Divay Chandra

The minimal important difference of exercise tests in severe COPD

Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease (COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4–6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St Georges Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohens effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1–20.1 m), 24.2 m (95% CI 23.4–25.4 m), 24.6 m (95% CI 23.4–25.7 m) and 26.4 m (95% CI 25.4–27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0–2.4 W), 3.2 W (95% CI 3.0–3.4 W), 3.2 W (95% CI 3.0–3.4 W) and 3.3 W (95% CI 3.0–3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26±2 m for 6MWD and 4±1 W for MCEC for patients with severe COPD.

Outcomes of noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease in the United States, 1998-2008.

RATIONALE The patterns and outcomes of noninvasive, positive-pressure ventilation (NIPPV) use in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) nationwide are unknown. OBJECTIVES To determine the prevalence and trends of noninvasive ventilation for acute COPD. METHODS We used data from the Healthcare Cost and Utilization Projects Nationwide Inpatient Sample to assess the pattern and outcomes of NIPPV use for acute exacerbations of COPD from 1998 to 2008. MEASUREMENTS AND MAIN RESULTS An estimated 7,511,267 admissions for acute exacerbations occurred from 1998 to 2008. There was a 462% increase in NIPPV use (from 1.0 to 4.5% of all admissions) and a 42% decline in invasive mechanical ventilation (IMV) use (from 6.0 to 3.5% of all admissions) during these years. This was accompanied by an increase in the size of a small cohort of patients requiring transition from NIPPV to IMV. In-hospital mortality in this group appeared to be worsening over time. By 2008, these patients had a high mortality rate (29.3%), which represented 61% higher odds of death compared with patients directly placed on IMV (95% confidence interval, 24-109%) and 677% greater odds of death compared with patients treated with NIPPV alone (95% confidence interval, 475-948%). With the exception of patients transitioned from NIPPV to IMV, in-hospital outcomes were favorable and improved steadily year by year. CONCLUSIONS The use of NIPPV has increased significantly over time among patients hospitalized for acute exacerbations of COPD, whereas the need for intubation and in-hospital mortality has declined. However, the rising mortality rate in a small but expanding group of patients requiring invasive mechanical ventilation after treatment with noninvasive ventilation needs further investigation.

