Toru Hiraga

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

Prognostic predictors for survival in patients with COPD using cardiopulmonary exercise testing

We studied the relationship between physiologic parameters in cardiopulmonary exercise testing (CPET) and prognosis in terms of survival time in patients with chronic obstructive pulmonary disease (COPD) in order to accurately assess the severity of the disease. From a group of 195 patients with COPD who had consecutively undergone CPET between July 1989 and October 1997, we enrolled 120 subjects (mean age 67·6 years, 104 males) with exertional dyspnoea into a cohort protocol. Of these subjects, 34 (28·3%) died during the 3–5‐year follow‐up period after CPET. By univariate analysis, the following factors were significantly associated with survival time: age, body mass index, %FVC, %FEV1, FEV1%, Paco2 at rest, severity of exercise‐induced hypoxemia evaluated by ΔPao2/ΔV̇o2 (Pao2‐slope), oxygen uptake, ventilation, tidal volume, Paco2 and oxygen pulse at maximum exercise, as well as prescribing long‐term oxygen therapy. By multivariate analysis, age and the Pao2‐slope showed significance as independent prognostic factors, and the Pao2‐slope was most closely associated with the survival time. These results reveal that CPET is a useful technique to accurately assess the relationship between the functional impairments and the prognosis of patients with COPD.

Effects of Ghrelin Treatment on Exercise Capacity in Underweight COPD Patients: a substudy of a multicenter, randomized, double-blind, placebo-controlled trial of ghrelin treatment

BackgroundThe aim of this substudy of the ghrelin treatment, multicenter, randomized, double-blind, placebo-controlled trial was to investigate the effects of ghrelin administration on exercise capacity and the underlying mechanisms in underweight patients with chronic obstructive pulmonary disease (COPD) using cardiopulmonary exercise testing.MethodsTwenty underweight COPD patients were randomized to pulmonary rehabilitation with intravenous ghrelin (2 μg/kg, n = 10) or placebo (n = 10) twice daily for 3 weeks in a double-blind fashion. The primary outcome was changes in peak oxygen uptake V•o2. Secondary outcomes included changes in exertional cardio-respiratory functions: O2-pulse, physiologic dead space/tidal volume-ratio (VD/VT), ventilatory equivalent for oxygen V•E/V•o2, and ventilatory equivalent for carbon dioxide V•E/V•co2.ResultsWith incremental exercise, at peak exercise, there was a significant difference in the mean difference (ghrelin minus placebo), i.e., treatment effect in: i) peak V•o2 (1.2 mL/kg/min, 95% CI: 0.2-2.3 mL/kg/min, between-group p = 0.025); ii) V•E/V•o2 (-4.2, 95% CI: -7.9 to -0.5, between-group p = 0.030); iii) V•E/V•co2 (-4.1, 95% CI: -8.2 to -0.1, between-group p = 0.045); iv) VD/VT (-0.04, 95% CI: -0.08 to -0.00, between-group p = 0.041); and v) O2-pulse (0.7 mL/beat, 95% CI: 0.3 to 1.2 mL/beat, between-group p = 0.003). Additionally, repeated-measures analysis of variance (ANOVA) indicated a significant time-course effect of ghrelin versus placebo in the peak V•o2 (p = 0.025).ConclusionGhrelin administration was associated with improved exertional capacity and improvements in ventilatory-cardiac parameters.Trial registrationUMIN (University Hospital Medical Information Network in Japan) C000000061

Acidosis and raised norepinephrine levels are associated with exercise dyspnoea in idiopathic pulmonary fibrosis

Background and objective:  Exertional dyspnoea limits patients with IPF in their activities of daily living. The mechanism, however, has not been elucidated. This study tested the hypothesis in IPF that exertional dyspnoea correlates with cardiopulmonary exercise responses, specifically changes in arterial blood pH and plasma norepinephrine (NE).

Serodiagnosis of Pulmonary Disease Due to Mycobacterium avium Complex Proven by Bronchial Wash Culture

Affi liations: From the Department of Pharmacy (Drs Ogale and Sullivan), University of Washington; the Center for Management of Complex Chronic Care (Dr Lee), Edward Hines Jr VA Hospital; and the Center for Pharmacoeconomic Research, Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL. Dr Ogale is currently at Genentech, Inc. Financial nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Ogale is an employee of Genentech, Inc. Drs Lee and Sullivan have received funding for their contribution to the Burden of Obstructive Lung Disease (BOLD) Initiative, which has been funded in part by unrestricted educational grants to the Operations Center ( www . boldcopd . org ) from ALTANA, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Novartis, Pfi zer, Schering-Plough, Sepracor, and the University of Kentucky. Drs Lee and Sullivan have received past research grants from AstraZeneca, Boehringer Ingelheim, Pfi zer, Novartis, and Glaxo SmithKline. Dr Lee has participated in past advisory boards for AstraZeneca and Novartis. Correspondence to: Todd A. Lee, PharmD, PhD, Edward Hines Jr VA Hospital (151-H), 5000 S 5th Ave, Hines, IL 60141; e-mail: todd.lee@va.gov

Analysis of the relationship between health status and mortality in hypercapnic patients with noninvasive ventilation

Health status and mortality are important outcomes in patients with advanced pulmonary diseases receiving noninvasive ventilation (NIV). However, their relationship has not been thoroughly investigated.

