Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial.

BACKGROUND: Sleep hypoventilation has been proposed as a cause of progressive hypercapnic respiratory failure and death in patients with severe chronic obstructive pulmonary disease (COPD). A study was undertaken to determine the effects of nocturnal non-invasive bi-level pressure support ventilation (NIV) on survival, lung function and quality of life in patients with severe hypercapnic COPD. METHOD: A multicentre, open-label, randomised controlled trial of NIV plus long-term oxygen therapy (LTOT) versus LTOT alone was performed in four Australian University Hospital sleep/respiratory medicine departments in patients with severe stable smoking-related COPD (forced expiratory volume in 1 s (FEV1.0) <1.5 litres or <50% predicted and ratio of FEV1.0 to forced vital capacity (FVC) <60% with awake arterial carbon dioxide tension (PaCO2) >46 mm Hg and on LTOT for at least 3 months) and age <80 years. Patients with sleep apnoea (apnoea-hypopnoea index >20/h) or morbid obesity (body mass index >40) were excluded. Outcome measures were survival, spirometry, arterial blood gases, polysomnography, general and disease-specific quality of life and mood. RESULTS: 144 patients were randomised (72 to NIV + LTOT and 72 to LTOT alone). NIV improved sleep quality and sleep-related hypercapnia acutely, and patients complied well with therapy (mean (SD) nightly use 4.5 (3.2) h). Compared with LTOT alone, NIV (mean follow-up 2.21 years, range 0.01-5.59) showed an improvement in survival with the adjusted but not the unadjusted Cox model (adjusted hazard ratio (HR) 0.63, 95% CI 0.40 to 0.99, p = 0.045; unadjusted HR 0.82, 95% CI 0.53 to 1.25, p = NS). FEV1.0 and PaCO2 measured at 6 and 12 months were not different between groups. Patients assigned to NIV + LTOT had reduced general and mental health and vigour. CONCLUSIONS: Nocturnal NIV in stable oxygen-dependent patients with hypercapnic COPD may improve survival, but this appears to be at the cost of worsening quality of life. TRIAL REGISTRATION NUMBER: ACTRN12605000205639.

Effects of moderate sleep deprivation and low-dose alcohol on driving simulator performance and perception in young men.

STUDY OBJECTIVE: To determine the combined effects of sleep restriction and low-dose alcohol on driving simulator performance, EEG, and subjective levels of sleepiness and performance in the mid-afternoon. DESIGN: Repeated measures with 4 experimental conditions. Normal sleep without alcohol, sleep restriction alone (4 hours) and sleep restriction in combination with 2 different low blood alcohol concentrations (0.025 g/dL and 0.035 g/dL). SETTING: Sleep Laboratory, Adelaide Institute for Sleep Health. PARTICIPANTS: Twenty-one healthy young men, aged 18-30 years, mean (+/-SD) = 22.5(+/-3.7) years, BMI = 25(+/-6.7) kg/m2; all had normal sleep patterns and were free of sleep disorders. MEASUREMENTS: Participants completed a 70-minute simulated driving session, commencing at 14:00. Driving parameters included steering deviation, braking reaction time, and number of collisions. Alpha and theta EEG activity and subjective driving performance and sleepiness were also measured throughout the driving task. RESULTS: All measures were significantly affected by time. Steering deviation increased significantly when sleep restriction was combined with the higher dose alcohol. This combination also resulted in a significant increase in alpha/theta EEG activity throughout the drive, as well as greater subjective sleepiness and negative driving performance ratings compared to control or sleep restriction alone. DISCUSSION: These data indicate that combining low-dose alcohol with moderate sleep restriction results in significant decrements to subjective alertness and performance as well as to some driving performance and EEG parameters. This highlights the potential risks of driving after consumption of low and legal doses of alcohol when also sleep restricted.

Sleep hypoventilation in hypercapnic chronic obstructive pulmonary disease: prevalence and associated factors.