Meta-analysis: Travel and Risk for Venous Thromboembolism

Context The body of evidence on the epidemiology of long-distance travel and venous thromboembolism (VTE) is heterogeneous and inconclusive. Contribution The reviewers found 14 eligible studies, which had significant between-study heterogeneity, and the pooled relative risk for VTE was 2.0 (95% CI, 1.5 to 2.7). The reviewers eliminated the heterogeneity by excluding 6 casecontrol studies in which control participants had been referred for VTE testing. The relative risk was 2.8 (CI, 2.2 to 3.7) in the remaining included studies and 1.2 (CI, 0.9 to 1.6) in the excluded studies. Implication By excluding studies with control participants who had a different risk for VTE than the source population for the case patients, the authors clarified a confusing body of evidence. The Editors Because of the rapid increase in air and other modes of travel in recent years, the potential risk for travel-related venous thromboembolism (VTE) is a growing public health concern (1). Worldwide, 2.5 billion passengers will travel by air in 2010 (2), which underscores the large global population at risk for this serious condition. In addition to the direct and indirect costs of evaluation and treatment, mortality risk is high: In ambulatory population-based cohorts, the estimated 28-day mortality for a first episode of VTE is 11% (3). Although a positive relationship between travel and VTE is often discussed and assumed to exist, the results of previous studies are surprisingly conflicting. Several epidemiologic studies have investigated this relationship over the past decade; approximately half have found no relationship between travel and VTE (48), whereas the rest have identified elevated risk (916). Demonstrating the presence and magnitude of such potential risk is crucial to determine the appropriateness of additional controlled trials or policy measures to prevent travel-related VTE. In addition, if a relationship exists, quantifying the doseresponse relationshiphow duration of travel relates to VTEis central to determining the travel circumstances under which sufficient risk could be present to justify preventive interventions. To determine whether travel is associated with risk for VTE, to quantify the doseresponse relationship, and to identify reasons for the contradictory findings reported by previous studies, we performed a systematic review and meta-analysis of studies of travel and risk for VTE. We hypothesized that travel would be associated with the risk for VTE and that this risk would increase with greater duration of travel. Methods We followed the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines during all stages of design, implementation, and reporting of this meta-analysis (17). Search Strategy and Data Sources We searched for all studies that provided an effect estimate for a potential association between travel and VTE. Inclusion criteria were observational studies or clinical trials that included patients who traveled by any mode of transportation; that used nontraveling persons for comparison; and that diagnosed VTE by appropriate radiologic investigation (ultrasonography or venography for deep venous thrombosis [DVT] and computed tomography or ventilationperfusion scan for pulmonary embolism [PE]), autopsy findings, or documentation of hospitalization for VTE. We excluded studies if they only evaluated treatments for VTE, rather than travel as a risk factor for VTE; if VTE was diagnosed by less rigorous criteria (such as by using only administrative codes in outpatients); or if no comparison group of nontravelers was included (which would preclude estimation of relative risks [RRs] associated with travel). We performed our search by using MEDLINE, EMBASE, BIOSIS, CINAHL, the Cochrane library, grey-literature sources (a system for information on grey literature in Europe, a British library inside database, and dissertation abstracts online); one of the investigators also hand-searched the reference lists of identified studies. For each database, the years searched included the earliest available online year of indexing up to March 2008, without language restrictions. We exploded each search term. Our MEDLINE search terms were ((travel[MeSH Terms] OR travel[Text Word]) OR (transportation[MeSH Terms] OR transportation[Text Word]) OR journey[All Fields] OR flying[All Fields]) AND ((thrombosis[MeSH Terms] OR thrombosis[Text Word]) OR (embolism[MeSH Terms] OR embolism[Text Word]) OR DVT[All Fields] OR PE[All Fields] OR clot[All Fields]) NOT (review[Publication Type] OR review literature as topic[MeSH Terms] OR review[Text Word]) NOT (case reports[Publication Type]). Study Selection Of 1560 identified abstracts, we excluded 1518 on screening because they were commentaries, general reviews, or case reports (Figure 1). Two investigators independently examined the full text of the remaining 42 studies to confirm eligibility for inclusion. The second reviewer was blinded to the study investigators and journal of publication. Interobserver agreement between the 2 reviewers for initial study inclusion was high (= 0.89). We resolved disagreement by mutual discussion and, if required, by consultation with a third investigator. Of the 42 studies, we excluded 15 because they lacked a nontraveling comparison group, 11 because they evaluated preventive measures for travel-related VTE, 1 because it did not use the required criteria for VTE diagnosis (18), and 1 because no events occurred and it also lacked a nontraveling comparison group (19). This resulted in the final selection of 14 studies, including 1 prospective cohort study (15), 1 retrospective cohort study (16), 1 casecrossover study (13), and 11 casecontrol studies (412, 14, 20). The investigators can provide a complete list of abstracts searched with reasons for exclusion on request. Figure 1. Study flow diagram. VTE = venous thromboembolism. Data Extraction and Quality Assessment We collected data on the year the study was performed, study design, study location, inclusion and exclusion criteria, number of participants, duration and mode of travel, duration of follow up, and adjusted relative risks and odds ratios with CIs. Two investigators performed independent data extraction by using a standardized data collection form. We resolved disagreement by mutual discussion and, if required, by consulting a third investigator. All prespecified data points were available from the published manuscripts, except for data on dose-response (duration of travel and risk for VTE) in 4 studies (1113, 15); we contacted the investigators to request the missing data but received no responses. Because no standardized criteria have been established for judging the quality of observational studies, quality scores can differ depending on the scale chosen, and interpretation of such scores is difficult (21), we selected a priori several important design characteristics that may affect study quality to evaluate as sources of heterogeneity, including inclusion and exclusion criteria, method of travel history assessment, selection criteria for control participants, matching criteria, and control for confounding. We were particularly interested in the selection criteria for control participants in casecontrol studies because of the potential for selection bias that could substantially alter the validity of the obtained results. We assessed potential recall bias by the method (self-report vs. travel records) and timing (before vs. after VTE evaluation) of travel history assessment. Statistical Analysis We obtained pooled risk estimates for risk for VTE with travel by using random-effects models, according to the method of DerSimonian and Laird (22), with inverse-variance weighting. We used the most fully multivariable-adjusted effect estimate and recorded the included covariates. Because travel-related VTE is an uncommon outcome, odds ratios from casecontrol studies approximate risk ratios or relative risks (RRs) from cohort studies, and we pooled them to generate 1 common RR. Henceforth, we will refer to odds ratios from casecontrol studies as RRs. We assessed heterogeneity among studies by using Cochrane Q and I 2 statistics. We evaluated the following predefined sources of potential heterogeneity: study design (cohort vs. casecrossover vs. casecontrol), selection criteria for control participants in casecontrol studies (referred for VTE evaluation vs. nonreferred), study location (Europe vs. North America vs. Australia or New Zealand), minimum duration of travel required for inclusion (<8 vs. 8 hours), duration of follow-up after travel completed (3 vs. >3 weeks), type of VTE studied (DVT vs. PE), mode of travel (air vs. surface [land or sea]), exposure assessment (self-report vs. travel records), and number of included covariates. We obtained effect estimates by mode of travel from the individual studies or, when such estimates were unavailable, from previously reported pooled estimates (5). We used meta-regression to examine sources of heterogeneity by using the Wald test in random-effects meta-regression models. We also used meta-regression to test for a doseresponse relationship between duration of travel and risk for VTE. We assessed potential publication bias by visually examining a funnel plot with the Begg test (23), a statistical analogue of the visual funnel graph, and the Egger test (24). We used STATA, version 9.0 (StataCorp, College Station, Texas), for all analyses. We defined statistical significance as a 2-tailed value less than 0.05. Role of the Funding Source Our study received no outside funding. Results Table 1 summarizes the characteristics of the 14 included studies. We identified 4055 cases of VTE, including 3980 cases in the 11 casecontrol studies (with 5413 control participants), 29 in the 2 cohort studies (10932 participants), and 46 in the casecrossover study (5408 participants). Seven of the studies reported statistically significant asso

