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The energy demand during physical exercise causes an increased oxygen uptake and supply to active tissues, which may increase the rate of free oxygen radical production and thereby affect the capacity of endogenous cellular defense systems. This could result in DNA base modifications, among which 8-hydroxydeoxyguanosine (8OHdG) is one of the most important and has widely been used as a biomarker of in vivo oxidative lesions. Therefore, we examined the effect of regular running exercise on the urinary levels of 8OHdG in 32 long-distance runners and in a group of untrained healthy subjects. The range of 8OHdG in urine was 0.12-6.45 mumol/mol creatinine in both groups, and no significant difference in the mean excretion levels between runners and control probands was observed. This gives no reason to believe that physical exercise in trained individuals may induce a disturbance of the oxidant-to-antioxidant balance.

Plasma beta-endorphin (beta-E) concentration was determined before, during, and after a standardized incremental exercise test to maximal capacity in eight type I diabetic patients and eight normal control subjects. Diabetic patients were studied under normoglycemic and hyperglycemic conditions in a single-blind random fashion to differentiate between the effects of acute hyperglycemia and of diabetes per se on the beta-E response to exercise. The perceived magnitude of leg effort elicited by exercise was evaluated using a category scale. Whereas plasma beta-E concentrations increased in control subjects with increasing workload, causing significantly higher beta-E levels at the end of exercise than at the beginning (P < .001), no such increase could be observed in the diabetic patients under normoglycemic and hyperglycemic conditions. In addition, baseline plasma beta-E concentrations were significantly lower in normoglycemic (P < .01) and hyperglycemic (P < .001) diabetic patients than in control subjects. Even during the recovery period, patients' beta-E levels remained significantly lower than those of control subjects. At submaximal levels of power output, the perceived intensity of leg effort was significantly higher in normoglycemic and hyperglycemic diabetic patients than in control subjects. We conclude that in type I diabetic patients, the ability of the endogenous opioid system to respond to exercise-induced stress is impaired under hyperglycemic and even under normoglycemic conditions. Considering the effect of endogenous opioids on stress tolerance, such changes may compromise exercise performance in diabetic patients.

The feasibility of nasal continuous positive airway pressure (CPAP) for heavy snoring associated with daytime sleepiness was studied in 118 consecutive patients with an apnea hypopnea index below 5. Fifty-nine of them reported daytime sleepiness in a questionnaire and were offered treatment with nasal CPAP. Whereas 48 patients refused it, the remaining 11 (19%) accepted nasal CPAP for home therapy. Acceptors and refusers did not differ in sleep structure, but acceptors had slightly more sleep-disordered breathing events per hour of sleep than refusers. The pressure needed to abolish snoring in these 11 patients was 7.3 +/- 1.6 cm H2O. Six months after prescription, the built-in time counters of the patients' devices were read. By dividing the hours of operation by the days since initiation of treatment, we found a mean daily use time of only 2.8 +/- 1.5 h. Nevertheless, eight patients (73%) reported that their sleepiness had improved with therapy. We conclude that only a minority of nonapneic snorers accept treatment with nasal CPAP on a long-term basis and that this subgroup is not predictable from polysomnography.

