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.

topics in practice management 
Frank T. Leone, MD, MS, FCCP; Sarah Evers-Casey, MPH, MTTS; Mary A. Mulholland, MHA, RN, CPC; David P.L. Sachs, MD
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Balancing population-based efforts to modify the social and environmental factors that promote tobacco dependence with efforts to improve the delivery of case-based treatments is necessary for realizing maximum reductions in the cost and consequences of the disease. Public health anti-smoking campaigns following the 1964 Surgeon General's report on the health risks of smoking have changed social norms, prevented initiation among youth and promoted abstinence among the addicted. However, the rate of progress enjoyed to date is unlikely to continue into the coming decades, given that current annual unassisted cessation rates among prevalent smokers remains fairly low. With over one billion patient interactions annually, there is an enormous unrealized capacity for healthcare systems to impact this problem. Clinicians report a perceived lack of reimbursement as a significant barrier to full integration of tobacco dependence into healthcare. A more complete understanding of the coding and documentation requirements for successful practice in this critically important area is a prerequisite to increasing engagement. This paper presents several case-based scenarios illustrating important practice management issues related to the treatment of tobacco dependence in healthcare.

original research 
Margaret L. Salisbury, MD; Meng Xia, MS; Yueren Zhou, MS; Susan Murray, ScD; Nabihah Tayob, ScD; Kevin K. Brown, MD; Athol U. Wells, MD; Shelley L. Schmidt, MD; Fernando J. Martinez, MD; Kevin R. Flaherty, MD
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Background:  Idiopathic pulmonary fibrosis is a progressive lung disease with variable course in individuals. The Gender-Age-Physiology (GAP) Index stage uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future pulmonary function decline. We assess whether the GAP stage predicts future pulmonary function decline, and whether interval pulmonary function change predicts mortality after accounting for stage.

Methods:  Patients with Idiopathic Pulmonary Fibrosis (n=657) were identified retrospectively at three tertiary referral centers and baseline GAP stage assessed. Mixed models describe average trajectories of forced vital capacity (FVC) and diffusion capacity (DLCO). Multivariable Cox proportional hazards models assess whether pulmonary function declines of 10% or more in 6 months predict mortality after accounting for stage.

Results:  Over 2 years, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or DLCO over 6 months independently predicted death or transplant (FVC HR=1.37, DLCO HR 1.30, both p≤0.03). GAP stage 2 patients with declining pulmonary function experienced a survival profile similar to GAP 3 patients with 1-year event-free survival of 59.3% (CI95% 49.4-67.8) versus 56.9% (CI95% 42.2-69.1).

Conclusions:  Baseline GAP stage predicts death or lung transplantation, but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of 10% or more over 6 months independently predicts death or lung transplant.

original research 
Laurent Fauchier, MD; Coralie Lecoq, MD; Nicolas Clementy, MD; Anne Bernard, MD; Denis Angoulvant, MD; Fabrice Ivanes, MD; Dominique Babuty, MD; Gregory Y.H. Lip, MD
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Background  It remains uncertain whether patients with atrial fibrillation (AF) and a single additional stroke risk factor (CHA2DS2-VASc score = 1 in males, 2 in females) should be treated with oral anticoagulation (OAC). We investigated the risk of ischemic stroke, systemic embolism and death in a community-based cohort of unselected AF patients with a 0-1 stroke risk factors, based on the CHA2DS2-VASc score.

Methods  Among 8962 patients with AF seen between 2000 and 2010, 2177 (24%) had 0 or 1 additional stroke risk factor, of which 53% were prescribed OAC.

Results  Over a follow-up of 979±1158 days, 151 (7%) had a major adverse event (stroke/systemic thromboembolism/death). Prescription of OAC was not associated with a better prognosis for stroke/systemic thromboembolism/death for ‘low risk’ patients (ie. CHA2DS2-VASc score = 0 for men or 1 for women) [adjusted Hazard Ratio(HR) 0.68, 95% CI 0.35-1.31, p=0.25 ]. OAC use was independently associated with a better prognosis in AF patients with a single additional stroke risk factor (ie. CHA2DS2-VASc score = 1 in males, 2 in females) [adjusted HR 0.59, 95% CI 0.40-0.86, p=0.007].