NSAID Exposure and Risk of Nonunion: A Meta-Analysis of Case–Control and Cohort Studies

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for postoperative pain control. However, concerns regarding the potential deleterious effects of NSAIDs on bone healing have compelled many physicians to avoid NSAIDs in patients with healing fractures, osteotomies, and fusions. We systematically reviewed and analyzed the best clinical evidence regarding the effects of NSAID exposure on bone healing. Medline, Embase, and Cochrane electronic databases were searched for prospective and retrospective clinical studies of fracture, osteotomy, and fusion studies of patients with NSAID exposure and nonunion as an outcome. Study quality was assessed using the Newcastle–Ottawa Scale. Data on study design, patient characteristics, and risk estimates were extracted. Pooled effect estimates were calculated. Subanalyses were performed by bone type and by NSAID dose, duration, and route of administration. In the initial analysis of 11 cohort and case-control studies, the pooled odds ratio for nonunion with NSAID exposure was 3.0 (95% confidence interval 1.6–5.6). A significant association between lower-quality studies and higher reported odds ratios for nonunion was observed. When only higher-quality studies were considered, seven spine fusion studies were analyzed, and no statistically significant association between NSAID exposure and nonunion was identified (odds ratio = 2.2, 95% confidence interval 0.8–6.3). There was no increased risk of nonunion with NSAID exposure when only the highest-quality studies were assessed. Randomized controlled trials assessing NSAID exposure in fracture, fusion, and osteotomy populations are warranted to confirm or refute the findings of this meta-analysis of observational studies.

Extracorporeal Membrane Oxygenation as a Bridge to Emergency Heart-Lung Transplantation in a Patient With Idiopathic Pulmonary Arterial Hypertension

Lung transplantation with or without cardiac transplantation offers the only hope of long-term, symptom-free survival for patients with advanced idiopathic pulmonary arterial hypertension. We describe a patient who underwent an emergency pulmonary embolectomy. During surgery, it was discovered that the patient had idiopathic pulmonary arterial hypertension. After the patient was weaned from cardiopulmonary bypass, pulmonary hypertension caused right-sided heart failure, and a right ventricular assist device was inserted to compensate. Because of profound bleeding from the endotracheal tube, the patient was placed on extracorporeal membrane oxygenation in the hope of bridging the patient to heart-lung transplantation. Extracorporeal membrane oxygenation was required for 10 days until a donor heart and lung became available. The patient recovered from the transplant operation and was discharged home 76 days later.

