Current Issue


Chest. 2014;146(5):1135-1136. doi:10.1378/chest.14-1194

Hepatocyte growth factor (HGF) (previously known as scatter factor) is a multifunctional cytokine that is secreted by mesenchymal cells, such as fibroblasts, and has effects on epithelial cell growth, morphogenesis, motility, and survival that are mediated by the proto-oncogenic receptor c-Met.1 It plays a key role in the development of organs such as the lung, where it promotes branching of airways and alveolar formation and has been implicated in lung repair.2 Stem cells expressing HGF have been identified in human lung and, by extrapolation from animal studies, are antifibrotic.3 Studies have shown that in mice deficient in c-Met there is a loss of alveolar wall integrity due to loss of alveolar cells, attenuation of the pulmonary vasculature, and an increase in oxidative stress, closely analogous to emphysema. Furthermore, treatment of primary alveolar cells with HGF promotes cell survival and enhanced production of antioxidants.4 Fibroblasts cultured from emphysematous lung produce less HGF than normal and it has been implicated in impaired alveolar repair in emphysema.5 With this background, it is surprising that so little attention has been paid to the role of HGF in COPD. However, in this issue of CHEST (see page 1159), Kanazawa et al,6 in a clinical study from Japan, show convincing evidence for reduced secretion of HGF in peripheral lung of patients with COPD compared with age-matched normal smokers and healthy control subjects and that this is correlated with disease severity and reduced gas transfer. This is consistent with a reduction in HGF having a role in emphysema, and, indeed, there is also a correlation between reduced HGF concentrations and low attenuation areas (emphysema) on the CT scan.

Chest. 2014;146(5):1136-1138. doi:10.1378/chest.14-0722

The prospective study by Shapiro et al1 in this issue of CHEST (see page 1176) has enhanced our previous knowledge of the incidence of laterality defects, including congenital heart disease (CHD), in patients with primary ciliary dyskinesia (PCD), an inherited, usually autosomal recessive disorder with impaired ciliary function leading to unexplained neonatal respiratory distress, recurrent otitis media, chronic nasal drainage and sinusitis, and chronic bronchitis leading to bronchiectasis.2 The nomenclature for abnormal thoracoabdominal asymmetry varies. In keeping with the article by Shapiro et al,1 this editorial refers to the mirror image of normal as “situs inversus” and any other organ distribution as “situs ambiguus” with combined situs ambiguus and CHD benign referred to as “heterotaxy.” Although traditionally, knowledge of abnormal thoracoabdominal asymmetry is important in trauma and surgery, and patients with asplenia (a subset of heterotaxy) may be at increased risk of infection, it is the cardiovascular defects that lead to morbidity in patients with heterotaxy. Another study looking for ciliary dysfunction in patients with heterotaxic CHD also pointed toward a significant overlap with 18 of 43 patients with heterotaxic CHD (41%) having abnormal ciliary motion and nasal nitric oxide levels below or near the PCD cutoff values.3 Learning points from both these studies are that a PCD-CHD overlap phenotype exists and that we should consider screening for CHD in patients with PCD and for PCD in patients with CHD, especially if they have certain phenotypic features (eg, productive cough and neonatal respiratory compromise in patients with CHD, evidence of heart failure and cardiac murmur in patients with PCD, or relevant family history in either group). However, questions remain, including (1) the precise incidence of this PCD-CHD overlap, (2) why it is more common in animal models of PCD, and (3) how much CHD could be attributed to ciliary dysfunction.

Chest. 2014;146(5):1138-1140. doi:10.1378/chest.14-0986

Despite the advancement of antimicrobial agents, sepsis remains a major global health issue and leading cause of death in low-income countries. In the United States, severe sepsis affects up to 750,000 Americans and is associated with a high mortality rate.1 In severe sepsis, atrial fibrillation (AF) also commonly occurs.2 Sepsis may precipitate AF per se, perhaps unmasking a propensity to develop the arrhythmia, or the association could reflect greater clinical vigilance or monitoring during treatment (or hospitalization) for severe sepsis. Nonetheless, the prognostic effects of sepsis-associated new-onset AF on the subsequent occurrence of AF and long-term outcomes remained uncertain until, in the present issue of CHEST, the article by Walkey et al3 (see page 1187) sheds some light on these questions.

Chest. 2014;146(5):1140-1142. doi:10.1378/chest.14-1210

Though mortality in ARDS has been improving, in unselected populations, mortality may still be as high as 40%.1 Patients with ARDS infrequently die of refractory hypoxemia and more often die due to sepsis and multiorgan failure, both complications of prolonged mechanical ventilation (MV). Inability to discontinue MV likely reflects disordered lung repair which may in part be due to excessive fibroblast activation. Markers of fibroblast activation such as procollagen III2 and transforming growth factor-β are elevated early in ARDS3 and are associated with increased mortality. Factors that have contributed to better ARDS outcomes include less-injurious MV strategies, judicious fluid management, and generally improved supportive care.4,5 As more patients with ARDS are surviving their acute illness, long-term outcomes for these patients have garnered increased attention. It has been shown in multiple studies that survivors of ARDS continue to have reduced health-related quality of life (HRQoL) for years after their acute illness.6 The cause of reduced HRQoL has most often been attributed to neuromuscular and psychosocial dysfunction.6 The contributions of residual pulmonary dysfunction have received less attention and a National Institutes of Health-sponsored ARDS workshop failed to identify fibroproliferation as a significant contributor to morbidity and mortality in the era of low-tidal-volume ventilation.7

Chest. 2014;146(5):1142-1144. doi:10.1378/chest.14-0912

Overuse of medical tests and treatments wastes health-care resources and leads to unnecessary complications, while underuse results in delayed or missed diagnoses and treatment opportunities.1 Such problems are well recognized, and there have been multiple attempts to correct inappropriate diagnostic testing and treatment over the past several decades.2 However, sustainable solutions have proven to be elusive.3

Point and Counterpoint

Chest. 2014;146(5):1145-1147. doi:10.1378/chest.14-1585

This case asks how a physician should respond to a 54-year-old former smoker (25 pack-years, quit 10 years ago) who returns to see the physician, requesting a low-dose chest CT scan to screen for lung cancer. “Doc, I know it is outside the guidelines. But I am worrying all the time that the residual scar from my pneumonia last year might be a lung cancer. And I am willing to pay cash for the study.” We are specifically asked to consider whether the physician should order the chest CT scan with the diagnosis “abnormal chest radiograph, [International Classification of Diseases, Ninth Revision] ICD-9 793.2.”

