Exercise-induced flow limitation, dynamic hyperinflation and exercise capacity in patients with bronchial asthma.

It is known that, in stable asthmatics at rest, tidal expiratory flow limitation (EFL) and dynamic hyperinflation (DH) are seldom present. This study investigated whether stable asthmatics develop tidal EFL and DH during exercise with concurrent limitation of maximal exercise work rate (WRmax). A total of 20 asthmatics in a stable condition and aged 32+/-13 yrs (mean+/-SD) with a forced expiratory volume in one second (FEV1) of 101+/-21% of the predicted value were studied. Only three patients exhibited an FEV1 below the normal limits. On a first visit, patients performed a symptom-limited incremental (20 W.min(-1)) bicycle exercise test. On the second visit, the occurrence of EFL (using the negative expiratory pressure technique) and DH (via reduction in inspiratory capacity) were assessed at rest and when cycling at 33, 66 and 90% of their predetermined WRmax. FEV1 was measured to detect exercise-induced asthma, 5 and 15 min after stopping exercise at 90% WRmax. Only one patient showed EFL at rest, whereas 13 showed EFL and DH during exercise. In these 13 asthmatics, exercise capacity was significantly reduced (WRmax 75+/-9% pred) compared to the seven non-EFL patients (WRmax 95+/-13% pred). Moreover, a significant correlation of WRmax (% pred) to the change in inspiratory capacity (percentage of resting value) from rest to 90% WRmax was found. Tidal EFL during exercise was not associated with exercise-induced asthma, which was detected in only three patients. In conclusion, tidal expiratory flow limitation and dynamic hyperinflation during exercise are common in stable asthmatics with normal spirometric results and without exercise-induced asthma, and may contribute to reduction in exercise capacity.

Evidence for left ventricular dysfunction in patients with obstructive sleep apnoea syndrome.

There is limited information on the development of left ventricular (LV) dysfunction in patients with obstructive sleep apnoea (OSA) in the absence of lung and cardiac comorbidity. This study aimed to investigate whether OSA patients without heart morbidity develop LV dysfunction, and to assess the effect of continuous positive airway pressure (CPAP) on LV function. Twenty-nine OSA patients and 12 control subjects were studied using technetium-99m ventriculography to estimate LV ejection fraction (LVEF), LV peak emptying rate (LVPER), time to peak emptying rate (TPER), peak filling rate (LVPFR) and time to peak filling rate (TPFR) before and after 6 months of treatment with CPAP. A significantly lower LVEF was found in OSA patients, compared to control subjects, (53+/-7 versus 61+/-6%) along with a reduced LVPER (2.82+/-0.58 versus 3.82+/-0.77 end-diastolic volumes x s(-1)). Furthermore, OSA patients had significantly lower LVPFR (2.67+/-0.71 versus 3.93+/-0.58 end-diastolic volumes x s(-1)) and delayed TPFR (0.19+/-0.04 versus 0.15+/-0.03 s) in comparison with the control group. Six-months of CPAP treatment was effective in significantly improving LVEF, LVPER, LVPFR and TPFR. In conclusion, obstructive sleep apnoea patients without any cardiovascular disease seem to develop left ventricular systolic and diastolic dysfunction, which may be reversed, either partially or completely, after 6 months of continuous positive airway pressure treatment.

Association between activation of the renin-angiotensin system and secondary erythrocytosis in patients with chronic obstructive pulmonary disease.

PURPOSE: An association between activation of the renin-angiotensin system and enhanced erythropoiesis has been observed in patients with several diseases, including congestive heart failure and hypertension. Our goal was to examine whether the renin-angiotensin system is associated with secondary erythrocytosis in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: Plasma renin activity, plasma aldosterone concentration, serum erythropoietin level, and serum angiotensin converting enzyme (ACE) activity were measured in 12 patients with COPD and secondary erythrocytosis [mean (+/-SD) hematocrit of 53% +/- 3%] and in 12 matched controls with COPD who did not have erythrocytosis (hematocrit 45% +/- 5%). All patients had chronic hypoxemia (PaO2 <60 mm Hg). RESULTS: Both plasma renin and aldosterone levels were threefold greater in patients with secondary erythrocytosis compared to controls. No difference in erythropoietin levels was observed between patients with or without secondary erythrocytosis. Renin levels (r = 0.45; P = 0.02) but not erythropoietin levels (r = 0.15; P = 0.47) were correlated with hematocrit in the entire sample. Renin levels and PaO2 were the only variables independently and significantly associated with hematocrit values in a multiple linear regression model. CONCLUSION: Activation of the renin-angiotensin system is associated with the development of secondary erythrocytosis in chronically hypoxemic patients with COPD. The exact mechanism is not yet fully understood, but angiotensin II may be responsible for inappropriately sustained erythropoietin secretion or direct stimulation of erythroid progenitors.