Sleep hypoventilation (SH) may be important in the development of hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD). The prevalence of SH, associated factors, and overnight changes in waking arterial blood gases (ABG), were assessed in 54 stable hypercapnic COPD patients without concomitant sleep apnoea or morbid obesity. Lung function assessment, anthropomorphic measurements, and polysomnography with ABG measurement before and after sleep were conducted in all patients. Transcutaneous carbon dioxide tension (Pt,CO2) was measured in sleep, using simultaneous arterial carbon dioxide tension (Pa,CO2) for in vivo calibration and to correct for drift in the sensor. Of the patients, 43% spent > or = 20% of sleep time with Pt,CO2 > 1.33 kPa (10 mmHg) above waking baseline. Severity of SH was best predicted by a combination of baseline Pa,CO2, body mass index and per cent rapid-eye movement (REM) sleep. REM-related hypoventilation correlated significantly with severity of inspiratory flow limitation in REM, and with apnoea/hypopnoea index. Pa,CO2 increased mean+/-SD 0.70+/-0.65 kPa (5.29+/-4.92 mmHg) from night to morning, and this change was highly significant. The change in Pa,CO2 was strongly correlated with severity of SH. Sleep hypoventilation is common in hypercapnic chronic obstructive pulmonary disease, and related to baseline arterial carbon dioxide tension, body mass index and indices of upper airway obstruction. Sleep hypoventilation is associated with significant increases in arterial carbon dioxide tension night-to-morning, and may contribute to long-term elevations in arterial carbon dioxide tension.

Long-term facilitation of ventilation is not present during wakefulness in healthy men or women.

Obstructive sleep apnea (OSA) is more common in men than in women for reasons that are unclear. The stability of the respiratory controller has been proposed to be important in OSA pathogenesis and may be involved in the gender difference in prevalence. Repetitive hypoxia elicits a progressive rise in ventilation in animals [long-term facilitation (LTF)]. There is uncertainty whether LTF occurs in humans, but if present it may stabilize respiration and possibly also the upper airway. This study was conducted to determine 1) whether LTF exists during wakefulness in healthy human subjects and, if so, whether it is more pronounced in women than men and 2) whether inspiratory pump and upper airway dilator muscle activities are affected differently by repetitive hypoxia. Twelve healthy young men and ten women in the luteal menstrual phase were fitted with a nasal mask and intramuscular genioglossal EMG (EMGgg) recording electrodes. After 5 min of rest, subjects were exposed to ten 2-min isocapnic hypoxic periods (approximately 9% O(2) in N(2), arterial O(2) saturation approximately 80%) separated by 2 min of room air. Inspired minute ventilation (Vi) and peak inspiratory EMGgg activity were averaged over 30-s intervals, and respiratory data were compared between genders during and after repetitive hypoxia by using ANOVA for repeated measures. Vi during recovery from repetitive hypoxia was not different from the resting level and not different between genders. There was no facilitation of EMGgg activity during or after repetitive hypoxia. EMGgg activity was reduced below baseline during recovery from repetitive hypoxia in women. In conclusion, we have found no evidence of LTF of ventilation or upper airway dilator muscle activity in healthy subjects during wakefulness.

Effect of CPAP on intrinsic PEEP, inspiratory effort, and lung volume in severe stable COPD.

BACKGROUND: Intrinsic positive end expiratory pressure (PEEPi) constitutes an inspiratory threshold load on the respiratory muscles, increasing work of breathing. The role of continuous positive airway pressure (CPAP) in alleviating PEEPi in patients with severe stable chronic obstructive pulmonary disease is uncertain. This study examined the effect of CPAP on the inspiratory threshold load, muscle effort, and lung volume in this patient group. METHODS: Nine patients were studied at baseline and with CPAP increasing in increments of 1 cm H(2)O to a maximum of 10 cm H(2)O. Breathing pattern and minute ventilation (I), dynamic PEEPi, expiratory muscle activity, diaphragmatic (PTPdi/min) and oesophageal (PTPoes/min) pressure-time product per minute, integrated diaphragmatic (EMGdi) and intercostal EMG (EMGic) and end expiratory lung volume (EELV) were measured. RESULTS: Expiratory muscle activity was present at baseline in one subject. In the remaining eight, PEEPi was reduced from a mean (SE) of 2.9 (0.6) cm H(2)O to 0.9 (0.1) cm H(2)O (p<0.05). In two subjects expiratory muscle activity contributed to PEEPi at higher pressures. There were no changes in respiratory pattern but I increased from 9.2 (0.6) l/min to 10.7 (1.1) l/min (p<0.05). EMGdi remained stable while EMGic increased significantly. PTPoes/min decreased, although this did not reach statistical significance. PTPdi/min decreased significantly from 242.1 (32.1) cm H(2)O.s/min to 112.9 (21.7) cm H(2)O.s/min). EELV increased by 1.1 (0.3) l (p<0.01). CONCLUSION: High levels of CPAP reduce PEEPi and indices of muscle effort in patients with severe stable COPD, but only at the expense of substantial increases in lung volume.

