Postnatal age influences the ability of rats to autoresuscitate from hypoxic-induced apnea

Failure to autoresuscitate from apnea by gasping has been suggested to have a role in sudden infant death. Little is known, however, about the factors that influence the ability of gasping to sustain life during acute hypoxia in the newborn. The present experiments were carried out on 105 rat pups to investigate the influence of postnatal age on the time to last gasp during a single hypoxic exposure and on the ability to autoresuscitate from primary apnea during repeated hypoxic exposures. On days 1-2, 5-6, 10-11, 15-16, and 19-20 postpartum, each pup was placed into a temperature-controlled chamber regulated to 37 +/- 1 degrees C and was exposed either to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2)-3% CO(2)), and the time to last gasp was determined, or repeated exposure to hypoxia was performed, and the ability to autoresuscitate from primary apnea was determined. Increases in postnatal age decreased the time to last gasp following a single hypoxic exposure and decreased the number of successful autoresuscitations following repeated hypoxic exposures. Thus our data provide evidence that postnatal age influences protective responses that may prevent death during hypoxia as may occur during episodes of prolonged sleep apnea.     

Perinatal nicotine exposure impairs ability of newborn rats to autoresuscitate from apnea during hypoxia

Failure toautoresuscitate by hypoxic gasping during prolonged sleep apnea hasbeen suggested to play a role in sudden infant death. Furthermore,maternal smoking has been repeatedly shown to be a risk factor forsudden infant death. The present experiments were carried out onnewborn rat pups to investigate the influence of perinatal exposure tonicotine (the primary pharmacological and addictive agent in tobacco)on their time to last gasp during a single hypoxic exposure and ontheir ability to autoresuscitate during repeated exposure to hypoxia.Pregnant rats received either nicotine (6 mg · kg¹ · 24 h¹) or vehiclecontinuously from day 6 of gestationto days 5 or 6 postpartum via an osmotic minipump.On days 5 or6 postpartum, pups were exposed eitherto a single period of hypoxia (97%N₂-3% CO₂) and their time to last gaspwas determined, or they were exposed repeatedly to hypoxia and theirability to autoresuscitate from primary apnea was determined. Perinatalexposure to nicotine did not alter the time to last gasp, but it didimpair the ability of pups to autoresuscitate from primary apnea. Aftervehicle, the pups were able to autoresuscitate from 18 ± 1 (SD)periods of hypoxia, whereas, after nicotine, the pups were able toautoresuscitate from only 12 ± 2 periods(P < 0.001) of hypoxia. Thus ourdata provide evidence that perinatal exposure to nicotine impairs the ability of newborn rats to autoresuscitate from primary apnea duringrepeated exposure to hypoxia, such as may occur during episodes ofprolonged sleep apnea.

     

Influence of adenosine A(1)-receptor blockade and vagotomy on the gasping and heart rate response to hypoxia in rats during early postnatal maturation.

Failure to autoresuscitate from apnea has been suggested to play a role in sudden infant death. Little is known, however, about factors that influence the gasping and heart rate response to severe hypoxia that are fundamental to successful autoresuscitation in the newborn. The present experiments were carried out on 184 rat pups to investigate the influence of the parasympathetic nervous system, as well as adenosine, in mediating the profound bradycardia that occurs with the onset of hypoxic-induced primary apnea and in modulating hypoxic gasping. On days 1 to 2, days 5 to 6, and days 10 to 11 postpartum and following bilateral cervical vagotomy (VAG) or administration of a selective adenosine A(1) receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine; DPCPX), each pup was exposed to a single period of severe hypoxia produced by breathing an anoxic gas mixture (97% N(2)-3% CO(2)). Exposure to severe hypoxia resulted in an age-dependent decrease in heart rate (P < 0.001), accentuated with increasing postnatal age, that was attenuated in all age groups by DPCPX but not by VAG. Furthermore, DPCPX but not VAG decreased the time to last gasp but increased the total number of gasps in the 1- to 2-day-old and 5- to 6-day-old pups but not in the 10- to 11-day-old pups during exposure to severe hypoxia. Thus our data provide evidence that adenosine acting via adenosine A(1) receptors plays a role in modulating hypoxic gasping and in mediating the profound bradycardia that occurs coincident with hypoxic-induced primary apnea in rats during early postnatal life.     

