Chronic Exertional Dyspnea and Respiratory Muscle Function in Patients with Chronic Obstructive Pulmonary Disease

The symptom of breathlessness is an important outcome measure in the management of patients with chronic obstructive pulmonary disease (COPD). Clinical ratings of dyspnea and routine lung function are weakly related to each other. However, in the clinical setting breathlessness in COPD is encountered under conditions of increased respiratory effort, impeded respiratory muscle action, or functional weakness. Thus, the present study was carried out to determine whether and to what extent clinical ratings of dyspnea and respiratory muscle dysfunction relate to each other. In 21 patients with COPD two methods were used to rate dyspnea: a modified Medical Research Council Scale (MRC) and the Baseline Dyspnea Index (BDI), which is a multidimensional instrument for measuring dyspnea based on three components: magnitude of task, magnitude of effort, and functional impairment. A baseline focal score was obtained as the sum of the three components. Measures were: pulmonary volumes; arterial blood gases; maximal voluntary ventilation (MVV); maximal inspiratory and expiratory pressures (MIP and MEP, respectively); and breathing patterns ventilation (V_E), tidal volume (V_T), and respiratory frequency (Rf). In 15 patients pleural pressure was also measured during both quiet breathing (Ppl_sw) and maximal inspiratory sniff maneuver at FRC (Pplsn). BDI and MRC ratings related to each other and showed comparable weak associations with standard parameters (FEV₁, Paco ₂, V _T), MIP, and MEP. In contrast, MVV closely and similarly related to both ratings. Ppl_sw (%Ppl_sn), a measure of respiratory effort, and Ppl_sw (%Ppl_sn)/V _T(%VC), an index of neuroventilatory dissociation, related significantly to both the BDI (r ²=−0.77 and r ²=−0.75, respectively) and the MRC (r ²= 0.81 and r ²= 0.74, respectively). Using MVV, Ppl_sw (%Ppl_sn), and Ppl_sw (%Ppl_sn)/V _T(%VC) in a stepwise multiple regression as independent variables with BDI rating as dependent variable, MVV explained an additional 14.5% of the variance of the BDI over the 67.8% predicted by Ppl_sw (%Ppl_sn). Our results demonstrate that the level of chronic exertional dyspnea in COPD increases as the ventilatory muscle derangement increases. The level of the relationships among dyspnea ratings and MVV and respiratory effort helps to explain some of the mechanisms of chronic dyspnea of COPD. These measures should be considered for therapeutic intervention to reduce dyspnea. Accepted for publication: 30 December 1996     

The Relation of Fat-free Mass to Maximum Exercise Performance in Patients with Chronic Obstructive Pulmonary Disease

To assess the factors determining maximum exercise performance in patients with chronic obstructive pulmonary disease (COPD), we examined nutritional status with special reference to body composition and pulmonary function in 50 stable COPD patients. Nutritional status was evaluated by body weight and body composition, including fat mass (FM) and fat-free mass (FFM) assessed by bioelectrical impedance analysis (BIA). Exercise performance was evaluated by maximum oxygen uptake (Vo _2max) on a cycle ergometer. A total of 50 patients (FEV₁= 0.98 L) was divided randomly into either a study group (group A, n= 25) or validation group (group B, n= 25). Stepwise regression analysis was performed in group A to determine the best predictors of Vo _2max from measurements of pulmonary function and nutritional status. Stepwise regression analysis revealed that Vo _2max was predicted best by the following equation in group A: Vo _2max (mL/min) = 10.223 × FFM (kg) + 4.188 × MVV (L/min) + 9.952 × DL_co (mL/min/mmHg) − 127.9 (r= 0.84, p < 0.001). This equation was then cross-validated in group B: Measured Vo _2max (mL/min) = 1.554 × Predicted Vo _2max (mL/min) − 324.0 (r= 0.87, p < 0.001). We conclude that FFM is an important factor in determining maximum exercise performance, along with pulmonary function parameters, in patients with COPD. Accepted for publication 15 February 2000     