Conclusion  Among AF patients with one single additional stroke risk factor (CHA2DS2-VASc score = 1 in males, 2 in females), OAC use was associated with an improved prognosis for stroke/systemic thromboembolism/death.

original research 
Wan-Jie Gu, MD; Xiang-Dong Wu, MSc; Fei Wang, MD, PhD; Zheng-Liang Ma, MD, PhD; Xiao-Ping Gu, MD, PhD
Topics: ,

BACKGROUND:  Potential benefits and possible risks associated with ultrasound guidance compared with traditional palpation for radial artery catheterization are not fully understood.

METHODS:  We searched PubMed, Embase, and the Cochrane Library through July 2015 to identify randomized controlled trials that evaluated ultrasound guidance compared with traditional palpation for radial artery catheterization. The primary outcome was first-attempt failure. Secondary outcomes included mean attempts to success, mean time to success, and hematoma complications. Random-effects model was used to estimate relative risks (RRs) with 95% confidence intervals (CIs).

RESULTS:  Twelve trials used dynamic two-dimensional (2D) ultrasound guidance (N = 1,992), and two used Doppler ultrasound guidance (N = 666). Compared with traditional palpation, dynamic 2D ultrasound guidance was associated with a reduced first-attempt failure (RR, 0.68; 95% CI, 0.52–0.87). Trial sequential analysis showed that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit establishing sufficient and conclusive evidence. Dynamic 2D ultrasound guidance further reduced mean attempts to success, mean time to success, and hematoma complications. No evidence of publication bias was detected. Compared with traditional palpation, Doppler ultrasound guidance had no benefit on first-attempt failure (RR, 1.00; 95% CI, 0.87–1.15), which was confirmed by trial sequential analysis as the cumulative Z-curve entered the futility area.

CONCLUSIONS:  The use of dynamic 2D ultrasound guidance for radial artery catheterization decreases first-attempt failure, mean attempts to success, mean time to success, and the occurrence of hematoma complications. Dynamic 2D ultrasound guidance is recommended as an adjunct to aid radial arterial catheterization.

evidence-based medicine 
Peter Gibson, MBBS; Gang Wang, MD, PhD; Lorcan McGarvey, MD; Anne E. Vertigan, PhD, MBA, BAppSc (SpPath); Kenneth W. Altman, MD, PhD; Surinder S. Birring, MB ChB, MD on behalf of the CHEST Expert Cough Panel

Background:  Unexplained chronic cough (UCC) causes significant quality of life impairment. There is a need to identify effective assessment and treatment approaches for UCC.

Methods:  This systematic review of randomized controlled clinical trials asked: What is the efficacy of treatment compared to usual care on cough severity, cough frequency, and cough-related quality of life in patients with unexplained chronic cough (UCC)? Studies of adults and adolescents >12 years with a chronic cough of >8 weeks duration that was unexplained after systematic investigation and treatment were included and assessed for relevance and quality. Based upon the systematic review, guideline suggestions were developed and voted upon using CHEST organization methodology.

Results:  11 RCTs and 5 systematic reviews were included. The 11 RCTs reported data on 570 participants with chronic cough who received a variety of interventions. Study quality was high in 10 RCTs. The studies used a variety of descriptors and assessments to identify unexplained chronic cough. While gabapentin and morphine showed positive effects on cough-related quality of life, only gabapentin was supported as a treatment recommendation. Studies of inhaled corticosteroids (ICS) suffered from intervention fidelity bias, and when this was addressed, ICS were not found to be effective for UCC. Esomeprazole was not effective for UCC without features of gastroesophageal acid reflux. Studies addressing non-acid gastroesophageal reflux were not identified. A multimodality speech pathology intervention improved cough severity.

