Chest. 2014;146(4):873-874. doi:10.1378/chest.14-1066

In this issue of CHEST (see page 890), Hurley1 performed a multilevel random effects analysis examining topical antibiotics (TAs) for the prevention of ventilator-associated pneumonia (VAP). Because TA use can confer herd protection in the ICU similar to vaccination programs in the community, contextual influences resulting from a population-based intervention cannot be estimated from a single trial. However, multilevel random effects analysis allows the estimation of contextual effects. Hurley1 found that the baseline incidence of VAP derived from observational studies was lower (23.7%; 95% CI, 20.6%-27.2%) than that in studies of TAs using concurrent control groups that either did or did not receive topical placebo (38% [95% CI, 29%-48%] vs 33% [95% CI, 20%-50%], respectively). This observed contextual influence could potentially inflate the apparent effect of TAs, especially within studies using topical placebo. The clinical importance of this observation is illustrated by investigations showing that TAs can promote the emergence of antimicrobial resistance and increase the burden of resistance genes in the gut biome of patients in the ICU.2,3 Without knowing the overall influence of TAs on antimicrobial resistance progression and clinical outcomes, their routine use cannot be endorsed, especially in areas where antibiotic resistance is already a clinically important problem.

Chest. 2014;146(4):875-876. doi:10.1378/chest.14-0603

Nicotine is addictive and dangerous.1 Similar to heroin and cocaine, it possesses both stimulant and relaxant properties and alters mood. When smoked, nicotine reaches the brain within 7 s where it cajoles the midbrain to unleash an army of chemical messengers, such as dopamine and β-endorphins, that induce (pleasant) psychotropic effects.1 With repeated use, there is downregulation of these chemoreceptors, leading to desensitization and habituation and coaxing individuals to smoke increasing numbers of cigarettes to achieve similar central effects. Attempts to quit cause very unpleasant withdrawal symptoms that compel smokers to take up the habit again.1 Globally, cigarette smoking kills 6 million people per year.2 Despite the known health hazards of tobacco, there remain > 1 billion smokers worldwide with one-third living in China.2 In response, governments around the world have implemented various measures to curb smoking rates, including high taxation of cigarettes and smoking bans in indoor workplaces, public transport systems, and shopping centers.2 Although these efforts have been effective in reducing smoking rates in westernized countries, alternative modes of nicotine delivery are rapidly gaining popularity and usurping the vacuum left behind by cigarettes.3 These devices have received far less scientific or regulatory scrutiny and are being promulgated widely to the public on the implicit notion that they are safe.

Topics: smoking , hookah
Chest. 2014;146(4):876-878. doi:10.1378/chest.14-0856

Cardiovascular physiology, in its simplest form, can be summed up by two very basic equations: right = left and V = IR (where V indicates voltage, and IR indicates the product of current and resistance). The former equation states that, in the absence of shunt, the left heart can only pump what it receives from the right. The latter equation, Ohm’s law, is transposed in cardiology as pressure = flow × resistance. In vivo, of course, this relationship is far more complex as the pulmonary circulation is not a set of rigid pipes, and the flow is pulsatile. The mechanism of right ventricle (RV) contraction remains enigmatic, and fully characterizing the RV-pulmonary artery coupling relationship is difficult.1 The challenge to clinicians and scientists is to move beyond these very basic equations, while respecting their principles.

Chest. 2014;146(4):878-880. doi:10.1378/chest.14-0654

The inability to be physically active is one of the key complaints expressed by patients with COPD. This is best considered as an exercise problem because it is the quantitative restriction to physical capacity more than the sensation of breathlessness or fatigue during exercise (something we all experience) that is the abnormal symptom. There is now a convincing body of evidence indicating that skeletal muscle dysfunction is a frequent and clinically relevant feature of COPD that contributes significantly to reduced exercise performance and, indeed, mortality independently from the severity of lung function impairment.1 The cause of this dysfunction has been debated, but a long-term downward spiral of inactivity and deconditioning is the key feature of its natural history, although other disease-related factors (eg, hypoxia, drug therapy, systemic inflammation) may contribute in selected patients.

Chest. 2014;146(4):881-883. doi:10.1378/chest.14-1900

The critically ill are a unique group of patients in a disaster response setting because they require resource-intensive care, advanced and costly therapies, and specialized settings and providers to deliver this care.1,2 They can present as a sudden surge of patients over a short period of time, pushing the limits of the health-care facility, or they can present over a sustained period of time, such as was the case of the 2009 influenza A(H1N1) pandemic, straining the larger regional health system. In many disasters, such as the London bombings, the critically ill can present as both an immediate surge and as a sustained intensive response, thus presenting varying response needs throughout the disaster.2,3 This variability with the most critically ill creates uncertainty in health-care response because local, regional, and national health-care systems may have resource limitations, a paucity of medical expertise, and structural compromise of health-care clinics and hospitals at any given moment. The current Ebola outbreak in West Africa best highlights the difficulties surrounding critically ill patients in a very resource-limited environment. However, regardless of the type of disaster and the extent of the critically ill, planning for this uncertainty in mass critical care is paramount to ensuring good patient outcomes.3-5

Second Opinion

Chest. 2014;146(4):884. doi:10.1378/chest.146.4.884

Evidence-Based Medicine: Commentary

Chest. 2014;146(4):885-889. doi:10.1378/chest.14-1485

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

Topics: cough , guidelines


Chest. 2014;146(4):890-898. doi:10.1378/chest.13-2926

Ventilator-associated pneumonia (VAP) develops in approximately 20% of patients in the ICU receiving prolonged mechanical ventilation (MV). Among the range of methods for preventing VAP, the evidence base for topical antibiotics (TAs), including selective digestive decontamination, appears to be the most compelling. However, several observations are puzzling, and the contextual influence resulting from concurrent use of both topical placebo and TA within an ICU remains untested. As with herd protection conferred by vaccination, contextual influences resulting from a population-based intervention cannot be estimated at the level of a single trial. Estimating contextual effects requires multilevel random-effects methods. In this way the dispersion in VAP incidence across groups from 206 studies, as cited in various-source systematic reviews, was calibrated. The benchmark mean VAP incidence derived from 49 observational groups of patients receiving MV is 23.7% (95% CI, 20.6%-27.2%). In contrast, for 20 and 15 concurrent control groups from the TA evidence base that did vs did not receive topical placebo, respectively, this incidence is 38% (95% CI, 29%-48%) and 33% (95% CI, 20%-50%). This contextual influence remains significant in a meta-regression model adjusted for group-level variables, such as within a trauma ICU context. The mean VAP incidence for five other categories of control groups from the broader evidence base is within four percentage points of the benchmark. The contextual effect of TA is paradoxic, peculiar, potent, perfidious, and potentially perilous. The TA evidence base requires reappraisal to consider this herd peril.

