Effects of erythropoietin on muscle O2 transport during exercise in patients with chronic renal failure.

Erythropoietin (rHuEPO) has proven to be effective in the treatment of anemia of chronic renal failure (CRF). Despite improving the quality of life, peak oxygen uptake after rHuEPO therapy is not improved as much as the increase in hemoglobin concentration ([Hb)] would predict. We hypothesized that this discrepancy is due to failure of O2 transport rates to rise in a manner proportional to [Hb]. To test this, eight patients with CRF undergoing regular hemodialysis were studied pre- and post-rHuEPO ([Hb] = 7.5 +/- 1.0 vs. 12.5 +/- 1.0 g x dl-1) using a standard incremental cycle exercise protocol. A group of 12 healthy sedentary subjects of similar age and anthropometric characteristics served as controls. Arterial and femoral venous blood gas data were obtained and coupled with simultaneous measurements of femoral venous blood flow (Qleg) by thermodilution to obtain O2 delivery and oxygen uptake (VO2). Despite a 68% increase in [Hb], peak VO2 increased by only 33%. This could be explained largely by reduced peak leg blood flow, limiting the gain in O2 delivery to 37%. At peak VO2, after rHuEPO, O2 supply limitation of maximal VO2 was found to occur, permitting the calculation of a value for muscle O2 conductance from capillary to mitochondria (DO2). While DO2 was slightly improved after rHuEPO, it was only 67% of that of sedentary control subjects. This kept maximal oxygen extraction at only 70%. Two important conclusions can be reached from this study. First, the increase in [Hb] produced by rHuEPO is accompanied by a significant reduction in peak blood flow to exercising muscle, which limits the gain in oxygen transport. Second, even after restoration of [Hb], O2 conductance from the muscle capillary to the mitochondria remains considerably below normal.

Cellular bioenergetics after erythropoietin therapy in chronic renal failure.

After erythropoietin (rHuEPO) therapy, patients with chronic renal failure (CRF) do not improve peak O2 uptake (VO2 peak) as much as expected from the rise in hemoglobin concentration ([Hb]). In a companion study, we explain this phenomenon by the concurrent effects of fall in muscle blood flow after rHuEPO and abnormal capillary O2 conductance observed in CRF patients. The latter is likely associated with a poor muscle microcirculatory network and capillary-myofiber dissociation due to uremic myopathy. Herein, cellular bioenergetics and its relationships with muscle O2 transport, before and after rHuEPO therapy, were examined in eight CRF patients (27 +/- 7.3 [SD] yr) studied pre- and post-rHuEPO ([Hb] = 7.8 +/- 0.7 vs. 11.7 +/- 0.7 g x dl-1) during an incremental cycling exercise protocol. Eight healthy sedentary subjects (26 +/- 3.1 yr) served as controls. We hypothesize that uremic myopathy provokes a cytosolic dysfunction but mitochondrial oxidative capacity is not abnormal. 31P-nuclear magnetic resonance spectra (31P-MRS) from the vastus medialis were obtained throughout the exercise protocol consisting of periods of 2 min exercise (at 1.67 Hz) at increasing work-loads interspersed by resting periods of 2.5 min. On a different day, after an identical exercise protocol, arterial and femoral venous blood gas data were obtained together with simultaneous measurements of femoral venous blood flow (Qleg) to calculate O2 delivery (QO2leg) and O2 uptake (VO2leg). Baseline resting [phosphocreatine] to [inorganic phosphate] ratio ([PCr]/[Pi]) did not change after rHuEPO (8.9 +/- 1.2 vs. 8.8 +/- 1.2, respectively), but it was significantly lower than in controls (10.9 +/- 1.5) (P = 0.01 each). At a given submaximal or peak VO2leg, no effects of rHuEPO were seen on cellular bioenergetics ([PCr]/[Pi] ratio, %[PCr] consumption halftime of [PCr] recovery after exercise), nor in intracellular pH (pHi). The post-rHuEPO bioenergetic status and pHi, at a given VO2leg, were below those observed in the control group. However, at a given pHi, no differences in 31P-MRS data were detected between post-rHuEPO and controls. After rHuEPO, at peak VO2, Qleg fell 20% (P < 0.04), limiting the change in QO2leg to 17%, a value that did not reach statistical significance. The corresponding O2 extraction ratio decreased from 73 +/- 4% to 68 +/- 8.2% (P < 0.03). These changes indicate that maximal O2 flow from microcirculation to mitochondria did not increase despite the 50% increase in [Hb] and explain how peak VO2leg and cellular bioenergetics (31P-MRS) did not change after rHuEPO. Differences in pHi, possibly due to lactate differences, between post-rHeEPO and controls appear to be a key factor in the abnormal muscle cell bioenergetics during exercise observed in CRF patients.