Conclusions:  The evidence supporting the diagnosis and management of UCC is limited. UCC requires further study to establish agreed terminology and the optimal methods of investigation using established criteria for intervention fidelity. Speech pathology based cough suppression is suggested as a treatment option for UCC. This guideline presents suggestions for diagnosis and treatment based on the best available evidence and identifies gaps in our knowledge and areas for future research.

evidence-based medicine  FREE TO VIEW
Momen M. Wahidi, MD, MBA, FCCP; Felix Herth, MD, FCCP; Kazuhiro Yasufuku, MD, PhD, FCCP; Ray Wesley Shepherd, MD, FCCP; Lonny Yarmus, DO, FCCP; Mohit Chawla, MD, FCCP; Carla Lamb, MD, FCCP; Kenneth R. Casey, MD, MPH, FCCP; Sheena Patel, MPH; Gerard A. Silvestri, MD, MS, FCCP; David J. Feller-Kopman, MD, FCCP
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Background:  Endobronchial ultrasound (EBUS) was introduced in the last decade, enabling real-time guidance of transbronchial needle aspiration (TBNA) of mediastinal and hilar structures and parabronchial lung masses. Many publications about EBUS-TBNA have led to a better understanding of the performance characteristics of this procedure. The goal of this document is to examine the current literature on the technical aspects of EBUS-TBNA as related to patient, technology, and proceduralist’s factors to provide evidence-based and expert guidance to clinicians.

Methods:  Rigorous methodology has been applied to provide a trustworthy evidence-based guideline and expert panel report. A group of approved panelists developed key clinical questions using the PICO (population, intervention, comparator, and outcome) format that addressed specific topics on the technical aspects of EBUS-TBNA. MEDLINE via PubMed and the Cochrane Library were systematically searched for relevant literature, supplemented by manual searches. References were screened for inclusion and recognized document evaluation tools were utilized to assess the quality of included studies, to extract meaningful data, and to grade the level of evidence to support each recommendation or suggestion.

Results:  Our systematic review and critical analysis of the literature on 15 PICO questions related to the technical aspects of EBUS-TBNA resulted in 12 statements: 7 evidence-based graded recommendations; and 5 ungraded consensus-based statements Three questions did not have sufficient evidence to generate a statement.

Conclusions:  Evidence on the technical aspects of EBUS-TBNA varies in strength, but is satisfactory in certain areas to guide clinicians on the best conditions to perform EBUS-guided tissue sampling. Additional research is needed to enhance our knowledge on the optimal performance of this effective procedure.

original research 
Tsuyoshi Tanabe, MD, Ph.D; Bruce K. Rubin, MD, MEngr, MBA
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Background:  IL-13 is Th2 cytokine that plays an important role in the pathogenesis of asthma. IL-13 exposure 14 days transforms cultured normal human bronchial epithelial (NHBE) cells to a goblet cell phenotype. We hypothesized that goblet cells would have a different pattern of cytokine secretion than ciliated airway cells.

Methods:  NHBE cells were grown for 14 days at air-liquid interface with IL-13 to produce a goblet cell phenotype (n=4) or with PBS to produce ciliated cells (n=4). We also acutely exposed ciliated cells to IL-13 for 24 hours (n=4). Apical (airside) and basolateral medium was collected and multiplex immunoassay of 27 cytokines and inflammatory mediators was performed. The pattern of mediator secretion was then compared.

Results:  The goblet cell phenotype secreted greater amounts of pro-inflammatory cytokines and mediators than ciliated cells and, for the most part, apical secretion was greater than secretion into the basolateral medium. Apical IL-4, IL-5 (p<0.0033) and IL -9 (p<0.001), and basolateral IL-9, IL-13 (p<0.0001), eotaxin, IL-17 (p<0.0033), bFGF (p<0.001), VEGF (p<0.0001) were secreted in greater amounts from goblet cells than from ciliated cells. IL-8 was secreted in higher concentration in both apical (p<0.0001) and basolateral (p<0.0033) compartments from the goblet cells. Ciliated cells exposed to IL-13 for just 24 hours had modestly increased apical IL-8 secretion (p<0.0033) but no increase in other cytokines.