Chest. 2014;146(5):1147-1149. doi:10.1378/chest.14-1587

A 54-year-old patient, former smoker (25 pack-year history, quit 10 years ago) states, “Doc, I know it is outside the guidelines. But I am worrying all the time that the residual scar from my pneumonia last year might be a lung cancer. And I am willing to pay cash for the study.” Should a chest CT scan be ordered with the diagnosis of abnormal chest radiograph?

Chest. 2014;146(5):1149-1150. doi:10.1378/chest.14-1586

Dr Simpson1 makes a compelling argument as to why, for the overwhelming majority of patients who do not meet the current criteria for lung cancer screening with chest CT scan, such scans should not be ordered. There is no evidence whatsoever that screening chest CT scans benefit patients who are not at high risk according to current guidelines. Dr Simpson makes the additional important point that the evidence base continues to evolve, and that following publication of ongoing and future trials, we may need to revisit whether even high-risk patients derive benefit, on average, from lung cancer screening. However, even if recommendations evolved such that there was no patient group for whom screening CT scans were recommended, one still could not conclude with certainty that no individual patient might benefit from such screening. Indeed, it is mathematically impossible to prove that screening cannot benefit a group of patients, let alone an individual patient.

Chest. 2014;146(5):1150-1151. doi:10.1378/chest.14-1588

Dr Halpern1 has made several very interesting points that warrant further discussion. Physicians indeed have the responsibility to follow screening guidelines, which are established by experts in the field after reviewing all available data, weighing the risks and benefits, and taking into consideration the overall value of a given screening test.2 This patient does seem to be experiencing some psychologic stress related to the residual scar, and this must, of course, be considered when deciding how to proceed. However, the potential downstream psychologic effects and costs and the potential harm to the patient must also be considered. Assuming that this patient does have a scar by radiograph, it is not far-fetched to predict that the CT scan will also be somewhat abnormal, and this could require further potentially harmful imaging and/or procedures in an attempt to offer consolation and closure to the patient. This is a perfect opportunity for the physician to discuss with the patient the natural radiologic evolution of pneumonia, help weigh the risks and benefits of CT imaging, and offer genuine words of reassurance and encouragement for continued smoking cessation.

Giants in Chest Medicine

Chest. 2014;146(5):1152-1154. doi:10.1378/chest.14-0622

Who is this man whose name is eponymously and famously attached to a laboratory diagnosis, based on a paper he wrote when he was a medical resident? Richard Light, MD, FCCP, was born and raised in Steamboat Springs, on the western slope of the Colorado Rockies, before it was a popular ski resort. His family ran a clothing supply business and a fox and mink farm. His grandfather had migrated from Missouri to Colorado in 1905, taking a horse-drawn stagecoach from Denver across the Rockies, and the Lights became prominent citizens of this rural western town.


Chest. 2014;146(5):1155-1158. doi:10.1378/chest.14-1212

The appropriate justification for using a diagnostic or therapeutic intervention is that it provides benefit to patients, society, or both. For decades, indwelling arterial catheters have been used very commonly in patients in the ICU, despite a complete absence of data addressing whether they confer any such benefits. Both of the main uses of arterial catheters, BP monitoring and blood sampling for laboratory testing, can be done without these invasive devices. Prominent among complications of arterial catheters are bloodstream infections and arterial thrombosis. To my knowledge, only a single observational study has assessed a patient-centered outcome related to arterial catheter use, and it found no evidence that they reduce hospital mortality in any patient subgroup. Given the potential dangers, widespread use, and uncertainty about consequences of arterial catheter use in ICUs, equipoise exists and randomized trials are needed. Multiple studies in different, well-characterized, patient subgroups are needed to clarify whether arterial catheters influence outcomes. These studies should assess the range of relevant outcomes, including mortality, medical resource use, patient comfort, complications, and costs.

Original Research: COPD

Chest. 2014;146(5):1159-1165. doi:10.1378/chest.14-0373

BACKGROUND:  Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of various lung diseases. This study was designed to determine the possible interactions of these growth factors in the development of COPD.

METHODS:  We measured the levels of HGF and VEGF in epithelial lining fluid obtained from central or peripheral airways using a bronchoscopic microsampling technique in 10 never smokers, 14 smokers without COPD, and 24 smokers with COPD. We also evaluated whether their levels were correlated with pulmonary function parameters and the grade of low attenuation area (LAA) observed in high-resolution CT scans.

RESULTS:  HGF and VEGF levels in the peripheral airways of smokers with COPD were significantly lower than those in never smokers and smokers without COPD. In smokers with COPD, HGF and VEGF levels of the peripheral airways inversely correlated with the degree of airway obstruction and diffusing capacity of the lung. The HGF and VEGF levels also correlated with the grade of LAA. Although the VEGF levels of smokers with and without COPD overlapped considerably, HGF levels were markedly higher in smokers without COPD.

CONCLUSIONS:  Upregulated HGF probably compensated for the reduced levels of VEGF and preserved the pulmonary function in smokers without COPD. By contrast, both HGF and VEGF levels were decreased in smokers with COPD, which likely led to the development of COPD. Thus, the level of HGF relative to that of VEGF may be a reliable indicator of the risk for COPD.

Chest. 2014;146(5):1166-1175. doi:10.1378/chest.13-2484

BACKGROUND:  Dose-dependent adverse lung effects due to indium exposure have been reported in a cross-sectional study. This is a 5-year longitudinal cohort study of indium-exposed and unexposed workers, assessing indium exposure levels and its clinical lung effects.

METHODS:  From 2008 to 2011, a 5-year follow-up study was conducted on 40 unexposed and 240 workers formerly or currently exposed to indium at 11 factories. Indium exposure was assessed by serum indium (In-S) (μg/L). Lung effects were assessed by subjective symptoms, serum biomarkers, spirometry, and chest high-resolution CT scan. Effect biomarkers used were Krebs von den Lungen and surfactant protein D.

RESULTS:  Mean values of In-S, Krebs von den Lungen, and surfactant protein D among the workers exposed to indium at baseline declined during the 5-year follow-up by 29.8%, 27.2%, and 27.5%, respectively. Of the exposed subjects with In-S levels > 20 μg/L, 26.3% experienced emphysematous progression on high-resolution CT scan. Ninety percent (18 of 20) of workers with emphysematous progression during follow-up were current smokers at baseline, and a trend of increasing incidence of emphysematous progression at higher In-S levels was observed among the smokers (P = .005). Emphysematous changes among subjects with In-S levels > 20 μg/L were likely to progress, after adjusting for age, mean duration since initial indium exposure, and smoking history (OR = 10.49, 95% CI = 1.54-71.36).

