[Show abstract][Hide abstract] ABSTRACT: Take-home summary:
Personalized pulmonary rehabilitation including occupational therapy improves the prognosis of patients with advanced COPD.
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±6.7 years) or with the proposed therapy (PPR-OT group: n=46; M:F =44:2; mean age: 68.7±7.1 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±10.0 years) and the PPR-OT group (n=85; M:F =78:7; mean age: 70.7±6.1 years) who completed the proposed therapy. Survival after CPET or HOT was analyzed using Cox proportional-hazards regression and Kaplan-Meier analyses.
In both studies, the program significantly improved all-cause mortality (retrospective study: risk ratio =0.389 [range: 0.172-0.800]; P=0.0094; log-rank test, P=0.0094; observational study: risk ratio =0.515 [range: 0.296-0.933]; P=0.0291; log-rank test, P=0.0232]. At 5 years and 7 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.
The PPR-OT program improved the survival of patients with advanced COPD probably because it modified life-threatening conditions.
Preview · Article · Sep 2015 · International Journal of COPD
[Show abstract][Hide abstract] ABSTRACT: A substudy of ghrelin treatment in a multicenter trial previously revealed that administration of ghrelin improves the exercise capacity of underweight COPD patients. To clarify exertional dyspnea more precisely, exploratory analysis was conducted on data from the substudy. Of 20 underweight COPD patients who were randomized to pulmonary rehabilitation with intravenous ghrelin (2 μg/kg, n = 10) or placebo (n = 10) twice daily for 3 weeks in the substudy, 16 (ghrelin = 9, placebo = 7) could be investigated for dyspnea break-point on the dyspnea-ratio (%) of Δoxygen uptake ([Formula: see text]) (= peak minus resting [Formula: see text]) curve. A significant treatment effect of ghrelin on percentage [Formula: see text] at the dyspnea break-point to Δ[Formula: see text] (p = 0.049) was achieved. In conclusion, underweight COPD patients benefitted from ghrelin treatment in terms of shifts to the early exercise phase of the dyspnea break-point during a standardized exercise program.
Full-text · Article · Feb 2015 · The Journal of Physiological Sciences
[Show abstract][Hide abstract] ABSTRACT: A commercial serodiagnostic kit for diagnosing pulmonary disease due to Mycobacterium avium complex (MAC-PD) was developed and launched in Japan in 2011.
To evaluate the performance of this kit in routine clinical settings.
In this retrospective single-centre study, data on serum levels of anti-glycopeptidolipid (GPL) core IgA antibody (U/ml) measured using the kit were analysed in patients diagnosed with MAC-PD according to American Thoracic Society criteria, in those with pulmonary tuberculosis (PTB) or pulmonary M. kansasii disease and in healthy volunteers.
The anti-GPL-core IgA antibody levels of serum were significantly higher (P < 0.0001) in patients with MAC-PD (n = 485) than in those with PTB (n = 133) or pulmonary M. kansasii disease (n = 23) or in healthy subjects (n = 265). When the cut-off level was set at 0.7 U/ml, the sensitivity and specificity were respectively 78.6% and 96.9%. Higher antibody levels were observed in patients with greater extent of disease on chest computed tomography (P < 0.0001).
The serodiagnostic kit revealed good sensitivity and specificity. The antibody levels may reflect disease activity. Additional work is needed to determine whether the diagnostic assay could be used in conjunction with current diagnostic criteria to improve the diagnosis of MAC-PD.
No preview · Article · Jan 2015 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] 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/ΔVO2 (Difference in ΔVO2 between at rest and at peak exercise)), progression of acidosis ([ΔpH/ΔVO2,/L·min-1] = Decrease in pH/ΔVO2), and sympathetic overactivity ([Δnorepinephrine (NE)/ΔVO2, ng/mL/L·min-1] = Increase in NE/ΔVO2). 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/ ΔVO2 [L/min]), steepest decrease in arterial blood pH (≤ -1.72/ΔVO2 [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.
