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J Appl Physiol 99: 1607-1612, 2005. First published June 9, 2005; doi:10.1152/japplphysiol.01267.2004
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HIGHLIGHTED TOPICS
Physiology and Pathophysiology of Sleep Apnea

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

James E. Fewell, Vienna K. Y. Ng, and Chunfen Zhang

Department of Physiology and Biophysics, Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada

Submitted 11 November 2004 ; accepted in final form 8 June 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
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°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.

autoresuscitation; sudden infant death syndrome

THE RESPIRATORY RESPONSE OF newborn mammals [e.g., mice (21), rabbits (2, 5, 10, 22), rats (8, 14), and sheep (42)] to unrelenting hypoxia typically passes through four stages: hyperpnea, primary apnea, gasping, and secondary apnea. The onset of gasping following primary apnea occurs when the arterial PO2 decreases to ~8–10 Torr; this is true during hypercapnic hypoxia produced by airway obstruction or during hypocapnic hypoxia produced by inhalation of a hypoxic gas mixture (16, 22). Peiper (25), Stevens (38), and Thach (40) have emphasized the importance of hypoxic gasping in "self-resuscitation" (1) or "autoresuscitation" (16) in human infants and that repeated exposure to hypoxia may lead to autoresuscitation failure and death. Recent reports by Poets et al. (26) and Sridhar et al. (35), where home memory monitor recordings of sudden infant deaths have been analyzed, have documented failure of hypoxic gasping to effect autoresuscitation and prevent death in a number of apneic infants. Considering the importance of gasping as the last operative mechanism used by mammals to ensure survival during exposure to severe hypoxia, it is important to be knowledgeable of factors that influence the onset, duration, and number of potential autoresuscitation producing gasps as a first step in understanding the integrated physiology of successful autoresuscitation as well as the pathophysiology of failed autoresuscitation from hypoxic-induced apnea.

Our laboratory has recently reported that naive 5- to 6-day-old rat pups, studied at thermoneutrality, display a triphasic pattern of gasping on exposure to unrelenting hypoxia (8). In these animals, hypoxic-induced primary apnea was followed by a period of rapid gasping that lasted 1–2 min; this period of rapid gasping was followed by a period of slower gasping of 1–2 gasps/min that lasted 6–8 min; finally, there was a period of rapid gasping that eventually waned and gave way to secondary apnea and death. In our experience, gasping occurs within 60–90 s of the onset of hypoxia, and naive 5- to 6-day-old rat pups may gasp up to 15 min and exhibit as many as 86 potential autoresuscitation producing gasps. Our laboratory and others have shown that one or more of the previously mentioned gasping characteristics are modulated in this age range of rat pups by factors such core temperature (28), glucose (44), catecholamines (45), nitric oxide (13), and glutamate (12). Given that all of these factors may be altered in one way or the other by exposure to hypoxia, our present experiments have been carried out to determine whether prior exposure to hypoxic-induced apnea, such as may occur during prolonged obstructive apnea or positional asphyxia, influences gasping on exposure to unrelenting hypoxia. Specifically, our experiments were designed to test the hypothesis that prior exposure to 1, 2, 3, 4, 9, and 14 hypoxic-induced apnea/autoresuscitation cycles (HIA/AR) modulates the onset, duration, and number of potential autoresuscitation producing gasps on exposure to unrelenting hypoxia in an exposure-dependent fashion. Furthermore, we have done experiments to determine whether the aforementioned gasping characteristics upon exposure to unrelenting hypoxia return to normal within a 120-min normoxic recovery period after exposure to 9 HIA/AR.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Ninety five, 5- to 6-day-old Sprague-Dawley rat pups were studied. Each pup, born by spontaneous vaginal delivery, was housed with its mother and siblings (22 ± 1°C, 20–30% relative humidity in a 12:12-h light-dark cycle) until an experiment. Although 22°C is below the thermoneutral zone of newborn rats (23), each pup had the opportunity to huddle with its siblings and dam in the nest and thus to thermoregulate behaviorally.

All experimental procedures described herein were carried out in accordance with the Guide to the Care and Use of Experimental Animals provided by the Canadian Council on Animal Care and with the approval of the Animal Care Committee of the University of Calgary.