CONCLUSIONS:  Long-term adverse effects on emphysematous changes were observed. The results suggest workers exposed to indium with In-S levels > 20 μg/L should be immediately removed from exposure.

Original Research: Genetic and Developmental Disorders

Chest. 2014;146(5):1176-1186. doi:10.1378/chest.13-1704

BACKGROUND:  Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.

METHODS:  In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD.

RESULTS:  Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P < .001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P < .001).

CONCLUSIONS:  At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov

Original Research: Critical Care

Chest. 2014;146(5):1187-1195. doi:10.1378/chest.14-0003

BACKGROUND:  New-onset atrial fibrillation (AF) is associated with adverse outcomes during a sepsis hospitalization; however, long-term outcomes following hospitalization with sepsis-associated new-onset AF are unclear.

METHODS:  We used a Medicare 5% sample to identify patients who survived hospitalization with sepsis between 1999 and 2010. AF status was defined as no AF, prior AF, or new-onset AF based on AF claims during and prior to a sepsis hospitalization. We used competing risk models to determine 5-year risks of AF occurrence, heart failure, ischemic stroke, and mortality after the sepsis hospitalization, according to AF status during the sepsis admission.

RESULTS:  We identified 138,722 sepsis survivors, of whom 95,536 (69%) had no AF during sepsis, 33,646 (24%) had prior AF, and 9,540 (7%) had new-onset AF during sepsis. AF occurrence following sepsis hospitalization was more common among patients with new-onset AF during sepsis (54.9%) than in patients with no AF during sepsis (15.5%). Compared with patients with no AF during sepsis, those with new-onset AF during sepsis had greater 5-year risks of hospitalization for heart failure (11.2% vs 8.2%; multivariable-adjusted hazard ratio [HR], 1.25; 95% CI, 1.16-1.34), ischemic stroke (5.3% vs 4.7%; HR, 1.22; 95% CI, 1.10-1.36), and death (74.8% vs 72.1%; HR, 1.04; 95% CI,1.01-1.07).

CONCLUSIONS:  Most sepsis survivors with new-onset AF during sepsis have AF occur after discharge from the sepsis hospitalization and have increased long-term risks of heart failure, ischemic stroke, and death. Our findings may have implications for posthospitalization surveillance of patients with new-onset AF during a sepsis hospitalization.

Chest. 2014;146(5):1196-1204. doi:10.1378/chest.13-2708

BACKGROUND:  In ARDS, the extent of fibroproliferative activity on chest high-resolution CT (HRCT) scan has been reported to correlate with poorer short-term outcomes and pulmonary-associated quality of life. However, clinical factors associated with HRCT scan fibroproliferation are incompletely characterized. We questioned if lung compliance assessed at the bedside would be associated with fibroproliferation on HRCT scans obtained during the resolution phase of ARDS.

METHODS:  We used data from a published randomized, controlled clinical trial in ARDS. All patients were cared for using a low tidal volume strategy. Demographic data and ventilator parameters were examined in association with radiologic scores from chest HRCT scans obtained 14 days after diagnosis.

RESULTS:  Data from 82 patients with ARDS were analyzed. Average static respiratory compliance over the first 14 days after diagnosis was inversely associated with chest HRCT scan reticulation (ρ = −0.46); this relationship persisted in multivariable analysis including APACHE (Acute Physiology and Chronic Health Evaluation) II scores, initial Pao2/Fio2, pneumonia diagnosis, and ventilator days. Average static respiratory compliance was also lower among patients with bronchiectasis at day 14 (P = .007). Initial static respiratory compliance obtained within the first day after ARDS diagnosis was correlated inversely with the presence of HRCT scan reticulation (ρ = −0.38) and was lower among patients who demonstrated bronchiectasis on the day 14 HRCT scan (P = .008).

CONCLUSIONS:  In patients with ARDS, diminished lung compliance measured bedside was associated with radiologic fibroproliferation 14 days post diagnosis. Establishing factors that predispose to development of excessive fibroproliferation with subsequent confirmation by chest HRCT scan represents a promising strategy to identify patients with ARDS at risk for poorer clinical outcomes.

Chest. 2014;146(5):1205-1213. doi:10.1378/chest.13-2618

OBJECTIVES:  This study evaluated the influence of the immune profile on the outcome at day 28 (D28) of patients admitted to the ICU for septic shock or severe sepsis.

METHODS:  We conducted an observational study using a prospective multicenter database and included all patients admitted to 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 1,981 included patients, 607 (31%) were immunocompromised (including nonneutropenic solid tumor [19.6%], nonneutropenic hematologic malignancies [26.3%], and all-cause neutropenia [28%]). Compared with immunocompetent patients, immunocompromised patients were younger, with less comorbidity, were more often admitted for medical reasons, and presented less often with septic shock. The D28 crude mortality was 31.3% in immunocompromised patients and 28.8% in immunocompetent patients (P = .26). However, after adjustment for other prognostic factors, immunodeficiency was an independent risk factor for death at D28 (subdistribution hazard ratio [sHR], 1.37; 95% CI, 1.12-1.67). The immunodeficiency profiles independently associated with death were AIDS (sHR = 1.9), non-neutropenic solid tumor (sHR = 1.8), nonneutropenic hematologic malignancies (sHR = 1.4), and all-cause neutropenia (sHR = 1.7).

CONCLUSIONS:  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.

Chest. 2014;146(5):1214-1225. doi:10.1378/chest.13-2110

BACKGROUND:  Outcomes after in-hospital CPR in older adults with chronic illness are unclear.

METHODS:  We examined inpatient Medicare data from 1994 through 2005 to identify CPR recipients. We grouped beneficiaries aged ≥ 67 years by severity of six chronic diseases—COPD, congestive heart failure (CHF), chronic kidney disease (CKD), malignancy, diabetes, and cirrhosis—and investigated survival to discharge, discharge destination, rehospitalizations, and long-term survival.