Is it necessary to treat all patients with idiopathic pulmonary fibrosis?

BACKGROUND AND AIM OF THE WORK: To investigate the clinical course of untreated patients with idiopathic pulmonary fibrosis (usual interstitial pneumonia) (IPF/UIP). METHODS: Forty-three patients with IPF/UIP, divided into two groups. Group I consisted of 29 patients treated at diagnosis, while Group II comprised 14 patients who did not receive treatment. The indication of treatment was established whenever patients referred to a significant progression of the degree of dyspnea during the year prior to diagnosis. RESULTS: At diagnosis, patients from Group I had lower FVC (mean +/- SEM, 56+/-3% vs 73+/-3%) (p = 0.0004) and a greater extent of ground glass pattern in high resolution CT scan (18+/-4% vs 4+/-1%) (p = 0.004) than those from Group II. In group I, a follow-up study was carried out on 26 patients for 24+/-4 months. Thirteen of these 26 patients (50%) died 11+/-4 months after the initial assessment. Serial pulmonary functional tests were performed on 19 patients. Thirteen patients from Group II were followed up for 23+/-3 months. Seven of these 13 patients were treated 12+/-3 months after the diagnosis because of progression of the disease. The remaining 6 patients remained untreated and with the disease stable at the end of the follow-up, representing 15% (6 out of 39) of the whole study group. No patients from this group died during the follow-up. At the end of the follow-up, there were no differences in lung function changes between treated patients (19 from Group I and 7 from Group II), and the 6 untreated patients. CONCLUSIONS: Some patients with IPF/UIP remain stable for extended periods of time without treatment.

Effects of F(I)O2 on leg VO2 during cycle ergometry in sedentary subjects.

In a recent study of completely sedentary normal young subjects, leg VO2max was reduced by hypoxia in proportion to mean capillary PO2 as F(I)O2 was reduced from 0.15 to 0.12. However, the increase in VO2max from F(I)O2 = 0.15 to 0.21 was less than expected for the increase in mean capillary PO2. This finding has led us to hypothesize that in sedentary subjects breathing room air, VO2max is not limited by O2 supply but rather by oxidative capacity of mitochondria. The present study sought to obtain further evidence for or against this hypothesis in sedentary subjects by assessing leg VO2max (VO2leg) breathing 100% O2, as well as in normoxia and hypoxia. Data from 18 subjects studied at F(I)O2 = 0.12, 0.15, and 0.21 and from six more studied at 0.12, 0.15, and 1.00 were analyzed. In all 24 we measured VO2leg by arterial and venous blood sampling and thermodilution leg blood flow during maximal cycle ergometry at each F(I)O2. VO2leg was not increased by room air or 100% O2 breathing relative to that observed at F(I)O2 = 0.15, but it was reduced while breathing 12% O2. The data at F(I)O2 = 0.12 and 0.15 conformed to the predictions of O2 supply limitation of maximal VO2 as previously. These results confirm and extend our prior observations that in sedentary, as opposed to trained subjects, muscle VO2max is O2 supply limited only in hypoxia.

Prophylaxis of gastrointestinal tract bleeding with magaldrate in patients admitted to a general hospital ward.