Alveolo-Capillary Protein Permeability and Lung Function in Patients with Late Pulmonary Complications after Allogeneic Bone Marrow Transplantation

A prospective study was performed to identify markers predictive for the development of pulmonary complications in the early (<50 days) and late (>50 days) phase after bone marrow transplantation (BMT). The characterization of BMT patients with early or late pulmonary complications revealed clear-cut differences. Early and long term increase of alveolo-capillary protein permeability was associated with smoking and was found in 20 patients developing pulmonary complications within 50 days after BMT (group 1). The 22 patients who developed such complications thereafter (group 2) had more acute graft vs host disease than 66 patients who remained free of these complications for a minimum of 1 year. Concentrations of bronchoalveolar lavage (BAL) fluid albumin (alb) and serum β₂-microglobulin (S-β₂m) were determined 10 days before BMT, on days 1, 30, and 40 after BMT, whereas lung function tests were performed before BMT, after discharge from the hospital, and 6 months as well 1 year after BMT. Using cut-off values for BAL fluid alb (>2.3 mg/dl) and S-β₂m (>0.8 mg/liter) we could significantly discriminate 12 patients out of 19 group 1 patients (early pulmonary complications) as well as 9 out of 21 group 2 patients (late pulmonary complications) from 12 out of 64 group 3 patients (without such complications) 1 day after BMT. Our results demonstrate that early increased alveolo-capillary protein permeability defines a patient population at risk to develop pulmonary complications later than 50 days after BMT with up to 1 year significantly decreased lung volumes (FEV1, 73% predicted, VC, 85% predicted). Accepted for publication: 12 June 1997     

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.     

Health-Related Quality of Life in Long Term Oxygen-Treated Chronic Obstructive Pulmonary Disease Patients

Chronic obstructive pulmonary disease (COPD) induces changes in daily activities and mood. Health-related quality of life (HRQL) measures are of particular relevance in the management of such patients, but predictors of HRQL have rarely been investigated. The aim of this study was to seek factors predicting HRQL in severe COPD patients under long term oxygen therapy (LTOT). The pulmonary function parameters at the start of LTOT were studied as potential predictors of future HRQL. HRQL was assessed after an average of 40 months follow-up by the Duke Health Profile (Duke) and by the St. George Respiratory Questionnaire (SGRQ). Sixty-one patients (47 males and 14 females) with a mean age of 66 years were included in the study. Stepwise multiple regression analyses conducted in each HRQL dimension identified few significantly predictive factors. By the Duke, higher Self-esteem scores were associated with higher Pao ₂ (p < 0.01) and with older age (p < 0.05); higher Social Health scores were associated with older age (p < 0.005), and higher Pain scores were associated with a higher FEV₁/FVC ratio (p < 0.05). By the SGRQ, the Activity score correlated with FEV₁/FVC (p < 0.05). The proportion of the variance in each score accounted for by covariates in the model did not exceed 10%. No other significant regression models could be identified using the other HRQL dimensions. Our findings demonstrated weak relations between lung function at the start of LTOT and some dimensions of HRQL measured by the Duke and the SGRQ at the end of follow-up. Accepted for publication: 9 July 1996     

Non-Invasive Estimation of Pulmonary Arterial Hypertension in Chronic Obstructive Pulmonary Disease

