Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

Intermittent hypoxia (IH) and sleep fragmentation (SF) are major manifestations of sleep apnea, a frequent condition in aging humans. Sleep perturbations are frequent in Alzheimer's disease (AD) and may underlie the progression of disease. We hypothesized that acute short-term IH, SF, and their combination (IH+SF) may reveal unique susceptibility in sleep integrity in a murine model of AD. The effects of acute IH, SF, and IH+SF on sleep architecture, delta power, sleep latency, and core body temperature were assessed in adult male human ApoE4-targeted replacement mice (hApoE4) and wild-type (WT) controls. Slow wave sleep (SWS) was significantly reduced, and rapid eye movement (REM) sleep was almost abolished during acute exposure to IH alone and IH+SF for 6 h in hApoE4, with milder effects in WT controls. Decreased delta power during SWS did not show postexposure rebound in hApoE4 unlike WT controls. IH and IH+SF induced hypothermia, which was more prominent in hApoE4 than WT controls. Mice subjected to SF also showed sleep deficits but without hypothermia. hApoE4 mice, unlike WT controls, exhibited increased sleep propensity, especially following IH and IH+SF, suggesting limited ability for sleep recovery in hApoE4 mice. These findings substantiate the potential impact of IH and SF in modulating sleep architecture and sleep homeostasis including maintenance of body temperature. Furthermore, the increased susceptibility and limited recovery ability of hApoE4 mice to sleep apnea suggests that early recognition and treatment of the latter in AD patients may restrict the progression and clinical manifestations of this frequent neurodegenerative disorder.     

Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin.

Respiratory long-term facilitation (LTF) is a long-lasting (>1 h) augmentation of respiratory motor output that occurs even after cessation of hypoxic stimuli, is serotonin-dependent, and is thought to prevent sleep-disordered breathing such as sleep apnea. Raphe nuclei, which modulate several physiological functions through serotonin, receive dense projections from orexin-containing neurons in the hypothalamus. We examined possible contributions of orexin to ventilatory LTF by measuring respiration in freely moving prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates before, during, and after exposure to intermittent hypoxia (IH; 5 x 5 min at 10% O2), sustained hypoxia (SH; 25 min at 10% O2), or sham stimulation. Respiratory data during quiet wakefulness (QW), slow wave sleep (SWS), and rapid-eye-movement sleep were separately calculated. Baseline ventilation before hypoxic stimulation and acute responses during stimulation did not differ between the ORX-KO and WT mice, although ventilation depended on vigilance state. Whereas the WT showed augmented minute ventilation (by 20.0 +/- 4.5% during QW and 26.5 +/- 5.3% during SWS; n = 8) for 2 h following IH, ORX-KO showed no significant increase (by -3.1 +/- 4.6% during QW and 0.3 +/- 5.2% during SWS; n = 8). Both genotypes showed no LTF after SH or sham stimulation. Sleep apnea indexes did not change following IH, even when LTF appeared in the WT mice. We conclude that LTF occurs during both sleep and wake periods, that orexin is necessary for eliciting LTF, and that LTF cannot prevent sleep apnea, at least in mice.     

Effects of high-frequency pressure waves applied to upper airway on respiration in central apnea.

We examined the effects of high-frequency (30-Hz) low-pressure oscillations on respiration in nine patients with central sleep apnea. All patients were studied during sleep and wore a nasal mask through which the oscillations were applied. All tests were performed during periods of repetitive central apneas. Respiratory efforts were monitored from the airflow and calibrated Respitrace signals. After several cycles of apnea were monitored, the oscillatory pressures were applied for brief periods (less than 5 s) at the midpoint of the central apneas. All trials in which arousal occurred were discarded, leaving a total of 106 trials in the nine patients. High-frequency oscillation of the upper airway stimulated respiratory effort(s) in 68% of all trials (72 of 106). Apnea length was significantly shortened in four of the nine patients. In one patient with a tracheostomy, the stimulus applied to his isolated upper airway evoked respiratory efforts during central apnea in 13 of 15 trials. We conclude that high-frequency oscillatory pressures applied to the upper airway can stimulate respiratory efforts during central apnea. This response may be mediated by upper airway receptors involved in nonrespiratory airway defense reflexes and may have implications in the treatment of patients with central sleep apnea.     