A randomized, placebo-controlled trial was performed to assess the effect of magaldrate (800 mg every 4 h) in reducing the rate of upper gastrointestinal tract bleeding among 100 consecutive patients with severe diseases admitted to a general hospital ward. Upper gastrointestinal tract bleeding occurred in 11 of 48 placebo-treated patients and in only 1 of 52 magaldrate-treated patients (p less than 0.01). Endoscopic examination of these patients showed gastric ulcer (two cases), multiple gastric mucosa ulcerations (nine), and no lesions (one). In three patients who received placebo the hemorrhage was clinically relevant and required transfusion of two or more blood units. Patients with two or more risk factors showed a higher rate of gastrointestinal hemorrhage (p less than 0.05). Respiratory failure and treatment with a high dose of corticosteroids were associated with the highest incidence of bleeding (p less than 0.05 for both). The only adverse reaction associated with magaldrate was a mild and self-limiting diarrhea in two cases. We conclude that patients seriously ill admitted to a general hospital ward should be treated with a prophylactic agent against stress-induced ulcer bleeding. Magaldrate is an effective and safe antacid to prevent gastrointestinal tract bleeding in such patients.

Nebulized glutathione induces bronchoconstriction in patients with mild asthma.

To assess the effects on bronchial responsiveness of nebulized glutathione (GSH), one of the most efficient scavengers of oxidant substances in the airways, we studied eight patients with mild asthma (FEV1, 88 +/- 11% predicted [SD]) in a randomized, double-blind, cross-over, placebo-controlled fashion. Bronchial challenge was measured using both FEV1 and total pulmonary resistance (Rrs) by the forced oscillation technique. Patients received nebulized GSH (600 mg with 4 ml of 0.9% sodium chloride) or placebo (identical saline solution) over a period of 25 min, 1 wk apart. Placebo provoked subclinical mild bronchoconstriction (changes from baseline: FEV1, -1%; Rrs, +17%); by contrast, GSH caused major airway narrowing (changes from baseline: FEV1, -19%; Rrs, +61%) and induced cough (four patients) or breathlessness (three patients). Differences between placebo and GSH after challenge were also noticeable in both FEV1 (p = 0.03) and Rrs (p = 0.02). Neither osmolarity (660 mosm.kg-1) nor pH (3.0) of the GSH solution accounted for these effects. Nebulized salbutamol (5.0 mg) given before the GSH challenge blocked GSH-induced bronchoconstriction. Furthermore, GSH-induced FEV1 falls were inversely correlated with metabisulfite bronchoprovocation (provocative dose [PD20], 1.49 +/- 1.83 mumol) but not with methacholine challenge. The detrimental effects of nebulized GSH on the airway bronchial tone in patients with mild asthma strongly suggests bronchoconstriction provoked by sulfite formation.

Risk factors of readmission to hospital for a COPD exacerbation: a prospective study.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are a leading cause of admission to hospital among men in many countries, although the factors causing exacerbations are largely unknown. The association between readmission for a COPD exacerbation and a wide range of modifiable potential risk factors, after adjusting for sociodemographic and clinical factors, has been assessed. METHODS: Three hundred and forty patients with COPD recruited during an admission for an exacerbation in four tertiary hospitals in the Barcelona area of Spain were followed for a mean period of 1.1 years. Information on potential risk factors, including clinical and functional status, medical care and prescriptions, medication adherence, lifestyle, health status, and social support, was collected at the recruitment admission. A Cox's proportional hazards model was used to obtain independent relative risks of readmission for COPD. RESULTS: During the follow up period 63% of patients were readmitted at least once, and 29% died. The final multivariate model showed the following risk (or protective) factors: > or =3 admissions for COPD in the year before recruitment (hazard ratio (HR)=1.66, 95% CI 1.16 to 2.39), forced expiratory volume in 1 second (FEV(1)) percentage predicted (0.97, 95% CI 0.96 to 0.99), oxygen tension (0.88, 95% CI 0.79 to 0.98), higher levels of usual physical activity (0.54, 95% CI 0.34 to 0.86), and taking anticholinergic drugs (1.81, 95% 1.11 to 2.94). Exposure to passive smoking was also related to an increased risk of readmission with COPD after adjustment for clinical factors (1.63, 95% CI 1.04 to 2.57) but did not remain in the final model. CONCLUSIONS: This is the first study to show a strong association between usual physical activity and reduced risk of readmission to hospital with COPD, which is potentially relevant for rehabilitation and other therapeutic strategies.