No preview · Article · Jun 2014 · COPD Journal of Chronic Obstructive Pulmonary Disease
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The 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. METHODS: Twenty underweight COPD patients were randomized to pulmonary rehabilitation with intravenous ghrelin (2 mug/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[bullet]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[bullet]E/V[bullet]o2, and ventilatory equivalent for carbon dioxide V[bullet]E/V[bullet]co2. RESULTS: With 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[bullet]o2 (1.2 mL/kg/min, 95% CI: 0.2-2.3 mL/kg/min, between-group p = 0.025); ii) V[bullet]E/V[bullet]o2 (-4.2, 95% CI: -7.9 to -0.5, between-group p = 0.030); iii) V[bullet]E/V[bullet]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[bullet]o2 (p = 0.025). CONCLUSION: Ghrelin administration was associated with improved exertional capacity and improvements in ventilatory-cardiac parameters.Trial registration: UMIN (University Hospital Medical Information Network in Japan: http://www.umin.ac.jp/ctr/) C000000061.
Preview · Article · Jun 2013 · BMC Pulmonary Medicine
[Show abstract][Hide abstract] ABSTRACT: To understand the mechanism of exertional dyspnea, we postulated that, despite hyperoxia during exercise, patients with idiopathic pulmonary fibrosis (IPF) might not regulate exertional acidosis by ventilatory compensation to stop exercise. The exercise responses during 30% O(2) or compressed air (CA) were examined in 13 patients with IPF. The Pa(O2), Pa(CO2), and H(CO3-) levels were higher during exercise with hyperoxia than with CA. At peak exercise, hyperoxia reduced the plasma lactate level. The dyspnea - ratio (%) of the ΔV˙o(2) (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point with hyperoxia and CA, preceded by a break point in the breathing frequency-ratio of the ΔV˙o(2). Accordingly, the dyspnea score and pH each reached similar levels with hyperoxia and CA to stop exercise. Regardless of breathing CA or 30% O(2), IPF patients did not regulate exertional acidosis by ventilatory compensation to stop exercise, resulting in reaching a specific pH.
No preview · Article · Dec 2012 · Respiratory Physiology & Neurobiology
[Show abstract][Hide abstract] ABSTRACT: 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.
This study aimed to determine whether tiotropium use results in a sustained reduction in sympathetic activation during exercise.
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.
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.
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.
Full-text · Article · May 2012 · International Journal of COPD
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
UMIN Clinical Trial Registry C000000061.
[Show abstract][Hide abstract] ABSTRACT: Although Mycobacterium avium complex pulmonary disease (MAC-PD) is a growing health problem, little is known about long-term radiographic outcome and factors for deterioration in patients with MAC-PD.
Data on patients with nodular bronchiectatic (NBE) MAC-PD who underwent regular follow-up for >5 years were retrospectively reviewed. Changes in plain chest radiograph (CXR) and baseline characteristics were compared between the stable and deteriorated groups.
Seventy-two patients were investigated, including 30 patients who were examined 10 years after the initial visit. One patient (1.4%) showed progressive or remarkably progressive disease on CXR at 1 year; this rate increased to 22.2% at 5 years and to 53.3% at 10 years. Body mass index (BMI) at the initial visit was lower in the deteriorated group than in the stable group. Cavitary disease and resistance to a macrolide were seen more frequently at the initial visit in the deteriorated group than in the stable group.
NBE MAC-PD is a slowly but substantially progressive long-term infection (5-10 years). Our data suggest that patients with lower BMI, cavitary disease and resistance to a macrolide at initial visit are more likely to progress to deteriorating disease.
No preview · Article · Mar 2012 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: 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 FEV(1) 46% predicted).
This was a single-blind trial, in which patients breathed 24% O(2) or compressed air (CA) in random order during two incremental cycle exercise tests.