Respiratory Adaptations in Intertidal Fish

SYNOPSIS: Intertidal rockpools provide a challenging environmentfor rockpool fish with rapid changes taking place in many environmentalparameters over a tidal cycle. Intertidal fish exhibit a numberof behavioural adaptations such as the avoidance of hypoxicsituations or remaining inactive during aerial "stranding."Other species are, however, well adapted to breathe air andexhibit morphological adaptations such as smaller gill areas,specialized buccopharyngeal epithelia and a proliferation ofcutaneous blood vessels in the skin. Oxygen consumption in rockpoolfish is comparable to non-intertidal fish and responds in asimilar manner to temperature changes. The ability to regulateoxygen consumption down to oxygen tensions below 40 Torr is,however, marked in rockpool species. Aerial and aquatic ratesof respiration are similar in those species which are able tobreathe air and the respiratory quotient normally remains between0.7 and 0.9. A number of intertidal fish are well adapted forcutaneous respiration, satisfying over half of their oxygenand carbon dioxide exchange through the skin. Ventilatory responsesto increased temperature, hyperoxia and hypoxia are similarto those of other fish but cardiac responses may differ in thatno change in heart rate is seen under hypoxia or hyperoxia.Ventilatory and cardiac responses to aerial respiration arewell adapted in some species maintaining ventilation and perfusionduring aerial exposure. A marked Bohr effect, low temperaturesensitivity and a temperature dependent Haldane effect havebeen measured in the haemoglobolin of some intertidal fish.These properties may assist oxygen transport and carbon dioxideexchange during cyclical changes in environmental parameterswithin an intertidal rockpool.     

Influence of Cheyne-Stokes respiration on ventricular response to atrial fibrillation in heart failure.

In subjects with sinus rhythm, respiration has a profound effect on heart rate variability (HRV) at high frequencies (HF). Because this HF respiratory arrhythmia is lost in atrial fibrillation (AF), it has been assumed that respiration does not influence the ventricular response. However, previous investigations have not considered the possibility that respiration might influence HRV at lower frequencies. We hypothesized that Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) would entrain HRV at very low frequency (VLF) in AF by modulating atrioventricular (AV) nodal refractory period and concealed conduction. Power spectral analysis of R-wave-to-R-wave (R-R) intervals and respiration during sleep were performed in 13 subjects with AF and CSR-CSA. As anticipated, no modulation of HRV was detected at HF during regular breathing. In contrast, VLF HRV was entrained by CSR-CSA [coherence between respiration and HRV of 0.69 (SD 0.22) at VLF during CSR-CSA vs. 0.20 (SD 0.19) at HF during regular breathing, P < 0.001]. Comparison of R-R intervals during CSR-CSA demonstrated a shorter AV node refractory period during hyperpnea than apnea [minimum R-R of 684 (SD 126) vs. 735 ms (SD 147), P < 0.001] and a lesser degree of concealed conduction [scatter of 178 (SD 56) vs. 246 ms (SD 72), P = 0.001]. We conclude that CSR-CSA entrains the ventricular response to AF, even in the absence of HF respiratory arrhythmia, by inducing rhythmic oscillations in AV node refractoriness and the degree of concealed conduction that may be a function of autonomic modulation of the AV node.     

Influence of core temperature on autoresuscitation during repeated exposure to hypoxia in normal rat pups.

