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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 
Earl S. Ford, MD, MPH
Topics: , , , , ,

Background:  Elevated urinary albumin-creatinine ratio (UACR) and decreased estimated glomerular filtration rate (eGFR) predict all-cause mortality, but whether these markers of kidney damage and function do so in adults with obstructive lung function (OLF) is unclear. The objective of this study was to examine the associations between UACR and eGFR and all-cause mortality in adults with OLF.

Methods:  Data of 5711 US adults aged 40-79 years including 1390 adults with any OLF who participated in the National Health and Nutrition Examination Survey III (1988-1994) were analyzed. Mortality follow-up was conducted through 2006.

Results:  During the median follow-up of 13.7 years, 650 adults with OLF died. After maximal adjustment, mean levels of UACR were higher in adults with moderate-severe OLF (7.5 mg/g, 95% confidence interval [CI]: 6.7―8.5) than in adults with normal pulmonary function (6.2 mg/g, 95% CI: 5.8―6.6) (P=0.003) and mild OLF (6.2 mg/g, 95% CI: 5.5―6.9) (P=0.014). Adjusted mean levels of eGFR were lower in adults with moderate-severe OLF (87.6 mL/min/1.73 m², 95%CI: 86.0―89.1) than in adults with normal lung function (89.6 mL/min/1.73 m², 95%CI: 88.9―90.3) (P=0.015). Among adults with OLF, hazard ratios for all-cause mortality increased as levels of UACR, modeled as categorical or continuous variables, increased (maximally-adjusted hazard ratio for quintile 5 vs 1: 2.23, 95% CI: 1.56―3.18). eGFR, modeled as a continuous variable but not as quintiles, was significantly associated with mortality.

Conclusions:  UACR and eGFR, in continuous form, were associated with all-cause mortality among US adults with OLF.

original research 
Robert K. Kanter, MD
Topics: , ,

Background -  In a pandemic, needs for ventilators might overwhelm the limited supply. Outcome predictors have been proposed to guide ventilator triage allocation decisions. However, pandemic triage predictors have not been validated. This quantitative simulation study evaluated outcomes resulting from allocation strategies varying in their performance for selecting short stay survivors as favorable candidates for ventilators.

Methods -  A quantitative simulation modeled a pandemic surge. Postulated numbers of potential daily admissions presented randomly from a specified population, with a limited number of available ventilators. Patients were triaged to ventilator care vs palliation, or turned away to palliation if no ventilator was available. Simulated triage was conducted according to a set of hypothetical triage tools varying in sensitivity and specificity to select favorable ventilator candidates, versus first-come-first-served allocation. Death was assumed for palliation. Survival or death was counted for ventilated patients according to the specified characteristic of each randomly selected patient.

Results -  Triage predictors with intermediate quality performance resulted in a median daily mortality of 80%, similar to first-come-first-served allocation. A poor quality predictor resulted in a worse mortality of 90%. Only a high quality predictor (sensitivity 90% & specificity 90%) resulted in a substantially lower 60% mortality.

Conclusions -  Performance of unvalidated pandemic ventilator triage predictors is unknown and possibly inferior to first-come-first-served allocation. Poor performance of unvalidated predictors proposed for triage would represent an inadequate plan for stewarding scarce resources and would deprive some patients of fair access to a ventilator, thus falling short of sound ethical foundations.

original research 
Bridget F. Collins; Laura C. Feemster; Seppo Rinne; David H. Au
Topics: , ,

Rationale:  Despite guideline recommendations, patients suspected of having chronic obstructive pulmonary disease (COPD) are often treated empirically rather than undergoing spirometry to confirm airflow obstruction (AFO). Accurate diagnosis and treatment are essential to provide high quality, value-oriented care. We sought to identify predictors associated with AFO among patients diagnosed with and treated for COPD prior to performance of confirmatory spirometry.

Methods:  We identified a cohort of Veterans with spirometry performed at Pacific NW VA medical centers between 2003 and 2007. We included only patients with an empiric diagnosis of COPD in the 2 years prior to spirometry who were also on an inhaled medication to treat COPD in the 1 year prior to spirometry. We used relative risk regression to identify predictors of airflow obstruction.

Results:  Among patients diagnosed with and empirically treated for COPD (n = 3,209), 62% had airflow obstruction. Risk factors such as older age, prior smoking status, and underweight status were associated with AFO on spirometry. In contrast, comorbidities often associated with somatic symptoms were associated with absence of AFO and included congestive heart failure, depression, diabetes, obesity and sleep apnea.

Conclusions:  Comorbidities associated with somatic complaints of dyspnea were associated with a lower risk of having airflow limitation, suggesting empiric diagnosis and treatment of COPD may lead to inappropriate treatment for individuals who do not have airflow obstruction.

original research 
Emad U. Hakemi, MD; Tareq Alyousef, MD; Geetanjali Dang, MD; Jalal Hakmei, MD; Rami Doukky, MD, MSc, FACC
Topics: ,

Background:  Elevated cardiac troponin levels have been shown to be associated with adverse outcome in patients with acute pulmonary embolism (PE). However, there is less data addressing the management implications of undetectable cardiac troponin-I (cTnI) using a highly sensitive assay. We hypothesized that undetectable cTnI predicts very low in-hospital adverse event rates.

Methods:  In a retrospective cohort study, we classified patients with confirmed acute PE according to cTnI detectability into cTnI+ and cTnI− groups. The Pulmonary Embolism Severity Index (PESI) was used for clinical risk determination. The primary outcome was a composite of hard events; defined as in-hospital death, cardiopulmonary resuscitation, or thrombolytic therapy. The secondary outcome was a composite of soft events; defined as intensive care unit admission, or inferior vena cava filter placement.