Theophylline induces a reduction in circulating interleukin-4 and interleukin-5 in atopic asthmatics.

Theophylline, a known phosphodiesterase inhibitor, has been widely used as an additional bronchodilator in asthmatic patients who are not adequately controlled on high-doses of inhaled steroids. However, there is growing evidence that theophylline may also have anti-inflammatory or immunomodulatory effects in asthma. This study investigated whether theophylline administration has an impact on serum levels of interleukin (IL)-4 and IL-5 in asthmatic patients. Eight asymptomatic patients aged 30+/-1.5 yrs (mean +/- SEM) with mild atopic asthma were given a single daily dose of theophylline 150 mg or placebo in an on (theophylline)-off (placebo)-on (theophylline)-off (placebo) protocol with a 3-week duration of each on- or off- interval. Determination of serum IL-4 and IL-5 was done at baseline for all subjects and on the last day of each 3-week interval for the patients under study. Serum IL-4 levels were: 35+/-6 (baseline), 19+/-3 (on-1 interval), 29.5+/-4 (off-2), 15+/-2 (on-3) and 26+/-4 pg x mL(-1) (off-4), while IL-5 levels were 27+/-5, 18+/-4, 28+/-5, 17+/-4 and 28+/-5 pg x mL(-1), respectively. Spirometry was unchanged during the study and serum theophylline levels at the end of the two on-periods were 4.5+/-0.05 and 4.2+/-0.07 microg x mL(-1), while all patients remained asymptomatic. In conclusion, the administration of a low, single, daily dose of oral theophylline in asymptomatic patients with mild atopic asthma seems to reduce circulating interleukin-4 and interleukin-5.

Decreased C4 complement component serum levels correlate with the degree of emphysema in patients with chronic bronchitis.

Patients with COPD who fulfill the diagnostic criteria of chronic bronchitis have been shown to exhibit lower serum levels of complement components C3 and C4 than healthy subjects, and this may indicate sustained complement activation as a result of recurrent respiratory tract infections. Since activation of complement leads to influx of inflammatory cells into the lung parenchyma with subsequent release of elastases and oxidants that cause damage to elastic lung tissue, we postulated that there might be a quantitative relationship between complement consumption and degree of elastic tissue destruction. In this study, we tried to investigate possible correlations between serum levels of C3 and C4 and degree of emphysema among patients with COPD of the bronchitic type. We studied 20 patients with chronic bronchitis aged 68+/-1 years (mean+/-SEM) without significant fluctuations of serum C3 and C4 levels over a 3-month period by performing detailed lung function tests, recording of emphysema score in chest radiogram, and the incidence of infective exacerbations during the past 3 years. Measured C3 and C4 serum levels were 124+/-9 and 28.5+/-2 mg/dL, respectively, lower than the respective levels in control subjects (141+/-3 and 39+/-2 mg/dL, respectively). Significant correlations were observed between levels of C4 and (1) incidence of respiratory tract infections during the past 3 years (r=-0.747, p<0.001), (2) radiologic emphysema score (r=-0.936, p<0.001), and (3) various functional indexes, such as midexpiratory flow rate, percent of predicted (r=0.629, p<0.01), forced expiratory flow rate at 50% of vital capacity, percent of predicted (r=0.606, p<0.01), residual volume/total lung capacity ratio (r=-0.651, p<0.01), and the exponential constant of static pressure-volume curve (r=-0.606, p<0.01). These results suggest that patients with chronic bronchitis with the lowest levels of C4 are those experiencing more frequent respiratory infections, tend to have more signs indicative of emphysema in their chest radiograph, have a more prominent small airways dysfunction and gas trapping, and present a greater defect in lung elastic recoil.