Genioglossus muscle activity at rest and in response to brief hypoxia in healthy men and women.

Obstructive sleep apnea (OSA) is more common in men than in women for reasons that are not clearly understood. An underlying difference between men and women in the respiratory-related neural control of upper airway dilator muscles has been suggested as a possible reason for the gender difference. We have compared three aspects of upper airway dilator muscle function in healthy men and women: 1) resting inspiratory genioglossus electromyogram (EMGgg) activity, 2) the respiratory EMGgg "afterdischarge" after a brief hypoxic stimulus, and 3) the relationship between the EMGgg and pharyngeal airway pressure. Inspired minute ventilation (VI), epiglottic pressure (P(epi)), and EMGgg and diaphragm EMG (EMGdi) activity were measured in 24 subjects (12 men, 12 women in the luteal menstrual phase) and were compared between genders while lying supine awake. Every 7-8 min over 2 h, subjects were exposed to 45-s periods of isocapnic hypoxia (9% O(2) in N(2)) that were abruptly terminated with one breath of 100% O(2). The relationship between P(epi) and EMGgg activity was also compared between genders. The results of 117 trials with satisfactory end-tidal PCO(2) control and no sighs or swallows are reported. There was no gender difference in the resting level of peak inspiratory EMGgg [3.7 +/- 0.8 (women) vs. 3.2 +/- 0.6% maximal activity (men)]. Repeated-measures ANOVA showed no gender or gender-by-time interaction effect between men and women in VI or EMGgg or EMGdi activity during or after the hypoxic stimulus. The relationship between P(epi) and EMGgg was not different between men (slope -0.63 +/- 0.20) and women (slope -0.69 +/- 0.33). These results do not support the hypothesis that the higher prevalence of OSA in men is related to an underlying gender difference in respiratory neural control of upper airway dilator muscles.

No difference in net uptake or disposal of lactate by trained and untrained forearms during incremental sodium lactate infusion.

A number of training adaptations in skeletal muscle might be expected to enhance lactate extraction during hyperlactataemia. The aim of the present study was to determine whether resting endurance-trained forearms exhibit an increased net lactate removal during hyperlactataemia. Six racquet-sport players attended the laboratory for two experiments, separated by 2 weeks. In the first experiment incremental handgrip exercise to fatigue was performed to identify trained (TRFA, n = 6) and untrained (UTFA, n = 5) forearms. In the second experiment net forearm lactate exchange was compared between TRFA and UTFA during an incremental infusion of sodium lactate. TRFA performed more work than UTFA during handgrip exercise [mean (SE) TRFA, 66.1 (9.5) J.100 ml(-1); UTFA, 35.1 (2.3) J.100 ml(-1); P = 0.02] and UTFA exhibited a greater increase in net lactate output relative to work load (P = 0.003). During lactate infusion net lactate uptake across the resting forearms increased linearly with the arterial lactate concentration in both groups (TRFA, r = -0.95 (0.03); UTFA, r= -0.92 (0.04); P < 0.02], with no difference in the regression slopes [TRFA, -1.06 (0.13); UTFA, -1.07 (0.27); P = 0.97] or y-intercepts [TRFA, 0.67 (0.20); UTFA, 1.36 (0.67); P = 0.37] between groups. Almost all of the lactate taken up was disposed of by both groups of forearms [TRFA, 99.6 (0.2)%; UTFA, 98.5 (1.0)%; P = 0.37]. It was concluded that the net uptake and removal of lactate by resting skeletal muscle is a function of the concentration of lactate in the blood perfusing the muscle rather than the muscle training status.