The feasibility and reliability of the combination of several noninvasive methods using a multivariate method of analysis to predict pulmonary artery hypertension (PAH) is evaluated in 20 patients with chronic obstructive pulmonary disease. These methods comprised arterial blood gases (Pao ₂, Paco ₂), pulmonary functional parameters (FEV₁), echo-Doppler parameters (tricuspid regurgitation jets, acceleration time on pulmonary valve), computed tomography measurements (transhilar distance, hilar thoracic index, and measurement of the descending branch of the right pulmonary artery to the lower lobe). A multiple stepwise regression analysis (including one Doppler parameter, two parameters of arterial blood gases, and one functional parameter) revealed a coefficient of determination (R ²) equal to 0.954 for mean pulmonary artery pressure (MPAP) with a standard error of estimate (S.E.E.) of 5.25 mmHg. A stepwise regression analysis including computed tomography and radiographic parameters revealed an R ² equal to 0.970 for PAP with a S.E.E. of 4.26 mmHg. Logistical regression analysis classified correctly 80% of patients with PAH using noninvasive methods such as the diameter of the main pulmonary artery and the diameter of the left pulmonary arterial branch calculated by computed tomography. Not only the presence of PAH but also the level of MPAP can be estimated by the combination of multiple stepwise and logistical regression analyses. Accepted for publication: 13 August 1998     

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.     

Exercise Capacity and Activities of Daily Living are Related in Patients With Chronic Obstructive Pulmonary Disease

IntroductionThe knowledge of the relationship between exercise capacity and activities of daily living (ADLs) is important to minimize the negative outcomes in ADLs resulting from reduced exercise capacity in patients with chronic obstructive pulmonary disease (COPD). There is a limited study about the association between exercise capacity and ADLs in patients with COPD. This study aimed to investigate the relationship between maximal exercise capacity and ADLs in patients with GOLD stage II–III COPD.MethodsTwenty-seven clinically stable GOLD stage II–III COPD patients were included (mean age = 58.59 ± 9.63 years and mean FEV₁ = 50.6 ± 13.7%) in this cross-sectional study. Maximal and submaximal exercise capacity were evaluated using an incremental shuttle walk test (ISWT) and 6-min walk test (6MWT), respectively. Activities of daily living were assessed using Glittre-ADL test.ResultsThe ISWT distance was significantly correlated with Glittre-ADL test time (r = −0.517, p = 0.006). There was also a negative correlation between 6MWT distance and Glittre-ADL test time (r = −0.506, p = 0.007).ConclusionA moderate relationship was found between maximal exercise capacity and general activities of daily living performance. The reduction in exercise capacity increases the negative influences in ADLs and strengthens our beliefs that exercise interventions in pulmonary rehabilitation could influence activities of daily living positively.     

Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure of Chronic Obstructive Pulmonary Disease

Noninvasive positive pressure ventilation (NPPV) has reemerged as an effective strategy for reducing morbidity and mortality associated with acute exacerbations of chronic obstructive pulmonary disease (COPD). During acute respiratory failure, dynamic hyperinflation, intrinsic PEEP, and increased airway resistance result in a mechanical workload that exceeds inspiratory muscle capacity. NPPV provides augmentation of alveolar ventilation and respiratory muscle rest. Observational, cohort, and, more recently, randomized controlled trials have demonstrated the ability of NPPV to decrease the need for endotracheal intubation and decrease complications and mortality. NPPV performs better in COPD patients without significant comorbid illness. It should be initiated during COPD exacerbations if arterial pH is less than 7.35 or if the patient is severely distressed. Pressure support ventilation (10–20 cmH₂O) via face mask is likely the optimal technique and, when successful, results in rapid clinical improvement. Accepted for publication: 17 October 1996     

乌司他丁对慢性阻塞性肺疾病患者血清IL-8及肺功能的影响

目的研究乌司他丁对慢性阻塞性肺疾病（COPD）患者血清IL-8及肺功能影响。方法慢性阻塞性肺疾病急性发作期患者随机分为两组,治疗组加用乌司他丁治疗,治疗前后观察血清IL-8、肺功能变化。结果两组治疗后均能改善血清IL-8表达,改善患者肺功能指标,且治疗组优于对照组。结论乌司他丁可显著抑制慢性阻塞性肺疾病急性发作期患者气道炎性反应并显著改善改善肺功能。     

Effect of Dynamic Hyperinflation on Cardiac Response to Exercise of Patients With Chronic Obstructive Pulmonary Disease