Cycle ergometer training plays an important role in the rehabilitation of patients with chronic obstructive pulmonary disease (COPD), but the usefulness of specific inspiratory muscle training as part of pulmonary rehabilitation remains uncertain. To determine whether inspiratory muscle training could intensify the known beneficial effects of cycle ergometer training on exercise performance in these patients, we compared the effect of an 8 week inspiratory muscle training combined with cycle ergometer training with that of an 8 week cycle ergometer training alone on inspiratory muscle performance and general exercise capacity. Patients were randomly assigned to the two training groups; 21 patients received additional inspiratory muscle training (Group 1) and 21 did not (Group 2). Maximal sniff assessed oesophageal and transdiaphragmatic pressures served as parameters for global inspiratory muscle strength and diaphragmatic strength, respectively. The duration for which the patient could breathe against a constant inspiratory pressure load was used as an index of inspiratory muscle endurance. Exercise capacity was determined by an incremental symptom-limited cycle ergometer test. After the training period, inspiratory muscle performance improved significantly in the patients with inspiratory muscle training, but not in those without. Both training regimens increased maximal power output and oxygen uptake, but this improvement was significantly greater in the patients with inspiratory muscle training than in those without.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of our study was to evaluate the effect of aminophylline on the contractile function of the human diaphragm during varying muscle fiber length. Ten healthy subjects were studied during maximal sniff maneuvers and bilateral phrenic nerve twitch stimulations, with and without intravenous infusion of aminophylline in a randomized fashion. The transdiaphragmatic pressures generated at various baseline lung volumes, from residual volume to 90% of total lung capacity, were recorded before and after the induction of diaphragm exhaustion. At all levels of lung volume, aminophylline did not have an effect on the contractility of the fresh diaphragm. In the exhausted diaphragm, however, the pressure values, induced by sniffs and twitch stimulations, were significantly improved by aminophylline. This positive effect on diaphragm contractility was also impressive at 60, 75, and 90% of total lung capacity. This indicates that aminophylline significantly improves the contractile function of the exhausted human diaphragm, even if the muscle fibers are shorter than optimal. This effect occurs regardless of the neuronal firing rate, whether it is low (twitch stimulation) or high (sniff maneuver).

Background: To date there are no data on the effects of lung transplantation on diaphragmatic function in patients with end stage chronic obstructive pulmonary disease (COPD). It is not known whether the relation between the transdiaphragmatic pressure (PDI) and lung volume is altered in recipients after transplantation as a result of changes in diaphragmatic structure caused by chronic hyperinflation. The effect of lung transplantation on diaphragmatic strength was determined in patients with COPD and the relation between postoperative PDI and lung volume analysed., Methods: Diaphragmatic strength was assessed in eight double lung transplant recipients, six single lung transplant recipients, and in 14 patients with COPD whose lung function was similar to those of the transplant recipients preoperatively. PDI obtained during unilateral and bilateral phrenic nerve stimulation at 1 Hz (twitch PDI) at functional residual capacity (FRC) and during maximal sniff manoeuvres (sniff PDI) at various levels of inspiratory vital capacity (VCin) served as parameters for diaphragmatic strength. Sniff PDI assessed at the various VCin levels were used to analyse the PDI/lung volume relation., Results: Lung transplantation caused a reduction in lung volume, especially in the double lung transplant recipients. As a consequence sniff PDI was higher in the double lung transplant recipients than in the patients with COPD at all levels of VCin analysed. However, sniff PDI values analysed at comparable intrathoracic gas volumes were not reduced in the patients with COPD when compared with those who underwent lung transplantation. Bilateral twitch PDI values were similar in the patients with COPD and in the lung transplant recipients. In the single lung transplant recipients unilateral twitch PDI values were similar on the transplanted and the non-transplanted side. The relation between PDI and lung volume was similar in the patients with COPD and in the lung transplant recipients., Conclusions: In patients with COPD lung transplantation leads to an increase the maximal sniff induced PDI values by placing the diaphragm in a more favourable position for pressure generation. Since patients with COPD and postoperative lung transplant recipients showed similar PDI/lung volume relations, this suggests that chronic pulmonary hyperinflation does not cause major functional alterations of the diaphragm.

Purpose: The aim of this study was to assess the usefulness of a specific inspiratory muscle training in Duchenne muscular dystrophy (DMD)., Patients and Methods: Fifteen patients with DMD started 6 months of training the inspiratory muscles and 15 patients served as a control group. Pulmonary and inspiratory muscle function parameters were assessed 3 months before and at the beginning of training, in the first and third month of training, at the end, and 6 months after its cessation. Maximal sniff assessed esophageal and transdiaphragmatic pressure values served as indices for global inspiratory muscle strength and diaphragmatic strength, respectively. Inspiratory muscle endurance was assessed by the length of time a certain inspiratory task could be maintained., Results: In 10 of the 15 patients, respiratory muscle function parameters improved significantly after 1 month of training. Further improvements were to be seen after 3 and after 6 months. Even 6 months after the end of training, those effects remained to a large extent. In the other five patients, there was no such improvement after 1 month of training, which was therefore discontinued. All these five patients had vital capacity values of less than 25 percent predicted and/or PaCO2 values of more than 45 mm Hg. The 15 control patients had no significant change in their respiratory muscle function parameters., Conclusion: We conclude that a specific inspiratory muscle training is useful in the early stage of DMD.