Differences in Physiological Response to Exercise in Patients With Different COPD Severity

BACKGROUND: Patients with COPD have reduced exercise tolerance associated with dyspnea. This exercise intolerance is primarily due to impaired ventilatory mechanics, but it is also associated with a combination of factors, including inefficient gas exchange, lactic acidosis at a low work rate, and exercise-induced hypoxemia. The survival prognosis of COPD patients with severely reduced exercise capacity is extremely poor, but the pathophysiology of these patients during exercise remains to be accurately established. The present study aimed to characterize life-threatening factors such as hypoxemia, acidosis, and sympathetic activation during exercise in these patients. METHODS: We monitored changes in life-threatening factors and compared these factors among quartile groups, defined according to their peak oxygen uptake status. Ninety-one COPD subjects (82 males, 9 females, average age 69.7 ± 6.8 y) consecutively underwent incremental cardiopulmonary exercise testing using a cycle ergometer. Arterial blood gases, lactate, and catecholamines were measured during cardiopulmonary exercise testing. RESULTS: The pathophysiology of the COPD differed among the 4 subject groups. Subjects with the most severely reduced exercise capacity (peak oxygen uptake ≤ 623 mL/min) were characterized by exercise-induced steep decrease in PaO2 slope (−78 ± 70 mm Hg/L/min), rapid progression of respiratory acidosis, little change in lactic acidosis, and sympathetic activation at low-intensity work load (plasma norepinephrine 1.41 ± 0.94 ng/mL at 20 watts work load), in addition to the limitation of increase in ventilation and impaired gas exchange. CONCLUSIONS: The mechanisms of exercise intolerance in COPD patients significantly differed among subjects with different exercise capacities. Subjects with the most severely reduced exercise capacity had the characteristics of exercise-induced hypoxemia, sympathetic overactivity, and progressive respiratory acidosis at low-intensity exercise. These life-threatening pathophysiological conditions could be improved by medication and/or pulmonary rehabilitation.

Effects of oxygen on exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease

Background and objective:  The results of studies on the oxygen response in patients with COPD should provide important clues to the pathophysiology of exertional dyspnoea. We investigated the exercise responses to hyperoxia in relation to dyspnoea profile, as well as cardiopulmonary, acidotic and sympathetic parameters in 35 patients with stable COPD (mean FEV1 46% predicted).

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

Background 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 μg or oxitropium 0.2 mg × 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.

Identification of Three Exercise-induced Mortality Risk Factors in Patients with COPD

Abstract The survival rate of chronic obstructive pulmonary disease (COPD) patients with severely reduced exercise capacity is extremely low. We recently identified three life-threatening pathophysiological conditions during cardiopulmonary exercise testing (CPET): (1) exercise-induced hypoxemia, (2) sympathetic overactivity, and (3) progressive respiratory acidosis at low-intensity exercise. The present prospective observation study aimed to determine whether these parameters constitute risk factors of mortality in moderate-to-very severe COPD. Ninety-six COPD patients were followed-up, monthly, for >3 years. Subsequently, spirometry and CPET were performed to examine parameters of exercise-induced hypoxemia ([PaO2 slope, mmHg/L · min−1] = Decrease in PaO2/ΔV˙ O2 (Difference in ΔV˙ O2 between at rest and at peak exercise)), progression of acidosis ([ΔpH/ΔV˙ O2,/L · min−1] = Decrease in pH/ΔV˙ O2), and sympathetic overactivity ([Δnorepinephrine (NE)/ΔV˙ O2, ng/mL/L · min−1] = Increase in NE/ΔV˙ O2). Univariate analysis revealed a significant association between the three conditions with increased mortality. Kaplan–Meier analysis showed that the quartile combining the steepest PaO2 slope (≤–55 mmHg/ΔV˙ O2 [L/min]), steepest decrease in arterial blood pH (≤ –1.72/ΔV˙ O2 [L/min]), and most rapid increase in plasma NE level (≥ 5.2 ng/VO2 [L/min]) during incremental exercise was associated with higher all-cause mortality. These conditions showed cumulative effects on COPD patients’ survival. Multivariate analyses revealed that these three life-threatening factors are also independent predictors of mortality based on age, heart rate and PaO2 at rest, body mass index, and forced expiratory volume in 1 s. Thus, these new exercise-induced mortality risk factors may lead to more efficient pulmonary rehabilitation programs for COPD patients based on patient-specific exercise-induced pathophysiological profiles.