PaO(2) and PaCO(2) were higher (P < 0.0001 and P < 0.05, respectively) at each exercise point while patients were breathing 24% O(2) compared with CA. At a standardized time point near peak exercise, use of O(2) resulted in reduced plasma lactate and plasma noradrenaline concentrations (P < 0.01). Peak minute ventilation/indirect maximum voluntary ventilation was similar while breathing 24% O(2) and CA. At peak exercise, the dyspnoea score, pH and plasma noradrenaline concentrations were similar while breathing 24% O(2) and CA. The dyspnoea-ratio (%) of Δoxygen uptake (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point while breathing 24% O(2) or CA.
Regardless of whether they breathed CA or 24% O(2) , patients with COPD did not develop ventilatory compensation for exertional acidosis, and the pH values measured were similar. Hyperoxia during a standardized exercise protocol did not alter the pattern of exertional dyspnoea in these patients, compared with breathing CA, although hyperoxia resulted in miscellaneous effects.
[Show abstract][Hide abstract] ABSTRACT: We investigated the susceptibility to conventional and newer antimycobacterial agents including rifabutin (RBT) and novel fluoroquinolones (NFQs) among 48 clinical Mycobacterium avium complex (MAC) isolates from patients with sputum culture-positive MAC disease who were undergoing standard chemotherapy. RBT and NFQs were superior to conventional agents because of higher rates of susceptibility and lower minimum inhibitory concentration. NFQs showed cross-resistance among quinolones. In contrast, RBT did not show cross-resistance to RFP. Most clarithromycin-resistant or rifampicin-resistant cases were susceptible to RBT and NFQs. In conclusion, RBT and NFQs possess good in vitro antimicrobial activity among clinical isolates of culture-positive pulmonary MAC disease, which suggests that a combination of such microbiologically active agents may improve clinical effectiveness more than standard chemotherapy regimens.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to investigate whether exertional dyspnea correlates with exercise responses, especially arterial blood pH and plasma norepinephrine (NE) changes, in patients with sequelae of tuberculosis (TBsq). Cardiopulmonary exercise testings were performed in 49 TBsq patients and 9 controls. Each group had a break point in the dyspnea, plasma lactate, and plasma NE changes during exercise, all of which occurred at a similar exercise point. In TBsq patients in both exercise phases before and after the dyspnea break point, the dyspnea-slope (DeltaBorg scale/Deltaminute ventilation) correlated with the pH-slope (DeltapH/Deltaoxygen uptake) (r = -0.616, p < 0.0001; r = -0.629, p < 0.0001, respectively, before and after the break point) and with the NE-slope (DeltaNE/Deltaoxygen uptake) (r = 0.443, p = 0.0012; r = 0.643, p < 0.0001, respectively, before and after the break point). In TBsq patients during exercise, increases in circulating NE levels and exertional acidosis were correlated with exertional dyspnea.
No preview · Article · May 2010 · The Journal of Physiological Sciences
[Show abstract][Hide abstract] ABSTRACT: 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).
Cardiopulmonary exercise testing with measurements of dyspnoea (Borg scale), plasma NE, plasma lactate and arterial blood gases were performed in 29 patients with IPF and in nine controls.
Both groups showed obvious break points in dyspnoea changes during exercise. In IPF, an abrupt change in the Borg scale, pH, PaCO(2) and plasma NE occurred in the late exercise phase after the 'break point'. Compared with controls, patients with IPF had significantly higher HCO(3)(-) levels and physiologic dead space/tidal volume during exercise. In IPF, during both exercise phases, the dyspnoea slope (DeltaBorg scale/Deltaminute ventilation) correlated with the pH slope (DeltapH/Deltaoxygen uptake) (before the break point: r = -0.537, P = 0.0022; r = -0.886, P < 0.0001, after the break point) and the NE slope (DeltaNE/Deltaoxygen uptake) (before the break point: r = 0.481, P = 0.0075; R = 0.784, P < 0.0001, after the break point).
In patients with IPF, exercise-induced acidosis and increases in circulating NE levels were associated with intensity of exertional dyspnoea.