Original Research: Critical Care

Chest. 2014;146(4):899-907. doi:10.1378/chest.13-3028

BACKGROUND:  Pulmonary aspiration is an important recognized cause of ARDS. Better characterization of patients who aspirate may allow identification of potential risks for aspiration that could be used in future studies to mitigate the occurrence of aspiration and its devastating complications.

METHODS:  We conducted a secondary analysis of the Lung Injury Prediction Score cohort to better characterize patients with aspiration, including their potential risk factors and related outcomes.

RESULTS:  Of the 5,584 subjects at risk for ARDS and who required hospitalization, 212 (3.8%) presented with aspiration. Subjects who aspirated were likely to be male (66% vs 56%, P < .007), slightly older (59 years vs 57 years), white (73% vs 61%, P = .0004), admitted from a nursing home (15% vs 5.9%, P < .0001), have a history of alcohol abuse (21% vs 8%, P < .0001), and have lower Glasgow Coma Scale (median, 13 vs 15; P < .0001). Aspiration subjects were sicker (higher APACHE [Acute Physiology and Chronic Health Evaluation] II score), required more mechanical ventilation (54% vs 32%, P < .0001), developed more moderate to severe ARDS (12% vs 3.8%, P < .0001), and were twofold more likely to die in-hospital, even after adjustment for severity of illness (OR = 2.1; 95% CI, 1.2-3.6). Neither obesity nor gastroesophageal reflux was associated with aspiration.

CONCLUSIONS:  Aspiration was more common in men with alcohol abuse history and a lower Glasgow Coma Scale who were admitted from a nursing home. It is independently associated with a significant increase in the risk for ARDS as well as morbidity and mortality. Findings from this study may facilitate the design of future clinical studies of aspiration-induced lung injury.

Chest. 2014;146(4):908-915. doi:10.1378/chest.13-2702

BACKGROUND:  The surviving sepsis guidelines recommend early aggressive fluid resuscitation within 6 h of sepsis onset. Although rapid fluid administration may offer benefit, studies on the timing of resuscitation are lacking. We hypothesized that there is an association between quicker, adequate fluid resuscitation and patient outcome from sepsis onset time.

METHODS:  This is a retrospective cohort study of consecutive adults with severe sepsis and septic shock admitted to a quaternary care medical ICU between January 2007 and December 2009. Data were collected from a previously validated electronic medical database. Multivariate regression modeling was performed, adjusting for age, admission weight, Sequential Organ Failure Assessment score, APACHE (Acute Physiology and Chronic Health Examination) III score, and total fluid administration within the first 6 h of sepsis onset time.

RESULTS:  Of 651 patients with severe sepsis and septic shock screened, 594 had detailed fluid data. In a univariate analysis, the median amount of fluid within the first 3 h for survivors at discharge was 2,085 mL (940-4,080 mL) and for nonsurvivors, 1,600 mL (600-3,010 mL; P = .007). In comparison, during the latter 3 h, the median amount was 660 mL (290-1,485 mL) vs 800 mL (360-1,680 mL; P = .09), respectively. After adjusting for confounders, the higher proportion of total fluid received within the first 3 h was associated with decreased hospital mortality (OR, 0.34; 95% CI, 0.15-0.75; P = .008).

CONCLUSIONS:  Earlier fluid resuscitation (within the first 3 h) is associated with a greater number of survivors with severe sepsis and septic shock.

Chest. 2014;146(4):916-923. doi:10.1378/chest.14-0477

BACKGROUND:  Approximately 65% of elderly patients with lung cancer who are admitted to the ICU will die within 6 months. Efforts to improve end-of-life care for this population must first understand the patient factors that underlie admission to the ICU.

METHODS:  We performed a retrospective cohort study examining all fee-for-service inpatient claims in the Surveillance, Epidemiology, and End Results (SEER)-Medicare registry for elderly patients (aged > 65 years) who had received a diagnosis of lung cancer between 1992 and 2005 and who were hospitalized for reasons other than resection of their lung cancer. We calculated yearly rates of ICU admission per 1,000 hospitalizations via room and board codes or International Classification of Diseases, Ninth Revision, Clinical Modification and diagnosis-related group codes for mechanical ventilation, stratified the rates by receipt of mechanical ventilation and ICU type (medical/surgical/cardiac vs intermediate), and compared these rates over time.

RESULTS:  A total of 175,756 patients with lung cancer in SEER were hospitalized for a reason other than surgical resection of their tumor during the study period, 49,373 (28%) of whom had at least one ICU stay. The rate of ICU admissions per 1,000 hospitalizations increased over the study period from 140.7 in 1992 to 201.7 in 2005 (P < .001). The majority of the increase in ICU admissions (per 1,000 hospitalizations) between 1992 and 2005 occurred among patients who were not mechanically ventilated (118.2 to 173.3, P < .001) and among those who were in intermediate ICUs (20.0 to 61.9, P < .001), but increased only moderately in medical/surgical/cardiac units (120.7 to 139.9, P < .001).

CONCLUSIONS:  ICU admission for patients with lung cancer increased over time, mostly among patients without mechanical ventilation who were largely cared for in intermediate ICUs.

Original Research: COPD

Chest. 2014;146(4):924-931. doi:10.1378/chest.13-1499

BACKGROUND:  Studies show that the incidence of COPD has remained high in southwest China despite the 1976 National Stove Improvement Program for indoor air quality. Chinese water-pipe tobacco smoking (commonly referred to as water-pipe smoking), which is thought to be less harmful under the assumption that no charcoal is used and water filters tobacco smoke, is popular in China. We investigated whether Chinese water-pipe use and exposure are associated with the risk of COPD.

METHODS:  This multicenter, cross-sectional study enrolled 1,238 individuals from 10 towns in the Fuyuan area, Yunnan Province, China. A matched design was used to estimate the impact of active and passive exposure to Chinese water-pipe smoking on COPD risk; multivariate analyses adjusted for other risk factors. We also collected the water from Chinese water pipes to assess the mutagenicity of its major components and simulated Chinese water-pipe smoke exposure fine particulate 2.5 (PM2.5) by using the High Volume Air Sampler and individuals’ sera to search for the potential protein biomarkers of COPD.

RESULTS:  The increased risk of COPD was profound for Chinese water-pipe smokers (adjusted OR, 10.61; 95% CI, 6.89-16.34), Chinese water-pipe passive smokers (adjusted OR, 5.50; 95% CI, 3.61-8.38), cigarette smokers (adjusted OR, 3.18; 95% CI, 2.06-4.91), and cigarette passive smokers (adjusted OR, 2.52; 95% CI, 1.62-3.91) compared with never-smoking control subjects. Chinese water-pipe use aggravates lungs with more PM2.5 compared with cigarettes. ChemR23 and tissue inhibitor of metalloproteinase-1 may be potential protein biomarkers of COPD.