We investigated 8 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) for diaphragmatic strength and the neuromechanical efficiency of the diaphragm while the abdomen was filled with dialysate and while it was empty. Maximum transdiaphragmatic pressure (Pdimax) served as parameter for diaphragmatic strength; diaphragmatic efficiency was assessed by simultaneously monitoring transdiaphragmatic pressure (Pdi) and diaphragmatic electromyogram (EMGdi) during room-air breathing and hyperoxic CO2-rebreathing. After instilling dialysate, Pdimax increased from 76.7 +/- 12.1 cmH2O to 92.2 +/- 16.3 cmH2O (P < 0.05). While the slopes of the regression lines relating minute ventilation (VE) to arterial CO2 tension, and the change in VE for a given change in Pdi during hypercapnic rebreathing were similar in both states, the slope of EMGdi vs Pdi was significantly steeper when the abdomen was filled (P < 0.05). The increase in Pdimax observed in the filled state may suggest an adaptive rightward shift in the diaphragm's force-length relationship in CAPD patients, although this mechanism is insufficient to prevent a reduction of neuromechanical efficiency of the diaphragm.

To investigate the activity of the endogenous opioid system in patients with insulin-dependent diabetes mellitus during ventilatory stress situations, we measured plasma beta-endorphin levels in six male and five female diabetic patients breathing against fatiguing inspiratory resistive loads. The patients had to generate with each inspiration an esophageal pressure (Pes) 80% of maximum until they were exhausted and could no longer develop target Pes. The loaded breathing run was repeated three times with a 1-min interval between each run. Duty cycle, tidal volume, and breathing frequency were constant in all tasks. For each run plasma beta-endorphin levels were measured, inspiratory effort sensation assessed using a modified Borg scale, and inspiratory muscle endurance evaluated by the length of time the task could be maintained (Tlim). A group of 11 sex-, age-, height-, and weight-matched healthy individuals served as control subjects. Tlim was significantly lower in the diabetic patients. Evaluating respiratory effort during the three test runs in control subjects at a time corresponding to the break point of loaded breathing in patients showed significantly lower Borg ratings in the control group than in the patient group. Baseline plasma beta-endorphin was significantly lower in the diabetic patients (10.6 +/- 2.1 versus 27.0 +/- 4.2 pg/ml, p < 0.01). Additionally, whereas resistive loaded breathing caused a further increase in plasma beta-endorphin concentration in the control group (p < 0.005), absolutely no increase was found in the diabetic patients. We conclude that the endogenous opioid system in insulin-dependent diabetic patients does not respond to stress caused by breathing against fatiguing inspiratory resistive loads.

Inspiratory muscle performance, ventilation, and gas exchange were studied during exercise in healthy subjects to look for typical changes of pattern of contraction at the ventilatory threshold (VT). The steepening of the slope of carbon dioxide output (VCO2) vs oxygen uptake (VO2) at the VT was accompanied by a nonlinear increase of the mean rate of esophageal pressure development (Pes/TI) vs the esophageal pressure time index (PTIes) reflecting both the relative force (Pbreath/Pesmax) and duration (TI/TTOT) required for inspiration. The esophageal pressure time integral within one breath (Pbreath.dTI) was one of the best single predictors of the ventilatory equivalent for oxygen (VE/VO2) at the VT. Moreover, we presented inspiratory muscle load indices as a mirror image of breathing pattern, with the obvious advantage that the ventilation component can be compared with better established methods of presenting ventilatory output. Inspiratory muscle performance during exercise should link the increased metabolic rate to ventilatory output. We conclude that 1) there exists an inspiratory muscle threshold that is well correlated to commonly used gas exchange thresholds, and 2) the efficiency of ventilation and gas exchange during exercise could be linked to pressure and timing of inspiratory muscle contraction.