RESULTS:  We identified 358,682 CPR recipients. Most patients with chronic disease were less likely to survive to discharge (eg, 14.8% in the advanced COPD group [P < .001] and 11.3% in the advanced malignancy group [P < .001]) than patients without chronic illness (17.3%). Among discharge survivors, the median long-term survival was shorter in patients with chronic illness (eg, 5.0, 3.5, and 2.8 months in the advanced COPD, malignancy, and cirrhosis groups, respectively; P < .001 for all) than without (26.7 months). Although 7.2% of CPR recipients without chronic disease were discharged home and survived at least 6 months without readmission, ≤ 2.0% of recipients with advanced COPD, CHF, malignancy, and cirrhosis (P < .001 for all) met these criteria. Adjusted analyses confirmed that most subgroups with chronic illness had lower hospital discharge survival, and among discharge survivors, most were discharged home less often, experienced more hospital readmissions, and had worse long-term survival.

CONCLUSIONS:  Older CPR recipients with any of the six underlying chronic diseases investigated generally have much worse outcomes than CPR recipients without chronic disease. These findings may substantially affect decisions about CPR in patients with chronic illness.

Original Research: Sleep Disorders

Chest. 2014;146(5):1226-1236. doi:10.1378/chest.14-0495

BACKGROUND:  Sleep-disturbed breathing (SDB) is common in patients with precapillary pulmonary hypertension (PH). Nocturnal oxygen therapy (NOT) and acetazolamide improve SDB in patients with PH, 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, crossover trial, 23 patients with arterial (n = 16) or chronic thromboembolic PH (n = 7) and SDB defined as a mean nocturnal oxygen saturation < 90% or dips (> 3%) > 10/h with daytime Pao2 ≥ 7.3 kPa were studied. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo each during 1 week separated by a 1-week washout period. Three-lead ECG 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 beats/min vs 72 ± 9 beats/min, P = .010) and early morning heart rate compared with placebo. At late evening, the heart rate-adjusted PQ time was increased under acetazolamide compared with placebo (mean difference, 10 milliseconds; 95% CI, 0-20 milliseconds; P = .042). In the morning under NOT, the heart rate-adjusted QT (QTc) interval was decreased compared with placebo (mean difference, −25 milliseconds; 95% CI, −45 to −6 milliseconds; P = .007), and the interval between the peak and the end of the T wave on the ECG was shorter compared with acetazolamide (mean difference, −11 milliseconds; 95% CI, −21 to −1 milliseconds; P = .028). Arrhythmias were rare and similar with all treatments.

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

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NTC-01427192; URL: www.clinicaltrials.gov

Original Research: Asthma

Chest. 2014;146(5):1237-1247. doi:10.1378/chest.14-0665

BACKGROUND:  Hyperventilation has been associated with adverse effects on lung function, symptoms, and well-being in asthma. We examined whether raising end-tidal CO2 levels (ie, Pco2) compared with slow breathing is associated with improvements in asthma control, including peak flow variability.

METHODS:  One hundred twenty patients with asthma were randomly assigned to capnometry-assisted respiratory training (CART) for raising Pco2 or slow breathing and awareness training (SLOW) for slowing respiratory rate. Patients received five weekly sessions and completed bid homework exercises over 4 weeks. Blinded assessments at baseline, posttreatment, 1- and 6-month follow-up of asthma control, Pco2, and diurnal peak flow variability were primary outcome measures. Additionally, we measured pulmonary function (spirometry, forced oscillation, exhaled nitric oxide, and methacholine challenge), symptoms, quality of life, and bronchodilator use. Because the control group received active treatment, we expected improvements in asthma control in both groups but more pronounced benefits from CART.

RESULTS:  Improvements were seen in 17 of 21 clinical indexes (81.0%) in both interventions, including the primary outcome variables asthma control (d = 0.81), peak flow variability (d = 0.54), quality of life, bronchodilator use, lung function, and airway hyperreactivity. Most improvements were sustained across the 6-month follow-up. Compared with slow breathing, CART showed greater increases in Pco2 (d = 1.45 vs 0.64 for CART vs SLOW, respectively) and greater reductions in respiratory impedance during treatment, less distress during methacholine challenge, and greater reduction in asthma symptoms at follow-up (P < .05).

CONCLUSIONS:  Brief interventions aimed at raising Pco2 or slowing respiratory rate provide significant, sustained, and clinically meaningful improvements in asthma control. Raising Pco2 was associated with greater benefits in aspects of lung function and long-term symptoms.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00975273; URL: www.clinicaltrials.gov

Original Research: Diffuse Lung Disease

Chest. 2014;146(5):1248-1255. doi:10.1378/chest.13-2866

BACKGROUND:  Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia and sometimes coexists with a histologic usual interstitial pneumonia (UIP) pattern. This study aimed to describe the distinct clinical features of PPFE with UIP pattern compared with idiopathic pulmonary fibrosis (IPF).

METHODS:  We conducted a retrospective review of the medical records of 110 consecutive patients with IPF with a histologic UIP pattern on surgical lung biopsy specimen. Patients meeting radiologic criteria for the diagnosis of PPFE based on high-resolution CT scan and with a histologic UIP pattern were included.

RESULTS:  Nine of eleven patients meeting radiologic criteria for the diagnosis of PPFE were histologically confirmed as having PPFE with UIP pattern. The PPFE with UIP pattern group showed a significantly higher residual volume (1.8 L vs 1.3 L, P < .01), higher Paco2 (44.6 mm Hg vs 41.7 mm Hg, P = .04), and higher complication rate of pneumothorax and pneumomediastinum than the 99 patients with IPF/UIP. The ratio of anteroposterior to transthoracic diameter in patients with PPFE with UIP pattern was significantly lower than that in patients with IPF/UIP (P = .04). Survival time tended to be shorter in patients with PPFE with UIP pattern.

CONCLUSIONS:  The results support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP and may well be classified as PPFE.

Chest. 2014;146(5):1256-1262. doi:10.1378/chest.14-0492

BACKGROUND:  The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary end points is an area of uncertainty. Using data from a large well-characterized clinical trial population, this article aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary end point.

METHODS:  Event rate estimates for death and hospitalization were determined from patients enrolled in National Institutes of Health-sponsored IPF Clinical Research Network clinical trials. Standard equations were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts.

RESULTS:  Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than those published. An IPF trial with death as its primary end point enrolling subjects designated as GAP stage 1 and 2 over 1 year with a minimum follow-up of 1 year would require an estimated 7,986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary end point enrolling subjects with GAP stage 2 and 3 over 2 years with a minimum follow-up of 1 year would require an estimated 794 subjects for the same power and hazard ratio.

CONCLUSIONS:  Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time-to-event primary end points such as death and death plus hospitalization.