Experimental Protocols

Experimental series I: prior exposure to HIA/AR and gasping characteristics during exposure to unrelenting hypoxia.   For an experiment, each 5- to 6-day-old pup was removed from its mother and siblings, weighed, and instrumented for measurement of cardiovascular and respiratory variables. Afterward, the pup was positioned prone in a metabolic chamber regulated to 37.0 ± 0.1°C into which flowed room air at a rate of 1 l/min. The time to first and last gasp as well as the total number of gasps to unrelenting hypoxia (i.e., 97% N2-3% CO2) was determined 5 min after each pup had experienced 0 (n = 13), 1 (n = 7), 2 (n = 7), 3 (n = 6), 4 (n = 9), 9 (n = 9), or 14 (n = 9) HIA/AR at 5-min intervals. For each HIA/AR, the gas that flowed into the chamber was changed from room air to 97% N2 and 3% CO2 until primary apnea occurred; the gas was then changed back to room air, and autoresuscitation was effected by gasping. When the gas mixture was changed, the flow rate was increased until the gas concentrations in the chamber had stabilized; the flow rate was then lowered to 1 l/min. Our laboratory has previously shown that naive 5- to 6-day-old pups studied at a thermoneutral temperature of 37.0°C tolerate an average of 15 episodes of HIA/AR before autoresuscitation failure (8). During an experiment, stages of the respiratory response to hypoxia were directly observed on the polygraph tracing.

Experimental series II: normoxic recovery time and gasping characteristics during exposure to unrelenting hypoxia after nine HIA/AR.   For an experiment, each 5- to 6-day-old pup was removed from its mother and siblings, weighed, and instrumented for measurement of cardiovascular and respiratory variables. Afterward, the pup was positioned prone in a metabolic chamber regulated to 37.0 ± 0.1°C into which flowed room air at a rate of 1 l/min. The time to first and last gasp as well as the total number of gasps to unrelenting hypoxia was then determined after each pup had experienced a normoxic recovery period of 5 min (n = 7), 15 min (n = 7), 30 min (n = 7), 60 min (n = 7), or 120 min (n = 7) after nine HIA/AR at 5-min intervals. To determine whether gasping had indeed returned to "normal," comparisons were also made with data obtained in pups (n = 13) from experimental series I that had not experienced hypoxic-induced apnea before being exposed to unrelenting hypoxia.

Experimental Apparatus

The metabolic chamber used in our experiments consisted of a double-walled Plexiglas cylinder (30 cm long, internal diameter 6 cm) into which flowed room air or 97% N2-3% CO2. Chamber ambient temperature was regulated to 37.0 ± 0.1°C by circulating water from a temperature controlled bath (Endocal Refrigerated Circulating Bath RTE-8DD, Neslab) through the space between the walls. Our laboratory has previously shown that 37.0 ± 0.1°C is the preferred ambient temperature of naive 5- to 6-day-old rat pups 20–30 min after they are placed in a thermocline with a linear temperature gradient of 25°C to 40°C (8).

Experimental Measurements and Calculations

During an experiment, the electrocardiogram, respiratory movements and chamber CO2 levels were recorded on a model 7 polygraph (Grass Instrument) at a paper speed of 10 mm/s. A bipolar lead II electrocardiogram was recorded from multistranded stainless steel wire electrodes (AS 633, Cooner Wire) sewn on the right shoulder (– electrode) and the left thigh (+ electrode) as described by Osborne (24); the electrodes were connected to a model 7HIP5 high-impedance probe coupled to a model 7P5 wide-band EEG alternating-current preamplifier (Grass Instrument). Respiratory movements were recorded from a mercury-in-silicone rubber strain gauge (model HgPC, DM Davis) placed around the chest; the strain gauge was connected to a bridge amplifier (Biomedical Technical Support Center, University of Calgary, Calgary, Alberta, Canada) that was coupled to a model 7P03 adapter panel (Grass Instrument).

Statistical Analysis

Statistical analysis was carried out by ANOVA and Newman-Keuls multiple-comparison tests. All results are reported as means ± SD, and P < 0.06 was considered to be of statistical significance.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Experimental Series I: Prior Exposure to HIA/AR and Gasping Characteristics During Exposure to Unrelenting Hypoxia

Prior exposure to HIA/AR at 5-min intervals did not significantly alter the time to first gasp (ANOVA P = 0.344) (Fig. 1), but it decreased the time to last gasp (ANOVA P < 0.001) (Fig. 2) after two HIA/AR and the total number of gasps (ANOVA P < 0.001) (Fig. 3) after three HIA/AR on exposure to unrelenting hypoxia. Exposure of naive pups to unrelenting hypoxia resulted in a reproducible respiratory response as previously reported (8): initially there was a period of hyperpnea and arousal that preceded primary apnea; primary apnea was followed by a period of rapid gasping (phase I of gasping) that was followed by a period of slower gasping (phase II of gasping) of 1–2 gasps/min; finally, there was a period of rapid gasping (phase III of gasping) that eventually waned and gave way to secondary apnea and death. The three phases of gasping became less identifiable as the number of prior HIA/AR were increased before exposure to unrelenting hypoxia (Fig. 4).



