Cardiovascular responses to orthostatic and other stressors in men and women are independent of sex.

1. Cardiovascular responses to the stress of orthostasis, forearm (FA) ischaemia (reactive hyperaemia) and FA exercise (postexercise hyperaemia) are well described. Although sex differences in responses to orthostatic stress have been reported, few studies have examined the impact of sex on reactive hyperaemia and none has commented with regard to postexercise hyperaemia. 2. We investigated 11 men (mean (+/-SEM) age 18.5 +/- 0.3 years) and 10 women (18.8 +/- 0.8 years), all of whom were sedentary, with women being studied in the mid-follicular phase of their menstrual cycle. We measured blood pressure (BP), heart rate (HR) and forearm blood flow (FBF) in response to a fixed sequence of orthostatic, ischaemic and exercise stressors. 3. Orthostatic stress (10 min at -50 mmHg lower body negative pressure; LBNP) induced presyncopal signs in one man and three women. In all other subjects, BP was well maintained, with FBF decreasing and HR increasing similarly in both sexes. The tachycardia was earlier in onset in men and reached significantly higher absolute levels in women during the final 5 min of LBNP, but the percentage changes and integrated responses of both HR and FBF were not different between sexes. 4. The increases in FBF following either 10 min FA ischaemia or 10 min FA exercise were similar in men and women in terms of peak blood flow, percentage change, rate of recovery and total blood flow response. 5. In conclusion, although women were less tolerant of orthostatic stress than men, the cardiovascular responses to this and the other stressors appeared essentially independent of sex.

Arterial hypoxaemia in endurance athletes is greater during running than cycling.

The effect of both training discipline and exercise modality on exercise-induced hypoxaemia (EIH) was examined in seven runners and six cyclists during 5 min high intensity treadmill and cycle exercise. There were no significant interactions between training discipline, exercise modality and arterial P(O(2)) (Pa(O(2))) when subject groups were considered separately but when pooled there were significant differences between exercise modalities. After min 2 of exercise arterial hydrogen ion concentration, minute ventilation, alveolar P(O(2)) (PA(O(2))) and Pa(O(2)) were all lower with treadmill running with the largest differential for the latter occurring at min 5 (treadmill, 80.8+/-1.8; cycle, 90.2+/-2.5, mmHg, N=13, P< or = 0.05). At every min of exercise, the differences in Pa(O(2)) between the ergometers were strongly associated with similar differences in PA(O(2)) and alveolar to arterial P(O(2)) (PA(O(2))-Pa(O(2))). It is concluded that the greater EIH with treadmill running is a consequence of the combined effect of a reduced lactic acidosis-induced hyperventilation and greater ventilation-perfusion inequality with this exercise mode.

Pulmonary gas exchange during exercise in highly trained cyclists with arterial hypoxemia.

The causes of exercise-induced hypoxemia (EIH) remain unclear. We studied the mechanisms of EIH in highly trained cyclists. Five subjects had no significant change from resting arterial PO(2) (Pa(O(2)); 92.1 +/- 2.6 Torr) during maximal exercise (C), and seven subjects (E) had a >10-Torr reduction in Pa(O(2)) (81.7 +/- 4.5 Torr). Later, they were studied at rest and during various exercise intensities by using the multiple inert gas elimination technique in normoxia and hypoxia (13.2% O(2)). During normoxia at 90% peak O(2) consumption, Pa(O(2)) was lower in E compared with C (87 +/- 4 vs. 97 +/- 6 Torr, P < 0.001) and alveolar-to-arterial O(2) tension difference (A-aDO(2)) was greater (33 +/- 4 vs. 23 +/- 1 Torr, P < 0. 001). Diffusion limitation accounted for 23 (E) and 13 Torr (C) of the A-aDO(2) (P < 0.01). There were no significant differences between groups in arterial PCO(2) (Pa(CO(2))) or ventilation-perfusion (VA/Q) inequality as measured by the log SD of the perfusion distribution (logSD(Q)). Stepwise multiple linear regression revealed that lung O(2) diffusing capacity (DL(O(2))), logSD(Q), and Pa(CO(2)) each accounted for approximately 30% of the variance in Pa(O(2)) (r = 0.95, P < 0.001). These data suggest that EIH has a multifactorial etiology related to DL(O(2)), VA/Q inequality, and ventilation.

Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptake.

