Alfonso Muriel, PhD; Roger D. Yusen, MD; Manuel Monreal, PhD
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Background  A comprehensive evaluation of temporal trends in the treatment of patients who have deep vein thrombosis (DVT) may assist with identification of modifiable factors that contribute to short-term outcomes.

Methods  We assessed temporal trends in length of hospital stay and use of pharmacological and interventional therapies among 26,695 adults with DVT enrolled in the RIETE registry between 2001 and 2014. We also examined temporal trends in risk-adjusted rates of all-cause, PE-related, and bleeding-related death to 30-days after diagnosis.

Results  The mean length of hospital stay decreased from 9.0 days in 2001-2005 to 7.6 days in 2010-2014 (P <0.01). For initial DVT treatment, the use of low-molecular weight-heparin decreased from 98% to 90% (P <0.01). Direct oral anticoagulants use increased from 0.5% in 2010 to 13.4% in 2014 (P <0.001). Risk-adjusted rates of 30-day all-cause mortality decreased from 3.9% in 2001-2005 to 2.7% in 2010-2014 (adjusted rate ratio per year, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P <0.01). VTE-related mortality showed a non-statistically significant downward trend (adjusted rate ratio per year, 0.70; 95% CI, 0.44 to 1.10; P =0.13), whereas 30-day bleeding-related mortality significantly decreased from 0.5% in 2001-2005 to 0.1% in 2010-2014 (adjusted rate ratio per year, 0.55; 95% CI, 0.40 to 0.77; P <0.01).

Conclusions  This international registry-based temporal analysis identified reductions in length of stay for adults hospitalized for DVT. The study also found a decreasing trend in adjusted rates of all-cause and bleeding-related mortality.

original research 
Helen A. Hawkins, Ph.D.; Craig M. Lilly, M.D., FCCP; David A. Kaster; Robert H. Groves, Jr., M.D., FCCP; Hargobind Khurana, M.D.
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Background  Recent studies have identified processes that are associated with more favorable length of stay outcomes when an ICU telemedicine program is implemented. Despite these studies, the relation of the acceptance of ICU telemedicine management services by individual ICUs to length of stay (LOS) outcomes is unknown.

Methods  This is a single ICU telemedicine center study that compares length of stay outcomes among 3 groups of intensivist staffed mixed medical surgical ICUs that used alternative co-management strategies. The proportion of provider orders recorded by an ICU telemedicine provider to all recorded orders were compared among ICUs that used a monitor and notify co-management approach, a direct intervention with timely notification process, and ICUs that used a mix of these two approaches. The primary outcome was acuity adjusted hospital length of stay.

Results  ICUs that used the direct intervention with timely notification strategy had a significantly larger proportion of provider orders recorded by ICU telemedicine physicians than the mixed methods of co-management group, which had a larger proportion than ICUs that used the monitor and notify method (p < 0.001). Acuity-adjusted hospital LOS was significantly lower for the direct intervention with timely notification co-management strategy 0.68 (.65 to .70) compared to the mixed methods group (0.70 (.69 to .72); p =0.01), which was significantly lower than the monitor and notify group (0.83 (.80 to .86); p< 0.001).

Conclusions  Direct intervention with timely notification strategies of ICU telemedicine co-management were associated with shorter LOS outcomes than monitor and notify co-management strategies.

original research 
Huan-long Liu, MD, PhD; Xue-yan Chen, MD, PhD; Jie-ru Li, MSc; Su-wen Su, MD, PhD; Tao Ding, MSc; Chen-xia Shi, MD, PhD; Yun-fa Jiang, MD, PhD; Zhong-ning Zhu, MD, PhD
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Background  Previous meta-analyses of PAH-specific therapy for pulmonary arterial hypertension (PAH) pooled PAH-specific combination therapy and monotherapy together. The flaw might threaten the authenticity of their findings.

Methods  PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that evaluated any PAH-specific medications in the treatment of PAH. We calculated odds ratio (OR) with 95% confidence intervals (CIs) for dichotomous data and standardized mean differences for continuous data.

Results  In total, 35 RCTs involving 6,702 patients were included. In monotherapy vs placebo/conventional therapy, significance was obtained in mortality reduction (OR:0.50; 95%CI:0.33-0.76; P=0.001), six-minute walk test (6MWD) (MD:31.10m; 95%CI: 25.40 to 36.80; P <0.00001), NYHA/WHO functional class (OR:2.48; 95%CI:1.51-4.07; P=0.0003), hemodynamic based on mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), and incidence of withdrawal due to adverse effects. In combination therapy vs monotherapy, significance was reached for 6MWD(MD:19.96m; 95%CI:15.35-24.57; P<0.00001), functional class(OR:1.65; 95%CI:1.20-2.28; P=0.002), hemodynamic, incidence of withdrawal due to adverse effects(OR: 2.01; 95%CI:1.54-2.61; P<0.00001 ), but not for mortality reduction(OR:0.98; 95%CI:0.57-1.68; P=0.94).

Conclusions  Our meta-analysis revealed that PAH-specific medications monotherapy could improve mortality, exercise capacity, functional class and hemodynamic when compared with placebo or conventional therapy. However, combination therapy could further improve exercise capacity, functional class and hemodynamic status compared with monotherapy, but had no proven effect on mortality. Combination therapy had a much higher incidence of withdrawal due to adverse effects than monotherapy.

original research 
Leif Bjermer, MD; Catherine Lemiere, MD; Jorge Maspero, MD; Sivan Weiss, MSc; James Zangrilli, MD; Matthew Germinaro, MD
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Background  This phase 3 study further characterizes the efficacy and safety of reslizumab (a humanized anti–interleukin-5 monoclonal antibody) in patients aged 12-75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid, and blood eosinophils ≥400cells/μL.