Risk factors for hospitalization for a chronic obstructive pulmonary disease exacerbation. EFRAM study.

Although exacerbation of chronic obstructive pulmonary disease (COPD) is important in terms of health and costs, there is little information about which are the risk factors. We estimated the association between modifiable and nonmodifiable potential risk factors of exacerbation and the admission for a COPD exacerbation, using a case-control approach. Cases were recruited among admissions for COPD exacerbation during 1 yr in four tertiary hospitals of the Barcelona area. Control subjects were recruited from hospital's register of discharges, having coincided with the referent case in a previous COPD admission but being clinically stable when the referent case was hospitalized. All patients completed a questionnaire and performed spirometry, blood gases, and physical examination. Information about potential risk factors was collected, including variables related to clinical status, characteristics of medical care, medical prescriptions, adherence to medication, lifestyle, quality of life, and social support. A total of 86 cases and 86 control subjects were included, mean age 69 yr, mean FEV(1) 39% of predicted. Multivariate logistic regression showed the following risk (or protective) factors of COPD hospitalization: three or more COPD admissions in the previous year (odds ratio [OR] 6.21, p = 0.008); FEV(1) (OR 0.96 per percentual unit, p < 0.0005); underprescription of long-term oxygen therapy (LTOT) (OR 22.64, p = 0.007); and current smoking (OR 0.30, p = 0.022). Among a wide range of potential risk factors we have found that only previous admissions, lower FEV(1), and underprescription of LTOT are independently associated with a higher risk of admission for a COPD exacerbation.

Patients hospitalized for COPD have a high prevalence of modifiable risk factors for exacerbation (EFRAM study).

There is little information available concerning the extent to which chronic obstructive pulmonarv disease (COPD) patients are satisfactorily managed, especially, regards factors supposedly related to COPD exacerbation. The present study assessed the prevalence rates of potentially modifiable risk factors of COPD exacerbation in patients hospitalized for this reason. A systematic sample of one out of two patients admitted for COPD exacerbation, during 1 yr, in four tertiary hospitals in the Barcelona area, Spain, was performed. Patients answered a questionnaire and underwent anthropometric measurements, spirometric tests and arterial blood gas sampling. Prevalence rates and 95% confidence intervals (95% CI) for risk factors were obtained, and the generalized estimating equation (GEE) method was used to allow for patients to provide information on different admissions. The study recruited 353 patients (29 female) with a total of 404 admissions age (mean+/-SD) 69+/-9, median forced expiratory volume in one second (FEV1) 31% of predicted and mean partial pressure of oxygen (PO2) 63+/-13 mmHg. Of these, 28% had not received an influenza vaccination; a high number (86%) did not attend rehabilitation programmes; 28% of patients with PO2 < or =55 mmHg were not using long-term oxygen therapy (LTOT); among LTOT users, 18% used it <15 h a day; 43% of the total failed in some of the essential inhaler manoeuvres; 26% were current smokers; 21% of noncurrent smokers were exposed to passive smoking at home; current occupational exposure was low (5%). In summary, the authors found a moderate to high prevalence of potentially modifiable risk factors in a large representative sample of patients hospitalized for a chronic obstructive pulmonary disease exacerbation, suggesting unsatisfactory features in their management.

Increase in pulmonary ventilation-perfusion inequality with age in healthy individuals.