A group of 15 competitive male cyclists [mean peak oxygen uptake, VO2peak 68.5 (SEM 1.5 ml x kg(-1) x min(-1))] exercised on a cycle ergometer in a protocol which began at an intensity of 150 W and was increased by 25 W every 2 min until the subject was exhausted. Blood samples were taken from the radial artery at the end of each exercise intensity to determine the partial pressures of blood gases and oxyhaemoglobin saturation (SaO2), with all values corrected for rectal temperature. The SaO2 was also monitored continuously by ear oximetry. A significant decrease in the partial pressure of oxygen in arterial blood (PaO2) was seen at the first exercise intensity (150 W, about 40% VO2peak). A further significant decrease in PaO2 occurred at 200 W, whereafter it remained stable but still significantly below the values at rest, with the lowest value being measured at 350 W [87.0 (SEM 1.9) mmHg]. The partial pressure of carbon dioxide in arterial blood (PaCO2) was unchanged up to an exercise intensity of 250 W whereafter it exhibited a significant downward trend to reach its lowest value at an exercise intensity of 375 W [34.5 (SEM 0.5) mmHg]. During both the first (150 W) and final exercise intensities (VO2peak) PaO2 was correlated significantly with both partial pressure of oxygen in alveolar gas (P(A)O2, r = 0.81 and r = 0.70, respectively) and alveolar-arterial difference in oxygen partial pressure (P(A-a)O2, r = 0.63 and r = 0.86, respectively) but not with PaCO2. At VO2peak PaO2 was significantly correlated with the ventilatory equivalents for both oxygen uptake and carbon dioxide output (r = 0.58 and r = 0.53, respectively). When both P(A)O2 and P(A-a)O2 were combined in a multiple linear regression model, at least 95% of the variance in PaO2 could be explained at both 150 W and VO2peak. A significant downward trend in SaO2 was seen with increasing exercise intensity with the lowest value at 375 W [94.6 (SEM 0.3)%]. Oximetry estimates of SaO2 were significantly higher than blood measurements at all times throughout exercise and no significant decrease from rest was seen until 350 W. The significant correlations between PaO2 and P(A)O2 with the first exercise intensity and at VO2peak led to the conclusion that inadequate hyperventilation is a major contributor to exercise-induced hypoxaemia.

Sleep apnoea related hypoxia is associated with cognitive disturbances in patients with tetraplegia.

Sleep disordered breathing is common in patients with tetraplegia. Nocturnal arterial hypoxemia and sleep fragmentation due to sleep apnoea may be associated with cognitive dysfunction. We therefore studied the influence of sleep disordered breathing on neuropsychological function in 37 representative tetraplegic patients (mean age 34 +/- 9.7 years). Thirty percent (11 of 37 patients) had clinically significant sleep disordered breathing, defined as apnoea plus hypopnoea index (AHI) greater than 15 per hour of sleep. Most apnoeas were obstructive in type. Seven patients (19%) desaturated to < 80% during the night. Neuropsychological variables were significantly correlated with measures of sleep hypoxia, but not with the AHI and the frequency of sleep arousals. The neuropsychological functions most affected by nocturnal desaturation were: verbal attention and concentration, immediate and short-term memory, cognitive flexibility, internal scanning and working memory. There appeared to be a weak association between the presence of severe sleep hypoxia and visual perception, attention and concentration but no association was found between sleep variables and depression scores. We concluded that sleep disordered breathing is common in patients with tetraplegia and may be accompanied with significant oxygen desaturation. The latter impairs daytime cognitive function in these patients, particularly attention, concentration, memory and learning skills. Cognitive disturbances resulting from sleep apnoea might adversely affect rehabilitation in patients with tetraplegia.

Tachykinins contribute to the acute airways response to allergen in sheep actively sensitized to Ascaris suum.

Tachykinins, found in sensory nerves, have effects in the airways which suggest that they may contribute to the pathogenesis of asthma. We aimed to find evidence for tachykinin involvement in the immediate airway response to allergen in a sheep model of experimental asthma. Twenty-four sheep were actively sensitized to Ascaris suum, then challenged with nebulized Ascaris extract in a dose-response fashion. Change in lung resistance (RL) in response to challenge was measured. Responder sheep (those with an increase in RL of > or = 100% over baseline) that had reproducible responses over three challenges were identified (n = 4 sheep) and a PC100 (number of breaths of extract required to induce a 100% increase in RL) was determined. The effect of the neutral endopeptidase inhibitor phosphoramidon, the NK-1 receptor-specific antagonist CP 96, 345 and capsaicin desensitization on the RL response to Ascaris challenge was then assessed. Administration of phosphoramidon before Ascaris decreased the PC100 to 31 +/- 7% of the PC100 seen with Ascaris alone (P < 0.05), whereas CP 96,345 and capsaicin desensitization increased the PC100 to 285 +/- 41% and 555 +/- 93% respectively (P < 0.05 for both). These findings suggest that endogenous tachykinins are released in response to allergen challenge and that they contribute to the immediate increase in RL.

