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original research 
Earl S. Ford, MD, MPH; Louise B. Murphy, PhD; Olga Khavjou, MA; Wayne H. Giles, MD, MS; James B. Holt, PhD; Janet B. Croft, PhD
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Background/objective:  Chronic obstructive pulmonary disease (COPD) remains a leading source of morbidity and mortality. Our objectives were to estimate 1) National US COPD-attributable annual medical (direct) costs by payer and absenteeism (indirect) in 2010 and projected medical costs through 2020 and 2) state-specific COPD-attributable medical and absenteeism costs in 2010.

Methods:  We used 2006-2010 Medical Expenditure Panel Survey, 2004 National Nursing Home Survey, and 2010 Centers for Medicare and Medicaid Services data to generate cost estimates and 2010 census data to project medical costs through 2020.

Results:  In 2010, total national medical costs attributable to COPD and its sequelae were estimated at $32.1 billion and total absenteeism costs were $3.9 billion for a total burden of COPD-attributable costs of $36 billion. An estimated 16.4 million days of work were lost because of COPD. Of the medical costs, 18% was paid for by private insurance, 51% by Medicare, and 25% by Medicaid. National medical costs are projected to increase from $32.1 billion in 2010 to $49.0 billion in 2020. Total state-specific costs in 2010 ranged from $49.1 million in Wyoming to $2.8 billion in California: medical costs ranged from $42.5 million in Alaska to $2.5 billion in Florida and absenteeism costs ranged from $8.4 million in Wyoming to $434.0 million in California.

Conclusion:  Costs attributable to COPD and its sequelae are substantial and are projected to increase through 2020. Evidence-based interventions that prevent tobacco use and reduce clinical complications of COPD may result in potential decreased COPD-attributable costs.

original research 
Jean-Louis Pepin, MD, PhD; John R. Cockcroft, FRCP; Dawn Midwinter, MSc; Sanjay Sharma, BSc; David B. Rubin, MD; Stefan Andreas, MD
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Background:  Increased arterial stiffness as measured by aortic pulse wave velocity (aPWV) predicts cardiovascular events and mortality, and is elevated in chronic obstructive pulmonary disease (COPD) patients. Prior investigation suggests that a long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) lowers aPWV in patients with baseline aPWV ≥11m/s. This study compared the effect of the ICS/LABA fluticasone furoate/vilanterol (FF/VI) 100/25mcg delivered via the ELLIPTA™ dry powder inhaler, with tiotropium bromide (TIO) 18mcg on aPWV.

Methods:  This multicenter, randomized, blinded, double-dummy, parallel group, 12-week study compared FF/VI and TIO, both administered once daily. The primary endpoint was aPWV change from baseline at 12 weeks. Safety endpoints included incidence of adverse events (AEs), vital signs and clinical laboratory tests.

Results:  257 COPD patients with aPWV ≥11m/s were randomized; 87% had prior cardiovascular events and/or risk. The mean difference in aPWV between FF/VI and TIO at Week 12 was not significant (P=0.484). As the study did not contain a placebo arm, a post-hoc analysis was performed to show that both treatments lowered aPWV by an approximate difference of 1m/s compared with baseline. The overall incidence of AEs was similar with FF/VI (24%) and TIO (18%). There were no changes of clinical concern for vital signs or clinical laboratory tests.

Conclusion:  No differences on aPWV were observed between FF/VI and TIO. However, further studies with a placebo arm are required to establish definitively whether long-acting bronchodilators lower aPWV. Both treatments demonstrated an acceptable tolerability profile.

Clinical Trial Investigation:  GlaxoSmithKline HZC115247; clinicaltrials.gov identifier: NCT01395888; http://clinicaltrials.gov/ct2/show/NCT01395888

original research 
Hiren J. Mehta, MD; Paras Malhotra, MD; Abbie Begnaud, MD; Andrea M. Penley, BSN, RN; Michael A. Jantz, MD
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Background:  Alveolar-pleural fistula with persistent air leak is a common problem causing significant morbidity, prolonged hospital stay and increased health care costs. When conventional therapy fails, an alternative to prolonged chest tube drainage or surgery is needed. New bronchoscopic techniques have been developed to close the air leak by reducing the flow of air through the leak. The objective of this study was to analyze our experience with bronchoscopic application of a synthetic hydrogel for the treatment of such fistulas.