Failure to autoresuscitate by hypoxic gasping during prolonged sleep apnea has been suggested to play a role in sudden infant death. Furthermore, thermal stress brought about by a contribution of infection, overwrapping, or excessive environmental heating has been shown to be associated with an increased risk of sudden infant death, particularly in prone sleeping infants. The present experiments were carried out on newborn rat pups to investigate the influence of "forced" changes in core temperature on their time to last gasp during a single hypoxic exposure and on their ability to autoresuscitate during repeated exposure to hypoxia. On day 5 or 6 postpartum the pups were placed in a temperature-controlled chamber regulated to 33, 35, 37, 39, or 41 degrees C and exposed to a single period of hypoxia (97% N(2)-3% CO(2)) and their time to last gasp was determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnea was determined. Increases in core temperature brought about by changes in ambient temperature from 33 to 41 degrees C decreased the time to last gasp after a single hypoxic exposure and decreased the number of successful autoresuscitations after repeated hypoxic exposures. Thus our data support the hypothesis that forced changes in core temperature brought about by changes in ambient temperature influence protective responses in newborns that may prevent death during hypoxia, as may occur during single or repeated episodes of prolonged sleep apnea.     

Ventilatory effect of an adenosine analogue in unanesthetized rabbits during development

The effect of an adenosine analogue N6-L-(R-phenylisopropyl)adenosine (R-PIA) on respiration was studied in rabbit pups (1-8 days old). Respiration was monitored by a noninvasive barometric method during natural sleep. The adenosine analogue was given by an indwelling intraperitoneal catheter. R-PIA given in a dose of 0.1 mumol/kg (380 micrograms/kg) body wt caused a decrease of the ventilation. The respiratory decrease could be reversed or prevented by pretreatment with theophylline (10 mg/kg). R-PIA caused a considerably more pronounced effect in 1- to 3-day-old animals than in 8-day-old animals. This effect was seen both when the ambient temperature was held at 28 (P less than 0.01) and 32 degrees C (P less than 0.05). Determination of R-PIA receptors in whole brains of rabbit pups of various ages showed that R-PIA bound with higher affinity to membranes from newborn animals (Kd 0.53 nM) than older animals (Kd 0.7-1.26). Since adenosine is released during hypoxia, it may be involved in "hypoxic depression" of respiration in neonates and apnea of prematurity. This might also explain the potent therapeutic effect of the adenosine antagonist theophylline on recurrent apnea in preterm infants.     

Invited review: Physiological and pathophysiological responses to intermittent hypoxia.

This mini-review summarizes the physiological adaptations to and pathophysiological consequences of intermittent hypoxia with special emphasis given to the pathophysiology associated with obstructive sleep apnea. Intermittent hypoxia is an effective stimulus for evoking the respiratory, cardiovascular, and metabolic adaptations normally associated with continuous chronic hypoxia. These adaptations are thought by some to be beneficial in that they may provide protection against disease as well as improve exercise performance in athletes. The long-term consequences of chronic intermittent hypoxia may have detrimental effects, including hypertension, cerebral and coronary vascular problems, developmental and neurocognitive deficits, and neurodegeneration due to the cumulative effects of persistent bouts of hypoxia. Emphasis is placed on reviewing the available data on intermittent hypoxia, making extensions from applicable information from acute and chronic hypoxia studies, and pointing out major gaps in information linking the genomic and cellular responses to intermittent hypoxia with physiological or pathophysiological responses.     

Invited review: Physiological consequences of intermittent hypoxia: systemic blood pressure.

One of the major manifestations of obstructive sleep apnea is profound and repeated hypoxia during sleep. Acute hypoxia leads to stimulation of the peripheral chemoreceptors, which in turn increases sympathetic outflow, acutely increasing blood pressure. The chronic effect of these repeated episodic or intermittent periods of hypoxia in humans is difficult to study because chronic cardiovascular changes may take many years to manifest. Rodents have been a tremendous source of information in short- and long-term studies of hypertension and other cardiovascular diseases. Recurrent short cycles of normoxia-hypoxia, when administered to rats for 35 days, allows examination of the chronic cardiovascular response to intermittent hypoxia patterned after the episodic desaturation seen in humans with sleep apnea. The result of this type of intermittent hypoxia in rats is a 10- to 14-mmHg increase in resting (unstimulated) mean blood pressure that lasts for several weeks after cessation of the daily cyclic hypoxia. Carotid body denervation, sympathetic nerve ablation, renal sympathectomy, adrenal medullectomy, and angiotensin II receptor blockade block the blood pressure increase. It appears that adrenergic and renin-angiotensin system overactivity contributes to the early chronic elevated blood pressure in rat intermittent hypoxia and perhaps to human hypertension associated with obstructive sleep apnea.     