Sleep apnoea in patients with quadriplegia.

BACKGROUND: This study was undertaken to establish the prevalence of, and the factors contributing towards, sleep disordered breathing in patients with quadriplegia. METHODS: Forty representative quadriplegic patients (time since injury > 6 months, injury level C8 and above, Frankel category A, B, or C; mean (SE) age 35.0 (1.7) years) had home sleep studies in which EEG, EOG, submental EMG, body movement, nasal airflow, respiratory effort, and pulse oximetry (SpO2) were measured. Patients reporting post traumatic amnesia of > 24 hours, drug or alcohol abuse or other major medical illness were excluded from the study. A questionnaire on medications and sleep was administered and supine blood pressure, awake SpO2, spirometric values, height, and neck circumference were measured. RESULTS: A pattern of sustained hypoventilation was not observed in any of the patients. Sleep apnoeas and hypopnoeas were, however, common. Eleven patients (27.5%) had a respiratory disturbance index (RDI, apnoeas plus hypopnoeas per hour of sleep) of > or = 15, with nadir SpO2 ranging from 49% to 95%. Twelve of the 40 (30%) had an apnoea index (AI) of > or = 5 and, of these, nine (75%) had predominantly obstructive apnoeas-that is, > 80% of apnoeas were obstructive or mixed. This represents a prevalence of sleep disordered breathing more than twice that observed in normal populations. For the study population RDI correlated with systolic and diastolic blood pressure and neck circumference. RDI was higher in patients who slept supine compared with those in other postures. Daytime sleepiness was a common complaint in the study population and sleep architecture was considerably disturbed with decreased REM sleep and increased stage 1 non-REM sleep. CONCLUSIONS: Sleep disordered breathing is common in quadriplegic patients and sleep disturbance is significant. The predominant type of apnoea is obstructive. As with non-quadriplegic patients with sleep apnoea, sleep disordered breathing in quadriplegics is associated with increased neck circumference and the supine sleep posture.

Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome.

To determine whether pulmonary hypertension (PH) can occur in obstructive sleep apnea syndrome (OSAS) in the absence of lung or primary cardiac disease, we studied 27 patients (26 males, mean age 49 +/- 10 yr) with OSAS (respiratory disturbance index [RDI] > 10 events/h) in whom clinically significant lung or cardiac diseases were excluded. Pulsed Doppler measurements of pulmonary hemodynamics, pulmonary function tests, arterial blood gas analysis, and polysomnography were performed. A total of 11 OSAS patients (41%) were found to have pulmonary hypertension. The levels of PH were relatively mild (Ppa < or = 26 mm Hg). There were no differences between PH and non-PH patients in body mass index (BMI), smoking history, or lung function. PH patients were more hypoxemic when awake than non-PH patients (PaO2 = 72.2 +/- 7.6 versus 77.6 +/- 7.3 mm Hg, respectively; p < 0.05) but did not differ in severity of sleep apnea (RDI = 51.9 +/- 25.1 versus 56.8 +/- 26.2 events/h, respectively; p = NS) or indices of sleep desaturation. The hypoxemia in PH patients could not be explained by impairment of lung function, greater body mass, or a higher prevalence of smoking, and PaO2 in the study population was significantly correlated with Ppa (r = -0.46, p < 0.02) but not with FEV1 or BMI. We conclude that lung disease is not a prerequisite for PH in OSAS.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia episodes during sleep in high tetraplegia.

To determine whether oxygen desaturation occurs during sleep in high tetraplegics, 10 neurologically stable male patients (aged 17 to 55 years) with complete motor lesions (C4 to C6) had continuous pulse oximetry recordings and sleep observations on two nights. The patients were studied during admissions for nonrespiratory problems (eg, pressure sores, urinary infection, respite). Lung function tests and daytime arterial blood gases were also measured. Mean forced vital capacity was 46% of predicted, but mean awake PaO2 and PaCO2 were normal (95.0 mmHg and 42.8 mmHg, respectively). Three subjects showed severe nocturnal oxygen desaturation spending greater than 10% of the time overnight with arterial oxyhaemoglobin saturation (SaO2) levels of less than 90%. For the group as a whole, the percentage of time spent under 90% SaO2 correlated with body mass index. Mean overnight SaO2 correlated inversely with body mass index and directly with maximal expiratory pressure, a measure of respiratory muscle strength. Low overnight SaO2 was also associated with higher levels of injury. The pattern of nocturnal oxygen desaturation observed was episodic and was suggestive of obstructive sleep apnoea during rapid eye movement (REM) sleep. Levels of nocturnal oxygen desaturation similar to those observed in the three most severely affected patients have been shown, in other disorders, to be associated with cognitive impairment, cardiovascular disease and increased mortality. Our results suggest up to a third of high tetraplegics may be at risk of potentially serious nocturnal hypoxic episodes.