Threshold levels of maternal nicotine impairing protective responses of newborn rats to intermittent hypoxia.

Experiments were carried out to determine the threshold level of maternal nicotine that impairs protective responses of rat pups to hypoxia. From days 6 or 7 of gestation, pregnant rats received either vehicle or nicotine (1.50, 3.00, or 6.00 mg of nicotine tartrate. kg body wt(-1).day(-1)) or vehicle continuously via a subcutaneous osmotic minipump. On postnatal days 5 or 6, pups were exposed to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2) or 3% CO(2)) and their time to last gasp was determined, or they were exposed to intermittent hypoxia and their ability to autoresuscitate from hypoxic-induced primary apnea was determined. Perinatal exposure to nicotine did not alter the time to last gasp or the total number of gasps when the pups were exposed to a single period of hypoxia. The number of successful autoresuscitations on repeated exposure to hypoxia was, however, decreased in pups whose dams had received either 3.00 or 6.00 mg of nicotine tartrate/kg body wt; these dosage regimens produced maternal serum nicotine concentrations of 19 +/- 6 and 35 +/- 8 ng/ml, respectively. Thus our experiments define the threshold level of maternal nicotine that significantly impairs protective responses of 5- to 6-day-old rat pups to intermittent hypoxia such as may occur in human infants during episodes of prolonged sleep apnea or positional asphyxia.     

Gasping and autoresuscitation in the developing rat: effect of antecedent intermittent hypoxia.

Gasping is a critically important mechanism for autoresuscitation and survival during extreme tissue hypoxia. Evidence of antecedent hypoxia in sudden infant death syndrome suggests that intermittently occurring hypoxic episodes may modify gasping and autoresuscitation. To examine this issue, an intermittent hypoxia (IH) profile consisting of alternating room air and 10% O(2)-balance N(2) every 90 s was applied to pregnant Sprague-Dawley rats (IHRA; n = 50) and to pups after a normal pregnancy (RAIH; n = 50) as well as to control pups (RARA; n = 50). At postnatal day 5, pups were exposed to 95% N(2)-5% CO(2), and gasping and the ability to autoresuscitate were assessed. Compared with RARA, IHRA- and RAIH-exposed pups had a reduced number of gasps, decreased overall gasp duration, and were less likely to autoresuscitate on introduction of room air to the breathing mixture during the last phase of gasping (P < 0.001 vs. RARA). We conclude that both prenatal and early postnatal IH adversely affect gasping and related survival mechanisms.     

Inhibitory effects of hyperthermia on mechanisms involved in autoresuscitation from hypoxic apnea in mice: a model for thermal stress causing SIDS.

The physiological mechanisms that might be involved in an association between heat stress and sudden infant death syndrome (SIDS) are obscure. We tested the hypothesis that a combination of acute hypoxia and elevated body temperature (T(B)) might prevent autoresuscitation from hypoxic apnea (AR). We exposed 21-day-old mice (total = 216) to hyperthermia (40.5-43.5 degrees C), hypoxia, or a combination of the two. Neither hyperthermia alone (40.5-42.5 degrees C) nor hypoxia alone was found to be lethal, but the combination produced failure to AR during the first hypoxic exposure with increasing frequency as T(B) increased. The ability to withstand multiple hypoxic exposures was also reduced as T(B) increased. In contrast, heat stress causing moderate T(B) increase (40.5 degrees C) had no effect on survival. Increased T(B) (43.5 degrees C) reduced gasping duration and number of gasps. It increased heart rate during anoxia but did not alter gasping rate. Furthermore, the oxygen-independent increase in heart rate observed before gasping failure was usually delayed until after the last gasp in hyperthermic animals. Mild dehydration occurred during T(B) elevation, but this did not appear to be a primary factor in AR failure. We conclude that a thermal stress, which by itself is nonlethal, frequently prevents AR from hypoxic apnea. This may be due, at least in part, to decreased gasp number and duration as well as to hyperthermia-related asynchrony of reflexes regulating heart and gasping frequencies during attempted AR.     

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.     

Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat

Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures.     

Intermittent hypoxia induces transient arousal delay in newborn mice.