CONCLUSIONS:  Chinese water-pipe smoking significantly increases the risk of COPD, including the risk to women who are exposed to the water-pipe smoke.

TRIAL REGISTRY:  Chinese Clinical Trial Registry; No.: ChiCTR-CCH-12002235; URL: www.chictr.org/cn/

Chest. 2014;146(4):932-940. doi:10.1378/chest.13-2483

BACKGROUND:  Skeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease. Increasing evidence implicates the renin-angiotensin system in control of muscle phenotype. We hypothesized that angiotensin-converting enzyme (ACE) inhibition would improve quadriceps function and exercise performance in COPD.

METHODS:  This double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps function in patients with COPD with quadriceps weakness. Primary outcomes were change in quadriceps endurance and atrophy signaling at 3 months. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the cross-sectional area (MTCSA), and incremental shuttle walk distance (ISWD) were secondary outcomes.

RESULTS:  Eighty patients were enrolled (mean [SD], 65 [8] years, FEV1 43% [21%] predicted, 53% men). Sixty-seven patients (31 fosinopril, 36 placebo) completed the trial. The treatment group demonstrated a significant reduction in systolic BP (Δ−10.5 mm Hg; 95% CI, −19.9 to −1.1; P = .03) and serum ACE activity (Δ−20.4 IU/L; 95% CI, −31.0 to −9.8; P < .001) compared with placebo. No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (Δ0.5 s; 95% CI, −13.3-14.3; P = .94) or atrogin-1 messenger RNA expression (Δ−0.03 arbitrary units; 95% CI, −0.32-0.26; P = .84). QMVC improved in both groups (fosinopril: Δ1.1 kg; 95% CI, 0.03-2.2; P = .045 vs placebo: Δ3.6 kg; 95% CI, 2.1-5.0; P < .0001) with a greater increase in the placebo arm (between-group, P = .009). No change was shown in the MTCSA (P = .09) or ISWD (P = .51).

CONCLUSIONS:  This randomized controlled trial found that ACE inhibition, using fosinopril for 3 months, did not improve quadriceps function or exercise performance in patients with COPD with quadriceps weakness.

TRIAL REGISTRY:  Current Controlled Trials; No.: ISRCTN05581879; URL: www.controlled-trials.com

Chest. 2014;146(4):941-950. doi:10.1378/chest.13-2946

BACKGROUND:  The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown.

METHODS:  Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score.

RESULTS:  At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV1), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George’s Respiratory Questionnaire score). Risks were similar for those with and without COPD.

CONCLUSIONS:  Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.

Chest. 2014;146(4):951-958. doi:10.1378/chest.13-2440

BACKGROUND:  Osteopontin (OPN) is a phosphorylated acidic glycoprotein that can function as both an extracellular matrix molecule and a cytokine. Published data support that OPN is upregulated in surgical lung tissue samples of patients with COPD. The aim of this study was to determine the levels of OPN in sputum supernatants of patients with COPD and to investigate possible associations with mediators and cells involved in the inflammatory and remodeling process as well as with the extent of emphysema.

METHODS:  Seventy-seven patients with COPD and 40 healthy subjects (20 smokers) were studied. All subjects underwent lung function tests, sputum induction for cell count identification, and OPN, transforming growth factor-β1, matrix metalloproteinase (MMP)-2, IL-8, and leukotriene-4 measurement in sputum supernatants. High-resolution CT (HRCT) scan of the chest was performed for quantification of emphysema.

RESULTS:  OPN levels (pg/mL) were significantly higher in patients with COPD compared with healthy smokers and nonsmokers (median [interquartile range], 1,340 [601, 6,227] vs 101 [77, 110] vs 68 [50, 89], respectively; P < .001). Regression analysis showed a significant association between OPN and sputum neutrophils, IL-8, MMP-2, and the extent of emphysema. The associations previously listed were not observed in healthy subjects.

CONCLUSIONS:  OPN levels are higher in patients with COPD compared with healthy subjects. OPN may play a role in the neutrophilic inflammation and in the pathogenesis of emphysema.

Original Research: Pulmonary Vascular Disease

Chest. 2014;146(4):959-966. doi:10.1378/chest.13-2300

BACKGROUND:  Stress testing of the pulmonary circulation (via increasing pulmonary blood flow) can reveal abnormal mean pulmonary artery pressure-cardiac output (mPpa-Q) responses, which may facilitate early diagnosis of pulmonary vascular disease. We investigated the application of dobutamine stress echocardiography (DSE) for the noninvasive assessment of mPpa-Q relationships.

METHODS:  DSE using an incremental dose protocol (≤ 20 μg/kg/min) was performed in 38 subjects (16 patients with pulmonary arterial hypertension [PAH] and 22 healthy control subjects). An additional 22 healthy control subjects underwent exercise stress echocardiography as a comparator group. Multipoint mPpa-Q plots were analyzed, and the pulmonary vascular distensibility coefficient α was calculated.

RESULTS:  DSE was feasible and informative in 93% of subjects. The average dobutamine-induced mPpa-Q slope was 1.1 ± 0.7 mm Hg/L/min in healthy control subjects and 5.1 ± 2.5 mm Hg/L/min in patients with PAH (P < .001). The dobutamine-induced α was markedly reduced in patients with PAH (0.003 ± 0.001 mm Hg vs 0.02 ± 0.01 mm Hg in control subjects, P < .001). When exercise and dobutamine stress were compared in healthy control subjects, the exercise-induced mPpa-Q slope was modestly higher (1.6 ± 0.7 mm Hg/L/min, P = .03 vs dobutamine). In patients with PAH, lower functional class status was associated with lower dobutamine-induced mPpa-Q slopes (P = .014), but not with resting total pulmonary vascular resistance.

CONCLUSIONS:  Noninvasive assessment of mPpa-Q relationships is feasible with dobutamine stress. DSE may potentially be a useful noninvasive technique for stress testing of the pulmonary vasculature.

Chest. 2014;146(4):967-973. doi:10.1378/chest.14-0100

BACKGROUND:  Patent foramen ovale (PFO) in pulmonary embolism (PE) is associated with an increased risk of complications. However, little is known about PFO and ischemic stroke prevalence, particularly in acute intermediate-risk PE. In addition, in this context, the so-called “gold standard” method of PFO diagnosis remains unknown. We aimed to evaluate PFO and ischemic stroke prevalence and determine which of transesophageal echocardiography (TEE) or transthoracic echocardiography (TTE) is the best PFO diagnostic method in this context.

METHODS:  We conducted a prospective monocentric study of consecutive patients with intermediate-risk PE in whom a TEE and TTE with contrast were performed. Brain MRI was used to confirm clinically obvious strokes or to diagnose subclinical ones.