Conclusions:  Inflammatory mediators released from goblet cells may act in an autocrine and paracrine manner to enhance inflammation, in diseases like asthma where there is increased IL-13 and goblet cell hyperplasia.

original research 
Ankit Bharat, MD; Nicole Graf, CNP; Andrew Mullen, PA; Jacob Kanter; Adin-Cristian Andrei, PhD; Peter H. S. Sporn, MD; Malcolm M. DeCamp, MD; Jacob I. Sznajder, MD
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Background:  Persistent air leak (PAL) greater than 5 days due to alveolopleural fistulae is a leading cause of morbidity following surgical resection. Elevated CO2 levels have been reported to inhibit alveolar epithelial proliferation and impair wound healing in vitro. Since the injured lung surface is in direct communication with pleural cavity, we investigated whether pleural gaseous milieu affected lung healing.

Methods:  O2 and CO2 in pleural gas were determined prospectively in consecutive patients (n=116) undergoing lung resection using infra-red spectroscopy based analyzer. Poisson and logistic regression were used to determine the relationship between time to resolution of air leaks and pleural O2 and CO2. Additionally, patients with pleural CO2 concentrations ≥6% on post-operative day 1 (n=20) were alternatively treated with supplemental O2 and extrapleural suction to reduce the pleural CO2 levels.

Findings:  Poisson analyses revealed that every one percent increase in CO2 was associated with a delay in resolution of air leak by 9 hours [95% CI (7.1, 10.8) hours, p<0.001]. Linear regression showed that every one percent increase in CO2 increased the odds of PAL by 10-folds (95% CI 2.2-47.8, p=0.003). In patients with pleural CO2≥6%, reduction in CO2 promoted resolution of air leak (6.0±1.2 vs 3.4±1.1 days, p<0.001).

Interpretation:  Pleural hypercarbia appears to be associated with persistent alveolopleural fistulae following lung resection. Analysis of pleural gases could allow for better chest tube management following lung resection, as patients with intrapleural hypercarbia appear to benefit from supplemental oxygen and suction, while patients without hypercarbia can be maintained on water seal drainage.

original research 
Sergio Koo, MPH; Atul Gupta, MD; Valentina Fainardi, MBBS; Cara Bossley, MD; Andrew Bush, MD; Sejal Saglani, MD; Louise Fleming, MD
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Background:  Ethnicity may influence response to treatment of asthmatic patients, but this is controversial. This study’s objective is to determine if ethnicity influences the response to intramuscular steroid (eliminating adherence as an issue).

Methods:  Children with severe therapy resistant asthma who had previously undergone a detailed assessment when potentially modifiable factors had been identified and addressed were admitted for further evaluation including assessment of steroid response. Children were classified as Caucasian, black, Asian or mixed Caucasian / black. Steroid responsiveness was defined according to symptoms (Asthma Control Test), inflammation (sputum eosinophils and exhaled nitric oxide), and spirometry (FEV1) which were measured before and 4 weeks after intramuscular triamcinolone. Data were collected regarding exacerbations. FeNO response was defined as a decrease to <24 ppb.

Results:  79 subjects were identified (Caucasian = 54 (68%), Black = 16 (20%), Asian = 5 (6%), Mixed Caucasian/Black = 4 (5%)). After triamcinolone, there was a significant drop in median FeNO in Caucasians (46.8 to 23.1 ppb, p < 0.001) but not in black children (52.2 to 34.5 ppb, p = 0.58). More Black children than Caucasian (86.7%) were FeNO non-responders (86.7 vs. 45.3%, p<0.05). More Black children had exacerbations compared to Caucasian children (61 vs. 17%, p<0.05)

Conclusions:  Black asthmatic children were less likely to have a FeNO response and had more exacerbations 4 weeks after triamcinolone compared to Caucasians. Further research is needed to understand the mechanisms of these differences, but they cannot be due to differences in adherence or access to care.

original research 
Aaron J. Charnay, B.S.; Jeanne E. Antisdel-Lomaglio, Ph.D.; Frank A. Zelko, Ph.D.; Casey M. Rand, B.S.; Michele Le, B.S.; Samantha C. Gordon, B.S.; Sally F. Vitez, B.S.; Jennifer W. Tse, B.S.; Cindy D. Brogadir, R.R.T; Michael N. Nelson, Ph.D.; Elizabeth M. Berry-Kravis, M.D., Ph.D.; Debra E. Weese-Mayer, M.D.

