Udenafil Improves Exercise Capacity in Patients with Chronic Obstructive Pulmonary Disease: A Prospective Study

Abstract

Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD), and there is no effective pharmacological treatment for COPD-associated PH. We evaluated the effect of udenafil, a phosphodiesterase-5 (PDE-5) inhibitor, on the exercise capacity of patients with severe COPD. Patients with severe and very severe COPD (forced expiratory volume in one second (FEV₁) <50% of predicted) received udenafil (50 mg daily) for 8 weeks. A 6-min walk test (6MWT), lung function test, Doppler echocardiography, and Saint George's Respiratory Questionnaire (SGRQ) were completed before and after therapy. The primary outcome was a change in the 6-min walk distance (6MWD). Thirty-eight patients were screened for eligibility, and 23 completed the study. After 8 weeks of udenafil treatment, the mean 6MWD increased from 315 to 348 m (p = 0.02), and median PASP decreased from 36 to 30 mmHg (p = 0.02). There were no changes in the SGRQ score, Borg dyspnea score, or pulmonary function parameters. The PDE-5 inhibitor udenafil improved exercise capacity and decreased pulmonary artery pressure in patients with severe COPD. However, due to the small sample size, uncontrolled design and high dropout rate, the efficacy of udenafil in severe COPD needs to be confirmed in a large-scale randomized controlled study. This study was registered at ClinicalTrials.gov (number: NCT01364181).     

Minimum Clinically Important Difference in Diffusing Capacity of the Lungs for Carbon Monoxide Among Patients with Severe and Very Severe Chronic Obstructive Pulmonary Disease

Background: The minimum clinically important difference (MCID) for diffusing capacity of the lungs for carbon monoxide (DLCO) has not yet been solidly established. Methods: We used the dataset of surgical cohort of National Emphysema Treatment Trial. Briefly, severe and very severe chronic obstructive pulmonary disease (COPD) patients who were candidate for volume reduction surgery and who could provide sufficient data at 12-month follow-up were included. We used two anchor methods using 6-minute walk distance (6MWD. MCID = 40 m) and forced expiratory volume in 1 sec (FEV₁. MCID = 100 ml) as anchors, and two distribution methods. We proposed MCID with a median of estimated values. We estimated MCID for DLCO in raw value and % change from the baseline independently. Results: The surgical cohort included 356 patients, whose average age was 66.6 ± 5.5 years, and the average % predicted FEV₁ was 27.8 ± 7.3%. The estimated MCID for DLCO in raw value and % change from the baseline were as follows: anchor method (average, 6MWD) 1.2 ml/min/mmHg, 17%; anchor method (average, FEV₁) 0.7 ml/min/mmHg, 11%; anchor method (receiver operating characteristic, 6MWD) 1.1 ml/min/mmHg, 10%; anchor method (receiver operating characteristic, FEV₁) 1.2 ml/min/mmHg, 3%; distribution method (0.3 units of standard deviation), 0.9 ml/min/mmHg, 11%; distribution method (standard error of measurement), 1.1 ml/min/mmHg. The median of these values was 1.1 ml/min/mmHg and 11%. Conclusion: We estimated the group-level MCID for DLCO for patients with severe and very severe COPD patients as 1.1 ml/min/mmHg and 11% of baseline DLCO.     

Effects of Pulmonary Hypertension on Exercise Capacity in Patients With Chronic Obstructive Pulmonary Disease

IntroductionThe impact of pulmonary hypertension (PH) on exercise tolerance in chronic obstructive pulmonary disease (COPD) has not been fully elucidated. It is necessary to characterize pulmonary hemodynamics in patients with moderate to severe COPD in order to improve their management. The aim of the study was to determine whether in COPD the presence of PH is associated with reduced exercise tolerance in a cohort of stable COPD patients.MethodsCross-sectional analysis of 174 COPD patients clinically stable: 109 without PH and 65 with PH (COPD-PH). We assessed socio-demographic data, lung function, quality of life, dyspnea, cardiopulmonary exercise testing (CPET), constant workload endurance time (CWET), and six-minute walk test (6MWT). We elaborated a logistic regression model to explore the impact of PH on exercise capacity in COPD patients.ResultsCOPD-PH patients showed lower exercise capacity both at maximal (CPET) (43(20) versus 68(27) Watts and 50(19)% versus 71(18)% predicted peak oxygen consumption (VO₂peak), COPD-PH and COPD, respectively), and at submaximal tests (6MWT) (382(94) versus 486(95) m). In addition, the COPD-PH group had lower endurance time than the non-PH COPD group (265(113) s and 295(164) s, respectively).ConclusionsThe presence of PH is an independent factor that impairs exercise capacity in COPD.     