Compensatory responses to upper airway obstruction in obese apneic men and women

Defective structural and neural upper airway properties both play a pivotal role in the pathogenesis of obstructive sleep apnea. A more favorable structural upper airway property [pharyngeal critical pressure under hypotonic conditions (passive Pcrit)] has been documented for women. However, the role of sex-related modulation in compensatory responses to upper airway obstruction (UAO), independent of the passive Pcrit, remains unclear. Obese apneic men and women underwent a standard polysomnography and physiological sleep studies to determine sleep apnea severity, passive Pcrit, and compensatory airflow and respiratory timing responses to prolonged periods of UAO. Sixty-two apneic men and women, pairwise matched by passive Pcrit, exhibited similar sleep apnea disease severity during rapid eye movement (REM) sleep, but women had markedly less severe disease during non-REM (NREM) sleep. By further matching men and women by body mass index and age (n = 24), we found that the lower NREM disease susceptibility in women was associated with an approximately twofold increase in peak inspiratory airflow (P = 0.003) and inspiratory duty cycle (P = 0.017) in response to prolonged periods of UAO and an ～20% lower minute ventilation during baseline unobstructed breathing (ventilatory demand) (P = 0.027). Thus, during UAO, women compared with men had greater upper airway and respiratory timing responses and a lower ventilatory demand that may account for sex differences in sleep-disordered breathing severity during NREM sleep, independent of upper airway structural properties and sleep apnea severity during REM sleep.     

Impact of repeated daily exposure to intermittent hypoxia and mild sustained hypercapnia on apnea severity

We examined whether exposure to intermittent hypoxia (IH) during wakefulness impacted on the apnea/hypopnea index (AHI) during sleep in individuals with sleep apnea. Participants were exposed to twelve 4-min episodes of hypoxia in the presence of sustained mild hypercapnia each day for 10 days. A control group was exposed to sustained mild hypercapnia for a similar duration. The intermittent hypoxia protocol was completed in the evening on day 1 and 10 and was followed by a sleep study. During all sleep studies, the change in esophageal pressure (ΔPes) from the beginning to the end of an apnea and the tidal volume immediately following apneic events were used to measure respiratory drive. Following exposure to IH on day 1 and 10, the AHI increased above baseline measures (day 1: 1.95 ± 0.42 fraction of baseline, P ≤ 0.01, vs. day 10: 1.53 ± 0.24 fraction of baseline, P < 0.06). The indexes were correlated to the hypoxic ventilatory response (HVR) measured during the IH protocol but were not correlated to the magnitude of ventilatory long-term facilitation (vLTF). Likewise, ΔPes and tidal volume measures were greater on day 1 and 10 compared with baseline (ΔPes: -8.37 ± 0.84 vs. -5.90 ± 1.30 cmH(2)0, P ≤ 0.04; tidal volume: 1,193.36 ± 101.85 vs. 1,015.14 ± 119.83 ml, P ≤ 0.01). This was not the case in the control group. Interestingly, the AHI on day 10 (0.78 ± 0.13 fraction of baseline, P ≤ 0.01) was significantly less than measures obtained during baseline and day 1 in the mild hypercapnia control group. We conclude that enhancement of the HVR initiated by exposure to IH may lead to increases in the AHI during sleep and that initiation of vLTF did not appear to impact on breathing stability. Lastly, our results suggest that repeated daily exposure to mild sustained hypercapnia may lead to a decrease in breathing events.     