Previous studies suggested that defective arousal might be a major mechanism in sleep-disordered breathing such as sudden infant death syndrome and obstructive sleep apnea. In this study, we examined the effects of intermittent hypoxia (IH) on the arousal response to hypoxia in 4-day-old mice. We hypothesized that IH would increase arousal latency, as previously reported in other species, and we measured the concomitant changes in ventilation to shed light on the relationship between breathing and arousal. Arousal was scored according to behavioral criteria. Breathing variables were measured noninvasively by use of whole-body flow plethysmography. In the hypoxic group (n = 14), the pups were exposed to 5% O(2) in N(2) for 3 min and returned to air for 6 min. This test was repeated eight times. The normoxic mice (n = 14) were constantly exposed to normoxia. The hypoxic mice showed a 60% increase in arousal latency (P < 0.0001). Normoxic controls showed virtually no arousals. IH depressed normoxic ventilation below baseline prehypoxic levels, while preserving the ventilatory response to hypoxia. The breathing pattern and arousal responses recovered fully after 2 h of normoxia. We conclude that IH rapidly and reversibly depressed breathing and delayed arousal in newborn mice. Both effects may be due to hypoxia-induced release of inhibitory neurotransmitters acting concomitantly on both functions.     

Some aspects of clinical relevance in the maturation of respiratory control in infants.

Two reflex mechanisms important for survival are discussed. Brain stem and cardiovascular mechanisms that are responsible for recovery from severe hypoxia (autoresuscitation) are important for survival in acutely hypoxic infants and adults. Failure of this mechanism may be important in sudden infant death syndrome (SIDS), because brain stem-mediated hypoxic gasping is essential for successful autoresuscitation and because SIDS infants appear to attempt to autoresuscitate just before death. A major function of another mechanism is to protect the airway from fluid aspiration. The various components of the laryngeal chemoreflex (LCR) change during maturation. The LCR is an important cause of prolonged apneic spells in infants. Consequently, it also may have a role in causing SIDS. Maturational changes and/or inadequacy of this reflex may be responsible for pulmonary aspiration and infectious pneumonia in both children and adults.     

Mechanisms underlying induced autoresuscitation failure in BALB/c and SWR mice.

Mechanisms underlying failure of autoresuscitation from hypoxic apnea were investigated. Failure was induced by repeated exposure to hypoxia. The influence of maturation was studied in adults, weanlings, and 10- and 5-day-old mice. Mice successful at autoresuscitation (BALB/c) as well as those prone to autoresuscitation failure (SWR weanlings) were studied. Hypoxic apnea was induced with 97% N2-3% CO2, and 21% O2 was given at its onset; electrocardiogram and ventilation were recorded. Hypoxic exposure was repeated if autoresuscitation (recovery of eupnea) occurred. Autoresuscitation failure (death) was induced in all mice. Young BALB/c mice tolerated more trials than older mice. SWR weanlings frequently failed to autoresuscitate on the initial exposure and tolerated fewer repeat trials overall than age-matched BALB/c mice. Induced autoresuscitation failure in all mice appeared to be unrelated to gasping regulation, because both gasp number and amplitude were similar during the failed trial and the previous successful trial. In most mice, failure was associated with absent recovery of heart rate during gasping. In BALB/c mice in particular, this persistent bradycardia was usually due to heart block, which occurred in 95% of failed trials. In addition, heart block occurred with increasing frequency on later successful trials, but conversion to sinus rhythm always preceded successful autoresuscitation. Heart block was also frequent in SWR mice and had similar consequences. BALB/c mice exposed to continuous anoxia survived longer than SWR mice, indicating increased endurance of components of the autoresuscitation mechanism not directly related to the ventilatory function of gasping (e.g., cardiovascular components).(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory responses to cold water immersion: neural pathways, interactions, and clinical consequences awake and asleep.

The ventilatory responses to immersion and changes in temperature are reviewed. A fall in skin temperature elicits a powerful cardiorespiratory response, termed "cold shock," comprising an initial gasp, hypertension, and hyperventilation despite a profound hypocapnia. The physiology and neural pathways of this are examined with data from original studies. The respiratory responses to skin cooling override both conscious and other autonomic respiratory controls and may act as a precursor to drowning. There is emerging evidence that the combination of the reestablishment of respiratory rhythm following apnea, hypoxemia, and coincident sympathetic nervous and cyclic vagal stimulation appears to be an arrhythmogenic trigger. The potential clinical implications of this during wakefulness and sleep are discussed in relation to sudden death during immersion, underwater birth, and sleep apnea. A drop in deep body temperature leads to a slowing of respiration, which is more profound than the reduced metabolic demand seen with hypothermia, leading to hypercapnia and hypoxia. The control of respiration is abnormal during hypothermia, and correction of the hypoxia by inhalation of oxygen may lead to a further depression of ventilation and even respiratory arrest. The immediate care of patients with hypothermia needs to take these factors into account to maximize the chances of a favorable outcome for the rescued casualty.     