RESULTS:  Forty-one patients with intermediate-risk PE were identified over a 9-month period. Contrast TEE revealed PFO in 56.1%, whereas contrast TTE showed PFO in only 19.5% (P < .001). Of note, all PFOs observed with TTE were also diagnosed by TEE. Ischemic stroke occurred in 17.1% and was always associated with PFO and large shunt.

CONCLUSIONS:  PFO and related ischemic strokes are frequent in intermediate-risk PE. TEE is much more efficient than TTE for PFO diagnosis. Considering the high risk of intracranial bleeding with thrombolysis in PE, which may be partly due to hemorrhagic transformation of subclinical strokes, screening PFO with TEE should be considered in intermediate-risk PE when thrombolytic treatment is discussed.

Original Research: Asthma

Chest. 2014;146(4):974-981. doi:10.1378/chest.14-0288

BACKGROUND:  Pediatric asthma lacks sensitive objective measures for asthma monitoring. The forced oscillation technique (FOT) offers strong feasibility across the pediatric age range, but relationships between FOT parameter day-to-day variability and pediatric asthma severity and control are unknown.

METHODS:  Day-to-day variability in FOT respiratory system resistance (Rrs) and respiratory system reactance (Xrs) compared with peak expiratory flow (PEF) were defined in 22 children with asthma (mean ± SD age, 10.4 ± 1.1 years) during a 5-day asthma camp. FOT was performed at 6 Hz in triplicate on each test occasion. Relationships between day-to-day FOT variability (expressed as within-subject SD [SDW] and asthma control and severity (defined according to GINA [Global Initiative for Asthma] recommendations) were explored. For comparison, normal baseline FOT values and variability, measured on two occasions, were defined in a separate cohort of 38 healthy children (age, 9.5 ± 1.0 years).

RESULTS:  Day-to-day Rrs variability was greater in persistent (n = 16) vs intermittent (n = 6) asthma (mean SDW, 0.69 cm H2O/L/s vs 0.39 cm H2O/L/s; P ≤ .01). Day-to-day Rrs variability was increased in uncontrolled (n = 13) vs partly controlled asthma (n = 9) (mean SDW, 0.75 cm H2O/L/s vs 0.42 cm H2O/L/s; P ≤ .05). PEF variability did not differentiate the groups. Day-to-day variability of Rrs and Xrs but not baseline values were increased in children with asthma vs control children (Rrs mean SDW, 0.61 cm H2O/L/s vs 0.33 cm H2O/L/s [P ≤ .05]; Xrs mean SDW, 0.24 cm H2O/L/s vs 0.15 cm H2O/L/s [P ≤ .05]).

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

TRIAL REGISTRY:  Australian and New Zealand Clinical Trials Registry; No.: ACTRN12614000885695; URL: www.anzctr.org.au

Original Research: Sleep Disorders

Chest. 2014;146(4):982-990. doi:10.1378/chest.13-2403

BACKGROUND:  OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population.

METHODS:  We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects.

RESULTS:  T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) (P < .001), respectively, for prevalent T2DM. Diabetic subjects with more severe OSA had worse glycemic control, with adjusted mean HbA1c levels 0.72% higher in patients with severe OSA than in those without sleep-disordered breathing (analysis of covariance, P < .001).

CONCLUSIONS:  Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM.

Original Research: Disorders of the Pleura

Chest. 2014;146(4):991-1000. doi:10.1378/chest.13-2481

BACKGROUND:  Malignant pleural effusion is associated with short life expectancy and significant morbidity. A randomized controlled trial comparing indwelling pleural catheters (IPCs) with talc pleurodesis found that IPCs reduced in-hospital time and the need for additional procedures but were associated with excess adverse events.

METHODS:  Using data from the clinical trial, we compared costs associated with use of IPCs and with talc pleurodesis. Resource use and adverse events were captured through case report forms over the 1-year trial follow-up. Costs for outpatient and inpatient visits, diagnostic imaging, nursing, and doctor time were obtained from the UK National Health Service reference costs and University of Kent’s Unit Costs of Health and Social Care 2011 and inflated to 2013 using the UK Consumer Price Index. Procedure supply costs were obtained from the manufacturer. Difference in mean costs was compared using nonparametric bootstrapping. All costs were converted to US dollars using the Organisation for Economic Co-operation and Development Purchasing Power Parity Index.

RESULTS:  Overall mean cost (SD) for managing patients with IPCs and talc pleurodesis was $4,993 ($5,529) and $4,581 ($4,359), respectively. The incremental mean cost difference was $401, with 95% CI of −$1,387 to $2,261. The mean cost related to ongoing drainage in the IPC group was $1,011 ($732) vs $57 ($213) in the talc pleurodesis group (P = .001). This included the cost of drainage bottles, dressing changes in the first month, and catheter removal. There was no significant difference in cost of the initial intervention or adverse events between the groups. For patients with survival < 14 weeks, IPC is significantly less costly than talc pleurodesis, with mean cost difference of −$1,719 (95% CI, −$3,376 to −$85).

CONCLUSIONS:  There is no significant difference in the mean cost of managing patients with IPCs compared with talc pleurodesis. For patients with limited survival, IPC appears less costly.

TRIAL REGISTRY:  isrctn.org; No.: ISRCTN87514420; URL: www.isrctn.org

Chest. 2014;146(4):1001-1006. doi:10.1378/chest.14-0299

BACKGROUND:  Definitive diagnosis of pleural disease (particularly malignancy) depends upon histologic proof obtained via pleural biopsy or positive pleural fluid cytology. Image-guided sampling is now standard practice. Local anesthetic thoracoscopy has a high diagnostic yield for malignant and nonmalignant disease, but is not always possible in frail patients, if pleural fluid is heavily loculated, or where the lung is adherent to the chest wall. Such cases can be converted during the same procedure as attempted thoracoscopy to cutting-needle biopsy. This study aimed to determine the diagnostic yield of a physician-led service in both planned biopsies and cases of failed thoracoscopy.

METHODS:  This study was a retrospective review of all ultrasound-guided, cutting-needle biopsies performed at the Oxford Centre for Respiratory Medicine between January 2010 and July 2013. Histologic results were assessed for the yield of pleural tissue, final diagnosis, and clinical follow-up in nonmalignant cases.

RESULTS:  Fifty ultrasound-guided biopsies were undertaken. Overall, 47 (94.0%) successfully obtained sufficient tissue for histologic diagnosis. Of the 50 biopsy procedures, 13 were conducted after failed thoracoscopy (5.2% of 252 attempted thoracoscopies over the same time period); of these 13, 11 (84.6%) obtained sufficient tissue. Thirteen of 50 biopsy specimens (26.0%) demonstrated pleural malignancy on histology (despite previous negative pleural fluid cytology), while 34 specimens (68.0%) were diagnosed as benign. Of the benign cases, 10 were pleural TB, two were sarcoidosis, and 22 were benign pleural thickening. There was one “false negative” of mesothelioma (median follow-up, 16 months).