Possible mechanisms of periodic breathing during sleep

To determine the effect of respiratory control system loop gain on periodic breathing during sleep, 10 volunteers were studied during stage 1-2 non-rapid-eye-movement (NREM) sleep while breathing room air (room air control), while hypoxic (hypoxia control), and while wearing a tight-fitting mask that augmented control system gain by mechanically increasing the effect of ventilation on arterial O2 saturation (SaO2) (hypoxia increased gain). Ventilatory responses to progressive hypoxia at two steady-state end-tidal PCO2 levels and to progressive hypercapnia at two levels of oxygenation were measured during wakefulness as indexes of controller gain. Under increased gain conditions, five male subjects developed periodic breathing with recurrent cycles of hyperventilation and apnea; the remaining subjects had nonperiodic patterns of hyperventilation. Periodic breathers had greater ventilatory response slopes to hypercapnia under either hyperoxic or hypoxic conditions than nonperiodic breathers (2.98 +/- 0.72 vs. 1.50 +/- 0.39 l.min-1.Torr-1; 4.39 +/- 2.05 vs. 1.72 +/- 0.86 l.min-1.Torr-1; for both, P less than 0.04) and greater ventilatory responsiveness to hypoxia at a PCO2 of 46.5 Torr (2.07 +/- 0.91 vs. 0.87 +/- 0.38 l.min-1.% fall in SaO2(-1); P less than 0.04). To assess whether spontaneous oscillations in ventilation contributed to periodic breathing, power spectrum analysis was used to detect significant cyclic patterns in ventilation during NREM sleep. Oscillations occurred more frequently in periodic breathers, and hypercapnic responses were higher in subjects with oscillations than those without. The results suggest that spontaneous oscillations in ventilation are common during sleep and can be converted to periodic breathing with apnea when loop gain is increased.     

Ischemia and reperfusion--from mechanism to translation

Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.     

Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans.

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O(2) saturation nadir 81.4 +/- 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 +/- 11 to 159 +/- 21 units/min (P = 0.001) and mean blood pressure from 92.1 +/- 2.9 to 95.5 +/- 2.9 mmHg (P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O(2) (Fi(O(2))) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 +/- 4 vs. +49 +/- 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (Fi(O(2)) 0.5, for 5 min) were not changed significantly (P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.     

Control mechanism for the upper airway collapse in patients with obstructive sleep apnea syndrome: a finite element study

Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent collapses of the upper airway, which lead to repetitive transient hypoxia, arousals and finally sleep fragmentation. Both anatomical and neuromuscular factors may play key roles in the pathophysiology of OSAS. The purpose of this paper was to study the control mechanism of OSAS from the mechanical point of view. A three-dimensional finite element model was developed, which not only reconstructed the realistic anatomical structure of the human upper airway, but also included surrounding structures such as the skull, neck, hyoid, cartilage and soft tissues. The respiration process during the normal and apnea states was simulated with the fluid-structure interaction method (FSI) and the computational fluid dynamics method (CFD). The airflow and deformation of the upper airway obtained from the FSI and the CFD method were compared and the results obtained under large negative pressure during an apnea episode were analyzed. The simulation results show that the FSI method is more feasible and effective than the CFD method. The concave configuration of the upper airway may accelerate the collapse of the upper airway in a positive feedback mechanism, which supplies meaningful information for clinical treatment and further research of OSAS.     

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.     

Adenine nucleotides, glutamate and respiratory function of heart mitochondria during acute hypoxia

The effect of acute hypoxia on adenine nucleotides, glutamate, aspartate, alanine and respiration of heart mitochondria was studied in rats. The losses of intramitochondrial adenine nucleotides (ATP+ADP+AMP) during hypoxia were related to depression of state 3 respiration supported by glutamate and malate, as well as decrease in uncoupled respiration. Hypoxia had less prominent effect on succinate-dependent state 3 respiration. Non-phosphorylating (state 4) respiratory rates and ADP/O ratios were slightly affected by oxygen deprivation. Glutamate fall in tissue and mitochondria of hypoxic hearts was concomitant with significant increase in tissue alanine and mitochondrial aspartate. The losses of intramitochondrial ATP and respiratory activity with NAD-dependent substrates during hypoxia were related to a decrease in mitochondrial glutamate. The results suggest that hypoxia-induced impairment of complex I of respiratory chain and a loss of glutamate from the matrix may limit energy-producing capacity of heart mitochondria.     

Prior exposure to hypoxic-induced apnea impairs protective responses of newborn rats in an exposure-dependent fashion: influence of normoxic recovery time.