Background:  Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-age patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay, and that CCHS-related physiologic factors would impact neurocognitive test results.

Methods:  We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0±8.5 months, range: 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them to the normative reference mean from the Bayley standardization sample, and examined associations between Bayley scores and CCHS disease-related factors.

Results:  Preschool CCHS patients fell significantly below the normative mean of 100 on Bayley indices of mental (mean 83.35 ± 24.75) and motor (mean 73.33 ± 20.48) development (P < 0.001 for both). Significantly lower Bayley mental and motor scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 hour/day artificial ventilation. Lower Bayley motor scores were also associated with seizures. Bayley scores differed among children with the three most common polyalanine repeat expansion mutation (PARM) genotypes (mental: P=0.001; motor: P=0.006), being essentially normal in children with the 20/25 genotype but significantly lower in the other genotype groups (P<0.05).

Conclusions:  These results confirm neurodevelopmental impairment of CCHS preschoolers, with severity related to physiologic compromise and PHOX2B genotype. These findings suggest that adverse effects begin early in the disease process, supporting the need for neurodevelopmental monitoring and intervention from early infancy.

original research 
Yoshihisa Shimada, M.D., Ph.D.; Hisashi Saji, M.D., Ph.D.; Yasufumi Kato, M.D., Ph.D.; Yujin Kudo, M.D., Ph.D.; Junichi Maeda, M.D., Ph.D.; Koichi Yoshida, M.D., Ph.D.; Masaru Hagiwara, M.D., Ph.D.; Jun Matsubayashi, M.D., Ph.D.; Masatoshi Kakihana, M.D., Ph.D.; Naohiro Kajiwara, M.D., Ph.D.; Tatsuo Ohira, M.D., Ph.D.; Norihiko Ikeda, M.D., Ph.D.
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Background:  Microscopic vascular invasion (MVI) in patients with non-small cell lung cancer (NSCLC) has been reported to be a strong predictor of poor outcomes, but it has not been a descriptor of the TNM classification. The purpose of this study was to determine whether the presence of MVI is related to a predictor of poor outcomes and to explore the degree of MVI according to tumor size.

Methods:  A total of 1884 patients with pT1-4N0-2 NSCLC who underwent complete resection comprised the study sample. Overall survival (OS) and recurrence-free proportion (RFP) were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to assess independent predictors of poor outcomes.

Results:  Of 1884 patients, 1097 (58.2%) had MVI. Multivariate analysis showed MVI was a significant independent predictor of unfavorable OS (HR, 1.666; p<0.001) and recurrence (HR, 2.268; p<0.001). The frequency of MVI varied according to tumor size, and in each cohort of tumor sizes < 2cm, >2cm-3cm, and >3cm-5cm, there were significant differences in survival outcome by MVI status. The proportions of patients with a 5-year recurrence-free period with tumor sizes < 2cm, >2cm-3cm, >3cm-5cm between MVI (+) and MVI (-) were 93.0% and 72.5% (p<0.001), 90.8% and 63.3% (p<0.001), and 86.4% and 59.9% (p<0.001), respectively.

Conclusions:  This study demonstrated MVI was a strong predictor of poor outcomes and the effect is more prominent in patients with tumor sizes < 5cm. Further analysis of survival and MVI should be collected for future revision of the TNM system.

original research 
Bryan R. Hay, MD; Meredith E. Pugh, MD, MSCI; Ivan M. Robbins, MD; Anna R. Hemnes, MD
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Introduction:  Evidence based guidelines recommend the use of parenteral prostaglandin (PP) therapy in patients with advanced pulmonary arterial hypertension (PAH). Despite this, many PAH patients die without PP therapy. We sought to examine the frequency of PP use at a large referral center and characterize those PAH patients who died without receiving PP.

Methods:  We conducted a single-center retrospective cohort analysis of consecutive PAH patients between 2008 and 2012. Clinical data and cause of death were compared between patients treated with PP (PAH-PP) and those who were not, but were not documented as poor PP candidates (PAH-nonPP).