Rehabilitation programmes in chronic obstructive pulmonary disease (COPD) require exercise training above the anaerobic threshold. However, not all COPD patients develop metabolic acidosis during exercise. The hypothesis of this study was that non-exercise variables, characterizing the mechanical load on the inspiratory muscles during breathing at rest, can be used to reliably predict which patients with COPD are not able to develop metabolic acidosis during exercise. Thirty participants with COPD performed a symptom-limited cycle ergometer test. The oesophageal pressure/time index (PTIoes: the product of pressure magnitude and duration), the mean rate of pressure development during inspiration (Poes/TI), and the mean airway resistance (Raw)/maximal oesophageal pressure (Poesmax) ratio served as indices for the mechanical load on the inspiratory muscles. The oxygen uptake (VO2) at which plasma standard bicarbonate was seen to decrease from its baseline value was taken as the anaerboic threshold (AT). Mean Raw was significantly higher in those patients in whom the AT could not be detected. No other lung function parameters measured at rest allowed the accurate selection of those patients who did or did not develop exercise metabolic acidosis. On the other hand, Raw/Poesmax, PTIoes and Poes/TI were significantly different in the two patient groups. Additionally, whereas in the patient group with identifiable AT exercise hyperpnoea produced a non-linear increase of Poes/TI with respect to PTIoes above the AT, in the patient group without identifiable AT there was a linear relationship between Poes/TI and PTIoes throughout exercise. We conclude that the determination of inspiratory muscle load indices at rest may be useful in pulmonary rehabilitation programmes, for identifying those patients with COPD who do not develop exercise induced metabolic acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of opioids on inspiratory muscle function under high mechanical load is still unknown. Even less clear is the extent to which opioids influence the shift of the electromyographic power spectrum of the inspiratory muscles to lower frequencies during ventilatory stress. We studied seven healthy subjects breathing against high inspiratory threshold loads until exhaustion while keeping the minute ventilation constantly high. We compared runs with and without administration of 0.2 mg kg-1 of morphine sulphate intramuscularly; two subjects were given 30 mg morphine sulphate so that we could study the effect of higher opioid concentration. The endurance time (Tlim), the diaphragmatic electromyogram (EMG), the transdiaphragmatic pressures (Pdi) and the ventilatory effort sensation were analysed. Morphine did not have any effect on Tlim or on the effort sensation elicited by the inspiratory resistance in both concentrations. Analysing the spectral shifts of the diaphragmatic EMG, we did not find any significant difference in the decrease of the centroid frequency between drug and control runs. Furthermore, the activation pattern of the diaphragm and the intercostal muscles, evaluated from the percentage contribution of oesophageal and gastric pressures on the transdiaphragmatic pressure swings, did not change following the administration of morphine. Our study shows that morphine does not change the function of the inspiratory muscles during high-resistive breathing. Morphine does not affect the electromyographic power spectrum of the diaphragm during those resistive breathing runs, either. This points out that during stressful ventilatory situations, the shift of the electromyographic power spectrum is attributed to a peripheral (muscular) event consequent to muscle fatigue and not to the elaboration of endogenous opioids.

To estimate reliability of self-reported compliance with nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA), we studied 63 OSA patients aged 53.7 +/- 1.2 years (mean +/- SEM) with an apnea hypopnea index (AHI) of 50.8 +/- 2.9 and lowest sleep SaO2 of 65.6 +/- 2.3 percent receiving nasal CPAP for 539 +/- 44 days. During a follow-up polysomnography (PSG) on the pressure prescribed for home therapy (10.3 +/- 0.3 cm H2O), the hours of operation shown on the built-in time counter of the patients' devices were read to determine objective compliance by dividing the run time by the days since initiation of therapy. This parameter was compared with subjective compliance reported in a self-administered questionnaire. Mean measured use time was 4.9 +/- 0.3 h per night, whereas reported daily use time calculated from reported nights a week and hours a night was 6.1 +/- 0.3 h per night. As predominantly patients with poor compliance misestimated daily use time, we conclude that self-reports are unable to distinguish between compliant and noncompliant patients.