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  		Fig. 1. Lack of influence of prior exposure to 0, 1, 2, 3, 4, 9, or 14 hypoxic-induced apnea/autoresuscitation cycles on the time to first gasp on exposure to unrelenting hypoxia in 5- to 6-day-old rat pups. Values are means ± SD. P = 0.344 by ANOVA.

 


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  		Fig. 2. Influence of prior exposure to 0, 1, 2, 3, 4, 9, or 14 hypoxic-induced apnea/autoresuscitation cycles on the time to last gasp upon exposure to unrelenting hypoxia in 5 to 6 day-old rat pups. Values are means ± SD. P ≤ 0.001 by ANOVA; *P ≤ 0.06 vs. 0 prior hypoxic-induced apneas by Newman-Keuls.

 


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  		Fig. 3. Influence of prior exposure to 0, 1, 2, 3, 4, 9, or 14 hypoxic-induced apnea/autoresuscitation cycles on the total number of gasps on exposure to unrelenting hypoxia in 5- to 6-day-old rat pups. Values are means ± SD. P ≤ 0.001 by ANOVA. *P ≤ 0.06 vs. 0 prior hypoxic-induced apneas by Newman-Keuls.

 


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  		Fig. 4. Influence of prior exposure to 0 (A), 4 (B), 9 (C), or 14 (D) hypoxic-induced apnea/autoresuscitation cycles on the gasping pattern in 5- to 6-day-old rat pups on exposure to unrelenting hypoxia.

 
Experimental Series II: Normoxic Recovery Time and Gasping Characteristics During Exposure to Unrelenting Hypoxia After Nine HIA/AC

Normoxic recovery time after nine HIA/AR significantly influenced the time to last gasp and the total number of gasps (Figs. 5 and 6) on exposure to unrelenting hypoxia but only at 120 min. After a normoxic recovery period of 120 min, the total 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.



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  		Fig. 5. Influence of normoxic recovery time on the time to last gasp on exposure to unrelenting hypoxia in 5- to 6-day-old rat pups after 9 hypoxic-induced apnea/autoresuscitation cycles. Values are means ± SD. NA, not applicable. P ≤ 0.001 by ANOVA. *P ≤ 0.06 vs. 0/NA from experimental series I by Newman-Keuls. {dagger}P ≤ 0.06 vs. 9/5 by Newman-Keuls.

 


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  		Fig. 6. Influence of normoxic recovery time on the total number of gasps on exposure to unrelenting hypoxia in 5- to 6-day-old rat pups after 9 hypoxic-induced apnea/autoresuscitation cycles. Values are means ± SD. P ≤ 0.001 by ANOVA. *P ≤ 0.06 vs. 0/NA from experimental series I by Newman-Keuls. {dagger}P ≤ 0.06 vs. 9/5 by Newman-Keuls.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Our experiments provide new information about factors that influence the newborn’s respiratory response to hypoxia. Novel findings of our study were that although prior exposure to hypoxic-induced apnea did not alter the time to first gasp, it significantly decreased the time to last gasp as well as the total number of gasps on exposure to unrelenting hypoxia in an exposure-dependent fashion. When the normoxic recovery time after nine HIA/AR was varied from 5 to 120 min, the time to last gasp as well as the total number of gasps on exposure to unrelenting hypoxia recovered partially but only at 120 min (i.e., the total number of gasps was similar but the time to last gasp was still decreased compared with that observed in naive animals exposed to hypoxia). Thus prior exposure to hypoxic-induced apnea as may occur during prolonged 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.