Results:  Of the 101 patients who were diagnosed with PAH and died, 61 received PP therapy. Of the 40 patients not treated with PP, 10 did not have documented evaluations for PP therapy (PAH-nonPP) while 30 were not considered candidates or refused PP therapy. Compared to PAH-PP, PAH-nonPP patients had a longer six-minute walk distance, a longer duration between time of diagnosis and date of worse functional class visit, were less likely to be functional class IV, and had significantly lower right atrial pressure. None of the PAH-non-PP patients died of progressive PAH.

Conclusions:  We found that the majority of patients who die with PAH are evaluated for PP therapy at a large referral center and the small minority of PAH-nonPP tended to have less severe disease and die of non-PAH related causes. Our data suggests that at large PH centers, the vast majority of patients who are appropriate candidates receive PP therapy.

original research 
Khagendra Dahal, MD; Sumit Kunwar, MD; Jharendra Rijal, MD; Peter Schulman, MD; Juyong Lee, MD, PHD
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Background:  The use of warfarin in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) can be problematic due to increased bleeding risk. We performed a systematic review and meta-analysis of observational studies that evaluated the use of warfarin in patients with AF and CKD to evaluate the risks of ischemic stroke/thromboembolism (IS/TE), major bleeding and mortality.

Methods:  PUBMED, EMBASE, CINAHL, ProQuest and Google Scholar databases were electronically searched through 1/12/2015. Additionally, manual search was performed for relevant references. Random-effects model was used to estimate the pooled hazard ratio (HR) with 95% confidence interval (CI). CKD was divided into non-end-stage CKD and end-stage CKD (on renal replacement therapy) and separate analyses were performed.

Results:  A total of 13 publications from 11 cohorts (6 retrospective and 5 prospective) including >48, 500 total patients with >11, 600 warfarin users were included in the meta-analysis. In patients with AF and non-end-stage CKD, warfarin resulted in a lower risk of ischemic stroke/thromboembolism (HR 0.70; 95% CI 0.54-0.89; P=0.004) and mortality (0.65; 0.59-0.72; P<0.00001) but had no effect on major bleeding (1.15; 0.88-1.49; P=0.31). In patients with AF and end-stage CKD, warfarin had no effect on the risks of stroke (1.12; 0.69-1.82; P=0.65) and mortality (0.96; 0.81-1.13; P=0.60) but increased the risks of major bleeding (1.30; 1.08-1.56; P=0.005).

Conclusions:  Based on this meta-analysis, the use of warfarin for AF may have an unfavorable risk/benefit ratio in patients with end-stage CKD but not in those with non-end stage CKD.

commentary  OPEN ACCESS
Frances Chung, MBBS; Hairil R. Abdullah, MBBS; Pu Liao, MD

  Today, there exists a high prevalence of obstructive sleep apnea (OSA) in the general population, a great proportion of which remains undiagnosed. The STOP-Bang questionnaire has been specifically developed to meet the need for a reliable, concise and easy-to-use screening tool. It consists of eight dichotomous (yes/no) items related to the clinical features of sleep apnea (Snoring, Tiredness, Observed apnea, high blood Pressure, BMI, age, neck circumference and male gender). The total score ranges from 0 to 8. Patients can be classified for their OSA risk based on their respective scores.

  The sensitivity of STOP-Bang score ≥3 to detect moderate-to-severe OSA (AHI > 15) and severe OSA (AHI > 30) is 93% and 100% respectively. The corresponding negative predictive values are 90% and 100%. As the STOP-Bang score increases from 0-2 to 7-8, the probability of moderate-to-severe OSA increases from 18% to 60%, and the probability of severe OSA rises from 4% to 38%. Patients with a STOP-Bang score of 0 to 2 can be classified as “low risk” for moderate-to-severe OSA, while those with a score of 5 to 8 can be classified as “high risk” for moderate-to-severe OSA. In patients whose STOP-Bang scores land in the mid-range (3 or 4), further criteria are required for classification. For example, a STOP score of ≥ 2 + BMI > 35 kg/m2 would classify that patient as having a high risk for moderate-to-severe OSA. In this way, patients can be stratified for their OSA risk according to their STOP-Bang scores.