Methods:  We conducted a retrospective study of patients with alveolar-pleural fistula with persistent air leaks, treated with synthetic hydrogel application via flexible bronchoscopy. Patient characteristics, underlying disease and outcome of endoscopic treatment were analyzed.

Results:  Between January 2009 and December 2013, 22 patients (14 men, 8 women; mean age ± SD, 62 ± 10 years) were treated with one to three applications of a synthetic hydrogel per patient. The primary etiology of persistent air leak was necrotizing pneumonia (n=8), post thoracic surgery (n=6), bullous emphysema (n=5), idiopathic interstitial pneumonia (n=2) and sarcoidosis (n=1). Nineteen patients (86%) had a complete resolution of the air leak leading to successful removal of chest tube 4.3 ± 0.9 days post last bronchoscopic application. The procedure was very well tolerated, with two patients coughing up the hydrogel and one having hypoxemia requiring bronchoscopic suctioning.

Conclusion:  Bronchoscopic administration of a synthetic hydrogel is an effective, nonsurgical, minimally invasive intervention for patients with persistent pulmonary air leaks secondary to alveolar-pleural fistula.

original research 
Violaine Tolsma, MD; Carole Schwebel, MD; Elie Azoulay, MD, PhD; Michael Darmon, MD, PhD; Bertrand Souweine, MD, PhD; Aurélien Vesin, MSc; Dany Goldgran-Toledano, MD; Maxime Lugosi, MD; Samir Jamali, MD; Christine Cheval, MD; Christophe Adrie, MD, PhD; Hatem Kallel, MD; Adrien Descorps-Declere, MD; Maïté Garrouste-Orgeas, MD, PhD; Lila Bouadma, MD, PhD; Jean-François Timsit, MD, PhD
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Objective:  to evaluate the influence of the immune profile on the outcome at day 28 (D28) of patients admitted in ICU for septic shock or severe sepsis.

Materials and Methods:  we conducted an observational study using a prospective multicenter database, and included all patients admitted in 11 ICUs for severe sepsis or septic shock, from January 1997 to August 2011. Seven profiles of immunodeficiency were defined. The prognostic analysis used a competitive risk model (Fine and Gray), in which being alive at ICU or hospital discharge before D28 competed with death.

Results:  among the 1981 included patients, 607 (31%) were immunocompromised (including non-neutropenic solid tumor (19.6%), non-neutropenic hematological malignancies (26.3%), all-cause neutropenia (28%)). Compared to immunocompetent patients, immunocompromised patients were younger, with less comorbidity, were more often admitted for medical reasons, and presented less often septic shock. The D28 crude mortality was 31.3% in immunocompromised patients and 28.8%, in immunocompetent patients (p=0.26). However, after adjustment for other prognostic factors, immunodeficiency was an independent risk factor for death at D28 (sHR 1.37 [1.12-1.67]). The immunodeficiency profiles independently associated with death were AIDS (sHR = 1.9), non-neutropenic solid tumor (sHR = 1.8), non-neutropenic hematological malignancies (sHR = 1.4), and all-cause neutropenia (sHR = 1.7).

Conclusion:  immunodeficiency is common in patients with severe sepsis or septic shock. Despite a similar crude mortality, immunodeficiency was associated with an increased risk of short-term mortality after multivariate analysis. Neutropenia and specific, but not all, profiles of immunodeficiency were independently associated with an increased risk of death.

original research 
Sameer Lakha, BA; Jorge E. Gomez, MD; Raja M. Flores, MD, MS; Juan P. Wisnivesky, MD, DrPH
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Background:  Visceral pleural invasion (VPI) may impact non-small cell lung cancer (NSCLC) survival. However, previous studies are mixed as to whether VPI is an independent prognostic factor in early-stage cancers, and whether its effect is size-dependent. In the current American Joint Committee on Cancer (AJCC) staging system, VPI leads to upstaging of cancers <3 cm but not of those 3-7 cm in size.

Methods:  Using the Surveillance, Epidemiology, and End Results registry, we identified 16,315 patients with stage I-II NSCLC treated with lobectomy. We used the Kaplan-Meier method and Cox regression to assess the association of VPI with lung-cancer specific (primary outcome) and overall survival. Based on these results we created a revised VPI staging classification.