Impaired Carbon Monoxide Diffusing Capacity is the Strongest Predictor of Exercise Intolerance in COPD

Abstract

Background: Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD) and forced expiratory volume in one second (FEV₁) is the traditional metric used to define the severity of COPD. However, there is dissociation between FEV₁ and exercise capacity in a large proportion of subjects with COPD. The aim of this study was to investigate whether other lung function parameters have an additive, predictive value for exercise capacity and whether this differs according to the COPD stage. Methods: Spirometry, body plethysmography and diffusing capacity for carbon monoxide (DLCO) were performed on 88 patients with COPD GOLD stages II-IV. Exercise capacity (EC) was determined in all subjects by symptom-limited, incremental cycle ergometer testing. Results: Significant relationships were found between EC and the majority of lung function parameters. DLCO, FEV₁ and inspiratory capacity (IC) were found to be the best predictors of EC in a stepwise regression analysis explaining 72% of EC. These lung function parameters explained 76% of EC in GOLD II, 72% in GOLD III and 40% in GOLD IV. DLCO alone was the best predictor of exercise capacity in all GOLD stages. Conclusions: Diffusing capacity was the strongest predictor of exercise capacity in all subjects. In addition to FEV₁, DLCO and IC provided a significantly higher predictive value regarding exercise capacity in COPD patients. This suggests that it is beneficial to add measurements of diffusing capacity and inspiratory capacity when clinically monitoring COPD patients.     

Nutritional Status of Patients with Chronic Obstructive Pulmonary Disease in Relation to their Physical Performance

Nutritional abnormalities and physical inactivity are highly prevalent in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to determine the association between nutritional status/body composition and physical performance in patients with COPD.

A cross-sectional observational study was conducted in outpatients with clinically stable, moderate to very severe COPD. In the assessment of nutritional status, we used dual energy X-ray absorptiometry, anthropometry, serum biomarkers, and the Mini-Nutritional Assessment (MNA) questionnaire. Physical performance was measured by the 6-minute walk distance (6MWD), 4-metre gait speed (4MGS), and physical activity. Univariate and multivariate analyses were performed.

In 111 patients (mean age 68 years, 69% men), the mean 6MWD was 376 ± 119 m, 4MGS 0.9 ± 0.2 m/s, and the average daily step count 8,059 ± 4,757. Patients with low exercise capacity (6MWD ≤ 350 m) had a significantly lower lean mass index (LMI) (p < 0.01), fat-free mass index (FFMI) (p < 0.01), bone mineral content (p < 0.01), bone mineral density (p < 0.01), T-score (p < 0.05), MNA score (p < 0.01), and serum albumin and prealbumin levels (p < 0.05). Patients with low physical activity (daily step count ≤ median) had lower LMI, FFMI, MNA score, serum prealbumin (for all comparisons p < 0.05) and vitamin D levels (p < 0.01). However, none of the nutritional variables showed an independent association with low physical performance in the multivariate models. In conclusion, patients with low physical performance have deficient nutritional status, but we could not demonstrate an independent relationship between nutritional parameters and physical performance.     

Effect of Terbutaline on Exercise Capacity and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease

The objective of this study was to investigate the effects of a single dose of a β₂-agonist, terbutaline (Bricanyl Turbuhaler?), on resting lung function and exercise capacity in patients with chronic obstructive lung disease. Using a double-blind, placebo-controlled, randomized crossover study and outpatients from a department of pulmonary medicine at a major inner-city hospital, we examined 26 individuals with chronic obstructive lung disease who met the criteria of 40% ≤ FEV₁≤ 70% of predicted, FEV₁/FVC ≤ 70%, and ΔFEV₁≤ 200 ml 20 min after inhalation of 1 mg of terbutaline. The patients inhaled 2.5 mg of terbutaline and matched placebo. At rest, terbutaline caused significant increases in D_LCO, MVV_12sec, and all spirometric indices derived from the flow-volume loop, the increases also being significantly larger than those after inhalation of 1 mg of terbutaline for FEV₁, FVC, and PEF. The peak work rate was unchanged after terbutaline. Oxygen uptake, ventilation, and tidal volume at peak work rate increased significantly, whereas carbon dioxide elimination increased insignificantly. Cumulative oxygen uptake and carbon dioxide elimination during progressive exercise to exhaustion and 10 min of recovery were significantly higher after terbutaline. We concluded that despite significant improvements in resting lung function, inhalation of 2.5 mg of terbutaline did not increase exercise capacity, but it increased cumulative oxygen uptake and carbon dioxide elimination during exercise and recovery, presumably because of a thermogenic effect of terbutaline. Accepted for publication: 29 April 1999     