Methods  Patients were randomized to receive reslizumab 0.3 or 3.0mg/kg or placebo once/every 4 weeks/16 weeks. Primary endpoint was change from baseline in pre-bronchodilator forced expiratory volume in 1 sec (FEV1) over 16 weeks. Secondary endpoints included forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF25-75%), patient-reported control of asthma symptoms, short-acting beta agonist (SABA) use, blood eosinophil levels, and safety.

Results  Reslizumab significantly improved FEV1 (difference vs placebo [reslizumab 0.3 and 3.0mg/kg]:115mL[95% CI 16-215; P= .0237] and 160mL[95% CI 60-259; P= .0018]). Clinically meaningful increases in FVC (130mL) and FEF25-75% (233mL/s) were observed with reslizumab 3.0mg/kg. Reslizumab improved Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) versus placebo (greater effects seen with 3.0mg/kg; P<0.05). The minimally important difference was reached for AQLQ (reslizumab 3.0mg/kg) but not ACQ. Asthma Symptom Utility Index and SABA use were improved with reslizumab. The most common adverse events were asthma worsening, headache, and nasopharyngitis; most were mild-to-moderate in severity.

Conclusions  Reslizumab improved lung function, asthma control and symptoms, and quality of life, and was well tolerated in patients with inadequately controlled asthma (despite standard therapy), and elevated blood eosinophils. Overall, the 3.0mg/kg dose of reslizumab provided greater improvements in asthma outcomes (vs 0.3mg/kg), with comparable safety.

original research 
Michelle Lisidati Franchini; Rodrigo Athanazio; Luis Fernando Amato-Lourenço; Waldir Carreirão-Neto; Paulo Hilario Nascimento Saldiva; Geraldo Lorenzi-Filho; Bruce K. Rubin; Naomi Kondo Nakagawa
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Background  Little is known on the effects of long-term nasal low flow oxygen (NLFO) on mucus and symptoms and how this is affected by dry or cold humidified gas. The aim of this study was to investigate the effects of dry-NLFO and cold bubble humidified-NLFO on nasal mucociliary clearance (MCC), mucus properties, inflammation and symptoms in subjects with chronic hypoxemia requiring long-term domiciliary oxygen therapy.

Methods  Eighteen subjects (mean 68 years, 7 male, 66% COPD) initiating NLFO were randomized to Dry-NLFO (n=10) or Humidified-NLFO (n=8). Subjects were assessed at baseline, 12 hours, 7 days, 30 days, 12 months and 24 months by measuring nasal MCC by saccharine transit test, mucus contact angle (surface tension), inflammation (cells and cytokine concentration in nasal lavage) and symptoms by the Sino-Nasal Outcome Test-20.

Results  Nasal MCC decreased significantly (40% longer saccharine times) and similarly in both groups over study. There was a significant association between impaired nasal MCC and lung function decline. Nasal lavage showed an increased proportion of macrophages, IL-8 and EGF concentrations with decreased IL-10 during the study. No changes in the proportion of ciliated cells or contact angle were observed. Coughing and sleep symptoms decreased similarly in both groups. There were no outcome differences when comparing dry to cold bubble humidified NLFO.

Conclusions  In subjects receiving chronic NLFO, cold bubble humidification does not adequately humidify inspired oxygen to prevent deterioration of MCC, mucus hydration, and pulmonary function. The unheated bubble humidification performed no better than no humidification. Registration at Clinicaltrials.gov (NCT02515786)

original research 
Kohei Hasegawa, MD, MPH; Yusuke Tsugawa, MD, MPH; Sunday Clark, ScD; Carly D. Eastin, MD; Susan Gabriel, MSc; Vivian Herrera, MPH; Jane C. Bittner, MPH; Carlos A. Camargo, Jr., MD, DrPH, FAAAAI
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Background  Little is known about the longitudinal change in quality of acute asthma care for hospitalized children and adults in the U.S. We investigated whether the concordance of inpatient asthma care with the national guidelines improved over time, identified hospital characteristics predictive of guideline concordance, and determined whether guideline-concordant care is associated with a shorter hospital length-of-stay (LOS).

Methods  Analysis of data from two multicenter chart review studies of hospitalized patients aged 2-54 years with acute asthma during two time periods: 1999-2000 and 2012-2013. Outcomes were guideline concordance at the patient- and hospital-levels, and association of patient composite concordance with hospital LOS.

Results  Analytic cohort for the comparison of guideline concordance comprised 1,634 patients: 834 patients from 1999-2000 versus 800 patients from 2012-2013. Over these ∼15 years, inpatient asthma care became more concordant at the hospital-level, with the mean composite score increasing from 74 to 82 (P<.001). However, during 2012-2013, wide variability in guideline concordance of acute asthma care remained across hospitals, with the greatest variation in provision of individualized written action plan at discharge (SD, 36). Guideline concordance was significantly lower in Midwestern and Southern hospitals compared to Northeastern hospitals. After adjusting for severity, patients who received care perfectly concordant with the guidelines had significantly shorter hospital LOS (-14%; 95%CI, -23% to -4%; P=.009).

Conclusions  Between 1999 and 2013, the guideline concordance of acute asthma care for hospitalized patients improved. However, inter-hospital variability remains substantial. Greater concordance with evidence-based guidelines was associated with a shorter hospital LOS.

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  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543