Gasping Generation in Developing Swiss–Webster Mice In Vitro and In Vivo

During hypoxia the respiratory network produces gasping in vivo and in vitro. To understand the mechanisms involved in such response and to validate in vitro findings, correlative studies are necessary. During perinatal age gasping generation is robust and then declines during postnatal development, possibly due to changes in either the rhythm generator (the pre-Bötzinger complex, PBC) and/or its motor outputs. We tested this hypothesis by recording respiratory response to hypoxia in vivo and in vitro during postnatal development. We found that postnatal age influences: (1) The hypoxia-induced pattern change in the PBC bursts, (2) The coupling between the PBC and the XII nucleus during prolonged hypoxia and (3) The ability of mice to gasp and autoresuscitate from hypoxic conditions. We conclude that the inability of mice to gasp during late postnatal development might be determined by a progressive uncoupling between the respiratory rhythm generator and its motor outputs in hypoxia.     

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.     

Hypoxia-mediated prolonged elevation of sympathetic nerve activity after periods of intermittent hypoxic apnea.

Obstructive sleep apnea (OSA) is associated with transient elevation of muscle sympathetic nerve activity (MSNA) during apneic events, which often produces elevated daytime MSNA in OSA patients. Hypoxia is postulated to be the primary stimulus for elevated daytime MSNA in OSA patients. Therefore, we studied the effects of 20 min of intermittent voluntary hypoxic apneas on MSNA during 180 min of recovery. Also, we compared MSNA during recovery after either 20 min of intermittent voluntary hypoxic apneas, hypercapnic hypoxia, or isocapnic hypoxia. Consistent with our hypothesis, both total MSNA and MSNA burst frequency were elevated after 20 min of intermittent hypoxic apnea compared with baseline (P < 0.05). Both total MSNA and MSNA burst frequency remained elevated throughout the 180-min recovery period and were statistically different from time control subjects throughout this period (P < 0.05). Finally, MSNA during recovery from intermittent hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia were not different (P = 0.50). Therefore, these data support the hypothesis that short-term exposure to intermittent hypoxic apnea results in sustained elevation of MSNA and that hypoxia is the primary mediator of this response.     

Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms

Arousal is an important defense against hypoxia during sleep. Rat pups exhibit progressive arousal impairment (habituation) with multiple hypoxia exposures. The mechanisms are unknown. The medullary raphe (MR) is involved in autonomic functions, including sleep, and receives abundant GABAergic inputs. We hypothesized that inhibiting MR neurons with muscimol, a GABA(A) receptor agonist, or preventing GABA reuptake with nipecotic acid, would impair arousal and enhance arousal habituation and that blocking GABA(A) receptors with bicuculline would enhance arousal and attenuate habituation. Postnatal day 15 (P15) to P25 rat pups were briefly anesthetized, and microinjections with aCSF, muscimol, bicuculline, or nipecotic acid were made into the MR. After a ～30-min recovery, pups were exposed to four 3-min episodes of hypoxia separated by 6 min of normoxia. The time to arousal from the onset of hypoxia (latency) was determined for each trial. Latency progressively increased across trials (habituation) in all groups. The overall latency was greater after muscimol and nipecotic acid compared with aCSF, bicuculline, or noninjected controls. Arousal habituation was reduced after bicuculline compared with aCSF, muscimol, nipecotic acid, or noninjected pups. Increases in latency were mirrored by decreases in chamber [O2] and oxyhemoglobin saturation. Heart rate increased during hypoxia and was greatest in muscimol-injected pups. Our results indicate that the MR plays an important, not previously described, role in arousal and arousal habituation during hypoxia and that these phenomena are modulated by GABAergic mechanisms. Arousal habituation may contribute to sudden infant death syndrome, which is associated with MR serotonergic and GABAergic receptor dysfunction.     