Newborn mammals display a characteristic respiratory response consisting of hyperpnea, primary apnea, gasping, and secondary apnea on exposure to unrelenting hypoxia [e.g., mice (21), rabbits (2, 5, 10, 22), rats (8, 14), and sheep (42)]. The onset of gasping after primary apnea occurs when the arterial PO2 decreases to ~8–10 Torr whether produced by airway obstruction resulting in hypercapnic hypoxia or inhalation of a hypoxic gas mixture resulting in hypocapnic hypoxia (16, 22). As seen in the present study, naive 5- to 6-day-old rats exhibit a triphasic pattern of gasping following primary apnea, which eventually wanes and gives way to secondary apnea and death (8, 13). As far as we are aware, the neurophysiological basis for the three phases of gasping that follow primary apnea is unknown. It may, however, result from firing of different populations of neurons in the lateral tegmental field of the medulla [the proposed neural substrate underlying gasping in the rat (9, 36, 43)], which have different thresholds and/or latencies to the hypoxic stimulus or perhaps it results from the influence of various neuromodulators on the firing pattern of a single population of neurons during hypoxia. In the present study, the three phases of gasping became less discernible as the number of prior HIA/AR were increased prior to exposure to unrelenting hypoxia.

Although the mechanism of the altered gasping pattern after prior exposure to hypoxic-induced apnea is unknown, it may have resulted from substrate depletion, altered neuroendocrine function, or synthesis and release of neuromodulators that influence hypoxic gasping. As previously mentioned, a number of factors have been shown to govern the time to last gasp in rats during early postnatal development on exposure to unrelenting hypoxia including core temperature (28), glucose (37, 44), catecholamines (45), excitatory amino acids (12), and nitric oxide (13). Our laboratory has previously shown that exposure to hypoxia induces a "regulated" decrease in core temperature (3) and that core temperature influences the time to last gasp as well as the total number of gasps in 5- to 6-day-old rat pups on exposure to unrelenting hypoxia. Variations in core temperature, however, are unlikely to have altered the gasping pattern after prior HIA/AR in our present experiments as core temperature was clamped at or near 37°C by regulating environmental temperature (23), and it is an increase rather than a decrease in core temperature that elicits a decrease in the time to last gasp by (28).

As oxygen levels decrease to very low levels, a transition from aerobic to anaerobic metabolism occurs throughout the body and energy for processes such as gasping is provided by glycolysis via the Embden-Meyerhof pathway, which utilizes carbohydrate (e.g., glucose and/or glycogen) as a substrate. With regard to provision of substrate, Stafford and Weatherall (37) have shown that neither liver glycogen nor blood glucose levels determine survival time (i.e., the time to last gasp) when newborn rats are exposed to nitrogen. Brain glucose levels, however, can decrease dramatically during anoxia despite normal or elevated plasma (and liver) glucose levels, indicating an imbalance between brain glucose supply and demand (19). For example, experiments carried out by Holowach-Thurston et al. (19) on intact newborn mice at 37°C have revealed that even though plasma glucose levels double during a 6-min exposure to anoxia, brain glucose decreases by ~72%. Brain glucose is likely a relatively important substrate for glycolysis in the newborn compared with the adult because basal brain glycogen is low and remains relatively stable during the first few minutes of anoxia perhaps due to the absence of enzymes (e.g., phosphoglucomutase) required for the utilization of brain glycogen (20, 29, 30). In rats pups, supplemental glucose has been shown to increase the time to last gasp during anoxic exposure when administered after the first few days of postnatal life (17, 18, 37, 44). Thus it is possible that the altered gasping pattern observed in our present experiments after repeated HIA/AR may have resulted from inadequate energy production via glycolysis secondary to low brain glucose levels. This postulate warrants investigation as does an investigation of the rate at which brain glucose is replenished in the newborn after bouts of hypoxic-induced apnea.