Results:  Overall, 3,389 (21%) patients had VPI. Kaplan-Meier analysis stratified by tumor size showed worse cancer-specific survival in patients with VPI (p<0.0001). VPI was independently associated with decreased lung cancer-specific survival (hazard ratio: 1.38, 95% confidence interval: 1.29-1.47) after controlling for tumor size and other confounders; this effect was not size-dependent. In our revised classification, tumors <7 cm with VPI were upstaged to the next T category.

Conclusions:  VPI is a prevalent finding associated with worse prognosis in early-stage lung cancer even among patients with tumors >3 cm in size, a factor not captured in the current staging system. Patients with VPI may be considered candidates for more aggressive treatment.

original research 
Matthew R. Salamonsen; Ada K.C. Lo; Arnold C.T. Ng; Farzad Bashirzadeh; William Y.S. Wang; David I.K. Fielding
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Rationale  The presence of entrapped lung changes the appropriate management of malignant pleural effusion from pleurodesis to insertion of an indwelling pleural catheter. No methods currently exist to identify entrapped lung prior to effusion drainage.

Objectives  To develop a method to identify entrapped lung using tissue movement and deformation (strain) analysis with ultrasound, and compare it to the existing technique of pleural elastance.

Methods  Prior to drainage, 81 patients with suspected malignant pleural effusion underwent thoracic ultrasound using an echocardiogram machine. Images of the atelectatic lower lobe were acquired during breath-hold, allowing motion and strain related to the cardiac impulse to be analysed using motion-mode and speckle-tracking imaging respectively. Pleural elastance was measured during effusion drainage. The gold standard diagnosis of entrapped lung was the consensus opinion of two interventional pulmonologists according to post-drainage imaging. Participants were randomly divided into development and validation sets.

Measurements and Main Results  Both total movement and strain were significantly reduced in entrapped lung. Using data from the development set, the area under the receiver-operating curves for the diagnosis of entrapped lung was 0.86 (speckle-tracking), 0.79 (motion-mode) and 0.69 (pleural elastance). Using respective cut-offs of 6%, 1mm and 19cmH2O on the validation set, the sensitivity/specificity was 71%/85% (speckle-tracking), 50%/85% (motion mode) and 40%/100% (pleural elastance).

Conclusions  This novel ultrasound technique can identify entrapped lung prior to effusion drainage, which could allow appropriate choice of definitive management (pleurodesis versus indwelling catheter), reducing the number of interventions required to treat malignant pleural effusion.

original research 
Daniel Horner, MD; Kerstin Hogg, PhD; Richard Body, PhD; Michael J. Nash, MD; Trevor Baglin, PhD; Kevin Mackway-Jones
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Background  There is currently little evidence defining the clinical importance of detecting and treating isolated distal deep vein thrombosis (IDDVT). International guidelines vary regarding diagnostic and therapeutic advice. The potential benefits of anticoagulation are unquantified. We sought to evaluate the feasibility of a randomized controlled study within a modern framework and provide a primary outcome point estimate.

Methods  An open label, external pilot randomised controlled trial. Consecutive, symptomatic, ambulatory IDDVT patients were approached for inclusion. Participants were allocated to receive either therapeutic anticoagulation or conservative management. Patients underwent colour duplex imaging at 7 and 21 days, and follow up at three months. Principal feasibility outcomes included recruitment rate and attrition. The principal clinical outcome was a composite including proximal propagation, pulmonary embolism, death attributable to venous thromboembolic disease or major bleeding. Analysis was by intention to treat.

Results  In total, 93 patients with IDDVT were screened and 70 (88·6% of those eligible) were recruited. All patients but 1 were followed up by direct contact after 90 days. Allocation crossover occurred in 15 (21·4%) patients.The principal clinical outcome occurred in 4/35 (11·4%) conservatively treated and 0/35 in the anticoagulated group (Absolute Risk Reduction 11·4%, 95% CI -1·5 to 26·7, p=0·11, number needed to treat of 9). There were no major bleeding episodes.

Conclusions  We have established the feasibility of definitive study regarding the value of therapeutic anticoagulation in IDDVT and provide an approximate point estimate for serious complications with a contemporary conservative strategy.