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

RATIONALE C-X-C motif chemokine 13 (CXCL13) mediates B-cell trafficking and is increased, proportionately to disease activity, in many antibody-mediated syndromes. Dysregulated B cells have recently been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. OBJECTIVES To determine if CXCL13 is associated with IPF progression. METHODS CXCL13 was measured in lungs by DNA microarray and immunohistochemistry, and in plasma by ELISA. MEASUREMENTS AND MAIN RESULTS CXCL13 mRNA was threefold and eightfold greater in IPF lungs (n = 92) compared with chronic obstructive pulmonary disease (COPD) (n = 191) and normal (n = 108) specimens, respectively (P < 0.0001). IPF lungs also showed increased CXCL13 staining. Plasma CXCL13 concentrations (pg/ml) were greater in 95 patients with IPF (94 ± 8) than in 128 subjects with COPD (53 ± 9) and 57 normal subjects (35 ± 3) (P < 0.0001). Circulating CXCL13 levels were highest in patients with IPF with pulmonary artery hypertension (P = 0.01) or acute exacerbations (P = 0.002). Six-month survival of patients with IPF in the highest quartile of plasma CXCL13 was 65 ± 10% versus 93 ± 10% in the others (hazard ratio, 5.5; 95% confidence interval, 1.8-16.9; P = 0.0008). CXCL13 increases by more than 50% in IPF serial assays, irrespective of initial values, also presaged respiratory failure (hazard ratio, 7.2; 95% confidence interval, 1.3-40.0; P = 0.008). In contrast, CXCL13 clinical associations in subjects with COPD were limited to modest correlations with FEV1 (P = 0.05) and progression of radiographic emphysema (P = 0.05). CONCLUSIONS CXCL13 is increased and is a prognostic biomarker in patients with IPF, and more so than in patients with COPD. This contrast indicates CXCL13 overexpressions are intrinsic to IPF, rather than an epiphenomenon of lung injury. The present data implicate CXCL13 and B cells in IPF pathogenesis, and support considerations for trials of specific B-cell-targeted therapies in patients with this intractable disease.

The Relationship Between Pulmonary Emphysema and Kidney Function in Smokers

BACKGROUND It has been reported that the prevalence of kidney dysfunction may be increased in patients exposed to tobacco with airflow obstruction. We hypothesized that kidney dysfunction would associate with emphysema rather than with airflow obstruction measured by the FEV₁. METHODS Five hundred eight current and former smokers completed a chest CT scan, pulmonary function tests, medical questionnaires, and measurement of serum creatinine. Glomerular filtration rates (eGFRs) were estimated using the method of the Chronic Kidney Disease Epidemiology Collaboration. Quantitative determinants of emphysema and airway dimension were measured from multidetector chest CT scans. RESULTS The mean age was 66 ± 7 years, and mean eGFR was 101 ± 22 mL/min/1.73 m². Univariate and multivariate analysis showed a significant association between radiographically measured emphysema and eGFR: Participants with 10% more emphysema had an eGFR that was lower by 4.4 mL/min/1.73 m² (P = .01), independent of airflow obstruction (FEV₁), age, sex, race, height, BMI, diabetes mellitus, hypertension, coronary artery disease, patient-reported dyspnea, pack-years of smoking, and current smoking. There was no association between eGFR and either FEV₁ or quantitative CT scan measures of airway dimension. CONCLUSIONS More severe emphysema, rather than airflow obstruction, is associated with kidney dysfunction in tobacco smokers, independent of common risk factors for kidney disease. This finding adds to recent observations of associations between emphysema and comorbidities of COPD, including osteoporosis and lung cancer, which are independent of the traditional measure of reduced FEV₁. The mechanisms and clinical implications of kidney dysfunction in patients with emphysema need further investigation.