Physical Activity Patterns in Patients in Different Stages of Chronic Obstructive Pulmonary Disease

It has previously been suggested that exercise capacity is decreased in COPD and that it is associated with degree of disease. The reduced exercise capacity may plausibly be due to low levels of physical activity in this patient group. The aim of the present study was to assess exercise capacity and physical activity in different stages of COPD and to examine the associations between exercise capacity, pulmonary function and degree of physical activity. A total of 44 COPD patients and 17 healthy subjects participated in the study. Exercise capacity was assessed using the 6-minute walking test and physical activity was assessed using an accelerometer worn all waking hours during 7 days. Mean exercise capacity was significantly lower in COPD patients compared with healthy subjects. Mean physical activity level and time spent at least moderately active were significantly lower in patients with moderate and severe COPD compared with healthy subjects while no differences in time spent sedentary were observed between the study groups. Pulmonary function, mean physical activity level and time spent at least moderately physically active were significantly associated with exercise capacity in the patients. We conclude that patients with moderate and severe COPD are less physically active compared with healthy subjects. Furthermore, mean physical activity level and physical activity of at least moderate intensity are positively associated with exercise capacity in COPD, while time spent sedentary is not, which stresses an important role of physical activity on exercise capacity in these patients.     

Peptic Ulceration in Patients with Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is frequently accompanied by peptic ulceration. Recent studies strongly suggest that the major cause is hypersecretion of gastric juice induced by hypoxemia or hypercapnia. To determine the incidence of peptic ulcers in COPD, we surveyed 267 patients with COPD seen at our hospital as inpatients or outpatients between 1984 and 1988. There were 90 patients with pulmonary emphysema, 93 with chronic bronchitis, and 84 with bronchiectasis. The prevalence of gastric ulcer in the patients with COPD was 23 out of the 267 patients (8.6%) surveyed. These included 13 patients with pulmonary emphysema, 6 with chronic bronchitis, and 4 with bronchiectasis. One-half of the patients with pulmonary emphysema had hypoxemia and hypercapnia: These observations suggest it is necessary to improve the abnormal blood gas concentration in patients with COPD in order to promote the healing of the peptic ulcer.     

Venous Thromboembolism in Patients with Chronic Obstructive Pulmonary Disease

ObjectiveOur aim was to compare the clinical characteristics, prophylaxis, treatment, and outcomes of venous thromboembolism in patients with and without previously diagnosed chronic obstructive pulmonary disease.MethodsWe analyzed the population-based Worcester Venous Thromboembolism Study of 2488 consecutive patients with validated venous thromboembolism to compare clinical characteristics, prophylaxis, treatment, and outcomes in patients with and without chronic obstructive pulmonary disease.ResultsOf 2488 patients with venous thromboembolism, 484 (19.5%) had a history of clinical chronic obstructive pulmonary disease and 2004 (80.5%) did not. Patients with chronic obstructive pulmonary disease were older (mean age 68 vs 63 years) and had a higher frequency of heart failure (35.5% vs 12.9%) and immobility (53.5% vs 43.3%) than patients without chronic obstructive pulmonary disease (all P < .0001). Patients with chronic obstructive pulmonary disease were more likely to die in hospital (6.8% vs 4%, P = .01) and within 30 days of venous thromboembolism diagnosis (12.6% vs 6.5%, P < .0001). Patients with chronic obstructive pulmonary disease demonstrated increased mortality despite a higher frequency of venous thromboembolism prophylaxis. Immobility doubled the risk of in-hospital death (adjusted odds ratio, 2.21; 95% confidence interval, 1.35-3.62) and death within 30 days of venous thromboembolism diagnosis (adjusted odds ratio, 2.04; 95% confidence interval, 1.43-2.91).ConclusionPatients with chronic obstructive pulmonary disease have an increased risk of dying during hospitalization and within 30 days of venous thromboembolism diagnosis. Immobility in patients with chronic obstructive pulmonary disease is an ominous risk factor for adverse outcomes.     