CONCLUSIONS:  Within this population, physician-based, ultrasound-guided, cutting-needle pleural biopsy obtained pleural tissue successfully in a high proportion of cases, including those of failed thoracoscopy.

Chest. 2014;146(4):1007-1012. doi:10.1378/chest.13-3004

OBJECTIVE:  The objective of this study was to compare the accuracy of a handheld digital manometer (DM) and U-tube (UT) manometer with an electronic transducer (ET) manometer during thoracentesis.

METHODS:  Thirty-three consecutive patients undergoing thoracentesis were enrolled in the study. Pleural pressure (Ppl) measurements were made using a handheld DM (Compass; Mirador Biomedical), a UT water manometer, and an ET (reference instrument). End-expiratory Ppl was recorded after catheter insertion, after each aspiration of 240 mL, and prior to catheter removal. Volume of fluid removed, symptoms during thoracentesis, pleural elastance, and pleural fluid chemistry were also evaluated.

RESULTS:  A total of 594 Ppl measurements were made in 30 patients during their thoracenteses. There was a strong linear correlation coefficient between elastance for the DM and ET (r = 0.9582, P < .001). Correlation was poor between the UT and ET (r = 0.0448, P = .84). Among the 15 patients who developed cough, recorded ET pressures ranged from −9 to +9 cm H2O at the time of symptom development, with a mean (SD) of −2.93 (4.89) cm H2O. ET and DM measurements among those patients with cough had a low correlation between these measurements (R2 = 0.104, P = .24). Nine patients developed chest discomfort and had ET pressures that ranged from −26 to +6 cm H2O, with a mean (SD) of −7.89 (9.97) cm H2O.

CONCLUSIONS:  The handheld DM provided a valid and easy-to-use method to measure Ppl during thoracentesis. Future studies are needed to investigate its usefulness in predicting clinically meaningful outcomes.

Original Research: Signs and Symptoms of Chest Diseases

Chest. 2014;146(4):1013-1020. doi:10.1378/chest.14-0131

BACKGROUND:  Protracted bacterial bronchitis (PBB) is a common and treatable cause of chronic wet cough in children in which the mechanisms are not understood. This study investigates the IL-1 pathway and a neutrophil gene expression signature in PBB.

METHODS:  BAL was collected from children in an experimental cohort (n = 21, PBB; n = 33, control subjects), and a second validation cohort (n = 36, PBB; n = 11, control subjects). IL-1β, IL-1 receptor antagonist (IL-1RA), and α-defensins 1-3 were assayed by enzyme-linked immunosorbent assay, western blot, and quantitative real-time polymerase chain reaction, together with selected IL-1 pathway members and neutrophil-related molecules.

RESULTS:  In the experimental cohort, children with symptomatic PBB had significantly higher levels of IL-1β and α-defensin gene and protein expression. Expression of the neutrophil chemokine receptor C-X-C motif receptor 2 was also higher in PBB. IL-1RA protein was higher, however, the IL-1RA:IL-1β ratio was lower in children with PBB than control subjects. In the validation cohort, protein and gene expression of IL-1β and α-defensins 1-3 were confirmed higher, as was gene expression of IL-1 pathway members and C-X-C motif receptor 2. IL-1β and α-defensin 1-3 levels lowered when PBB was treated and resolved. In children with recurrent PBB, gene expression of the IL-1β signaling molecules pellino-1 and IL-1 receptor-associated kinase 2 was significantly higher. IL-1β protein levels correlated with BAL neutrophilia and the duration and severity of cough symptoms. IL-1β and α-defensin 1-3 levels were highly correlated.

CONCLUSIONS:  PBB is characterized by increased IL-1β pathway activation. IL-1β and related mediators were associated with BAL neutrophils, cough symptoms, and disease recurrence, providing insight into PBB pathogenesis.

Original Research: Lung Cancer

Chest. 2014;146(4):1021-1028. doi:10.1378/chest.13-2924

BACKGROUND:  The practice of treating a solitary pulmonary nodule (SPN) suspicious for stage I non-small cell lung cancer (NSCLC) with stereotactic ablative radiotherapy (SABR) in the absence of pathology is growing. In the absence of randomized evidence, the appropriate prior probability threshold of lung cancer of when such a strategy is warranted can be informed using decision analysis.

METHODS:  A decision tree and Markov model were constructed to evaluate the relative merits of surveillance, a PET scan-directed SABR strategy (without pathology), or a PET scan-biopsy-SABR strategy, when faced with an SPN at different prior probabilities for lung cancer. Diagnostic characteristics, as well as disease, treatment, and toxicity parameters, were extracted from the literature. Deterministic analysis and probabilistic sensitivity analyses were performed to inform the appropriate lung cancer prior probability threshold between treatment strategies.

RESULTS:  In the reference case analysis, the prior probability threshold between surveillance and PET scan-biopsy-SABR was 17.0%; between PET scan-directed SABR and PET scan-biopsy-SABR, the threshold was 85.0%. The latter finding was confirmed on probabilistic sensitivity analysis (85.2%; 95% CI, 80.0% to 87.2%). This predicted lung cancer prior probability threshold was most sensitive to the diagnostic sensitivity of transthoracic biopsy (range, 77.2% to 94.0%) and the detection rate of false negatives on CT scan surveillance (range, 82.4% to 92.3%).

CONCLUSIONS:  This model suggests that if there are concerns about morbidity related to biopsy for an SPN, a PET scan-directed SABR strategy is warranted when the prior probability of lung cancer exceeds a point estimate of 85%.

Original Research: Chest Infections

Chest. 2014;146(4):1029-1037. doi:10.1378/chest.13-2853

BACKGROUND:  Active smoking increases the risk of developing community-acquired pneumonia (CAP) and invasive pneumococcal disease, although its impact on mortality in pneumococcal CAP outcomes remains unclear. The aim of this study was to investigate the influence of current smoking status on pneumococcal CAP mortality.

METHODS:  We performed a multicenter, prospective, observational cohort study in 4,288 hospitalized patients with CAP. The study group consisted of 892 patients with pneumococcal CAP: 204 current smokers (22.8%), 387 nonsmokers (43.4%), and 301 exsmokers (33.7%).