Clinical Trial Registration  www.controlled-trials.com/ISRCTN75175695

original research 
Li Bo Ruan; Liang He; Shan Zhao; Ping Zhu; Wei Yuan Li
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Background:  Several recent studies have described Heart-type fatty acid-binding protein (H-FABP) from early blood samples as a predictor of outcome in acute pulmonary embolism (PE). This systematic review aims to determine the prognostic value of H-FABP aimed for use in patients with acute PE.

Methods:  Studies published prior to January 2013 in PubMed, Ovid, and Embase were reviewed and the relationship between H-FABP and the risk of acute PE-related death or serious complications was evaluated. A summary estimate was calculated using the bivariate random-effects approach, and covariate analysis was used to examine sources of heterogeneity between studies.

Results:  A systematic search revealed 6 studies containing a total of 618 patients. Elevated H-FABP was significantly associated with short-term death (within 30 days of embolism, odds ratio (OR) 40.78, 95% confidence interval [CI] 11.87 - 140.09) and with complicated clinical events (OR 32.71, 95% CI 11.98 - 89.26). The prevalence of serious complications and death in acute PE were 51% (95% CI 43% - 59%) and 31% (95% CI 24% -39%), respectively. The combined sensitivity and specificity for the prediction of death and serious complications were 98% and 86%, respectively.

Conclusion:  H-FABP is associated with an increased risk of mortality or complicated clinical events in patients with acute PE across different studies with a high degree of clinical and methodological diversity. The result suggests that H-FABP has significant prognostic value for acute PE.

original research 
Abraham Schoe, MD; Emile F. Schippers, MD, PhD; Stefan Ebmeyer, MD; Joachim Struck, PhD; Robert J.M. Klautz, MD, PhD; Evert de Jonge, MD, PhD; Jaap T. van Dissel, MD, PhD
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Background:  In cardiac surgery, preoperative mortality risk assessment tools like the EuroSCORE helps to guide physicians in optimizing perioperative care of patients. In this study, we investigated the value of preoperative levels of inflammatory (PCT) and vasoactive (CT-proAVP, MR-proANP, MR-proADM, CT-proET-1) biomarkers for risk assessment of mortality and morbidity and compared it with the EuroSCORE.

Methods:  We performed a prospective observational cohort study in a single center academic medical hospital and analyzed 746 consecutive patients undergoing elective cardiac surgery. In a directly pre-operative blood sample, we assessed PCT, CT-proAVP, MR-proANP, MR-proADM, CT-proET-1.

Results:  In single-variable logistic regression models all biomarkers predicted 30-days mortality. The biomarkers CT-proET-1 (c-statistic 0.785; CI 95% 0.687 – 0.883) and MR-proADM (c-statistic 0.780; CI 95% 0.671 – 0.889) predicted 30-days mortality with the highest c-statistic. For the EuroSCORE the c-statistic was 0.689; CI 95% 0.594 – 0.784.There was a significant improvement of the prediction of 30-days mortality when the EuroSCORE was combined with MR-proADM (c statistic 0.792; CI 95% 0.699 - 0.884) or CT-proET-1 (c-statistic 0.798; CI 95% 0.715 - 0.880). The model with EuroSCORE, MR-proADM and CT-proET1 had the highest c-statistic (0.803; CI 95% 0.717 – 0.890) and was significantly better compared to the EuroSCORE alone.

Conclusion:  In elective cardiac surgery pre-operative levels of MR-proADM and CT-proET-1 are predictors of 30-days mortality and could improve the predictive accuracy of the EuroSCORE. Further research should confirm the place of these new biomarkers in the prediction of mortality and identification of patients at risk.

original research 
Lorinda Chung, MD, MS; Harrison W. Farber, MD; Raymond Benza, MD, FACC, FAHA; Dave P. Miller, MS; Lori Parsons, BS; Paul M. Hassoun, MD; Michael McGoon, MD; Mark R. Nicolls, MD; Roham T. Zamanian, MD, FCCP
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Background:  Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population.

Methods:  The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations.

Results:  Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4±2.7% and 51.2±4.0%, respectively, compared with 80.9±2.7% and 76.4±4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ≤110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group.