Arterial oxygen tension (PaO2) is known to decrease with age, and this is accompanied by a number of changes in mechanical properties of the lungs, including loss of elastic recoil and increase in closing volume. The changes in respiratory mechanics with age could induce greater ventilation/perfusion (VA/Q) mismatch and thus explain the decrease in PaO2. In 64 normal subjects aged 18 to 71 yr (lifetime nonsmokers with normal spirometry), we measured VA/Q inequality and arterial respiratory blood gases (PaO2 and PaCO2) at rest in the seated position. VA/Q mismatch, represented by the second moments of the blood flow and ventilation distributions (log SDQ and log SDV) increased with age, but only slightly (mean log SDQ was 0.36 at age 20 yr and 0.47 at age 70 yr). PaO2 fell by a correspondingly small amount of 6 mm Hg. Previously established upper 95% confidence limits for log SDQ (0.60) and log SDV (0.65) in subjects at age 20 yr were confirmed. At age 70 yr, the upper limits of reference for log SDQ are 0.70 and for log SDV 0.75. The study shows that an increased alveolar-arterial O2 gradient with age is due to VA/Q inequality rather than to shunting.

Muscle angiogenic growth factor gene responses to exercise in chronic renal failure.

Patients with chronic renal failure (CRF) have impaired exercise capacity even after erythropoietin treatment. We recently showed that although this is explained in part by reduced convective O(2) delivery to muscles, there is also an impairment of O(2) transport from muscle capillaries to the mitochondria. Given the importance of the capillary surface area for capillary mitochondrial O(2) transport and reports of reduced capillarity in CRF, we hypothesized that the angiogenic gene response to exercise is impaired in such patients. Six patients with CRF and six control subjects matched for age, size, and sedentary lifestyle exercised on a single occasion for 1 h at similar work intensities averaging 50% of maximal capacity. Exercise was confined to the knee extensors of a single leg by means of a specially designed leg-kick ergometer. A percutaneous biopsy of the quadriceps was taken within 30 min of cessation of exercise and compared with a similar biopsy done at different times without any prior exercise for 24 h. Conventional Northern blots were prepared and probed for vascular endothelial growth factor (VEGF; the major putative angiogenic growth factor for muscle), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-beta(1). Data during both rest and exercise were successfully obtained in four subjects of each group. We also assessed muscle capillarity and mitochondrial oxidative capacity to relate to these changes. Mitochondrial oxidative capacity was normal, whereas capillary number per fiber was 12% lower than in normal subjects. VEGF mRNA abundance was increased after exercise by about one order of magnitude, with no reduction in response in CRF. For bFGF and TGF-beta(1), exercise elicited no response in either group. Reduced muscle capillarity in CRF does not, therefore, stem from reduced transcription of VEGF. To the extent that VEGF is important to exercise-induced angiogenesis in muscle, we suspect a posttranscriptional aberration in this response occurs in CRF to explain reduced capillarity.

Chronic obstructive pulmonary disease stage and health-related quality of life. The Quality of Life of Chronic Obstructive Pulmonary Disease Study Group.

BACKGROUND: The American Thoracic Society recently recommended that chronic obstructive pulmonary disease be staged on the basis of the percentage of predicted FEV1. OBJECTIVE: To examine 1) the relation between the american Thoracic Society system for staging chronic obstructive pulmonary disease and health-related quality of life and 2) the effect of self-reported comorbid conditions on health-related quality of life. DESIGN: Cross-sectional study. SETTING: Outpatient clinics of respiratory departments of four hospitals and one primary health care center in spain. PATIENTS: 321 consecutive male patients with chronic obstructive pulmonary disease. MEASUREMENTS: Functional respiratory impairment, FEV1, respiratory symptoms, and health-related quality of life. Respiratory symptoms and health-related quality of life were measured by using the Spanish version of the St. George's Respiratory Questionnaire and the Nottingham Health Profile. RESULTS: Patient scores on the St. George's Respiratory Questionnaire were moderately to strongly associated with disease staging (r = 0.27 to 0.51). Compared with reference values, values for health-related quality of life for patients with stage I disease were substantially higher on the St. George's Respiratory Questionnaire (6 and 34; p < 0.001) and values for impairment were significantly greater in stage 1 patients with comorbid conditions (19 and 36; P = 0.001). At least one concomitant chronic condition was found in 84% of study patients. Comorbid conditions only partly influenced the observed pattern of deterioration of health-related quality of life with worsening stages of disease. CONCLUSION: Staging criteria for chronic obstructive pulmonary disease based on percentage of predicted FEV1 separated groups of patients with varying degrees of impairment in health-related quality of life. Contrary to expectations, even patients with mild disease showed substantially compromised health-related quality of life. Comorbid conditions influenced the relation between chronic obstructive pulmonary disease and health-related quality of life.