Background: The high prevalence of obstructive sleep apnoea (OSA) in patients with systemic hypertension and of hypertension in patients with OSA suggests a causal link between the two disorders. This study was carried out to determine whether nasal continuous positive airway pressure (CPAP) and weight loss affect daytime hypertension in OSA., Methods: Sixty hypertensive patients with OSA took part in the study; 33 accepted nasal CPAP and used their machine for 5.7 (0.2) hours per night, and the remaining 27 patients refused nasal CPAP and upper airway surgery so the only therapeutic intervention was a recommendation of weight loss. A significant change in hypertension during follow up was defined as either a change in mean blood pressure of at least 10 mm Hg (or more than 8%) without a change in drug treatment, or a reduction in drug dosage with mean blood pressure within these limits. Weight loss was defined as a body mass index of at least 5% below the baseline value., Results: After 512 (41) days, hypertension had become less severe in seven of 12 patients (58%) treated with weight loss only, in eight of 28 patients (29%) with nasal CPAP only, in two of five patients with nasal CPAP and weight loss, and in one of 15 patients without nasal CPAP or weight loss. Multivariate analysis of variance with the outcome of hypertension at follow up as the dependent variable revealed that only the percentage change in body mass index significantly contributed to the course of hypertension., Conclusion: The course of hypertension in OSA is more closely linked to weight loss than to elimination of sleep apnoea by nasal CPAP.

The ventilatory response to hyperoxic progressive hypercapnia was examined by comparing 3 test groups: 7 diabetic patients with AN, 8 diabetic patients without AN, and 8 normal control subjects. In each group, a significant linear correlation was found between PaCO2 and VE. The slopes of the regression curves relating PaCO2 to VE were significantly steeper in the healthy control subjects and diabetic patients without AN than in those with AN (P < 0.01). We conclude that the ventilatory response to progressive hypercapnia is reduced in diabetic patients with AN. By analyzing the power spectrum and the amplitude behavior of the diaphragmatic EMG (calculated from the fc and RMS, respectively), we could exclude a disturbance of neural descending pathways and respiratory muscle dysfunction as possible causal mechanisms for the impaired ventilatory response to increasing CO2. By using lung function analysis, causal factors such as alterations in respiratory system mechanics also could be excluded. As diabetes is known to affect the endogenous opioid system, which, in turn, affects the ventilatory response to CO2, naloxone, as a specific opioid antagonist, was administered in all 3 test groups. Naloxone produced a significant increase of ventilatory response to hypercapnia in the healthy control subjects (P < 0.01), but produced no effect in either of the diabetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to evaluate the difference between Type 1 (insulin-dependent) diabetic patients and healthy control subjects regarding inspiratory muscle load during exercise hypernea. For this purpose an incremental progressive exercise test on a cycle ergometer was performed by 36 Type 1 diabetic patients and 40 healthy subjects. In order to determine the mechanical load on the inspiratory muscles breath by breath, we selected the following two parameters, which represent the pressure generated by the inspiratory muscles as well as the duration and velocity of their contraction: (1) the oesophageal tension time index, which is the product of the duty cycle (ratio of inspiratory time to total breath cycle duration) and the mean oesophageal pressure expressed as a percentage of the maximal oesophageal pressure and (2) the mean oesophageal pressure change per time unit during the inspiratory phase of each breathing manoeuver, which is expressed as a fraction of the subject's maximal oesophageal pressure. Comparison of the two groups revealed that at similar levels of ventilation the mechanical load on the inspiratory muscles was significantly higher in the Type 1 diabetic patients than in the control subjects. When the loading was stopped the maximal ventilation was lower in the patients. Nevertheless, they reported a degree of respiratory effort sensation comparable to the control group, which seems to have been caused by an increase of the mechanical load on the ventilatory muscles.

In order to investigate pulmonary gas exchange and cardiopulmonary performance in Type 1 diabetes, 36 patients underwent a progressive incremental exercise test on a cycle ergometer. Cardiopulmonary variables were measured, and arterial blood gases determined on samples obtained from an indwelling catheter in the radial artery. The results were compared with those from 40 control subjects. In the patients, the maximum power (Wmax) and maximum oxygen uptake (VO2max) were lower than in the control subjects (Wmax 186 +/- 52 (+/- SD) vs 233 +/- 48 W, p less than 0.05; VO2max 2.56 +/- 0.71 vs 3.17 + 0.77 l min-1, p less than 0.05). At comparable levels of power output, however, no significant abnormality was observed in the difference between alveolar and arterial oxygen pressure (P(A-a)O2), and the ratio of physiological dead space to tidal volume (VD/VT ratio). These data indicate that in Type 1 diabetic patients, despite their reduced maximum oxygen uptake, gas transfer during exercise is not limited and thus does not contribute to the impairment of exercise capacity.