Conclusions:  Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment.

Registered at:  www.clinicaltrials.gov #NCT00370214

original research 
Andrew J. Admon, MD, MPH; Christopher W. Seymour, MD, MSc; Hayley B. Gershengorn, MD; Hannah Wunsch, MD, MSc; Colin R. Cooke, MD, MSc, MS
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Background:  Variation in the use of intensive care units (ICU) for low-risk conditions contributes to health system inefficiency. We sought to examine the relationship between ICU utilization for patients with pulmonary embolism (PE) and cost, mortality, readmission, and procedure use.

Methods:  We performed a retrospective cohort study including 61,249 adults with PE discharged from 263 hospitals in three states between 2007 and 2010. We generated hospital-specific ICU admission rate quartiles and used a series of multilevel models to evaluate relationships between admission rates and risk-adjusted in-hospital mortality, readmission, and costs, and between ICU admission rates and several critical care procedures.

Results:  Hospitals quartiles varied in unadjusted ICU admission rates for PE (range ≤15% to >31%). Among all patients, there was a small trend towards increased use of arterial catheterization (0.6% to 1.1%, p<0.01) in hospital quartiles with higher levels of ICU admission. However, use of invasive mechanical ventilation (14.4 to 7.9%, <0.01), non-invasive ventilation (6.6% to 3.0%, p<0.01), central venous catheterization (14.6% to 11.3%, p<0.02), and thrombolytics (11.0% to 4.7%, p<0.01) in ICU patients declined across hospital quartiles. There was no relationship between ICU admission rate and risk-adjusted hospital mortality, costs, or readmission.

Conclusions:  Hospitals vary widely in ICU admission rates for acute PE without a detectable impact on mortality, cost, or readmission. Patients admitted to ICUs in higher utilizing hospitals received many critical care procedures less often, suggesting that these patients may have had weaker indications for ICU admission. Hospitals with greater ICU admission may be appropriate targets for improving efficiency in ICU admissions.

original research 
Diana Bonderman, MD; Ingrid Pretsch, MD; Regina Steringer-Mascherbauer, MD; Pavel Jansa, MD; Stephan Rosenkranz, MD; Caroline Tufaro, MS; Andja Bojic, MD; Carolyn S.P. Lam, MD; Reiner Frey, MD; Michael Ochan Kilama, MD; Sigrun Unger; Lothar Roessig, MD; Irene M. Lang, MD
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Background:  Deficient nitric oxide– soluble guanylate cyclase (sGC)–cGMP signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel sGC stimulator, were characterized in patients with PH and HFpEF.

Methods:  Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics.

Results:  There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11; P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI 0.4 to 17]; P = .04) and decreased systolic blood pressure (–12 mm Hg [95% CI –22 to –1]; P = .03) and right ventricular end-diastolic area (–5.6 cm2 [95% CI –11 to –0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated.

Conclusions:  In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters.

Trial registry:  ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov

original research 
Paul D. Robinson, MBChB, MRCPCH, FRACP, PhD; Nathan J. Brown, PhD; Martin Turner, PhD; Peter Van Asperen, FRACP, MD; Hiran Selvadurai, FRACP, PhD; Gregory G. King, MBChB, PhD
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Background:  Paediatric asthma lacks sensitive objective measures for asthma monitoring. The forced oscillation technique (FOT) offers strong feasibility across the paediatric age range but relationships between FOT parameter day-to-day variability and paediatric asthma severity and control are unknown.

Methods:  Day-to-day variability in FOT respiratory system resistance (Rrs) and reactance (Xrs), in comparison to peak expiratory flow (PEF), were defined in 22 asthmatic children, mean (SD) age 10.4 (1.1) years, during a five day asthma camp. FOT was performed at 6Hz in triplicate on each test occasion. Relationships between day-to-day FOT variability (expressed as within-subject SD, SDW) and Asthma control and severity (defined according to GINA recommendations) were explored. For comparison, normal baseline FOT values and variability was defined in a separate cohort of 38 healthy children (mean (SD) age 9.5 (1.0) years), measured on two occasions.