Daily variation in circulating cytokines and acute-phase proteins correlates with clinical and laboratory indices in community-acquired pneumonia.

Our objective was to investigate the initial levels of circulating proinflammatory cytokines, such as interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), of certain acute-phase proteins, such as C-reactive protein (CRP), fibrinogen (FBN) and albumin, and of the glycoprotein fibronectin at presentation and their daily variation during the clinical course of community-acquired pneumonia (CAP) in relation to clinical and laboratory indices of infection. Thirty otherwise healthy hospitalized patients aged 48 +/- 3 years (mean +/- SEM) and with bacteriologically confirmed CAP were studied prospectively. IL-1 beta and IL-6 were found to be 15-fold higher on admission (122 +/- 9 pg mL-1 and 60 +/- 4 pg mL-1 respectively), whereas TNF-alpha was three-fold higher (102 +/- 5 pg mL-1) than those of controls, all of them showing a decline towards normal. Initial CRP levels were increased 90-fold (416 +/- 1 mg L-1), whereas fibronectin levels were reduced (242 +/- 9 mg dL-1). The presence of parapneumonic effusion was associated with a higher TNF-alpha serum level (127 +/- 7 vs. 86 +/- 4 pg mL-1, P = 0.0002), a more rapid daily decline in TNF-alpha (-7.2 +/- 0.7 vs. -3.8 +/- 0.5 pg mL-1 day-1, P = 0.0005), a slower rate of decline in CRP (-42.8 +/- 3.0 vs. -54.6 +/- 3.0 mg L-1 day-1, P = 0.02) and a slower rate of increase in FBN (5.9 +/- 1.0 vs. 11.7 +/- 1.0 mg dL-1 day-1), P = 0.001]. Furthermore, daily progression of serum levels of cytokines and acute-phase proteins correlated strongly with pyrexia, erythrocyte sedimentation rate (ESR), neutrophil count, alveolar-arterial oxygen difference and radiographic resolution, clinically manifested by improvement in the patients' condition.

Lack of evidence for diaphragmatic fatigue over the course of the night in obstructive sleep apnoea.

The aim of this study was to determine whether diaphragmatic fatigue develops over the course of the night in patients with obstructive sleep apnoea (OSA). Patients with severe OSA underwent overnight polysomnography with the addition of gastric and oesophageal catheters for measurement of transdiaphragmatic pressure (Pdi) (n = 7) and a gastro-oesophageal electrode for determination of diaphragmatic electromyogram (EMGdi) (n = 5). Analyses of Pdi and EMGdi were performed to detect fatigue during the large inspiratory efforts at the end of apnoeas in Stage 2 sleep at the beginning and end of the night. Measurements included Pdi values, shape analysis of the Pdi waveform, the relaxation rate (tau R) of Pdi, EMGdi and its relationship to Pdi, and the centroid frequency (fc) of EMGdi. End of apnoeic Pdi and EMGdi increased from the beginning to end of the night (e.g. 19 +/- 14% increase in Pdi; p < 0.05). The rate of increase in Pdi and EMGdi during apnoeas did not change. The Pdi versus EMGdi relationship was linear, and remained unchanged over the course of the night. There was no significant change in the shape of the Pdi waveform, and there were no changes in tau R from the beginning to the end of the night (0.13 +/- 0.01 s for both periods). There was also no shift in the fc of the EMGdi power spectrum (94 +/- 5 vs 93 +/- 6 Hz; NS), and no change in the relationship of fc to Pdi or EMGdi from the beginning to the end of the night. These findings do not support the development of diaphragmatic fatigue over the course of the night in obstructive sleep apnoea.

Mechanism of apnea lengthening across the night in obstructive sleep apnea.