IntroductionAlthough the major limitation to exercise performance in patients with COPD is dynamic hyperinflation (DH), little is known about its relation with cardiac response to exercise. Our objectives were to compare the exercise response of stroke volume (SV) and cardiac output (CO) between COPD patients with or without DH and control subjects, and to assess the main determinants.MethodsFifty-seven stable COPD patients without cardiac comorbidity and 25 healthy subjects were recruited. Clinical evaluation, baseline function tests, computed tomography and echocardiography were conducted in all subjects. Patients performed consecutive incremental exercise tests with measurement of operating lung volumes and non-invasive measurement of SV, CO and oxygen uptake (VO₂) by an inert gas rebreathing method. Biomarkers of systemic inflammation and oxidative stress, tissue damage/repair, cardiac involvement and airway inflammation were measured.ResultsCOPD patients showed a lower SV/VO₂ slope than control subjects, while CO response was compensated by a higher heart rate increase. COPD patients with DH experienced a reduction of SV/VO₂ and CO/VO₂ compared to those without DH. In COPD patients, the end-expiratory lung volume (EELV) increase was related to SV/VO₂ and CO/VO₂ slopes, and it was the only independent predictor of cardiac response to exercise. However, in the regression models without EELV, plasma IL-1β and high-sensitivity cardiac troponin T were also retained as independent predictors of SV/VO₂ slope.ConclusionDynamic hyperinflation decreases the cardiac response to exercise of COPD patients. This effect is related to systemic inflammation and myocardial stress but not with left ventricle diastolic dysfunction.     

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).     

慢阻肺病人肺功能与精神障碍的相关性研究

目的探讨慢性阻塞性肺疾病患者肺功能和精神障碍的相关性。方法入选慢性阻塞性肺疾病患者120例,按照精神状态分为精神障碍组48例和精神正常组72例,分析并比较其肺功能状态。结果和精神正常组相比,精神障碍组肺功能损害程度较重,以重度和极重度者居多,两组之间的差异具有统计学意义（P〈0.01）。结论慢性阻塞性肺疾病患者合并精神障碍者肺功能损害更为严重,对这类患者的临床诊治,更应考虑其肺功能特点,制定科学完善的方案。     

Antioxidant Function of Ambroxol in Mononuclear and Polymorphonuclear Cells in Vitro

This study quantifies the antioxidant function of ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine) in vitro. Polymorphonuclear cells (PMN) and mononuclear cells were isolated from the blood of healthy volunteers (n= 46) to determine reactive oxygen species (ROS) by luminol-enhanced chemiluminescence. Ambroxol or the controls N-acetylcysteine (NAC), nacystelyn (NAL), glutathione (GSH), superoxide dismutase (SOD), catalase, and the combination of SOD/catalase were incubated for 1 or 2 h with zymosan-activated cells in vitro using concentrations ranging from 10⁻⁶ to 10⁻³ mol/liter. Reduction of ROS-mediated luminescence was similar within the cell types. Ambroxol (10⁻⁴ mol/liter) reduced ROS about 75% (1-h incubation) and 98% (2-h incubation), respectively (p < 0.001). SOD and SOD/catalase, but not the H₂O₂-catalyzing substances (NAC, NAL, GSH, and catalase), reduced cellular ROS. This indicates that inflammatory cells predominantly generate O⁻ ₂, which can be scavenged by ambroxol. The antioxidant function of ambroxol with increasing incubation time suggests additional cellular antiinflammatory properties of this substance. Our results indicate that good antioxidant function of ambroxol is related mainly to direct scavenger function of reactive oxygen metabolites such as O⁻ ₂. However, an antioxidative effect of ambroxol may also be associated with the reduction of prooxidative metabolism in inflammatory cells. Concluding from this observation, and because of the well known high affinity of ambroxol for lung tissue, ambroxol may be an alternative in antioxidant augmentation therapy, particularly in pulmonary diseases characterized by an overburden of toxic oxygen metabolites. Accepted for publication: 5 December 1996     

Mycobacterium avium-intracellulare Pulmonary Infection in Patients Without Known Predisposing Lung Disease