Results:  Day-to-day Rrs variability was greater in persistent (n=16) vs. intermittent (n=6) asthma (mean SDW 0.69 vs. 0.39cm.H2O.L-1.s, p≤0.01). Day-to-day Rrs variability was increased in uncontrolled (n=13) vs. partly controlled asthma (n=9) (mean SDW 0.75 vs. 0.42cm.H2O.L-1.s, p≤0.05). PEF variability did not differentiate the groups. Day-to-day variability of Rrs and Xrs, but not baseline values, were increased in asthmatics vs. controls: Rrs mean SDW 0.61 vs. 0.33cm. H2O.L-1.s, p≤0.05, and Xrs mean SDW 0.24 vs. 0.15cm.H2O.L-1.s, p≤0.05, respectively.

Conclusions:  Increased day-to-day FOT variability exists in asthmatic school-aged children. Day-to-day Rrs variability was associated with asthma severity and with asthma control. FOT may be useful objective monitoring tool in paediatric asthma and warrants further study.

original research 
D.S. Schumacher, MD; S. Müller-Mottet, MD; E.D. Hasler, MD; F.F. Hildenbrand, MD; S. Keusch, MD; R. Speich, MD, FCCP; K.E. Bloch, MD, FCCP; S. Ulrich, MD
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Background:  Sleep-disturbed breathing (SDB) is common in patients with pre-capillary pulmonary hypertension (PH). Nocturnal oxygen therapy (NOT) and acetazolamide improve SDB in PH-patients and NOT improves exercise capacity. We investigated the effect of NOT and acetazolamide on nocturnal cardiac conduction, repolarization and arrhythmias in patients with PH and SDB.

Methods:  In a randomized, placebo-controlled, double-blind, cross-over trial 23 patients with arterial (n=16) or chronic thromboembolic PH (n=7) and SDB defined as a mean nocturnal oxygen saturation (SpO2)<90% or dips(>3%)>10/h with daytime PaO2≥7.3kPa were studied. Participants received NOT (3l/min), acetazolamide tablets (2x250mg), and sham-NOT/placebo each during one week separated by a one-week washout period. Three-lead electrocardiography was recorded during overnight polysomnography at the end of each treatment period. Repolarization indices were averaged over three cardiac cycles at late evening and at early morning and nocturnal arrhythmias were counted.

Results:  NOT was associated with a lower overnight (68±10 vs. 72±9bpm, p=0.010) and early morning heart rate compared with placebo. At late evening, the PQc-time was increased under acetazolamide compared with placebo (mean difference 10ms, 95%CI 0 to 20ms, p=0.042). In the morning under NOT, the QTc-interval was decreased compared with placebo (mean difference -25ms, 95%CI -45 to -6ms, p=0.007) and the TpTec-interval shorter compared with acetazolamide (mean difference -11ms, 95%CI -21 to -1ms, p=0.028). Arrhythmias were rare and similar with all treatments.

Conclusions:  In PH-patients with SDB, NOT reduces nocturnal heart rate and QTc in the morning thus favorably modifying prognostic markers.

Clinical Trial Registration:  This trial is registered at clinicalTrials.gov: NTC-01427192.

original research 
Bhakti K. Patel, MD; Anne S. Pohlman, MSN; Jesse B. Hall, MD; John P. Kress, MD
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Background:  Intensive care unit-acquired weakness has immediate and long-term consequences for critically ill patients. Strategies for the prevention of weakness include modification of known risk factors such as hyperglycemia and immobility. Intensive insulin therapy has been proposed to prevent critical illness polyneuropathy. However, insulin and early mobilization’s effect on clinically apparent weakness is not well known.

Methods:  This is a secondary analysis of all mechanically ventilated patients (n=104) previously enrolled in a randomized controlled trial of early occupational and physical therapy versus conventional therapy which evaluated the endpoint of functional independence. Every patient had intensive insulin therapy and blinded muscle strength testing on hospital discharge to determine the incidence of clinically apparent weakness. The effects of insulin dose and early mobilization on the incidence of intensive care unit-acquired weakness were assessed.

Results:  On logistic regression analyses, early mobilization and increasing insulin dose prevented the incidence of intensive care unit-acquired weakness (OR 0.18, p=0.001; OR 0.001, p=0.011, respectively) independent of known risk factors for weakness. Early mobilization also significantly reduced insulin requirements to achieve similar glycemic goals as compared to control patients (0.07 vs. 0.2 units/kg/day, p<0.001).