contemporary reviews in sleep medicine 
Kelly M. Brown, M.D.; Beth A. Malow, M.D., M.S.
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Insomnia in children is complex and frequently multifactorial. This review discusses the major categories of insomnia, as well as common causes. The consequences of insomnia, including issues with mood, behavior and cognition, are discussed. Sleep disorders are much more prevalent in certain pediatric populations, such as children with autism spectrum disorders. The evaluation of insomnia in children includes a focused history and exam, and occasionally actigraphy or polysomnography. Behavioral and pharmacological therapies are discussed, as well as future directions for research and clinical practice.

contemporary reviews in critical care medicine 
Bandarn Suetrong; Keith R. Walley
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Increased blood lactate concentration (hyperlactatemia) and lactic acidosis (hyperlactatemia and serum pH < 7.35) are common in patients with severe sepsis or septic shock and are associated with significant morbidity and mortality. In some patients most of the lactate that is produced in shock states is due to inadequate oxygen delivery resulting in tissue hypoxia causing anaerobic glycolysis. However, lactate formation during sepsis is not entirely related to tissue hypoxia nor reversible by increasing oxygen delivery. In this review we initially outline the metabolism of lactate and etiology of lactic acidosis. Then we address the pathophysiology of lactic acidosis in sepsis. We discuss the clinical implications of serum lactate measurement in diagnosis, monitoring, and prognostication in acute and intensive care settings. Finally, we explore treatment of lactic acidosis and its impact on clinical outcome.

original research 
Galit Aviram, MD; Eugene Soikher, MD; Achiude Bendet, MD; Hezzy Shmueli, MD; Tomer Ziv-Baran, PhD; Yoav Amitai, MD; Limor Friedensohn, MD; Shlomo Berliner, MD, PhD; Ahuava Meilik, PhD; Yan Topilsky, MD
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BACKGROUND:  Preliminary reports suggest that a small left atrium (LA) is associated with severe acute pulmonary embolisms (PE). This study used data derived from volumetric analyses of computerized tomographic pulmonary angiography (CTPA) to investigate whether a reduced LA volume can predict adverse outcome in a large series of patients with acute PE.

METHODS:  We retrospectively analyzed 756 consecutive patients diagnosed with acute PE by non-gated CTPA between 1/2007-12/2010. Each CTPA was investigated with volumetric analysis software which automatically provides the volumes of the LA, right atrium (RA), right ventricle (RV), and left ventricle (LV). A classification tree divided the cardiac chamber volumes and ratios into categories according to mortality. Cox regression assessed the association between these categories and 30-day mortality after adjustment for age, gender and clinical background.

RESULTS:  The final study group consisted of 636 patients who had successful volumetric segmentation and complete outcome data. Eighty-four patients (13.2%) died within 30 days of PE diagnosis. There was a higher mortality rate among patients with an LA volume ≤62 ml compared to those with LA volume >62 ml (19.6% vs 8.9%, respectively, hazard ratio [HR]=2.44, P < .001), an LV volume ≤67 ml (16.4% vs 8.3%, HR=1.8, P = .024) and an RA/LA volume ratio >1.2 (17% vs 9.4%, HR=2.1, P = .002). A reduced LA volume was the best predictor of adverse outcome.

CONCLUSIONS:  Decreased LA volume is associated with higher mortality and is the first among the various cardiac compartments to predict mortality in patients with acute PE.

original research 
Alex A. Balekian, MD, MSHS; Joshua M. Fisher, BA; Michael K. Gould, MD, MS
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Background:  The Choosing Wisely recommendations from the Society of Thoracic Surgeons include avoiding brain imaging in asymptomatic patients with early-stage non-small cell lung cancer (NSCLC). We aimed to describe use of brain imaging among National Lung Screening Trial (NLST) participants with stage IA NSCLC, and to identify factors associated with receipt of brain imaging.

Methods:  We identified clinical stage IA patients who received computed tomography (CT) or magnetic resonance (MR) brain imaging within 60 days after diagnosis but before definitive surgical staging. Using multivariate logistic regression, we identified variables associated with undergoing brain imaging.