慢性阻塞性肺疾病患者平衡障碍发生率及其评价方法研究

背景 慢性阻塞性肺疾病(COPD)患者的平衡功能受损,跌倒风险增加,但目前国内对COPD患者平衡障碍的流行病学研究较少.Berg平衡量表(BBS)是评估平衡功能的金标准,但耗时长,使用繁琐,不适合门诊应用.简单有效的评价COPD患者平衡障碍的工具有利于快速筛选具有平衡障碍发生风险的门诊COPD患者.目的 探讨COPD患...     

Echocardiographic Detection of Occult Cor Pulmonale During Exercise in Patients with Chronic Obstructive Pulmonary Disease

We tested the ability of cycle ergometer exercise echocardiography to detect cases of occult cor pulmonale among 25 patients with chronic obstructive pulmonary disease (COPD). The M-mode echocardiographic ventricular septal motion, left ventricular shape determined by short-axis two-dimensional (2-D) echocardiography, and right and left ventricular pressure curves were recorded at rest and during exercise and were compared between patients. The ventricular septal motion was normal at rest in all of the patients. In nine patients (dip group), there was marked downward ventricular septal motion in early diastole during exercise, indicating distortion of the left ventricular shape. There were no distinct changes in the remaining 16 patients (non-dip group). At rest, the cardiac index was significantly lower, and right ventricular systolic and mean pulmonary artery pressures were significantly higher in the dip group than in the non-dip group. However, no significant difference was noted in the right ventricular end-diastolic pressure between the two groups at rest. The right ventricular systolic and end-diastolic pressures were greater during exercise in the dip group than in the non-dip group. In all of the patients in the dip group, the right ventricular pressure exceeded the left ventricular pressure only in early diastole, coinciding with the early diastolic dip of the ventricular septum, during exercise. In conclusion, occult cor pulmonale can be diagnosed accurately by the appearance of an early diastolic dip of the ventricular septum and distorted left ventricular shape during exercise in patients with COPD.     

Cardiac Autonomic Function and Cardiovascular Response to Exercise in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is associated with impaired exercise tolerance, but it has not been established to what extent cardiac autonomic function impacts on exercise capacity. Objective: To evaluate whether there is an association between airflow limitation and cardiac autonomic function and whether cardiac autonomic function plays a role in exercise intolerance and daily physical activity (PA) in patients with COPD. Methods: Univariate and multivariate analyses were performed to evaluate the association between both 6-minute walking test (6MWT) and PA (steps per day) and pulmonary function, cardiac autonomic function (HR at rest, HRR and heart rate variability, HRV) in patients with COPD. Results: In 154 COPD patients (87 females, mean [SD]: age 62.5 [10.7] years, FEV₁%predicted (43.0 [19.2]%), mean HR at rest was elevated (86.4 [16.4] beats/min) and HRV was reduced (33.69 [28.96] ms) compared to published control data. There was a significant correlation between FEV₁ and HR at rest (r = -0.32, p < 0.001), between HR at rest and 6MWD (r = -0.26, p = 0.001) and between HR at rest and PA (r = -0.29, p = 0.010). No correlation was found between HRV and 6MWD (r = 0.089, p = 0.262) and PA (r = 0.075, p = 0.322). In multivariate analysis both HR and FEV₁ were independent predictors of exercise capacity in patients with COPD. Conclusions: In patients with COPD the degree of airflow limitation is associated with HR at rest. The degree of airflow limitation and cardiac autonomic function, as quantified by HR at rest, are independently associated with exercise capacity in patients with COPD.     