Sleep fragmentation and ventilatory responsiveness to hypercapnia.

It has been postulated that sleep disruption may change ventilatory chemoresponsiveness to hypercapnia and hypoxia and thereby contribute to the development of respiratory failure in some patients with obstructive sleep apnea syndrome (OSAS) or with other respiratory disorders. Some studies have demonstrated a reduction in ventilatory chemoresponsiveness in normal subjects after one night of total sleep deprivation. However, sleep fragmentation rather than total sleep deprivation is usual in patients. In this study, therefore, we measured hypercapnic ventilatory responsiveness (HCVR) and spirometry in 13 healthy male subjects (18 to 30 yr of age) after two consecutive nights of severe sleep fragmentation (arousal to an auditory stimulus after each minute of sleep) and compared the results with those obtained in the same subjects after normal sleep. Sleep fragmentation and normal sleep were separated by a week, and the order of intervention was randomized from patient to patient. No significant differences were observed in the slope or position of the HCVR curve after sleep fragmentation or in forced expiratory volumes. Although it is possible that a more prolonged period of sleep fragmentation than that used in this study may have an effect on HCVR, the results suggest that sleep fragmentation is an unlikely cause of progressive respiratory failure in patients with OSAS or with other respiratory disorders.

Obligatory nasal breathing: effects on snoring and sleep apnoea.

OBJECTIVE: To test the effects on snoring and sleep disordered breathing of a dental prosthesis (Snore-No-More) which is designed to decrease snoring by preventing mouth breathing during sleep. DESIGN: A crossover controlled trial. Each subject was studied on two nights a week apart. There was a control (no treatment) night and an experimental (treatment) night. The order of control and experimental nights was randomised. SETTING: The Royal Adelaide Hospital Sleep Laboratory. PARTICIPANTS: Fourteen male volunteers (age range, 36-59 years) were studied. All had a history of chronic snoring but denied other symptoms of obstructive sleep apnoea syndrome. INTERVENTIONS: On experimental nights subjects wore the dental prosthesis for the whole study period. On control nights no device was worn. MAIN OUTCOME MEASURES: Studies were conducted overnight during the subject's normal sleep period. The following measurements were made: (i) frequency and loudness of snores; (ii) frequency of disordered breathing events (apnoeas and hypopnoeas); (iii) mean and minimum arterial oxygen saturation while asleep; and (iv) sleep stages. RESULTS: The dental prosthesis did not change the mean frequency or mean intensity of snores. The number of sleep disordered breathing events per hour of sleep decreased by approximately one-third on experimental nights (mean +/- SEM events/h: control, 24.7 +/- 5.3; experimental, 16.1 +/- 3.3, P less than 0.05). Neither sleep architecture nor arterial oxygen saturation differed between control and experimental nights. CONCLUSION: Snores using the dental prosthesis Snore-No-More to produce obligatory nasal breathing are unlikely to experience clinical benefit.

The effects of aminophylline on sleep and sleep-disordered breathing in patients with obstructive sleep apnea syndrome.

The methylxanthine derivatives are known to have respiratory stimulant properties. To determine whether these drugs would improve obstructive sleep apnea, 10 male patients with obstructive sleep apnea (OSA) (Apnea Index greater than 15/h) were given infusions of aminophylline and a saline placebo on 2 separate nights a week apart, using a randomized crossover design. There was a significant decrease during aminophylline infusion in the frequency of those apneas, which contained periods of complete respiratory inactivity (central and mixed apneas; placebo, 4.3 +/- 1.8/h; aminophylline, 0.7 +/- 0.5/h; p less than 0.05). There was no change in either the frequency (placebo, 31.8 +/- 5.9/h; aminophylline, 28.7 +/- 8.7/h; NS) or duration of obstructive apneas. Mean and minimal arterial oxygen saturation values were also unchanged. Sleep architecture was markedly disturbed by aminophylline. There was a reduction in sleep efficiency (placebo, 84.8 +/- 2.0%; aminophylline, 60.2 +/- 5.0%; p less than 0.005), an increase in sleep fragmentation (sleep stage shifts/h: placebo, 11.6 +/- 1.3: aminophylline, 21.0 +/- 2.9; p less than 0.05) and less Stage 2 and more Stage 1 non-REM sleep. We conclude that aminophylline reduces central apnea and the central component of mixed apneas but has no effect on obstructive apnea. Theophylline is therefore unlikely to be therapeutically useful in patients with OSA, and because it leads to marked sleep disruption, its long-term use could conceivably increase the propensity to upper airway occlusion during sleep.