Original Research: Pulmonary Vascular Disease

Chest. 2014;146(5):1263-1273. doi:10.1378/chest.14-0193

BACKGROUND:  Hospitalization is an important outcome in pulmonary arterial hypertension (PAH), shown previously to correlate with survival. Using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), we sought to characterize first-time hospitalizations and their effect on subsequent hospitalization and survival in patients with newly diagnosed disease.

METHODS:  Patients with newly diagnosed PAH (n = 862, World Health Organization group 1) were evaluated for first-time hospitalization. The hospitalizations were categorized as PAH related or PAH unrelated based on the case report form. Categories for PAH-related and PAH-unrelated hospitalization were defined before independent review. Patient demographics and disease characteristics are described as well as freedom from hospitalization and survival.

RESULTS:  Of 862 patients, 490 (56.8%) had one or more hospitalizations postenrollment: 257 (52.4%) PAH related, 214 (43.7%) PAH unrelated, and 19 (3.9%) of undetermined causes. The most common causes of PAH-related hospitalization were congestive heart failure and placement/removal of a central venous catheter. Patients with PAH-related hospitalizations were more likely to receive parenteral therapy, be in functional class III/IV, and have higher risk scores before hospitalization at enrollment. Following discharge, 25.4% ± 3.2% and 31.0% ± 4.0% of patients with PAH-related and PAH-unrelated first hospitalization, respectively, remained hospitalization-free for 3 years (P = .11). Survival estimates at 3 years postdischarge were 56.8% ± 3.5% and 67.8% ± 3.6% (P = .037) for patients with PAH-related and PAH-unrelated hospitalization, respectively.

CONCLUSIONS:  In the REVEAL Registry, PAH-related hospitalization was associated with relatively more rehospitalizations and worse survival at 3 years.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov

Chest. 2014;146(5):1274-1285. doi:10.1378/chest.14-0106

BACKGROUND:  Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate 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 soluble guanylate cyclase 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, 0.4-17]; P = .04) and decreased systolic BP (−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: Pulmonary Procedures

Chest. 2014;146(5):1286-1293. doi:10.1378/chest.13-2876

BACKGROUND:  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. Our objectives were to develop a method to identify entrapped lung using tissue movement and deformation (strain) analysis with ultrasonography and compare it to the existing technique of pleural elastance (PEL).

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 analyzed using motion mode (M mode) and speckle-tracking imaging, respectively. PEL was measured during effusion drainage. The gold-standard diagnosis of entrapped lung was the consensus opinion of two interventional pulmonologists according to postdrainage imaging. Participants were randomly divided into development and validation sets.

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 (M mode), and 0.69 (PEL). Using respective cutoffs of 6%, 1 mm, and 19 cm H2O on the validation set, the sensitivity/specificity was 71%/85% (speckle tracking), 50%/85% (M mode), and 40%/100% (PEL).

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

Original Research: Signs and Symptoms of Chest Diseases

Chest. 2014;146(5):1294-1299. doi:10.1378/chest.14-0066

BACKGROUND:  Aspiration pneumonia is a leading cause of death in people with Parkinson 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. They completed a capsaicin challenge with three randomized blocks of 0, 50, 100, and 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 sensitivity of the participant to the cough stimulus (UTC) were measured. The dysphagia severity of participants with PD was identified with 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).

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

Original Research: Cardiothoracic Surgery

Chest. 2014;146(5):1300-1309. doi:10.1378/chest.14-0058

BACKGROUND:  It is unclear whether thoracoscopic (video-assisted thoracoscopic surgery [VATS]) pneumonectomy improves outcomes compared with open approaches.

METHODS:  One hundred seven consecutive pneumonectomies performed at an experienced center from January 2002 to December 2012 were studied retrospectively. Forty cases were open, and 50 successful VATS and 17 conversions were combined (intent-to-treat [ITT] analysis).

RESULTS:  The VATS cohort had more preoperative comorbidities (three vs two, P = .003), women (57% vs 30%, P = .009), and older ages (65 years vs 63 years, P = .07). Although advanced clinical stage was less for VATS (26% vs 50% stage III, P = .035), final pathologic staging was similar (25% vs 38%, P = .77). Pursuing a VATS approach yielded similar complications (two vs two, median, P = .73) with no catastrophic intraoperative events like bleeding. Successful VATS pneumonectomy rates rose from 50%-82% by the second half of the series (P < .001). Completion pneumonectomy cases (13.4% VATS, 7.5% open) had similar outcomes. Having similar initial discomforts as patients undergoing open surgery, more patients undergoing VATS were pain-free at 1 year (53% vs 19%, P = .03). Conversions resulted in longer ICU stays (4 days vs 2 days, P = .01). Advanced clinical stage (III-IV) ITT VATS had longer median overall survival (OS) (42 months vs 13 months, log-rank P = .042). Successful VATS cases with early pathologic stage (0-II) had a median OS of 80 vs 16 months for converted and 28 months for open (log rank = 0.083).

CONCLUSIONS:  Attempting thoracoscopic pneumonectomy at an experienced center appears safe but does not yield the early pain/complication reductions observed for VATS lobectomy. There may be long-term pain/survival advantages for certain stages that warrant further study and refinement of this approach.

Chest. 2014;146(5):1310-1318. doi:10.1378/chest.13-2615

BACKGROUND:  In cardiac surgery, preoperative mortality risk assessment tools like the EuroSCORE help to guide physicians in optimizing perioperative care of patients. We investigated the value of preoperative levels of inflammatory (procalcitonin [PCT]) and vasoactive (C-terminal pro-arginine vasopressin [CT-proAVP], midregional pro-atrial natriuretic peptide [MR-proANP], midregional proadrenomedullin [MR-proADM], and C-terminal pro-endothelin-1 [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 preoperative blood sample, we assessed PCT, CT-proAVP, MR-proANP, MR-proADM, and CT-proET-1 levels.

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

CONCLUSIONS:  In elective cardiac surgery, preoperative levels of MR-proADM and CT-proET-1 are predictors of 30-day 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: Chest Infections

Chest. 2014;146(5):1319-1326. doi:10.1378/chest.14-0626

BACKGROUND:  NBS LabChip G2-3 is a novel, ultrafast, chip-type portable real-time polymerase chain reaction (PCR) system. We evaluated the clinical usefulness of this system in detecting pulmonary TB and assessed its diagnostic performance compared with a conventional tube-type PCR system.

