Ghrelin Treatment of Cachectic Patients with Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: Pulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated. METHODOLOGY/PRINCIPAL FINDINGS: In a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 µg/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p = 0.033) and was maintained at Week 7 (+47 m, within-group p = 0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p = 0.026), in MRC (between-group p = 0.030), and in maximal expiratory pressure (MEP; between-group p = 0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p = 0.049) and MEP (p = 0.021). Ghrelin treatment was well tolerated. CONCLUSIONS/SIGNIFICANCE: In cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD. TRIAL REGISTRATION: UMIN Clinical Trial Registry C000000061

Effects of tiotropium on sympathetic activation during exercise in stable chronic obstructive pulmonary disease patients

Kenji Yoshimura, Ryoji Maekura, Toru Hiraga, Seigo Kitada, Keisuke Miki, Mari Miki, Yoshitaka TateishiDepartment of Respiratory Medicine, Toneyama National Hospital, Osaka, JapanBackground: Tiotropium partially relieves exertional dyspnea and reduces the risk of congestive heart failure in chronic obstructive pulmonary disease (COPD) patients. However, its effect on the sympathetic activation response to exercise is unknown.Aims: This study aimed to determine whether tiotropium use results in a sustained reduction in sympathetic activation during exercise.Methods: We conducted a 12-week, open-label (treatments: tiotropium 18 &amp;micro;g or oxitropium 0.2 mg &amp;times; 3 mg), crossover study in 17 COPD patients. Treatment order was randomized across subjects. The subjects underwent a pulmonary function test and two modes of cardiopulmonary exercise (constant work rate and incremental exercise) testing using a cycle ergometer, with measurement of arterial catecholamines after each treatment period.Results: Forced expiratory volume in 1 second and forced vital capacity were significantly larger in the tiotropium treatment group. In constant exercise testing, exercise endurance time was longer, with improvement in dyspnea during exercise and reduction in dynamic hyperinflation in the tiotropium treatment group. Similarly, in incremental exercise testing, exercise time, carbon dioxide production, and minute ventilation at peak exercise were significantly higher in the tiotropium treatment group. Plasma norepinephrine concentrations and dyspnea intensity were also lower during submaximal isotime exercise and throughout the incremental workload exercise in the tiotropium treatment group.Conclusion: Tiotropium suppressed the increase of sympathetic activation during exercise at the end of the 6-week treatment, as compared with the effect of oxipropium. This effect might be attributed to improvement in lung function and exercise capacity and reduction in exertional dyspnea, which were associated with decreases in respiratory frequency and heart rate and reduced progression of arterial acidosis.Keywords: chronic obstructive pulmonary disease (COPD), anticholinergics, exercise testing, sympathetic activation&amp;nbsp

Personalized pulmonary rehabilitation and occupational therapy based on cardiopulmonary exercise testing for patients with advanced chronic obstructive pulmonary disease

Ryoji Maekura, Toru Hiraga, Keisuke Miki, Seigo Kitada, Mari Miki, Kenji Yoshimura, Hiroshi Yamamoto, Toshiko Kawabe, Masahide Mori Department of Respiratory Medicine and Rehabilitation, National Hospital Organization Toneyama Hospital, Toyonaka City, Osaka, Japan Take-home summary: Personalized pulmonary rehabilitation including occupational therapy improves the prognosis of patients with advanced COPD. Purpose: We previously reported that patients with chronic obstructive pulmonary disease (COPD) exhibit three exercise-induced life-threatening conditions: hypoxemia, sympathetic overactivity, and respiratory acidosis. We aimed to verify whether mortality in patients with advanced COPD could be reduced by a personalized pulmonary rehabilitation (PPR) program in hospital, which determines individual safe ranges and includes occupational therapy (PPR-OT), to prevent desaturation and sympathetic nerve activation during daily activities. Patients and methods: The novel PPR-OT program was evaluated in a retrospective study of patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Grade D) who underwent cardiopulmonary exercise testing (CPET) between April 1990 and December 1999. They received regular treatment without the proposed therapy (control group: n=61; male-to-female ratio [M:F] =57:4; mean age: 68.5&plusmn;6.7&nbsp;years) or with the proposed therapy (PPR-OT group: n=46; M:F =44:2; mean age: 68.7&plusmn;7.1&nbsp;years). A prospective observational study included patients with COPD receiving home oxygen therapy (HOT) between April 1995 and March 2007 to compare the survival rates of the control group (n=47; M:F ratio =34:13; mean age: 71.3&plusmn;10.0&nbsp;years) and the PPR-OT group (n=85; M:F =78:7; mean age: 70.7&plusmn;6.1&nbsp;years) who completed the proposed therapy. Survival after CPET or HOT was analyzed using Cox proportional-hazards regression and Kaplan&ndash;Meier analyses. Results: In both studies, the program significantly improved all-cause mortality (retrospective study: risk ratio =0.389 [range: 0.172&ndash;0.800]; P=0.0094; log-rank test, P=0.0094; observational study: risk ratio =0.515 [range: 0.296&ndash;0.933]; P=0.0291; log-rank test, P=0.0232]. At 5&nbsp;years and 7&nbsp;years, all-cause mortality was extremely low in patients in the PPR-OT group receiving HOT (18.8% and 28.2%, respectively), compared to that in the control group (34.0% and 44.7%, respectively). Survival of patients with life-threatening pathophysiological conditions also greatly improved. Conclusion: The PPR-OT program improved the survival of patients with advanced COPD probably because it modified life-threatening conditions. Keywords: COPD, prognosis, pulmonary rehabilitation, occupational therapy, cardiopulmonary exercise testin