The effects of posture on obstructive sleep apnea.

To determine whether the adoption of a more upright sleep posture would improve breathing and gas exchange in patients with obstructive sleep apnea syndrome (OSAS), 13 male patients with OSAS were studied during an all-night polysomnographic study while lying supine or sitting at a 60-degree angle. In the upright posture, the frequency of obstructive apnea was decreased (lying, 48.9 +/- 5.4/h; sitting, 19.6 +/- 6.9/h; p less than 0.0005) and arterial oxyhemoglobulin saturation (Sao2) was increased (nREM; mean lying, 90.6 +/- 0.8%; mean sitting, 92.1 +/- 0.5%, p less than 0.005; minimum lying, 64.8 +/- 3.2%, minimum sitting, 80.8 +/- 2.1%, p less than 0.005). In approximately half the patients studied, obstructive sleep apnea was essentially abolished by the postural intervention. These patients were more obese and had lower Pao2 and higher Paco2 values awake than the remaining patients in whom the response was either incomplete or absent. Arousal from sleep was less frequent in the upright posture, but sleep efficiency and overall sleep architecture were unchanged. This simple maneuver may be useful for treating some patients with OSAS.

Treatment of obstructive sleep apnea syndrome with nasal continuous positive airway pressure.

To help define the place of nasal continuous positive airway pressure (n-CPAP) treatment in a general sleep apnea population we studied 12 of 13 consecutively diagnosed patients with obstructive sleep apnea syndrome (OSAS). The immediate effects of n-CPAP were tested during a nighttime sleep study divided into two approximately equal parts (control and n-CPAP). Nasal CPAP of 5-10 cm H2O decreased apnea index (apneas per hour of sleep) (control 35.1, n-CPAP 5.7; p less than 0.001) and significantly improved oxyhemoglobin saturation (SaO2). The effect was independent of body weight and the presence of cardiorespiratory complications. However, in three patients with lung disease and markedly elevated PaCO2, significant sleep-related hypoxemia persisted at the relatively low pressures required to open the upper airway. Long-term home-based n-CPAP was offered to 11 patients. (One patient was considered unsuitable because of persisting profound sleep-related hypoxemia). Seven patients consented and were followed for periods ranging from 1 to 18 months. All patients reported dramatic reversal of daytime hypersomnolence; three complained of minor nasal stuffiness but compliance was good and only one stopped using the mask (after 12 months). Apnea index decreased following home use of n-CPAP (before 35.9, after 18.1; p less than 0.01) but overall respiratory instability (apnea + hypopnea) and SaO2 were not significantly improved. It is concluded that n-CPAP is a highly effective means of preventing upper airway occlusion in OSAS and, except for some patients with coexisting lung disease, it totally reverses the accompanying gas exchange disturbance. Long-term home-based n-CPAP therapy is acceptable to a majority of patients, is free of serious side effects, and appears to result in a partial reversal of the underlying breathing disorder.

Kinetics of copper(II) uptake by apoazurin in complexing media.

We have studied the kinetics of copper uptake by apoazurin in imidazole and 1-methylimidazole buffers in the pH range of 7-9 with mu = 0.5 M and copper(II) in large excess. The reaction has been monitored by measuring the visible absorbance and circular dichroism as a function of time. The uptake occurs in a stepwise fashion, and at least two intermediates are implicated. Overall, the rate of uptake varies inversely with the concentration of the proton and the (complexing) buffer, but depends directly on the copper concentration. A model involving a weakly absorbing intermediate is proposed to rationalize the data taken at the lower end of the pH range. According to the model the intermediate forms with a second order rate constant of about 30 M-1 S-1 and is probably described as a ternary complex of copper, buffer, and one or more of the histidine ligands of the binding site. This then decays by a pH-dependent process to give product. At higher pH values there is evidence that relaxation to product occurs via a second intermediate form in which the cysteine ligand is bound to copper. The relevance of these results to the question of how copper is selectively incorporated into the protein is considered. Finally, a milder, more reliable route to the preparation of apoazurin is described.