Acute cardiovascular responses to arousal from non-REM sleep during normoxia and hypoxia.

STUDY OBJECTIVES: There is uncertainty concerning the relative contribution of arousal, chemoreceptor stimulation, and their potentially interactive effects, to the acute cardiovascular changes observed during sleep in patients with sleep-disordered breathing. The purpose of this study was to compare cardiovascular responses (heart rate, skin blood flow, and pulse transit time, a non-invasive measure of arterial wall stiffness) to auditory induced arousal from stage 2 sleep under conditions of normoxia and overnight mild hypoxia. DESIGN: Randomised crossover. SETTING: Sleep Disorders Unit in a 270-bed teaching hospital. PARTICIPANTS: Eleven healthy male subjects. INTERVENTIONS: Subjects slept wearing a facemask and breathed room air (one night; SaO2 approximately 98%) or an hypoxic gas mixture (two nights; SaO2 approximately 92%). Once in stage 2 sleep, subjects were administered one of 10 auditory tones (500 Hz, range 54-90 dB, 5-sec duration) via earphones or a sham tone (recording with no tone). MEASUREMENTS AND RESULTS: Cardiovascular responses were examined beat-by-beat for 20 seconds before and 30 seconds after auditory tones associated with arousals (3-10 second EEG changes) and after sham tones. Sleep efficiency and the percentage of sleep spent in each stage were not different between hypoxia and normoxia nights. Baseline heart rate was elevated on hypoxia nights compared with normoxia nights (59.5+/-1.7 vs. 54.4+/-1.6 b x min(-1), p=0.007). Heart rate, pulse transit time, and skin blood flow showed significant changes after arousal consistent with rapid parasympathetic withdrawal and sympathetic nervous system activation. No changes were observed after sham tones. There were no differences in time course or magnitude of cardiovascular responses between hypoxia and normoxia nights. CONCLUSIONS: We conclude that while mild hypoxia stimulates autonomic activity it does not augment the cardiovascular response to arousal from stage 2 sleep in normal subjects.

Ventilatory decline after hypoxia and hypercapnia is not different between healthy young men and women.

The gradual decay in ventilation after removal of a respiratory stimulus has been proposed to protect against cyclic breathing disorders such as obstructive sleep apnea (OSA). The male predominance of OSA, and the increased incidence of OSA in women after menopause, indicates that the respiratory-stimulating effect of progesterone may provide protection against OSA by altering the rate of poststimulus ventilatory decline (PSVD). It was therefore hypothesized that PSVD is longer in premenopausal women than in men and is longer in the luteal menstrual phase compared with the follicular phase. PSVD was measured in 12 men and in 11 women at both their luteal and follicular phases, after cessation of isocapnic hypoxia and normoxic hypercapnia. PSVD was compared between genders and between women in the luteal and follicular phases by repeated-measures ANOVA. There were no significant differences in PSVD between any of the groups after either respiratory stimulus. This suggests that the higher occurrence of OSA in men does not reflect an underlying gender difference in PSVD and implies the increased prevalence of OSA in women after menopause is not representative of an effect of progesterone on PSVD.

Automated VO2max calibrator for open-circuit indirect calorimetry systems.

The complete calibration of indirect calorimetry systems involves simultaneous checks of gas analyzers, volume device, and software, and this requires a machine that can mimic accurately and precisely the ventilation and expired gases of an athlete. While previous calibrators have been built successfully, none have matched the ventilatory flows produced by athletes during high intensity exercise. A calibrator able to simulate high aerobic power (VO2max calibrator) was fabricated and tested against conventional indirect calorimetry systems that use chain-compensated gasometers to measure expired volume (VE systems) and calibrated electronic gas analyzers. The calibrator was also checked against a system that measures inspired volume (VI system) with a turbine ventilometer. The pooled data from both VE and VI systems for predicted VO2 ranging from 2.9 to 7.9 L.min-1 and ventilation ranging from 89 to 246 L.min-1 how that the absolute accuracy (bias) of values measured by conventional indirect calorimetry systems compared with those predicted by the calibrator was excellent. The bias was < 35 mL.min-1 for VO2 and carbon dioxide production, < 0.50 L.min-1 for ventilator (VE BTPS), -0.02% absolute for the percentage of expired O2 and +0.02% absolute for the percentage of expired CO2. Overall, the precision of the measured VO2, VCO2, and VE BTPS was approximately 1%. This VO2max calibrator is a versatile device that can be used for routine calibration of most indirect calorimetry systems that assess the ventilation and aerobic power of athletes.