Conclusions:  Early mobilization’s dual effect in reducing clinically relevant intensive care unit-acquired weakness and promoting euglycemia suggests its potential utility as an alternative to intensive insulin therapy.

original research 
Jennifer P. Stevens, MD, MS; George Silva; Jean Gillis, RN, MPH; Victor Novack, MD, PhD; Daniel Talmor, MD, MPH; Michael Klompas, MD, MPH; Michael D. Howell, MD, MPH
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Background.  The United States Centers for Disease Control has implemented a new, multi-tiered definition for ventilator-associated events (VAE) to replace their former definition of ventilator-associated pneumonia (VAP). We hypothesized that the new definition could be implemented in an automated, efficient, and reliable manner using the electronic health record and that the new definition would identify different patients than those identified under the previous definition.

Methods.  We conducted a retrospective cohort analysis using an automated algorithm to analyze all patients admitted to the intensive care unit at a single urban, tertiary care hospital from 2008 to 2013.

Results.  We identified 26,466 consecutive admissions to the intensive care unit, 10,998 (42%) of whom were mechanically ventilated, 675 (3%) of whom were identified as having any VAE. Any VAE was associated with an adjusted increased risk of death (OR 1.91, 95% CI 1.53 – 2.37, p<0.0001). The automated algorithm was reliable (sensitivity of 93.5%, 95% CI 77.2% - 98.8%; specificity of 100%, 95% CI 98.8% - 100% versus a human abstractor). Comparison of patients with VAE and with the former VAP definition yielded little agreement (kappa=0.06).

Conclusions.  A fully automated method of identifying VAEs is efficient and reliable within a single institution. While VAEs are strongly associated with worse patient outcomes, additional research is required to evaluate whether and which interventions can successfully prevent VAEs.

original research 
Michelle S. Troche, Ph.D./CCC-SLP; Alexandra E. Brandimore, M.A./CCC-SLP; Michael S. Okun, M.D.; Paul W. Davenport, Ph.D.; Karen W. Hegland, Ph.D./CCC-SLP
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Background:  Aspiration pneumonia is a leading cause of death in persons with Parkinson’s disease (PD). The pathogenesis of these infections is largely attributed to the presence of dysphagia with silent aspiration, or aspiration without an appropriate cough response. The goal of this study was to test reflex cough thresholds and associated urge-to-cough (UTC) ratings in participants with PD with and without dysphagia.

Methods:  Twenty participants with PD were recruited for this study. Participants completed a capsaicin challenge with three randomized blocks of 0, 50, 100 & 200 μM capsaicin and rated their UTC by modified Borg scale. The concentration of capsaicin that elicited a two cough response, total number of coughs, and the sensitivity of the participant to the cough stimulus (UTC) was measured. The dysphagia severity of participants with PD was identified based on the penetration-aspiration scale.

Results:  Most participants with PD did not have a consistent two-cough response to 200 μM capsaicin. UTC ratings and total number of coughs produced at 200 μM capsaicin were significantly influenced by dysphagia severity, but not by general PD severity, age, or disease duration. Increasing levels of dysphagia severity resulted in significantly blunted cough sensitivity (UTC) in participants with PD.

Conclusions:  UTC ratings may be important in understanding the mechanism underlying morbidity related to aspiration pneumonia in people with PD and dysphagia. Further understanding decreased UTC in people with PD and dysphagia will be essential for the development of strategies and treatments to address deficits of airway protection in this population.

original research 
James F. Donohue, MD; Nicola A. Hanania, MD; Barry Make, MD; Matthew C. Miles, MD; Donald A. Mahler, MD; Lisa Curry, BS; Robert Tosiello, MS; Alistair Wheeler, MD; Donald P. Tashkin, MD
Topics: , , ,

Background:  Arformoterol tartrate (arformoterol, 15 µg twice daily) is a nebulized long-acting β2-agonist approved for maintenance treatment of COPD.

Methods:  This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥40 years with baseline FEV1 ≤65% predicted, FEV1 >0.50L, FEV1/FVC ≤70%, and ≥15 pack-year smoking history) received arformoterol (N=420) or placebo (N=421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization.