Race/Ethnicity Differences in the Inpatient Management of Acute Asthma in the United States

BACKGROUND The only published US study on racial/ethnic disparities in inpatient asthma management was performed in 1989-1990 at a single center. The authors reported that black and Hispanic children were provided substandard care at hospital discharge compared to white children. The purpose of the present analysis was to reexamine this important issue in a large multicenter study. METHODS A cohort study of 1,232 children and adults hospitalized with a physician diagnosis of acute asthma at 30 hospitals in 22 US states was used. RESULTS The cohort included 562 children (age range, 2 to 17 years; 39% white; 42% black; and 19% Hispanic) and 670 adults (age range, 18 to 54 years; 44% white; 44% black; and 12% Hispanic). There were no significant racial/ethnic differences in the choice of inpatient medications or length of stay among either children or adults. At hospital discharge, Hispanic children were less likely to receive an asthma action plan (37%) compared to white children (60%) or black children (63%; p < 0.001). Multivariate adjustment for eight variables (including socioeconomic status, hospital admissions for asthma in the past year, medication use prior to presentation, physical examination findings, and hospital admission location) attenuated the statistical significance of this association (odds ratio, 0.5; 95% confidence interval, 0.1 to 2.5). CONCLUSIONS We did not identify racial/ethnic disparities in the inpatient treatment and outcomes for children or adults with acute asthma. At hospital discharge, Hispanic children were less likely to receive an asthma action plan compared to white or black children, possibly due to language or socioeconomic differences.

Finding an alternative diagnosis does not justify increased use of CT-pulmonary angiography

BackgroundThe increased use of computed tomography pulmonary angiography (CTPA) is often justified by finding alternative diagnoses explaining patients’ symptoms. However, this has not been rigorously examined.MethodsWe retrospectively reviewed CTPA done at our center over an eleven year period (2000 – 2010) in patients with suspected pulmonary embolus (PE). We then reviewed in detail the medical records of a representative sample of patients in three index years – 2000, 2005 and 2008. We determined whether CTPA revealed pulmonary pathology other than PE that was not readily identifiable from the patient’s history, physical examination and prior chest X-ray. We also assessed whether the use of pre-test probability guided diagnostic strategy for PE.ResultsA total of 12,640 CTPA were performed at our center from year 2000 to 2010. The number of CTPA performed increased from 84 in 2000 to 2287 in 2010, a 27 fold increase. Only 7.6 percent of all CTPA and 3.2 percent of avoidable CTPAs (low or intermediate pre-test probability and negative D-dimer) revealed previously unknown findings of any clinical significance. When we compared 2008 to 2000 and 2005, more CTPAs were performed in younger patients (mean age (years) for 2000: 67, 2005: 63, and 2008: 60, (p=0.004, one–way ANOVA)). Patients were less acutely ill with fewer risk factors for PE. Assessment of pre-test probability of PE and D-dimer measurement were rarely used to select appropriate patients for CTPA (pre-test probability of PE documented in chart (% total) in year 2000: 4.1%, 2005: 1.6%, 2008: 3.1%).ConclusionsOur data do not support the argument that increased CTPA use is justified by finding an alternative pulmonary pathology that could explain patients’ symptoms. CTPA is being increasingly used as the first and only test for suspected PE.

Optimizing the 6-Min Walk Test as a Measure of Exercise Capacity in COPD

BACKGROUND It is uncertain whether the effort and expense of performing a second walk for the 6-min walk test improves test performance. Hence, we attempted to quantify the improvement in 6-min walk distance if an additional walk were to be performed. METHODS We studied patients consecutively enrolled into the National Emphysema Treatment Trial who prior to randomization and after 6 to 10 weeks of pulmonary rehabilitation performed two 6-min walks on consecutive days (N = 396). Patients also performed two 6-min walks at 6-month follow-up after randomization to lung volume reduction surgery (n = 74) or optimal medical therapy (n = 64). We compared change in the first walk distance to change in the second, average-of-two, and best-of-two walk distances. RESULTS Compared with the change in the first walk distance, change in the average-of-two and best-of-two walk distances had better validity and precision. Specifically, 6 months after randomization to lung volume reduction surgery, changes in the average-of-two (r = 0.66 vs r = 0.58, P = .01) and best-of-two walk distances (r = 0.67 vs r = 0.58, P = .04) better correlated with the change in maximal exercise capacity (ie, better validity). Additionally, the variance of change was 14% to 25% less for the average-of-two walk distances and 14% to 33% less for the best-of-two walk distances than the variance of change in the single walk distance, indicating better precision. CONCLUSIONS Adding a second walk to the 6-min walk test significantly improves its performance in measuring response to a therapeutic intervention, improves the validity of COPD clinical trials, and would result in a 14% to 33% reduction in sample size requirements. Hence, it should be strongly considered by clinicians and researchers as an outcome measure for therapeutic interventions in patients with COPD.