Results:  Among 643 clinical Stage IA patients, 77 patients (12%) received at least one brain imaging study. Of 7 patients (1.1%) who were upstaged to Stage IV, only two underwent brain imaging and neither had documentation of brain metastasis. Brain imaging frequency by enrollment center varied from 0%-80%. All patients who underwent brain imaging subsequently underwent surgery with curative intent, suggesting strongly that imaging revealed no evidence of intracranial metastases. In multivariate analyses, primary tumor size >20mm [OR 2.50 (95% CI 1.50 – 4.16), p<0.001] and age 65 – 69 [OR 2.78 (95% CI 1.38 – 5.57), p<0.01] were independently associated with greater use of brain imaging.

Conclusions:  Among NLST patients with stage IA NSCLC, one in eight underwent brain imaging, but none ultimately had intracranial metastases. Larger tumor size and older age were associated with greater use of brain imaging. Wide variation in use between centers suggests either lack of awareness or disagreement about this Choosing Wisely recommendation.

original research 
A.B. Chang, MBBS, PhD; J.J. Oppenheimer, MD; M. Weinberger, MD, FCCP; K. Weir, PhD; B.K. Rubin, MD; R.S. Irwin, Master FCCP

Background:  Use of appropriate cough pathways or algorithms may reduce the morbidity of chronic cough, lead to earlier diagnosis of chronic underlying illness and reduce the unnecessary costs and medications. We undertook 3 systematic reviews to examine three related key questions (KQ). In children aged ≤ 14 years with chronic cough (>4 weeks duration); KQ1-Do cough management protocols (or algorithms) improve clinical outcomes? KQ2-Should the cough management or testing algorithm differ depending on the duration and/or severity? KQ3-Should the cough management or testing algorithm differ depending on the associated characteristics of the cough and clinical history?

Methods:  We used the CHEST expert cough panel’s protocol. Two authors screened searches, selected and extracted data. Only systematic reviews, randomized controlled trials and cohort studies published in English were included.

Results:  Data were presented in PRISMA flowcharts and summary tabulated. Nine studies were included in KQ1 (RCT=1, cohort studies=7), 8 in KQ3 (RCT=2, cohort=6) but none in KQ2.

Conclusion:  There is high quality evidence that in children aged ≤14 years with chronic cough (>4 weeks duration); the use of cough management protocols (or algorithms) improves clinical outcomes and; cough management or testing algorithm should differ depending on the associated characteristics of the cough and clinical history. It remains uncertain whether the management or testing algorithm should depend on the duration and/or severity of chronic cough. Pending new data, chronic cough in children should be defined as >4 weeks duration and children should be systematically evaluated with treatment targeted to the underlying etiology irrespective of the cough severity.

translating basic research into clinical practice 
Amanda T. Goodwin, MBChB; Gisli Jenkins, PhD

Idiopathic pulmonary fibrosis (IPF) is a devastating and incurable progressive fibrotic lung condition associated with a significant disease burden. In recent years there has been an exponential increase in the number of pre-clinical and clinical studies performed in IPF. However, IPF is defined according to rigid diagnostic criteria, hence a significant subset of patients with ‘unclassifiable’ disease have been excluded from these studies. The traditional diagnostic classification of all progressive fibrotic lung diseases uses specific clinical, radiological and histopathological features to define each condition. However, the considerable heterogeneity within each form of pulmonary fibrosis has raised the possibility of distinct pathophysiological mechanisms culminating in a common phenotype. Thus, the classification of fibrotic lung diseases according to the driving molecular mechanisms, rather than specific user-defined histopathological and radiological features, could improve several aspects of clinical care. Discoveries from basic science research have defined multiple complex molecular pathways involved in the pathogenesis of pulmonary fibrosis, which may provide markers for the molecular endotyping of this disease. In addition, these molecular pathways have revealed potential therapeutic targets. Importantly, re-classifying progressive fibrotic lung diseases according to molecular endotypes may allow for the more accurate assessment of prognosis and individualised treatment. Furthermore, the recent developments that have been applied to a narrow group of patients with IPF may be applicable to other progressive fibrotic lung diseases. This review presents the latest developments from translational research in this area, and explains how molecular endotyping could revolutionise the diagnosis, stratification and treatment of pulmonary fibrosis.

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