The aim of our study was to examine the effect of posture on inspiratory muscle activity response to hypercapnia. Recent research has revealed that in normal subjects the activation of the rib cage muscles and of the diaphragm is actually greater in the upright than in the supine position during resting tidal breathing. In this study we examined whether the upright position necessarily entails a greater activation of the inspiratory muscles also under conditions of ventilatory stress. For this purpose we compared the responses to CO2-rebreathing in the supine and sitting positions in five volunteers, by simultaneously recording the electromyogram of the diaphragm (EMGdi) and the intercostal muscles (EMGint). The electromyogram was recorded by means of surface electrodes to measure the EMG amplitude. While the slopes of ventilatory (VE) response to increasing arterial CO2 tension (PaCO2) were similar in the two positions, both the EMGdi-VE and EMGint-VE relationship showed steeper slopes in the supine than in the sitting position. In each CO2 run the increases in EMGdi were linearly related to those in EMGint. This relationship was not affected by the body position. These results suggested that, in spite of similar ventilatory responses to CO2-rebreathing in the lying and sitting positions, the supine position, in humans, required a higher activation of the inspiratory muscles.

Phrenic nerve latency was studied in 14 male type 1 diabetic patients with impaired diaphragm function and in 14 healthy control subjects. The diabetics showed significantly decreased values regarding inspiratory vital capacity and forced volume in 1 s compared with the control subjects. All other lung function parameters were similar in both groups. Although motor and sensory nerve conduction studies provided evidence for peripheral neuropathy in all patients, phrenic nerve latencies turned out to be normal. These results rule out a neuropathic disorder of the phrenic nerve. Thus, impaired diaphragm function in type 1 diabetic patients is not caused by phrenic neuropathy.

An incremental cycle ergometer test performed with a total of 40 healthy subjects (25 male, 15 female) was used to study the mechanical load on the ventilatory muscles. The parameters for the mechanical load on the ventilatory muscles are the time integral of the oesophageal pressure and the mean oesophageal pressure change per time unit (dPoe/dTI) of each breathing manoeuvre. The pressure-time integral is the area delimited by the oesophageal pressure trace and the inspiratory time axis. It is expressed as a fraction of the product of the subject's maximum oesophageal pressure (Poe(max)) and total breath cycle duration (TTOT). This parameter is called oesophageal tension time index (TTIoe). The relationship between minute ventilation and these two parameters during ergometer test showed gender-specific variations because of the differences between men and women as to anthropometric data, lung function parameters and maximum ventilatory muscle strength. Moreover, the dPoe/dTI values significantly depend on the breathing frequency. The present study has provided evidence that, in general, the TTIoe and dPoe/dTI values in terms of a specific minute ventilation (VE) are higher in women than in men. Parameters for the mechanical load on the ventilatory muscles regarding the level of pressure to be generated as well as the duration and velocity of muscle contraction should therefore also allow for the gender of the patients.

The study examined pulmonary function parameters of 36 patients with insulin-dependent diabetes mellitus and analyzed their inspiratory muscle performance. The control group consisted of 40 healthy reference persons of a sex ratio, age, height, and weight distribution similar to those of the patients. The pulmonary function test included the measurement of the lung volumes and the maximal expiratory flow-volume curves. The values of maximal sniff esophageal (Pes) and transdiaphragmatic pressures (Pdi) were used as parameters for global inspiratory muscle strength and diaphragm strength, respectively. The 12-s maximum voluntary ventilation (MVV) test supplied the parameter of inspiratory muscle endurance. The diabetic patients showed a highly significant decreased value for their inspiratory vital capacity (VCin) compared with that of the control subjects (4.75 +/- 0.84 versus 5.36 +/- 1.37 L; p less than 0.01). Inspiratory muscle performance in the diabetic patients was also restricted. Sniff Pes was significantly lower in the diabetic group (p less than 0.05); sniff Pdi (p less than 0.01) and MVV (p less than 0.05) were also low. The results did not correlate with either the duration of diabetes or the quality of metabolic control measured by glycosylated hemoglobin concentration. The reduction of VCin in diabetic patients may have been caused partly by the reduced capacity of the inspiratory muscles.