Lactate kinetics in resting and exercising forearms during moderate-intensity supine leg exercise.

Arterial blood lactate was elevated by supine leg exercise (20 min at approximately 65% maximal oxygen uptake) in five untrained male subjects, and the contribution to blood lactate removal from passive uptake vs. metabolic disposal was compared in resting and lightly exercising (15% maximal voluntary contraction static handgrip) forearm skeletal muscle. An integrated form of the Fick equation was used to predict venous lactate levels resulting solely from passive equilibration of lactate between incoming arterial blood and the forearm muscles. In the resting forearm, predicted and measured venous lactate levels were closely correlated during the exercise period (r = 0.995, P < 0.001), indicating that lactate removal could be accounted for in terms of passive uptake alone. In the lightly exercising forearm, measured venous lactate levels were higher than both the arterial and predicted venous levels, indicating net lactate production. It was concluded that most of the blood lactate generated by moderate-intensity supine leg exercise is taken up passively and not metabolized by resting skeletal muscle and that the rate of lactate disposal is unlikely to be enhanced in lightly exercising muscle.

Lactate disposal in resting trained and untrained forearm skeletal muscle during high intensity leg exercise.

At a given oxygen uptake (VO2) and exercise intensity blood lactate concentrations are lower following endurance training. While decreased production of lactate by trained skeletal muscle is the commonly accepted cause, the contribution from increased lactate removal, comprising both uptake and metabolic disposal, has been less frequently examined. In the present study the role of resting skeletal muscle in the removal of an arterial lactate load (approximately 11 mmol.l-1) generated during high intensity supine leg exercise (20 min at approximately 83% maximal oxygen uptake) was compared in the untrained (UT) and trained (T) forearms of five male squash players. Forearm blood flow and the venoarterial lactate concentration gradient were measured and a modified form of the Fick equation used to determine the relative contributions to lactate removal of passive uptake and metabolic disposal. Significant lactate uptake and disposal were observed in both forearms without any change in forearm VO2. Neither the quantity of lactate taken up [UT, 344.2 (SEM 118.8) mumol.100 ml-1; T, 330.3 (SEM 85.3) mumol.100 ml-1] nor the quantity disposed of [UT, 284.0 (SEM 123.3) mumol.100 ml-1, approximately 83% of lactate uptake; T, 300.8 (SEM 77.7) mumol.100 ml-1, approximately 91% of lactate uptake] differed between the two forearms. It is concluded that while significant lactate disposal occurs in resting skeletal muscle during high intensity exercise the lower blood lactate concentrations following endurance training are unlikely to result from an increase in lactate removal by resting trained skeletal muscle.

Plasma volume, osmolarity, total protein and electrolytes during treadmill running and cycle ergometer exercise.

While haemoconcentration due to loss of plasma volume is well established during cycling, the existence of similar changes during running remains contentious. This study compared the changes in plasma volume and associated blood indices during 60 min of running and cycling at the same relative intensity (approximately 65% VO2max), with all changes referenced to blood indices obtained after 30 min seated at rest on a cycle ergometer. Plasma osmolarity increased similarly with both forms of exercise but was less than predicted for water loss alone, such that there was a net loss of sodium during exercise and of potassium postexercise, with essentially no loss of protein. Plasma volume decreased similarly (approximately 6.5%) in both exercise trials, but while that with cycling was initiated by exercise itself and was essentially maximal within 5 min, the reduction in plasma volume in the running trial was induced by adopting the upright posture and was complete before exercise began. These data would indicate that different mechanisms are responsible for the changes in plasma volume induced by running and cycling, while the similarity of change would suggest that there is a lower limit to any reduction in plasma volume, regardless of mechanism. Furthermore, the observation that the changes in plasma volume were complete before or early in exercise, would imply that oral water ingestion during prolonged exercise, which is essential for thermoregulation, may be more concerned with homeostasis of extravascular water rather than plasma volume.