Experiments were carried out to determine whether prior exposure to hypoxic-induced apnea impairs protective responses of newborn rats. Ninety-five, 5- to 6-day-old rat pups were instrumented for respiratory measurements and placed prone in a metabolic chamber regulated to 37.0 degrees C. The time to first and last gasp as well as the number of gasps were determined on exposure to unrelenting hypoxia after each pup had experienced 0, 1, 2, 3, 4, 9, or 14 hypoxic-induced apnea/autoresuscitation cycles (HIA/AR) at 5-min intervals. Prior exposure to HIA/AR did not significantly alter the time to first gasp, but it decreased the time to last gasp after two HIA/AR and the number of gasps after three HIA/AR on exposure to unrelenting hypoxia. When the normoxic recovery time after 9 HIA/AR was varied from 5 to 120 min, the time to last gasp as well as the total number of gasps increased on exposure to unrelenting hypoxia but only at 120 min (i.e., the number of gasps was similar but the time to last gasp was still decreased compared with that observed in naive animals exposed to unrelenting hypoxia). Thus prior exposure to hypoxic-induced apnea as may occur during obstructive sleep apnea or positional asphyxia decreases the number and duration of potential autoresuscitation producing gasps on exposure to unrelenting hypoxia for a period of up to and exceeding 120 min, respectively. The mechanism by which prior exposure to hypoxic-induced apnea influences the duration and number of hypoxic-induced gasps is unknown.     

Impact of age on breathing and resistive pressure in people with and without sleep apnea.

We investigated the effect of age on breathing and total pulmonary resistance (RL) during sleep by studying elderly (>65 yr) and young (25-38 yr) people without sleep apnea (EN and YN, respectively) matched for body mass index (BMI). To determine the impact of sleep apnea on age-related changes in breathing, we studied elderly and young apneic patients (EA and YA, respectively) matched for apnea and BMI. In all groups (n = 11), breathing during periods of stable sleep was analyzed to evaluate the intrinsic variability of respiratory control mechanisms. In the absence of sleep apnea, the variability of the breathing was similar in the elderly and young [mean (+/- SD) coefficient of variation (CV) of tidal volume (VT); wake: EN 21.0 +/- 14.9%, YN 14.7 +/- 5.5%; sleep: EN 14.0 +/- 6.0%; YN 11.5 +/- 6.4%]. In patients with sleep apnea, breathing during stable sleep was more irregular, but there were no age-related differences (CV of VT; wake: EA 22.0 +/- 11.6%, YA 16.7 +/- 11.3%; sleep: EA 32.8 +/- 24.9%, YA 25.2 +/- 16.3%). In addition, EN tended to have a higher RL (n = 6, RL midinspiration, wake: EN 7.1 +/- 3.0; YN 9.1 +/- 6.4 cmH(2)O. l(-1). s, sleep: EN 17.5 +/- 11.7; YN 9.8 +/- 2.0 cmH(2)O. l(-1). s). We conclude that aging per se does not contribute to the intrinsic variability of respiratory control mechanisms, although there may be a lower probability of finding elderly people without respiratory instability.     

Cardiovascular and respiratory responses to apneas with and without face immersion in exercising humans.

The effect of the diving response on alveolar gas exchange was investigated in 15 subjects. During steady-state exercise (80 W) on a cycle ergometer, the subjects performed 40-s apneas in air and 40-s apneas with face immersion in cold (10 degrees C) water. Heart rate decreased and blood pressure increased during apneas, and the responses were augmented by face immersion. Oxygen uptake from the lungs decreased during apnea in air (-22% compared with eupneic control) and was further reduced during apnea with face immersion (-25% compared with eupneic control). The plasma lactate concentration increased from control (11%) after apnea in air and even more after apnea with face immersion (20%), suggesting an increased anaerobic metabolism during apneas. The lung oxygen store was depleted more slowly during apnea with face immersion because of the augmented diving response, probably including a decrease in cardiac output. Venous oxygen stores were probably reduced by the cardiovascular responses. The turnover times of these gas stores would have been prolonged, reducing their effect on the oxygen uptake in the lungs. Thus the human diving response has an oxygen-conserving effect.