METHODS:  A total of 247 sputum samples were collected from patients suspected of having pulmonary TB. After the decontamination process, these samples were examined by fluorescence staining for acid-fast bacilli, cultures with both solid and liquid media, and real-time PCR with the NBS LabChip and a conventional tube-type system. The diagnostic accuracy of the NBS LabChip system and the agreement between the two assays were evaluated.

RESULTS:  Considering mycobacterial culture results as a gold standard, the overall sensitivity and specificity of the NBS LabChip was 83.8% (95% CI, 73.8%-91.1%) and 94.0% (95% CI, 89.3%-97.1%), respectively. For the detection of TB from the smear-positive samples, the sensitivity and specificity of the NBS LabChip was 96.0% (95% CI, 86.3%-99.5%) and 83.3% (95% CI, 72.3%-95.7%), respectively. For the smear-negative samples, the sensitivity and specificity of the NBS LabChip was 63.3% (95% CI, 43.9%-80.1%) and 95.0% (95% CI, 90.4%-97.8%), respectively. There were no significant differences in the sensitivity and specificity between the NBS LabChip and a conventional tube-type system, although the NBS LabChip shortened the PCR time (27 min for 45 cycles).

CONCLUSIONS:  The NBS LabChip G2-3 system has potential as an ultrafast, cost-effective diagnostic tool for pulmonary TB with high sensitivity and specificity.

Original Research: Occupational and Environmental Lung Diseases

Chest. 2014;146(5):1327-1336. doi:10.1378/chest.14-0298

BACKGROUND:  Excessive erythrocytosis (EE) is a prevalent condition in populations living at high altitudes (> 2,500 m above sea level). Few large population-based studies have explored the association between EE and multiple subject-specific traits including oxygen saturation, iron status indicators, and pulmonary function.

METHODS:  We enrolled a sex-stratified and age-stratified sample of 1,065 high-altitude residents aged ≥ 35 years from Puno, Peru (3,825 m above sea level) and conducted a standardized questionnaire and physical examination that included spirometry, pulse oximetry, and a blood sample for multiple clinical markers. Our primary objectives were to estimate the prevalence of EE, characterize the clinical profile and iron status indicators of subjects with EE, and describe subject-specific traits associated with EE.

RESULTS:  Overall prevalence of EE was 4.5% (95% CI, 3.3%-6.0%). Oxygen saturation was significantly lower among EE than non-EE group subjects (85.3% vs 90.1%, P < .001) but no difference was found in iron status indicators between both groups (P > .09 for all values). In multivariable logistic regression, we found that age ≥ 65 years (OR = 2.45, 95% CI, 1.16-5.09), male sex (3.86, 1.78-9.08), having metabolic syndrome (2.66, 1.27-5.75) or being overweight (5.20, 1.95-16.77), pulse oximetry < 85% (14.90, 6.43-34.90), and % predicted FVC < 80% (13.62, 4.40-41.80) were strongly associated with EE. Attributable fractions for EE were greatest for being overweight (26.7%), followed by male sex (21.5%), pulse oximetry < 85% (16.4%), having metabolic syndrome (14.4%), and % predicted FVC < 80% (9.3%).

CONCLUSIONS:  We found a lower prevalence of EE than in previous reports in the Peruvian Andes. Although the presence of hypoxemia and decreased vital capacity were strongly associated with excessive erythrocytosis, being overweight or having metabolic syndrome were associated with an important fraction of cases in our study population.

Original Research: Cardiovascular Disease

Chest. 2014;146(5):1337-1346. doi:10.1378/chest.14-0533

BACKGROUND:  Our objective was to determine stroke and thromboembolism event rates in patients with atrial fibrillation (AF) classified as “low risk” using the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) score and to ascertain event rates in this group in relation to the stroke risk assessment advocated in the 2012 European Society of Cardiology (ESC) guidelines (based on the CHA2DS2-VASc [congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category] score). We tested the hypothesis that the stroke risk assessment scheme advocated in the ESC guidelines would be able to further refine stroke risk stratification in the low-risk category defined by the ATRIA score.

METHODS:  In our cohort of 207,543 incident patients with AF from 1999 to 2012, we identified 72,452 subjects who had an ATRIA score of 0 to 5 (low risk).

RESULTS:  Even among these patients categorized as low risk using the ATRIA score, the 1-year stroke/thromboembolic event rate ranged from 1.13 to 36.94 per 100 person-years, when subdivided by CHA2DS2-VASc scores. In patients with an ATRIA score 0 to 5, C statistics at 1 year follow-up in the Cox regression model were significantly improved from 0.626 (95% CI, 0.612-0.640) to 0.665 (95% CI, 0.651-0.679) when the CHA2DS2-VASc score was used for categorizing stroke risk instead of the ATRIA score (P < .001).

CONCLUSIONS:  Patients categorized as low risk using an ATRIA score 0 to 5 are not necessarily low risk, with 1-year event rates as high as 36.94 per 100 person-years. Thus, the stroke risk stratification scheme recommended in the ESC guidelines (based on the CHA2DS2-VASc score) would be best at identifying the “truly low risk” subjects with AF who do not need any antithrombotic therapy.

Translating Basic Research Into Clinical Practice

Chest. 2014;146(5):1347-1357. doi:10.1378/chest.14-0049

Allergen-specific immunotherapy (AIT) was described as a therapeutic option for the treatment of allergies > 100 years ago. It is based on administration of allergen extracts and leads to the development of clinical allergen tolerance in selected patients. According to current knowledge, AIT results in the restoration of immune tolerance toward the allergen of interest. It is mainly accompanied by the induction of regulatory and suppressive subsets of T and B cells, the production of IgG4 isotype allergen-specific blocking antibodies, and decreased inflammatory responses to allergens by effector cells in inflamed tissues. Currently, AIT is mainly applied subcutaneously or sublingually and is suitable for both children and adults for pollen, pet dander, house dust mite, and venom allergies. It not only affects rhinoconjunctival symptoms but also has documented short- and long-term benefits in asthma treatment. Clinically, a fast onset of tolerance is achieved during desensitization, with a tolerable amount of side effects. The disease modification effect leads to decreased disease severity, less drug usage, prevention of future allergen sensitizations, and a long-term curative effect. Increasing safety while maintaining or even augmenting efficiency is the main goal of research for novel vaccine development and improvement of treatment schemes in AIT. This article reviews the principles of allergen-specific immune tolerance development and the effects of AIT in the clinical context.