Adjustment of DLCO for hemoglobin concentration.

The equation proposed by Cotes and coworkers is currently considered as the most acceptable to correct carbon monoxide diffusing capacity (DLCO) for hemoglobin concentration [Hb] by both the American Thoracic Society (ATS) and the European Respiratory Society (ERS) guidelines for standardization of DLCO. In a previous study on 24 anemic patients undergoing bone marrow transplantation (1), we found that DLCO is underestimated using the equation of Cotes and coworkers. To further explore this finding, 28 anemic patients ([Hb] = 8.2 +/- 1.0 (SD) g/dl) with chronic renal failure were prospectively studied during the recovery period of anemia (5.4 +/- 3.5 mo). In all 28 subjects, the slope deltaDLCO/delta[Hb] computed as ratio of overall change in DLCO to overall change in [Hb] throughout the study period was 1.40 +/- 0.72 ml CO/min/mm Hg/g/dl. The individual relationship between measured DLCO and [Hb] closely fitted a simple linear regression. The resulting equations for adjustment of DLCO (DLCOadj) to a standard [Hb] of 14.6 g/dl for men and 13.4 g/dl for women are: [equations: see text]. The present adjustment function for DLCO is linear and independent of the observed DLCO values, whereas the formulas previously proposed are curvilinear, DLCO correction varying with the measured DLCO values. For a measured DLCO of 15 ml CO/min/mm Hg and [Hb] ranging from 7 to 12 g/dl, the present DLCO adjustment is higher (by 2.7 ml CO/min/mm Hg, on average) than that proposed by Cotes and coworkers. This difference appears to be relevant for a precise interpretation of DLCO in patients with normocytic anemia in different clinical conditions.

Gas exchange response to a PAF receptor antagonist, SR 27417A, in acute asthma: a pilot study.

The pathogenic role of platelet-activating factor (PAF) in asthma has been questioned due to the limited or negative efficacy of PAF antagonists; however, in acute asthma (AA), where the endogenous release of PAF may be enhanced, the effects of PAF antagonist receptors have not been investigated. It was postulated that inhaled PAF provokes gas exchange defects in mild asthma likely to be related to airway vascular leakage. The response to a potent, selective PAF receptor antagonist, SR 27471A, on pulmonary gas exchange was studied, more specifically ventilation-perfusion (VA'/Q') distributions, in patients with AA within 48 h of hospitalization. A randomized, double-blind, placebo-controlled, parallel group (n=6, each) design was used. After baseline measurements, either placebo or SR 27417A (20 mg, orally) was administered and measurements were repeated 3 h later. Conventional anti-asthma medication was not interrupted. Despite a near-complete inhibition of the in vitro, platelet aggregation tests by 40 nM PAF (mean+/-SEM from 72+/-9 to 6+/-2%) and 80 nM PAF (from 81+/-7 to 6+/-3% both p<0.01) by SR 27471A indicating a good bioactivity of the compound, no significant changes in baseline forced expiratory volume in one second, (40+/-6%), respiratory system resistance (6.2+/-0.7 cmH2O x L(-1) x s), alveolar-arterial pressure difference for oxygen (5.2+/-0.4 kPa), arterial oxygen tension (9.0+/-0.5 kPa) or VA'/Q' distributions, as expressed by the dispersion of pulmonary blood flow (LogSD Q, 1.07+/-0.09; normal values <0.60), were observed. It is concluded that SR 27417A has limited value when added to the conventional treatment of acute asthma. These findings minimize the potential pathogenic role of endogenous platelet-activating factor as a relevant mediator of airway inflammation during acute asthma.