RESULTS:  Mortality at 30 days was 3.9%: 4.9% in current smokers vs 4.3% in nonsmokers and 2.6% in exsmokers. Current smokers with CAP were younger (51 years vs 74 years), with more alcohol abuse and fewer cardiac, renal, and asthma diseases. Current smokers had lower CURB-65 (confusion, uremia, respiratory rate, BP, age ≥ 65 years) scores, although 40% had severe sepsis at diagnosis. Current smoking was an independent risk factor (OR, 5.0; 95% CI, 1.8-13.5; P = .001) for 30-day mortality of pneumococcal CAP after adjusting for age (OR, 1.06; P = .001), liver disease (OR, 4.5), sepsis (OR, 2.3), antibiotic adherence to guidelines, and first antibiotic dose given < 6 h. The independent risk effect of current smokers remained when compared only with nonsmokers (OR, 4.0; 95% CI, 1.3-12.6; P = .015) or to exsmokers (OR, 3.9; 95% CI, 1.09-4.95; P = .02).

CONCLUSIONS:  Current smokers with pneumococcal CAP often develop severe sepsis and require hospitalization at a younger age, despite fewer comorbid conditions. Smoking increases the risk of 30-day mortality independently of tobacco-related comorbidity, age, and comorbid conditions. Current smokers should be actively targeted for preventive strategies.

Chest. 2014;146(4):1038-1045. doi:10.1378/chest.13-3065

BACKGROUND:  The genus Acinetobacter, well known as a nosocomial pathogen, can also cause severe community-onset pneumonia. Previous small case series have suggested fulminant disease and a pooled hospital mortality of > 60%.

METHODS:  We conducted a prospective observational study of all episodes of bacteremic, community-onset, and radiologically confirmed pneumonia due to Acinetobacter species at a tertiary referral hospital in tropical Australia from 1997 to 2012 following the introduction of routine empirical treatment protocols covering Acinetobacter. Demographic, clinical, microbiologic, and outcome data were collected.

RESULTS:  There were 41 episodes of bacteremic community-onset Acinetobacter pneumonia, of which 36 had no indicators suggesting health-care-associated infection. Of these, 38 (93%) were Indigenous Australians, one-half were men, the average age was 44.1 years, and 36 episodes (88%) occurred during the rainy season. All patients had at least one risk factor, with hazardous alcohol intake in 82%. Of the 37 isolates available for molecular speciation, 35 were Acinetobacter baumannii and two were Acinetobacter nosocomialis. All isolates were susceptible in vitro to gentamicin, meropenem, and ciprofloxacin, but only one was fully susceptible to ceftriaxone. ICU admission was required in 80%. All 41 patients received appropriate antibiotics within the first 24 h of admission, and 28- and 90-day mortality were both low at 11%.

CONCLUSIONS:  Community-acquired Acinetobacter pneumonia is a severe disease, with the majority of patients requiring ICU admission. Most patients have risk factors, particularly hazardous alcohol use. Despite this severity, correct initial empirical antibiotic therapy in all patients was associated with low mortality.

Original Research: Diffuse Lung Disease

Chest. 2014;146(4):1046-1054. doi:10.1378/chest.14-0015

BACKGROUND:  Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. The objective of this study was to evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis.

METHODS:  This study consisted of a randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicenter trial lasting 3 months and an open-label study from month 3 to month 6. Adults with a clinical and histologic diagnosis of cutaneous sarcoidosis were included in nine hospital centers in France. Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for 3 months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide, 100 mg to 200 mg daily. The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement in three target lesions scored for area and infiltration, were compared across randomization groups.

RESULTS:  The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients in the thalidomide group (20%) vs four out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of −1% [95% CI, −26% to +24%] for thalidomide vs placebo, P = 1.0). Eight patients with side effects were recorded in the thalidomide group vs three in the placebo group. We observed a large number of adverse event-related discontinuations in patients taking thalidomide in the first 3 months (four patients with thalidomide, zero with placebo) and in the 3 following months (five patients).

CONCLUSIONS:  At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT0030552; URL: www.clinicaltrials.gov

Chest. 2014;146(4):1055-1063. doi:10.1378/chest.13-2688

BACKGROUND:  The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates, and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells and, thus, may contribute to lung fibrosis in IPF.

METHODS:  Serum, lung tissue, and lung function values were obtained from four independent locations (Sydney, NSW, and Perth, WA, Australia; San Francisco, CA; and Modena, Italy). Patients with IPF were followed for a minimum of 1 year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under nonstimulatory conditions. Fibulin-1 levels in serum, and secreted or deposited by fibroblasts, were measured by western blot and in lung tissue by immunohistochemistry.

RESULTS:  Serum fibulin-1 levels were increased in patients with IPF compared with subjects without lung disease (P = .006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (P = .02) and correlated negatively with lung function (r = −0.9, P < .05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (P < .05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (area under the curve , 0.71; 95% CI, 0.57-0.86; P = .012).

CONCLUSIONS:  Fibulin-1 is a novel potential biomarker for disease progression in IPF and raises the possibility that it could be used as a target for the development of new treatments.

Chest. 2014;146(4):1064-1072. doi:10.1378/chest.14-0139

BACKGROUND:  Cardiac death is the leading cause of mortality associated with sarcoidosis in Japan. However, the involvement of sarcoidosis infiltration often remains undetected. Recently, late gadolinium enhancement with cardiovascular MRI (LGE-CMR) imaging has been introduced for the detection of myocardial infiltrative disease, as it enables the detection of even minor myocardial damage. We investigated the incidence and prognostic value of LGE-CMR in patients with extracardiac sarcoidosis without cardiac manifestations.

METHODS:  Sixty-one consecutive patients who met the histologic and clinical criteria for sarcoidosis, and who did not have signs or symptoms of cardiovascular involvement, were prospectively recruited. LGE-CMR was performed at the time of enrollment, and patients were classified into positive or negative late gadolinium enhancement groups based on the findings. The study end point was a composite of all-cause death, symptomatic arrhythmia, and heart failure necessitating admission.

RESULTS:  Patients were predominantly middle aged (57 ± 15 years) and female (66%), and most had stable disease activity that did not require treatment with immunosuppressants. LGE-CMR detected cardiac involvement in eight patients (13%). Interventricular septal thinning detected by echocardiography was an independent predictor of LGE-CMR-detected cardiac involvement. During the follow-up period of 50 ± 12 months, no significant difference in adverse events was noted between patients in the LGE-CMR-positive and LGE-CMR-negative groups.

CONCLUSIONS:  LGE-CMR detected cardiac involvement in 13% of patients with sarcoidosis without cardiac manifestation, but both patients with and without LGE had relatively low event rates.

TRIAL REGISTRY:  Japan Primary Registries Network; No.: UMIN000001549; URL: www.umin.ac.jp

Original Research: Cardiovascular Disease

Chest. 2014;146(4):1073-1080. doi:10.1378/chest.13-2443

BACKGROUND:  Ischemic events (IEs) and intracranial hemorrhages (ICHs) are feared complications of atrial fibrillation (AF) and of antithrombotic treatment in patients with these conditions.