Pulmonary rehabilitation for COPD improves exercise time rather than exercise tolerance: effects and mechanisms

Keisuke Miki,1 Ryoji Maekura,1 Seigo Kitada,1 Mari Miki,1 Kenji Yoshimura,1 Hiroshi Yamamoto,2 Toshiko Kawabe,2 Hiroyuki Kagawa,1 Yohei Oshitani,1 Akitoshi Satomi,1 Kohei Nishida,1 Nobuhiko Sawa,1 Kimiko Inoue2 1Department of Respiratory Medicine, 2Department of Rehabilitation Medicine, National Hospital Organization, Toneyama National Hospital, Toyonaka, Japan Background: COPD patients undergoing pulmonary rehabilitation (PR) show various responses. The purpose of this study was to investigate the possible mechanisms and predictors of the response to PR in COPD patients.Methods: Thirty-six stable COPD patients underwent PR including a 4-week high-intensity exercise training program, and they were evaluated by cardiopulmonary exercise testing. All patients (mean age 69 years, severe and very severe COPD 94%) were classified into four groups by whether the exercise time (Tex) or the peak oxygen uptake (VO2) increased after PR: two factors increased (both the Tex and the peak VO2 increased); two factors decreased; time only increased (the Tex increased, but the peak VO2 economized); and VO2 only increased (the Tex decreased, but the peak VO2 increased). Within all patients, the relationships between baseline variables and the post-to-pre-change ratio of the time&ndash;slope, Tex/(peak minus resting VO2), were investigated.Results: Compared with the two factors increased group (n=11), in the time only increased group (n=18), the mean differences from pre-PR at peak exercise in 1) minute ventilation (VE) (P=0.004), VO2 (P&lt;0.0001), and carbon dioxide output (VCO2) (P&lt;0.0001) were lower, 2) VE/VO2 (P=0.034) and VE/VCO2 (P=0.006) were higher, and 3) the dead space/tidal volume ratio (VD/VT) and the dyspnea level were similar. After PR, there was no significant difference in the ratio of the observed peak heart rate (HR) to the predicted peak HR (220 &ndash; age [years]) between the two groups. A significant negative correlation with the baseline time&ndash;slope (r=-0.496, P=0.002) and a positive correlation with the baseline body mass index (BMI) (r=0.496, P=0.002) were obtained.Conclusions: PR in COPD patients improves Tex rather than exercise tolerance, economizing oxygen requirements, resulting in reduced ventilatory requirements without cardiac loads followed by reduced exertional dyspnea. In addition, the time&ndash;slope and BMI could be used to predict PR responses beforehand. Keywords: cardiopulmonary exercise testing, oxygen requirement, ventilatory equivalents, body weight, carbon dioxide outpu

Clinical Evaluation of Anti-Tuberculous Glycolipid Immunoglobulin G Antibody Assay for Rapid Serodiagnosis of Pulmonary Tuberculosis

Previously we reported the development of a highly sensitive enzyme-linked immunosorbent assay specific for anti-tuberculous glycolipid (anti-TBGL) for the rapid serodiagnosis of tuberculosis. In this study, the usefulness of an anti-TBGL antibody assay kit for rapid serodiagnosis was evaluated in a controlled multicenter study. Antibody titers in sera from 318 patients with active pulmonary tuberculosis (216 positive for Mycobacterium tuberculosis in smear and/or culture tests and 102 smear and culture negative and clinically diagnosed), 58 patients with old tuberculosis, 177 patients with other respiratory diseases, 156 patients with nonrespiratory diseases, and 454 healthy subjects were examined. Sera from 256 younger healthy subjects from among the 454 healthy subjects were examined as a control. When the cutoff point of anti-TBGL antibody titer was determined as 2.0 U/ml, the sensitivity for active tuberculosis patients was 81.1% and the specificity was 95.7%. Sensitivity in patients with smear-negative and culture-negative active pulmonary tuberculosis was 73.5%. Even in patients with noncavitary minimally advanced lesions, the positivity rate (60.0%) and the antibody titer (4.6 ± 9.4 U/ml) were significantly higher than those in the healthy group. These results indicate that this assay using anti-TBGL antibody is useful for the rapid serodiagnosis of active pulmonary tuberculosis