Impaired muscle oxygen transfer in patients with chronic renal failure.

We hypothesized that impaired O2 transport plays a role in limiting exercise in patients with chronic renal failure (CRF). Six CRF patients (25 +/- 6 yr) and six controls (24 +/- 6 yr) were examined twice during incremental single-leg isolated quadriceps exercise. Leg O2 delivery (QO2(leg)) and leg O2 uptake (VO2(leg)) were obtained when subjects breathed gas of three inspired O2 fractions (FI(O2)) (0.13, 0.21, and 1.0). On a different day, myoglobin O2 saturation and muscle bioenergetics were measured by proton and phosphorus magnetic resonance spectroscopy. CRF patients, but not controls, showed O2 supply dependency of peak VO2 (VO2(peak)) by a proportional relationship between peak VO2(leg) at each inspired O2 fraction (0.59 +/- 0.20, 0.47 +/- 0.10, 0.43 +/- 0.10 l/min, respectively) and 1) work rate (933 +/- 372, 733 +/- 163, 667 +/- 207 g), 2) QO(2leg) (0.80 +/- 0.20, 0.64 +/- 0.10, 0.59 +/- 0.10 l/min), and 3) cell PO2 (6.3 +/- 5.4, 1.7 +/- 1.3, 1.2 +/- 0.7 mmHg). CRF patients breathing 100% O2 and controls breathing 21% O2 had similar peak QO2(leg) (0.80 +/- 0.20 vs. 0.79 +/- 0.10 l/min) and similar peak VO2(leg) (0.59 +/- 0.20 vs. 0.57 +/- 0.10 l/min). However, mean capillary PO2 (47.9 +/- 4.0 vs. 38.2 +/- 4.6 mmHg) and the capillary-to-myocite gradient (40.7 +/- 6.2 vs. 34.4 +/- 4.0 mmHg) were both higher in CRF patients than in controls (P < 0.03 each). We conclude that low muscle O2 conductance, but not limited mitochondrial oxidative capacity, plays a role in limiting exercise tolerance in these patients.

Effects of endurance training on skeletal muscle bioenergetics in chronic obstructive pulmonary disease.

Physiologic adaptations after an 8-wk endurance training program were examined in 13 patients with chronic obstructive pulmonary disease (COPD) (age, 64 +/- 4 [SD] yr; FEV1, 43 +/- 9% pred; PaO2, 72 +/- 8 mm Hg; and PaCO2, 36 +/- 2 mm Hg) and in eight healthy sedentary control subjects (61 +/- 4 yr). Both pre- and post-training studies included: (1) whole-body oxygen consumption (V O2) and one-leg O2 uptake (V O2leg) during exercise; and (2) intracellular pH (pHi) and inorganic phosphate to phosphocreatine ratio ([Pi]/[PCr]) during exercise; and half-time of [PCr] recovery. After training, the two groups increased peak V O2 (p < 0.05 each) and showed a similar fall in submaximal femoral venous lactate levels (p < 0.05 each). However, control subjects increased peak V E (p < 0.01) and raised peak O2 delivery (p = 0.05), not shown in patients with COPD. Both groups increased post-training O2 extraction ratio (p < 0.05). The most consistent finding, however, was in patients with COPD, who had a substantial improvement in cellular bioenergetics: (1) half-time of [PCr] recovery fell from 50 +/- 8 to 34 +/- 7 s (p = 0.02); and (2) at a given submaximal work rate, [Pi]/[PCr] ratio decreased and pHi increased (p < 0.05 each). We conclude that beneficial effects of training in patients with COPD essentially occurred at muscle level during submaximal exercise.