Recent Advances in Chest Medicine

Chest. 2014;146(5):1358-1368. doi:10.1378/chest.14-0917

Both inherited and acquired immunodeficiency and chronic pulmonary disease predispose to the development of a variety of pulmonary syndromes in response to Aspergillus, a fungus that is ubiquitous in the environment. These syndromes include invasive aspergillosis, which is now recognized to occur in patients with critical illness without neutropenia and in those with mild degrees of immunosuppression, including from corticosteroid use in the setting of COPD. Chronic pulmonary aspergillosis includes simple aspergilloma, which is occasionally complicated by life-threatening hemoptysis, and progressive destructive cavitary disease requiring antifungal therapy. Allergic bronchopulmonary aspergillosis occurs almost exclusively in patients with asthma or cystic fibrosis. Recent advances in each of these syndromes include a greater understanding of the underlying pathophysiology and hosts at risk; improved diagnostic algorithms; and the availability of more effective and well-tolerated therapies. Improvement in outcomes for Aspergillus pulmonary syndromes requires that physicians recognize the varied and sometimes subtle presentations, be aware of populations at risk of illness, and institute potentially life-saving therapies early in the disease course.

Medical Ethics

Chest. 2014;146(5):1369-1374. doi:10.1378/chest.13-2024

Throughout medical history, physicians have rarely formed unions and/or carried out strikes. In a profession faced with the turmoil of health reform and increasing pressure to change their practices and lifestyles, will physicians resort to unionization for collective bargaining, and will a strike weapon be used to fight back against the array of corporate and government powers involved in the transformation of the American health-care system? This article examines the question of whether there could be such a thing as an ethical physician strike. Although physicians have not historically used collective bargaining or the strike weapon, the rapidly changing practice environment in the United States might push physicians and other health-care professionals toward unionization. This article considers the ethical questions that would arise if physicians started taking advantage of labor laws, and it lays out criteria for an ethical strike.

Contemporary Reviews in Critical Care Medicine

Chest. 2014;146(5):1375-1386. doi:10.1378/chest.14-0523

Coma after cardiac arrest (CA) is an important cause of admission to the ICU. Prognosis of post-CA coma has significantly improved over the past decade, particularly because of aggressive postresuscitation care and the use of therapeutic targeted temperature management (TTM). TTM and sedatives used to maintain controlled cooling might delay neurologic reflexes and reduce the accuracy of clinical examination. In the early ICU phase, patients’ good recovery may often be indistinguishable (based on neurologic examination alone) from patients who eventually will have a poor prognosis. Prognostication of post-CA coma, therefore, has evolved toward a multimodal approach that combines neurologic examination with EEG and evoked potentials. Blood biomarkers (eg, neuron-specific enolase [NSE] and soluble 100-β protein) are useful complements for coma prognostication; however, results vary among commercial laboratory assays, and applying one single cutoff level (eg, > 33 μg/L for NSE) for poor prognostication is not recommended. Neuroimaging, mainly diffusion MRI, is emerging as a promising tool for prognostication, but its precise role needs further study before it can be widely used. This multimodal approach might reduce false-positive rates of poor prognosis, thereby providing optimal prognostication of comatose CA survivors. The aim of this review is to summarize studies and the principal tools presently available for outcome prediction and to describe a practical approach to the multimodal prognostication of coma after CA, with a particular focus on neuromonitoring tools. We also propose an algorithm for the optimal use of such multimodal tools during the early ICU phase of post-CA coma.

Contemporary Reviews in Sleep Medicine

Chest. 2014;146(5):1387-1394. doi:10.1378/chest.14-0970

The recently released third edition of the International Classification of Sleep Disorders (ICSD) is a fully revised version of the American Academy of Sleep Medicine’s manual of sleep disorders nosology, published in cooperation with international sleep societies. It is the key reference work for the diagnosis of sleep disorders. The ICSD-3 is built on the same basic outline as the ICSD-2, identifying seven major categories that include insomnia disorders, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, sleep-related movement disorders, parasomnias, and other sleep disorders. Significant modifications have been made to the nosology of insomnia, narcolepsy, and parasomnias. Major features and changes of the manual are reviewed in this article. The rationales for these changes are also discussed.

Evidence-Based Medicine

Chest. 2014;146(5):1395-1402. doi:10.1378/chest.14-1484

BACKGROUND:  This series of guidance documents on cough, which will be published over time, is a hybrid of two processes: (1) evidence-based guidelines and (2) trustworthy consensus statements based on a robust and transparent process.

METHODS:  The CHEST Guidelines Oversight Committee selected a nonconflicted Panel Chair and jointly assembled an international panel of experts in each clinical area with few, if any, conflicts of interest. PICO (population, intervention, comparator, outcome)-based key questions and parameters of eligibility were developed for each clinical topic to inform the comprehensive literature search. Existing guidelines, systematic reviews, and primary studies were assessed for relevance and quality. Data elements were extracted into evidence tables and synthesized to provide summary statistics. These, in turn, are presented to support the evidence-based graded recommendations. A highly structured consensus-based Delphi approach was used to provide expert advice on all guidance statements. Transparency of process was documented.

RESULTS:  Evidence-based guideline recommendations and consensus-based suggestions were carefully crafted to provide direction to health-care providers and investigators who treat and/or study patients with cough. Manuscripts and tables summarize the evidence in each clinical area supporting the recommendations and suggestions.

CONCLUSIONS:  The resulting guidance statements are based on a rigorous methodology and transparency of process. Unless otherwise stated, the recommendations and suggestions meet the guidelines for trustworthiness developed by the Institute of Medicine and can be applied with confidence by physicians, nurses, other health-care providers, investigators, and patients.

Topics: cough , guidelines , consensus

Special Features

Chest. 2014;146(5):1403-1412. doi:10.1378/chest.13-2674

This review is on the pulmonary complications of snakebites, which can have fatal consequences. We identified three common themes as reported in the literature regarding envenomation: generalized neuromuscular paralysis affecting airway and respiratory muscles, pulmonary edema, and pulmonary hemorrhages or thrombosis due to coagulopathy. Respiratory paralysis and pulmonary edema can be due to either elapid or viper bites, whereas pulmonary complications of coagulopathy are exclusively reported with viper bites. The evidence for each complication, timeline of appearance, response to treatment, and details of pathophysiology are discussed.