METHODS:  Patients with AF admitted to the EDs of the Bologna, Italy, area with acute IE or ICH were prospectively recorded over 6 months.

RESULTS:  A total of 178 patients (60 male patients; median age: 85 years) presented with acute IE. Antithrombotic therapy was as follows: (1) vitamin K antagonists (VKAs) in 31 patients (17.4%), with international normalized ratio (INR) at admission of < 2.0 in 16 patients, 2.0 to 3.0 in 13 patients, and > 3.0 in two patients; (2) aspirin (acetylsalicylic acid) (ASA) in 107 patients (60.1%); and (3) no treatment in 40 patients (22.5%), mainly because AF was not diagnosed. Twenty patients (eight male patients; median age: 82 years) presented with acute ICH: 13 (65%) received VKAs (INR, 2.0-3.0 in 11 patients and > 3.0 in two patients), while six (30%) received ASA. Most IEs (88%) and ICHs (95%) occurred in patients aged > 70 years. A modeling analysis of patients aged > 70 years was used to estimate annual incidence in subjects anticoagulated with VKAs in our Network of Anticoagulation Centers (NACs), or those expected to have AF but not included in NACs. The expected incidence of IE was 12.0%/y (95% CI, 10.7-13.3) in non-NACs and 0.57%/y (95% CI, 0.42-0.76) in NACs (absolute risk reduction [ARR], 11.4%/y; relative risk reduction [RRR], 95%; P < .0001). The incidence of ICH was 0.63%/y (95% CI, 0.34-1.04) and 0.30%/y (95% CI, 0.19-0.44), respectively (ARR, 0.33%/y; RRR, 52.4%/y; P = .04).

CONCLUSIONS:  IEs occurred mainly in elderly patients who received ASA or no treatment. One-half of patients with IEs receiving anticoagulant treatment had subtherapeutic INRs. Therapeutic approaches to elderly subjects with AF require an effective anticoagulant treatment strategy.

Translating Basic Research into Clinical Practice

Chest. 2014;146(4):1081-1091. doi:10.1378/chest.14-0397

Acute lung injury (ALI) and ARDS fall within a spectrum of pulmonary disease that is characterized by hypoxemia, noncardiogenic pulmonary edema, and dysregulated and excessive inflammation. While mortality rates have improved with the advent of specialized ICUs and lung protective mechanical ventilation strategies, few other therapies have proven effective in the management of ARDS, which remains a significant clinical problem. Further development of biomarkers of disease severity, response to therapy, and prognosis is urgently needed. Several novel pathways have been identified and studied with respect to the pathogenesis of ALI and ARDS that show promise in bridging some of these gaps. This review will focus on the roles of matrix metalloproteinases and protein tyrosine kinases in the pathobiology of ALI in humans, and in animal models and in vitro studies. These molecules can act independently, as well as coordinately, in a feed-forward manner via activation of tyrosine kinase-regulated pathways that are pivotal in the development of ARDS. Specific signaling events involving proteolytic processing by matrix metalloproteinases that contribute to ALI, including cytokine and chemokine activation and release, neutrophil recruitment, transmigration and activation, and disruption of the intact alveolar-capillary barrier, will be explored in the context of these novel molecular pathways.

Medical Ethics

Chest. 2014;146(4):1092-1101. doi:10.1378/chest.14-0130

How one defines death may vary. It is important for clinicians to recognize those aspects of a patient’s religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only.

Contemporary Reviews in Critical Care Medicine

Chest. 2014;146(4):1102-1113. doi:10.1378/chest.14-0555

Advances in critical care practice have led to a substantial decline in the incidence of ARDS over the past several years. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction. Despite decades of research, there is no proven pharmacologic treatment of ARDS, and mortality from ARDS remains high. Consequently, recent initiatives have broadened the scope of lung injury research to include targeted prevention of ARDS. Prediction scores have been developed to identify patients at risk for ARDS, and clinical trials testing aspirin and inhaled budesonide/formoterol for ARDS prevention are ongoing. Future trials aimed at preventing ARDS face several key challenges. ARDS has not been validated as an end point for pivotal clinical trials, and caution is needed when testing toxic therapies that may prevent ARDS yet potentially increase mortality.

Contemporary Reviews in Sleep Medicine

Chest. 2014;146(4):1114-1122. doi:10.1378/chest.14-0596

The prevalence of chronic kidney disease (CKD) is increasing, which presents challenges for both patients and health-care budgets. Although this phenomenon has been attributed to the growth in diabetes, hypertension, and obesity, sleep apnea and nocturnal hypoxemia may also contribute to the pathogenesis of CKD and its progression to kidney failure. Two pathophysiologic mechanisms responsible for CKD are glomerular hyperfiltration and chronic intrarenal hypoxia, resulting in tubulointerstitial injury, the final common pathway to end-stage kidney disease (ESKD). Multiple descriptive studies have demonstrated an association between CKD and sleep apnea. Although sleep apnea is common in patients with CKD and associated with significant nocturnal hypoxemia, it is often relatively free of sleep-related symptoms, making it difficult to detect without objective nocturnal monitoring. Nevertheless, sleep apnea and nocturnal hypoxemia have been associated with loss of kidney function and kidney injury, suggesting that they contribute to the pathogenesis of continued deterioration in kidney function. There are several pathways through which sleep apnea may achieve this, including a direct effect of intrarenal hypoxia and activation of the systemic and renal renin-angiotensin system. Further research is required to better understand these relationships and determine whether specific interventions in patients with sleep apnea have an impact on clinical outcomes, such as reducing the prevalence of CKD and delaying its progression to ESKD.

Special Features

Chest. 2014;146(4):1123-1130. doi:10.1378/chest.14-0460

The mechanisms of anthracycline-dependent cardiotoxicity have been studied widely, with the suggested principal mechanism of anthracycline damage being the generation of reactive oxygen species by iron-anthracycline complexes, leading to lipid peroxidation and membrane damage. An increasing number of researchers studying cardiovascular events associated with anthracycline-based chemotherapy are addressing cardiac extracellular matrix (ECM) remodeling. The heart is an efficient muscular pump, with the cardiomyocytes and intramural coronary vasculature of the heart tethered in an ECM consisting of a network of fibrillar, structural proteins, mostly collagens. Increasing evidence suggests that the ECM plays a complex and diverse role in the processes initiated by anthracycline-class drugs that lead to cardiac damage. This review discusses adverse myocardial remodeling induced by anthracyclines and focuses on their mechanisms of action.