Periods of intermittent hypoxic apnea can alter chemoreflex control of sympathetic nerve activity in humans

Obstructive sleep apnea is associated with sustained elevation of muscle sympathetic nerve activity (MSNA) and altered chemoreflex control of MSNA, both of which likely play an important role in the development of hypertension in these patients. Additionally, short-term exposure to intermittent hypoxic apneas can produce a sustained elevation of MSNA. Therefore, we tested the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Twenty-one subjects were randomly assigned to one of three groups (hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia). Subjects were exposed to 30 s of the perturbation every minute for 20 min. Chemoreflex control of MSNA was assessed during baseline, 1 min posttreatment, and every 15 min throughout 180 min of recovery by the MSNA response to a single hypoxic apnea. Recovery hypoxic apneas were matched to a baseline hypoxic apnea with a similar nadir oxygen saturation. A significant main effect for chemoreflex control of MSNA was observed after 20 min of intermittent hypoxic apneas (P <0.001). The MSNA response to a single hypoxic apnea was attenuated 1 min postexposure compared with baseline (P <0.001), became augmented within 30 min of recovery, and remained augmented through 165 min of recovery (P <0.05). Comparison of treatment groups revealed no differences in the chemoreflex control of MSNA during recovery (P=0.69). These data support the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Furthermore, this response appears to be mediated by hypoxia.     

Invited review: Neural network plasticity in respiratory control.

Respiratory network plasticity is a modification in respiratory control that persists longer than the stimuli that evoke it or that changes the behavior produced by the network. Different durations and patterns of hypoxia can induce different types of respiratory memories. Lateral pontine neurons are required for decreases in respiratory frequency that follow brief hypoxia. Changes in synchrony and firing rates of ventrolateral and midline medullary neurons may contribute to the long-term facilitation of breathing after brief intermittent hypoxia. Long-term changes in central respiratory motor control may occur after spinal cord injury, and the brain stem network implicated in the production of the respiratory rhythm could be reconfigured to produce the cough motor pattern. Preliminary analysis suggests that elements of brain stem respiratory neural networks respond differently to hypoxia and hypercapnia and interact with areas involved in cardiovascular control. Plasticity or alterations in these networks may contribute to the chronic upregulation of sympathetic nerve activity and hypertension in sleep apnea syndrome and may also be involved in sudden infant death syndrome.     

Selected Contribution: Regulation of sleep-wake states in response to intermittent hypoxic stimuli applied only in sleep.

Recurrent sleep-related hypoxia occurs in common disorders such as obstructive sleep apnea (OSA). The marked changes in sleep after treatment suggest that stimuli associated with OSA (e.g., intermittent hypoxia) may significantly modulate sleep regulation. However, no studies have investigated the independent effects of intermittent sleep-related hypoxia on sleep regulation and recovery sleep after removal of intermittent hypoxia. Ten rats were implanted with telemetry units to record the electroencephalogram (EEG), neck electromyogram, and body temperature. After >7 days recovery, a computer algorithm detected sleep-wake states and triggered hypoxic stimuli (10% O2) or room air stimuli only during sleep for a 3-h period. Sleep-wake states were also recorded for a 3-h recovery period after the stimuli. Each rat received an average of 69.0 +/- 6.9 hypoxic stimuli during sleep. The non-rapid eye movement (non-REM) and rapid-eye-movement (REM) sleep episodes averaged 50.1 +/- 3.2 and 58.9 +/- 6.6 s, respectively, with the hypoxic stimuli, with 32.3 +/- 3.2 and 58.6 +/- 4.8 s of these periods being spent in hypoxia. Compared with results for room air controls, hypoxic stimuli led to increased wakefulness (P < 0.005), nonsignificant changes in non-REM sleep, and reduced REM sleep (P < 0.001). With hypoxic stimuli, wakefulness episodes were longer and more frequent, non-REM periods were shorter and more frequent, and REM episodes were shorter and less frequent (P < 0.015). Hypoxic stimuli also increased faster frequencies in the EEG (P < 0.005). These effects of hypoxic stimuli were reversed on return to room air. There was a rebound increase in REM sleep, increased slower non-REM EEG frequencies, and decreased wakefulness (P < 0.001). The results show that sleep-specific hypoxia leads to significant modulation of sleep-wake regulation both during and after application of the intermittent hypoxic stimuli. This study is the first to determine the independent effects of sleep-related hypoxia on sleep regulation that approximates OSA before and after treatment.     

Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus

Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.