Hypoxia is a potent stimulus for the adrenomedullary secretion of catecholamines, which mediate important respiratory, cardiovascular, and metabolic adaptations to oxygen lack during the perinatal period (4, 27). In the rat, which is born relatively immature, functional innervation of the adrenal medulla by the splanchnic nerves is not apparent until the second week of postnatal life (31, 32, 34). Adrenal chromaffin cells, however, possess a developmentally regulated oxygen-sensing mechanism, similar to that of carotid body type I cells (41), which mediate a "nonneurogenic" release of catecholamines in response to hypoxia until splanchnic control of adrenomedullary catecholamine secretion is functional (27). The role of catecholamines in hypoxic-induced gasping was shown in experiments carried out by Yuan et al. (45), who reported that the time to last gasp on exposure to unrelenting hypoxia was decreased in 1- and 8-day-old rat pups after adrenalectomy compared with that observed in sham-operated controls. Considering this and the evidence that hypoxia causes adrenal catecholamine depletion in rat pups (27), the altered gasping pattern observed in our present experiments after HIA/AR may have resulted from adrenal catecholamine depletion and the lack of a "normal" adrenal catecholamine response. This postulate warrants investigation as does an investigation of the rate at which adrenal catecholamines are replenished in the newborn after bouts of hypoxic-induced apnea. Although Slotkin and Kirshner (33) have shown that it takes up to 96 h for adrenal vesicular catecholamines to return to control levels following insulin administration in adult rats, as far as we are aware, the rate at which adrenal vesicular catecholamine replenishment occurs in the newborn after hypoxic-induced depletion is unknown.

Gozal et al. (13) and Gozal and Torres (12) have shown that nitric oxide and glutamate, signaling molecules that influence neuronal excitability, play important roles in initiating and modulating the pattern of gasping in rat pups during exposure to anoxia. In their experiments, pretreatment of 5-day-old rat pups with N-nitro-L-arginine, a nitric oxide synthase blocker, significantly increased the time to first gasp and gasping duration without altering the total number of gasps. Pre-treatment of 5-day-old rat pups with MK-801 {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate, a noncompetitive N-methyl-D-aspartate glutamate receptor channel antagonist} also prolonged the duration of primary apnea and increased the time to last gasp. Thus their data support the postulate that these neuromodulators favor the early appearance of gasps but limit anoxic tolerance during exposure to anoxia. Given that exposure to anoxia results in massive glutamate release (39) and activation of the brain nitric oxide system (e.g., Ref. 6), it is possible that these neuromodulators played a role in modulating gasping in our experiments after repetitive HIA/AR in our experiments. This warrants further investigation.

The results of our experiments extend the observations of Gozal et al. (11), who recently reported that prolonged exposure to intermittent hypoxemia in the fetus or newborn alters the gasping pattern of 5-day-old pups on exposure to unrelenting hypoxia. In their experiments, intermittent fetal hypoxemia was produced by alternating the dam’s fraction of inspired oxygen between 0.21 and 0.10 at 90-s intervals from day 5 of gestation to term, and intermittent newborn hypoxemia was produced by alternating the pup’s fraction of inspired oxygen between 0.21 and 0.10 at 90-s intervals within 12 h of parturition until day 5 of postnatal life. Neither perturbation altered the time to first gasp, but both decreased the time to last gasp as well as the total number of gasps at day 5 of postnatal life when exposed to unrelenting hypoxia. In the present experiments, decreases in the time to last gasp and the total number of gasps were produced by prior exposure to as few as two and three HIA/AR, respectively, which induces a more severe level of hypoxia. Although the mechanisms of action may be different, it is interesting that such different low-oxygen-exposure regimens in essence have the same effect on hypoxic gasping in the 5-day-old rat pup.

In infants, spontaneous recovery from obstructive sleep apnea or positional asphyxia during sleep is thought to occur early as a result of arousal from sleep or later as a result of hypoxic gasping when it is known as autoresuscitation (15, 40). Peiper (25), Stevens (38), and Thach (40) have emphasized the importance of gasping in self-resuscitation or autoresuscitation during apnea in human infants and that repeated episodes of apnea might lead to autoresuscitation failure and death. Why autoresuscitation fails is unclear, but our present experiments show that the duration and number of potential autoresuscitation producing gasps on exposure to unrelenting hypoxia are decreased by prior exposure to hypoxia and that this "impairment" lasts upward of 120 min. If oxygen does not become available immediately on the initiation of gasping, as conceivably may occur in infants, hypoxic secondary to obstructive sleep apnea or positional asphyxia, a decrease in the duration and/or number of gasps could diminish the chance of a successful autoresuscitation.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This study was supported by the Canadian Institutes of Health Research.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Sherry Moore for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. E. Fewell, Heritage Medical Research Bldg., 206, Univ. of Calgary, 3330 Hospital Dr., NW, Calgary, Alberta, Canada T2N 4N1 (e-mail: fewell{at}ucalgary.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
V. Marchenko and R. F. Rogers
Selective loss of high-frequency oscillations in phrenic and hypoglossal activity in the decerebrate rat during gasping
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1414 - R1429.
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