Topics in Practice Management

Chest. 2014;146(5):1413-1419. doi:10.1378/chest.13-2367

Most physicians are unfamiliar with the details of the Resource-Based Relative Value Scale (RBRVS) and how changes in the RBRVS influence Medicare and private reimbursement rates. Physicians in a wide variety of settings may benefit from understanding the RBRVS, including physicians who are employees, because many organizations use relative value units as productivity measures. Despite the complexity of the RBRVS, its logic and ideal are simple: In theory, the resource usage (comprising physician work, practice expense, and liability insurance premium costs) for one service is relative to the resource usage of all others. Ensuring relativity when new services are introduced or existing services are changed is, therefore, critical. Since the inception of the RBRVS, the American Medical Association’s Relative Value Scale Update Committee (RUC) has made recommendations to the Centers for Medicare & Medicaid Services on changes to relative value units. The RUC’s core focus is to develop estimates of physician work, but work estimates also partly determine practice expense payments. Critics have attributed various health-care system problems, including declining and growing gaps between primary care and specialist incomes, to the RUC’s role in the RBRVS update process. There are persistent concerns regarding the quality of data used in the process and the potential for services to be overvalued. The Affordable Care Act addresses some of these concerns by increasing payments to primary care physicians, requiring reevaluation of the data underlying work relative value units, and reviewing misvalued codes.


Chest. 2014;146(5):1420. doi:10.1378/chest.14-0342

What is there to do
sitting on the paper-covered leather slab
wearing a chic green smock
with velcro closings at the back
what is there to do
but study all those charts
charts of body parts
posted on the wall, note
the intricate little sculpture
that is each human vertabra
fitting into the socket of
the next in line.
Depending on how long the wait
you may memorize
cervical (seven), thoracic (twelve), lumbar (five),
the five fused bones of the sacrum
note that the larger lumbar
carry more weight
have forward and lateral flex, reflect
on how your cervical vertabrae
don't flex much at all any more.
Or you may imagine
you see a seahorse
there on the wall before you
darting and diving, inviting
you leap off your leather perch,
plunge into the sea, become a mermaid
riding sidesaddle on her steed
before the doctor comes.

Chest. 2014;146(5):1421. doi:10.1378/chest.14-0624

institutional Power
made of your “might’s “ and “maybe’s”
smashed our faces into disease
pushed our heads down
till we could not speak,
and dared not breathe.
you would not hear
and still staged
the unseen Beasts
that ‘might’ infect,
and ‘maybe’ kill.
baldly, you cloaked each ‘Might’
and every ‘Maybe’
in righteous white Robes
to hide the Terror
of what you did not know,
and dared not say
 ‘they are too unlearned to Know;
 to Trust, too slow’
before your Rule
we breathed
every ‘might’, and each ‘maybe’.
we knew them well.
Why now do you scurry so Scared
from each ‘might’, and every ‘maybe’
Why mark us do-not-touch
Why shut us out
Why paint us less than you
protecting your Fears with our Pain.
You smear our faces with dirty disease—
our tears cannot clear the Stains you leave.


Chest. 2014;146(5):1422. doi:10.1378/chest.14-2167

The authors have reported to CHEST that an error appeared in Table 6 in “Antithrombotic Therapy in Neonates and Children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines” (Chest 2012; 141[2][Suppl]:e737S-e801S). The second line under part III Maintenance oral anticoagulation dose guidelines reads 1.15-1.9 in the first column.

Chest. 2014;146(5):1422. doi:10.1378/chest.14-2254

The authors have reported to CHEST that the sponsor statement included in “A Preliminary Quality of Life Questionnaire Bronchiectasis: A Patient-Reported Outcome Measure for Bronchiectasis” (Chest 2014;146(2):437-448) should be rewritten and expanded to clarify the role of the sponsors.

Selected Reports

Chest. 2014;146(5):e149-e152. doi:10.1378/chest.13-2879

Antiphospholipid syndrome is an autoimmune disorder characterized by a hypercoagulable state, leading to arterial and venous thrombosis. We present a 23-year-old patient, suspected of having Budd-Chiari syndrome due to antiphospholipid syndrome, who developed severe and progressive hypoxemia, requiring prolonged mechanical ventilation. After a detailed but unsuccessful workup, a contrast CT scan revealed an occluded superior vena cava and azygos vein-superior vena cava junction and massive right-to-left shunting through a network of systemic to pulmonary venous collaterals. Restoring normal blood flow from the azygos vein into the right atrium by stenting the azygos-superior vena cava junction resolved the hypoxemia immediately. Within the same procedure, the hepatic outflow obstruction was successfully treated by stenting a severe stenosis of the suprahepatic inferior vena cava caused by calcified thrombus.

Chest. 2014;146(5):e153-e155. doi:10.1378/chest.14-0515

Neuroborreliosis can cause multiple cranial and peripheral neuropathies; however, involvement of both recurrent laryngeal nerves is rare. We report the case of a 90-year-old man who presented with dysphonia and right upper and lower extremity weakness. His course was complicated by bilateral vocal cord paralysis and respiratory failure requiring tracheostomy. The diagnosis of borreliosis was made by detection of IgM and IgG antibodies against Borrelia burgdorferi on enzyme immunoassay and Western blot. The patient received IV ceftriaxone for 2 weeks, followed by complete recovery of motor and vocal function over 2 months. Our case is the third report of bilateral vocal cord paralysis in the literature, and the first one, to our knowledge, presenting with respiratory failure requiring an artificial airway. Physicians should be aware of this unusual complication of neuroborreliosis.

Ultrasound Corner

Chest. 2014;146(5):e156-e159. doi:10.1378/chest.13-3029

Pulmonary, Critical Care, and Sleep Pearls

Chest. 2014;146(5):e160-e162. doi:10.1378/chest.14-0411

A 70-year-old man underwent total hip replacement surgery under general anesthesia, endotracheal intubation, and controlled ventilation, with the patient in left lateral position. Intraoperatively, the patient was hemodynamically stable, with a normal range of pulse, ECG trace, oxygen saturation as measured by pulse oximetry (Spo2), and end-tidal CO2 (etco2). Five minutes after insertion of the hip prosthesis, his heart rate dropped to 30 beats/min, BP to 40/30 mm Hg, Spo2 to 70%, and etco2 to 10 mm Hg.

Chest. 2014;146(5):e163-e166. doi:10.1378/chest.13-3077

A 54-year-old woman developed a witnessed generalized tonic clonic seizure at work. Paramedics recorded a blood glucose level of 30 mg/dL. Despite normalizing the blood glucose level, the patient’s mental status did not improve, and she was intubated in the field. Given the limited view of the glottis, a tracheal tube introducer (Bougie) was used to facilitate intubation.


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