[Show abstract][Hide abstract] ABSTRACT: The causes of both exertional pulmonary hypertension and pulmonary hypertension in general in chronic obstructive pulmonary disease (COPD) remain to be elucidated. To further understand the pathophysiology in COPD patients, it may be important to recognize the existence of exertional pulmonary hypertension and to determine the severity of exertional hypoxemia. However, little is known about their relationship. To investigate whether the severity of exertional hypoxemia, as evaluated by the Deltaartery oxygen tension/Deltaoxygen consumption (PaO(2)-slope) correlates with the mean pulmonary artery pressure (Ppa), cardiopulmonary exercise testing with haemodynamics was done in 10 patients with moderate to very severe COPD. The PaO(2)-slope was significantly correlated with the mean Ppa from 25% to 40% of the maximum Watts (Wmax), and was most significant at 30% Wmax (r = -0.904, P<0.0001). In this phase, all parameters, except for the mean Ppa and the mixed venous oxygen tension, were not markedly changed from resting levels. At 30% Wmax, the mean Ppa (mean, 27 mmHg) with no or mild hypoxemia was also significantly correlated with the Deltaartery oxygen saturation/Deltaoxygen consumption (SpO(2)-slope) (r = -0.789, P = 0.004). On stepwise multiple regression analysis, the PaO(2)-slope was the most significant predictor of mean Ppa at 30% Wmax. In conclusion, the PaO(2)-slope and the SpO(2)-slope reflect Ppa during the early exercise phase. Thus, assessment of these parameters could be useful to evaluate the cardiopulmonary haemodynamic pathophysiology of COPD patients.
No preview · Article · Jan 2008 · Clinical physiology and functional imaging
[Show abstract][Hide abstract] ABSTRACT: The distribution of Mycobacterium avium-intracellulare complex (MAC) in residences was examined. MAC was only recovered from bathrooms but not from other sites of residences. The
appearance ratio in the bathrooms of patients with pulmonary MAC was significantly higher than that in healthy volunteers'
bathrooms (P = .01). For 2 patients, the genotypes of environmental isolates were identical to their respective clinical isolates.
[Show abstract][Hide abstract] ABSTRACT: The present authors have previously reported the usefulness of a serodiagnostic test to detect serum glycopeptidolipid (GPL) core antibody in diagnosing Mycobacterium avium complex (MAC) lung disease in immunocompetent patients. The aim of the present study was to investigate correlations between the levels of antibody against GPL core and chest computed tomography (CCT) findings in patients with MAC lung disease. A total of 47 patients with MAC-positive culture from their sputum and who had radiographic abnormalities were investigated. Thirty-three patients met the American Thoracic Society criteria for MAC disease; 14 did not. All patients underwent both CCT examination and the serodiagnostic test for MAC at the same time. Small nodular shadows were seen on CCT in all 47 patients and bronchiectasis shadows were seen in 39 (83%) of them. There was a significant positive correlation between the extent of the disease and the level of GPL core immunoglobulin (Ig)A antibody. The levels of GPL core IgA antibody were significantly elevated in patients who had nodular shadows (10-30 mm) compared with patients who had small nodular shadows (<10 mm). The present results document that the levels of immunoglobulin A antibody against glycopeptidolipid core correlate with the chest computed tomography findings of Mycobacterium avium complex lung disease.
Full-text · Article · Jul 2007 · European Respiratory Journal
[Show abstract][Hide abstract] ABSTRACT: A 33-year-old man had a high fever and was given Cefcapene and Oseltamivir without a definite diagnosis of influenza. Three days later an abnormal chest shadow was pointed out. Chest CT revealed ground-glass opacities and air-space consolidation in bilateral lung fields. Although he was given antibiotics, lung infiltrates increased and his symptoms worsened. Therefore, he was transferred to our hospital. Corticosteroid pulse-therapy resulted in prompt improvement of chest infiltrates and his symptoms. The drug-induced lymphocyte stimulating test results indicated 170% of oseltamivir and 150% of cefcapene. Considering the clinical course and laboratory data, this was probably drug-induced lung injury caused by oseltamivir.