We tried to characterize the clinical features and findings on chest high resolution computed tomography (HRCT) of patients with Mycobacterium avium-intracellulare (MAI) pulmonary infection without known predisposing lung disease and with no immunodeficiency. We also aimed to clarify the small airway and alveolar inflammation using bronchoalveolar lavage (BAL) from the affected regions. MAI infection was diagnosed in 53 patients from respiratory samples, including sputum and materials obtained using a fiberoptic bronchoscope. None had a predisposing lung disease or immunodeficiency, as assessed by medical history, routine laboratory data, and previously normal chest radiographs and/or CT scans. The mean age of the 53 patients was 60 ± 11 years, and 48 were nonsmoking females. They had few respiratory symptoms, although 42% had chronic paranasal sinusitis. Chest HRCT findings showed centrilobular small nodules and ectasia of small bronchi and/or bronchioles located mainly in segment (S) 2, 3, 4, and 5. S1, which is usually affected by pulmonary tuberculosis, was completely free of these opacities. The BAL study revealed that the predominant cells were activated T lymphocytes and neutrophils. The CD4⁺/CD8⁺ ratio increased significantly. Bacteriology was negative for other bacteria and fungi. Although our patients did not present with distinct respiratory symptoms, the regions affected by MAI showed a chronic inflammation of mainly neutrophils and activated T lymphocytes. The presence of chronic sinusitis may be merely coincidental. However, its high prevalence and the finding of bronchiectasis in chest HRCT raise the question of whether silent bronchiectasis may be a predisposition. Accepted for publication: 18 June 1998     

Short Term Effects of Bracing on Exercise Performance in Mild Idiopathic Thoracic Scoliosis

In adolescent idiopathic thoracic scoliosis (ITS) working capacity may be reduced during exercise. Despite concern about its usefulness, bracing is still being used in ITS. Thus the effects of bracing on exercise performance need to be examined. We studied six females, ages 12–15 years who had mild ITS (Cobb angle range 20–35°). Pulmonary volumes, maximal voluntary ventilation (MVV), breathing pattern, the lowest (most negative in sign) pleural pressure during sniff maneuver (Ppl_sn), and pleural pressure swings (Ppl_sw) were measured first. Then, Ppl_sw, O₂ uptake (Vo ₂), CO₂ output (Vco ₂), heart rate (HR) at rest and during progressive incremental exercise on a cycling ergometer (10 watts/min) were recorded. The exercise test was performed under control conditions without bracing (C) and after 7 days of bracing with the brace on (B). Dyspnea was measured by a modified Borg scale. At rest, bracing mildly affected total lung capacity and forced vital capacity (p <0.03 for both) but not breathing pattern, Ppl_sn, or Ppl_sw(%Ppl_sn), a measure of respiratory effort. Furthermore, bracing did not consistently affect maximum work rate (WR_max). In both B and C VO₂ was below (<70%) the predicted value, Ve was below (<45%) MVV, and HR reserve was <15 beats/min, indicating some cardiovascular deconditioning. On the other hand, respiratory frequency (Rf) increased more in B than in C (p < 0.03). In addition, Ppl_sw, Ppl_sw(%Ppl_sn), and Ppl_sw(%Pplsn)/Vt, an index of neuroventilatory dissociation (NVD) of the respiratory pump, were greater in B (p < 0.03 for all). At a similar work rate, the Borg rating score was greater with bracing on than off, and the difference (ΔBorg) tended to relate to concurrent changes in Ppl_sw(%Ppl_sn)/Vt (r ²= 0.71; p < 0.07). We conclude that bracing affects respiratory effort, NVD, and dyspnea score during progressive exercise. These effects are consistent with increased lung elastance. Diminished exercise tolerance in patients with mild ITS probably reflects impaired physical fitness but is not affected by bracing. Training programs proposed for this subset of patients to increase peripheral muscle performance might also consider NVD of the respiratory pump. Accepted for publication: 27 January 1997