We have previously shown in patients with obstructive sleep apnea (OSA) that the length of apneas increases from the beginning to the end of the night (Chest 1994;106:1695-1701). To investigate this, in light of recent evidence that neural feedback related to inspiratory effort during apneas plays an important role in apnea termination (Am. J. Respir. Crit. Care Med. 1994;149:707-714), we measured transdiaphragmatic pressure (Pdi) and the diaphragm tension-time index (TTdi = Pdi/Pdi(max)) Ti/Ttot) during overnight polysomnography in seven male subjects with severe OSA (mean apnea-hypopnea index [AHI] = 64.1 +/- 8.8 [SD] events/h). We assessed apnea duration, SaO2, and inspiratory effort during apneas at the start and end of the night in Stage 2 sleep. Mean apnea duration increased from 26.6 +/- 2.0 s (SEM) to 32.6 =/- 2.5 s (p < 0.05). The rate of fall in SaO2 during apneas decreased, and end-apneic SaO2 remained unchanged across the night, suggesting a possible role for metabolic factors in mediating the increase in apnea duration. Both Pdi and TTdi at end-apnea just prior to arousal increased significantly from the beginning to the end of the night (e.g., Pdi from 41.0 +/- 4.9 to 49.9 +/- 7.9 cm H20; p < 0.05). These findings, together with those in previous studies, suggest that there is a blunting over the night of the arousal response to neural stimuli produced during obstructed inspiratory effort, which plays a major role in mediating apnea lengthening across the night in OSA.

Relationship of peak exercise capacity with indexes of peripheral muscle vasodilation.

Since leg muscles receive the majority of cardiac output and consume a large proportion of total oxygen consumption (VO2) during cycle exercise, maximum leg blood flow may be an important determinant of peak VO2 (VO2peak). We investigated the relationships between parameters of active hyperemia after thigh tourniquet occlusion (alone or with calf exercise) with whole body peak exercise capacity during maximum cycle exercise. Twenty-one healthy male subjects, aged 19-39 yr. performed maximum incremental cycle exercise. Calf blood flow, conductance (blood flow/mean blood pressure), vasodilatory capacity (peak/baseline conductance), and duration of vasodilation were then determined with venous occlusive plethysmography under two conditions: 1) after thigh tourniquet occlusion for 10 min; 2) after ischemic calf exercise (thigh tourniquet occlusion with calf exercise to exhaustion). Group mean VO2peak was 120 +/- 35% (standard deviation) predicted. There was a significant relationship between VO2peak/ lean body mass and peak calf conductance after maximum ischemic calf exercise (r = 0.556; P < 0.01). However, VO2peak/lean body mass was more closely correlated with the duration of vasodilation after thigh tourniquet occlusion with ischemic calf exercise (r = 0.861; P < 0.001). These results suggest that the duration of calf vasodilation after maximal ischemic calf exercise appears to be a better index of cycle exercise capacity in healthy subjects.

Acute effects of glyburide on the regulation of peripheral blood flow in normal humans.

Recent animal studies have demonstrated that selective blockade of ATP-sensitive K+ (KATP) channels of vascular smooth muscle results in a significant increase in peripheral vascular tone. The main aim of this study was to assess whether glyburide, a selective blocker of KATP channels and commonly used antidiabetic agent, influences resting blood flow and reactive hyperemic response of peripheral tissues of normal subjects. Baseline calf blood flow was measured non-invasively in six normal subjects with femoral venous occlusive plethysmography. Calf blood flow was also serially measured every 30-60 s after the release of calf arterial occlusion (10 min duration). Reactive hyperemia was expressed in terms of peak post-occlusive flow, duration of hyperemia and reactive hyperemic volume. In each subject, baseline flow and reactive hyperemia were measured before (control) and every hour for 5 h after the oral ingestion of either 7.5 mg glyburide or a placebo on two separate days. Baseline calf flow declined by 30 and 42% of control values after 1 and 2 h of glyburide intake (P < 0.05) with a return to control values by hours 3, 4 and 5. Peak post-occlusive flow after 1, 2 and 3 h of glyburide ingestion was lower than control values by 22, 30 and 28%, respectively (P < 0.05). The duration of reactive hyperemia after 2 and 3 h of glyburide ingestion was significantly longer than control values (P < 0.05), whereas reactive hyperemic volume remained unaffected by glyburide intake. Placebo elicited no significant changes in baseline flow or reactive hyperemia throughout the 5-h experimental period.(ABSTRACT TRUNCATED AT 250 WORDS)