Chest. 2014;146(4):1131. doi:10.1378/chest.14-0361

                  for Kate Gale
To my first patient where
I wept, not profusely,
not a Good-Lord-of-tears
where the floor is mopped
with me, but rather
the controlled sobs
of a man who talks
about the weather
to see if there’s an airway
and there is, now,
another patient,
another day,
another shift,
with this future
married so long
to the past
that they no longer
sleep in the same bed,
from the other room
before the lights go out,
“I love you”
and then
“Did you hear me?”
But they’re sound

Chest. 2014;146(4):1131. doi:10.1378/chest.14-0362

Do not make things too hard.
There are lungs and there are hearts,
as well as forests and breeze.
The Bundle of His is not something
you will fix alone.
Don’t get sick.
Don’t get the patient sick.
Don’t curse in front of patients.
Let them curse.
If you have rocks in your pockets,
you might want to put them down somewhere
to lighten your load.
If your stomach is hard and knotty,
imagine the patient’s stomach.
If you can’t stand the sight of blood,
keep in mind that after awhile
you can stand the sight of blood.
If they’re shivering, try to keep them warm.
If they’re bleeding, try to stop it.
If it’s broken, try to splint it.
If they need someone to listen to their story about Vietnam,
Then eat.

Chest. 2014;146(4):1132-1133. doi:10.1378/chest.14-0360

hitting her head
on the ceiling,
getting caught,
in the chandelier,
she is in room 4,
on the top
of the doorway.
When you go in,
please ask her
to remove her shoes;
we don’t need footprints
on the ceiling.
And the man
in room 3
who got thrown
into a demolished vehicle,
straightening the steering wheel
and fixing the windshield,
he had a femoral break
that miraculously
got thrown back
into place,
completely healed.
You can tell him to go home.
There’s things he can fix
in his own kitchen.
We need that room
for the boy
in room 2
who didn’t want to be born
so he crawled back inside
his mother’s womb,
if he could stay there,
pay rent
if needed.
The problem—
at least one of the many—
is that he’s about to turn
and his mother
has swollen up to the size
of two mothers,
having gained
almost two hundred pounds
in the matter of a few moments.
She says she’s hungry,
eating for three.
Her daughter is in there also,
a woman recently divorced.
You’ll find a spare
umbilical cord
in one of the drawers.
If you can,
offer one end
and if they’re open to it
and they take hold,
give a tug,
not sharp,
but enough
so that
her family
can somersault
their way
back home
where everyone
in the E.R.
wants to be
in the first place.

Selected Reports

Chest. 2014;146(4):e121-e125. doi:10.1378/chest.13-2791

Streptococcus anginosus has long been recognized to cause invasive pyogenic infections. This holds true for thoracic infections where S anginosus has a propensity for abscess and empyema formation. Early diagnosis is important given the significant morbidity and mortality associated with thoracic S anginosus infections. Yet, distinguishing thoracic S anginosus clinically is difficult. We present three cases of thoracic S anginosus that demonstrated radiographic extension across tissue planes, including the interlobar fissure, diaphragm, and chest wall. Few infectious etiologies are known to cross tissue planes. Accordingly, we propose S anginosus be considered among the differential diagnosis of potential infectious etiologies causing radiographic extension across tissue planes.

Chest. 2014;146(4):e126-e129. doi:10.1378/chest.13-1573

We report the first case, to our knowledge, of amatoxin hepatotoxicity in Iowa and explore the ethical and decisional challenges of offering an investigational treatment of a rare disease. Acute liver failure due to ingestion of amatoxin-containing mushrooms is a relatively rare entity. Once amatoxin poisoning is identified, there is no clearly effective treatment, leading to a broad range of theoretically beneficial, anecdotally successful, or investigational options. The evolution of hepatotoxicity led us to offer investigational treatment with silibinin, an extract of Mediterranean milk thistle. We explore the pitfalls in medical decision-making experienced by both the patient and the physician in the face of ambiguity. The patient did well following silibinin infusion, but we are left uncertain as to whether the patient truly responded to treatment or was simply destined to recover.

Ultrasound Corner

Chest. 2014;146(4):e130-e133. doi:10.1378/chest.13-1822

A 72-year-old man was brought to the ED after passing melena for 1 day and multiple falls. The patient had recently undergone a lobectomy for non-small cell lung cancer and was recovering in a rehabilitation facility. He had a history of ischemic stroke and was taking an oral direct thrombin inhibitor. At presentation, he was conversant and hemodynamically stable, his hemoglobin level was 4.4 g/dL, international normalized ratio was 4.4, and lactate level was 2.1 mmol/L. IV access was obtained, and a Foley catheter was inserted. A nasogastric tube was placed and revealed scant coffee-ground drainage. Treatment was started with continuous infusion of IV proton pump inhibitors, and the patient received one unit of packed RBCs and two units of fresh frozen plasma. Shortly thereafter, the patient became diaphoretic, unresponsive, and tachypneic, and he demonstrated diffuse abdominal tenderness. He was intubated for airway protection. Examination revealed pallor, anuria, clear breath sounds, and a rigid abdomen. Repeated testing revealed his lactate level was elevated to 8 mmol/L, and hemoglobin level was 3.5 g/dL. A focused assessment with sonography for trauma (FAST) examination was performed to evaluate the abdominal findings and to search for a focus of bleeding. The ultrasound findings are shown in Videos 1-3.

Pulmonary, Critical Care, and Sleep Pearls

Chest. 2014;146(4):e134-e137. doi:10.1378/chest.13-2927

A 40-year-old white woman presented with 1-week history of mild cough, fever, and progressive nonmassive bright-red blood hemoptysis. She denied dyspnea, sputum production, epistaxis, hematemesis, or weight loss. She was an active smoker for the past 20 years with history of chronic pancreatitis and chronic pain requiring jejunal tube feeding and chronic IV analgesics. She had no history of malignancy or lung disease and had been in her usual state of health until the symptom onset a week prior.

Topics: hemoptysis , lung
Chest. 2014;146(4):e138-e142. doi:10.1378/chest.14-0203

A 60-year-old woman was referred to the pulmonary clinic for evaluation of lung nodules. Her medical history was notable for hypothyroidism, anxiety, and a ruptured breast implant for which incomplete surgical resection and evacuation had been performed 10 years previously. She was a lifelong nonsmoker and worked as a gym instructor. The patient denied occupational exposures and had not traveled recently. Medications included levothyroxine and alprazolam. Except for a 1-month history of occasional dry cough, the review of systems was negative. The patient’s physician queried whether the previously ruptured silicone breast implant may have played a role in the genesis of the nodules and referred the patient to our institution for further management. The lack of systemic symptoms relative to the degree of lung involvement provided an early diagnostic clue.


Chest. 2014;146(4):e143. doi:10.1378/chest.14-1408
Chest. 2014;146(4):e143-e144. doi:10.1378/chest.14-1460
Chest. 2014;146(4):e145. doi:10.1378/chest.14-1459
Chest. 2014;146(4):e146. doi:10.1378/chest.14-1095
Chest. 2014;146(4):e146-e148. doi:10.1378/chest.14-1228

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