Results:  Among 298 consecutive patients with confirmed acute PE; 161(55%) were cTnI+ and 137(45%) were cTnI−. No deaths (0%) occurred in the cTnI− group vs. 9(6%) in the cTnI+ group (P=0.004). No hard events (0%) were observed in the cTnI− group vs. 15(9%) in the cTnI+ group (P<0.001). Soft events were observed at a lower rate in the cTn– group [21(15%) vs. 69(43%), P<0.001]. Patients in cTnI− groups had higher survival free of hard (P=0.001) or soft (P<0.001) events, irrespective of clinical risk. Furthermore, cTnI provided incremental prognostic value beyond clinical, electrocardiographic, and imaging data (P<0.001).

Conclusions:  Highly sensitive cTnI assay provides an excellent prognostic negative predictive value, thus it has a role in identifying candidates for out-of-hospital treatment of acute PE.

original research 
Ari R. Manuel, MBBS; Nicholas Hart, PhD; John R. Stradling, MD
Topics: , , ,

Introduction  Obesity hypoventilation syndrome (OHS) conventionally includes awake hypercapnia, but an isolated raised bicarbonate, even in the absence of awake hypercapnia, may represent evidence of ‘early’ OHS. We have investigated whether such individuals exhibit certain features characteristic of established obesity hypoventilation syndrome.

Methods  Obese subjects (BMI >30 kgs/m2) were identified from a variety of sources, and divided into those with: 1) normal blood gases and normal acid-base balance, 2) an isolated raised base excess (≥2mmol/l), and 3) awake hypercapnia (>6kPa, i.e. established OHS). Two-point ventilatory responses to hypoxia and hypercapnia were performed. Polygraphic sleep studies were done to identify intermittent and prolonged hypoxia.

Results  71 subjects (BMI 47.2 SD 9.8, age 52.1 SD 8.8) were recruited into the above three groups (33, 22, and 16 respectively). The PaCO2 and base excess values were: 5.15, 5.42, 6.62 kPa, and +0.12, +3.01, +4.78 mmol/l respectively. For nearly all the ventilatory response and sleep study measures, group 2 (with only an isolated raised base excess) represented an intermediate group, and for some of the measures they were more similar to the third group with established OHS.

Conclusion  These data suggest that obese individuals with a raised base excess, despite normocapnia whilst awake, should probably be regarded as having early obesity-related hypoventilation. This has important implications for clinical management as well as randomized controlled treatment trials, as they may represent a group with a more reversible disease process.

original research 
Engi F. Attia, MD; Kathleen M. Akgün, MD; Cherry Wongtrakool, MD; Matthew Bidwell Goetz, MD; Maria C. Rodriguez-Barradas, MD; David Rimland, MD; Sheldon T. Brown, MD; Guy W. Soo Hoo, MD; Joon Kim, MD; Patty J. Lee, MD; Lynn M. Schnapp, MD; Amir Sharafkhaneh, MD, PhD; Amy Justice, MD, PhD; Kristina Crothers, MD
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Background:  The association between HIV and emphysema remains incompletely understood. We sought to determine whether HIV is an independent risk factor for emphysema severity and whether markers of HIV severity and systemic biomarkers of inflammation (interleukin-6), altered coagulation (D-dimer) and immune activation (soluble CD14) are associated with emphysema.

Methods:  We performed a cross-sectional analysis of 114 HIV-infected and 89 HIV-uninfected participants in the Examinations of HIV-Associated Lung Emphysema study. Subjects underwent chest CT with blinded semi-quantitative interpretation of emphysema severity, distribution and type. We generated multivariable logistic regression models to determine the risk of HIV for radiographic emphysema, defined as >10% lung involvement. Similar analyses examined associations of plasma biomarkers, HIV RNA, and recent and nadir CD4 cell counts with emphysema among HIV-infected subjects.

Results:  HIV-infected individuals had greater radiographic emphysema severity with increased lower lung zone and diffuse involvement. HIV was associated with significantly increased risk for >10% emphysema in analyses adjusted for cigarette smoking pack-years (OR 2.24; 95% CI, 1.12 – 4.48). In multivariable analyses restricted to HIV-infected individuals, nadir CD4 <200 (OR 2.98; 95% CI, 1.14 – 7.81) and high soluble CD14 (upper 25th percentile) (OR 2.55; 95% CI, 1.04 – 6.22) were associated with increased risk of >10% emphysema. Interleukin-6 and D-dimer were not associated with emphysema in HIV.

Conclusions:  HIV is an independent risk factor for radiographic emphysema. Emphysema severity was significantly greater among HIV-infected individuals. Among those with HIV, nadir CD4 <200 and elevated soluble CD14 were associated with emphysema, highlighting potential mechanisms linking HIV with emphysema.

evidence-based medicine 
Richard S. Irwin, MD, Master FCCP; Cynthia T. French, PhD, MS, ANP-BC; Sandra Zelman Lewis, PhD; Rebecca L. Diekemper, MPH; Philip M. Gold, MD, FCCP on behalf of the CHEST Expert Cough Panel

This overview will demonstrate that cough is a common and potentially expensive health care problem. Improvement in the quality of care of those with cough has been the focus of study for a variety of disciplines in medicine. The purpose of the Cough Guideline and Expert Panel is to synthesize current knowledge in a form that will aide clinical decision making for the diagnosis and management of cough across disciplines and also identify gaps in knowledge and treatment options.

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
Topics: , ,

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
Topics: , , , ,

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
Topics: , , ,

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
Topics: , , , ,

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
Topics: ,

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.

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