Results:  Among 841 patients randomized, 103 had ≥1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year post-randomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively). Twelve (2.9%) patients receiving arformoterol and 10 (2.4%) patients receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P=0.003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac SAEs; however, time to first cardiac SAE was not significantly different. Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051L, P=0.030 and 0.075L, P=0.018, respectively). Significant improvements in QoL (overall SGRQ and CCQ) were observed with arformoterol versus placebo (P<0.05).

Conclusion:  Arformoterol demonstrated a ∼40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year versus placebo. Arformoterol was well-tolerated and improved lung function versus placebo.

ClinicalTrials.gov:  NCT00909779

original research 
Nita Khandelwal, MD, MSc; Ruth A. Engelberg, Ph.D; David Benkeser, MPH; Norma B. Coe, PhD; J. Randall Curtis, MD, MPH
Topics: , ,

Rationale:  Although end-of-life care in the ICU accounts for a large proportion of healthcare costs, few studies have examined the association between costs and satisfaction with care.

Objective:  To investigate the association of ICU costs with family- and nurse-assessed quality of dying and family satisfaction.

Design:  An observational study surveying families and nurses for patients who died in the ICU or within 30 hours of transfer from the ICU.

Patients/Setting:  607 patients from two Seattle hospitals.

Methods:  Survey data were linked with administrative records to obtain ICU and hospital costs. Regression analyses assessed the association between costs and outcomes assessing satisfaction with care: nurse and family-assessed quality-of-dying (QODD-1) and Family Satisfaction in the ICU (FS-ICU).

Main Results:  For family-reported outcomes, patient insurance status was an important modifier of results. For underinsured patients, higher daily ICU costs were significantly associated with higher FS-ICU and QODD-1 (p<.01 and p=0.01, respectively); this association was absent for privately insured or Medicare patients (p=0.50 and p=0.85, QODD-1, FS-ICU, respectively). However, higher nurse-assessed QODD-1 was significantly associated with lower average daily ICU cost and total hospital cost (p<.01, p=0.05, respectively).

Conclusions:  Family-rated satisfaction with care and quality of dying varied depending on insurance status, with underinsured families rating satisfaction with care and quality of dying higher when average daily ICU costs were higher. However, patients with higher costs were assessed by nurses as having a poorer quality of dying. These findings highlight important differences between family and clinician perspectives and the important role of insurance status.

original research 
Leandro Cruz Mantoani, MSc; Karina Couto Furlanetto, MSc; Demétria Kovelis, MSc; Mahara Proença, MSc; Juliana Zabatiero, MSc; Gianna Bisca, MSc; Andréa Morita, PT; Fabio Pitta, PhD
Topics: , , ,

Background:  Programs aimed at increasing physical activity in daily life (PADL) have generated growing interest in order to prevent the deleterious effects of physical inactivity. Recent literature has shown that a short-term protocol using pedometers increased PADL in smokers with normal lung function. However, the long-term effects of such a protocol were not yet studied.

Objectives:  To evaluate the results of 1-year follow-up after a program aimed at increasing PADL in smokers with normal lung function.

Methods:  24 smokers were followed (15 males; 51 [41-57] years; BMI 26 [22-29] kg.m-2; 20 [20-30] cigarettes/day). Subjects were assessed at baseline, immediately after completion of the program and one year later concerning PADL, lung function, six-minute walking distance (6MWD), smoking habits, quality of life, anxiety and depression. The 5-month program used pedometers and informative booklets as interventions.

Results:  The gains achieved after the program were maintained in the long term: steps/day (post-program vs 1-year follow-up: 10572 [9804-12237] vs 10438 [9151-12862]); 6MWD (625 [530-694] m, 88 [81-97] %predicted vs 609 [539-694] m, 89 [81-96] %predicted), anxiety (34 [26-41] vs 35 [36-47] points) and depression (6 [2-9] vs 5 [2-11] points) (p>0.05 for all). One year after the program, 20% of the subjects had quit smoking.

Conclusions:  In smokers with normal lung function, improvements in daily physical activity, exercise capacity, anxiety and depression obtained through a 5-month program aimed at increasing physical activity are sustained one year after completion of the program. Furthermore, such a program can contribute to smoking cessation in this population.

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