Electrocardiographic Characteristics of Patients with Chronic Obstructive Pulmonary Disease

Abstract

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease. Electrocardiography (ECG) carries information about cardiac disease and prognosis, but studies comparing ECG characteristics between patients with and without COPD are lacking. We related ECG characteristics of patients with COPD, to ECG characteristics of patients without COPD, and determined whether ECG abnormalities are related to COPD severity. A cross-sectional study was conducted within a cohort of 243 COPD patients, aged 65 years or older. All patients underwent extensive examinations, including resting 12-lead ECG and pulmonary function tests. The reference group (n = 293) was a sample from the general population, also aged 65 or older, without COPD. Abnormal ECGs were more prevalent in COPD patients (50%) than in patients without COPD (36%, p = 0.054). Conduction abnormalities were the most common ECG abnormality in COPD patients (28%) being significantly more prevalent than in patients without COPD (11%, p < 0.001). The mean heart rate was higher in COPD patients (72 bpm (SD 14)) compared to controls (65 bpm (SD 13), p < 0.001), and QTc prolongation was less frequent in COPD patients (9% versus 14%, p = 0.01). The prevalence of ECG abnormalities increased with severity of pulmonary obstruction. ECG abnormalities, especially conduction abnormalities are common in COPD patients, and the prevalence of ECG abnormalities increases with severity of COPD. This underlines the importance of an integrated-care approach for COPD patients, paying attention to early detection of unrecognized coexisting cardiac disorders.     

Sleep Disordered Breathing in Patients with Chronic Obstructive Pulmonary Disease

Sleep-related disordered breathing (SDB) and its influence on desaturation were examined in stable COPD patients with waking SpO₂ > 90%. With respiratory inductance plethysmography, thoracic-abdominal respiratory movements for all events with more than 4% desaturation were analyzed in 26 patients. Types of SDB were confirmed by full polysomnography. Irregular breathing induced desaturation, while stable respiration continued during some desaturation events. Three types of altered ventilation were observed: hypoventilation, paradoxical movement and periodic breathing. An unusual type of paradoxical movement, with normal airflow despite progressive desaturation, was observed in REM sleep. Patients were divided into desaturation (15 patients) and non-desaturation (11 patients) groups. Daytime arterial blood gas, lung function values, and 6-min walking distance did not differ. Awake, mode, maximum and minimum nocturnal SpO₂ were lower in the desaturation group. SDB-induced desaturation events in the desaturation group were more frequent (9.2 ± 3.5 vs. 1.8 ± 2.2 times), a greater SpO₂ decrease (11.4 ± 7.1% vs. 5.2 ± 2.1%) and longer duration (73.2 ± 34.8 vs. 18.8 ± 39.0 min). Patterns of SDB in the desaturation group were hypoventilation (74.4 ± 23.4%), paradoxical movement (10.2 ± 14.5%), periodic breathing (12.1 ± 18.3%) and unclassified (5.8 ± 11.2%). These results reveal that lower SpO₂ and SDB influence nocturnal desaturation in stable COPD patients.     

Paraoxonase 1 Activity in Patients with Chronic Obstructive Pulmonary Disease

Introduction: Paraoxonase 1 (PON1) is an antioxidative enzyme manly associated with high density lipoproteins (HDL) in the peripheral blood. The aim of this study was to determine the PON1 paraoxonase and arylesterase activities in patients with chronic obstructive pulmonary disease (COPD). We also aimed to determine the concentration of reduced thiol groups as a marker of protein oxidation. Materials and methods: The study included 105 patients with stable COPD and 44 healthy controls. PON1 activities and thiols concentration were assayed in sera by spectrophotometry. Results: PON1 basal (POX) and salt-stimulated paraoxonase activity (POX1) as well as arylesterase activity (ARE) were significantly reduced in COPD patients. In addition, concentration of reduced thiol groups was significantly decreased in COPD group. PON1 activities were similar in patients with different disease severity (GOLD stages). However, a significant reduction in POX, POX1 and ARE was observed already in GOLD II stage when compared to controls. POX and POX1 showed modest while ARE yielded very good power for discrimination between healthy subjects and COPD patients. Univariate and multivariate logistic regression analysis indicated that ARE is a good COPD predictor. Conclusion: Reduction of PON1 activity observed in COPD patients could be partly caused by oxidative environment. Lower concentrations of reduced thiol groups in COPD patients suggest that a decrease in PON1 activity could reflect oxidative changes of enzyme free cysteine residues. Furthermore, decreased PON1 arylesterase activity might indicate a down-regulation of PON1 concentration. Our results suggest that ARE could be considered as potential biomarker for COPD diagnosis.