Failure Of Autoresuscitation Research Articles

Looper, an updated closed loop feature detection platform for automated neonate cardio-respiratory measurements and data analysis

Facemask pneumotachography is a common, precise experimental approach for measuring respiratory outcomes in neonate rodents (P7-8), particularly in autoresuscitation experiments that inform upon Sudden Infant Death Syndrome where failure of autoresuscitation is hypothesized to be a common endpoint. However, current approaches rely on direct, real-time waveform inspection by an observer and their highly variable reaction times to execute responsive changes in assay gas exposures. Looper, represents a novel and significant improvement on typical observer-based interpretation of live data to initiate challenge and recovery gas applications to uncover nuanced features in neonate cardiorespiratory physiology. Leveraging our previously published Breathe Easy software, we have expanded the analytical capabilities of the software to analyze key features within a typical autoresuscitation cycle. Utilizing the software output, we have further developed machine learning approaches that enable real-time prediction of cardio-respiratory failure based distinct waveform features more than 10min in advance, setting the stage for novel experiments to identify critical interventional windows for enhancing resuscitation. R01HL161142 R01HL130249. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Concurrent, dual perturbations of the 5-HT and NA systems reveal dynamic interplay in regulating the neonate autoresuscitation reflex

Sudden Infant Death Syndrome (SIDS) is a leading cause of infant mortality worldwide. Failure of the neonate auto-resuscitation reflex is hypothesized to be a common endpoint in many SIDS cases. Although SIDS is idiopathic, postmortem studies indicate abnormalities in the serotonergic (5-HT) and noradrenergic (NA) systems of the respiratory network. To better understand the contributions and interactions of these two systems in autoresuscitation, we combined a novel series of Cre- and FLPo- recombinase driver mouse lines and conditional inhibitory and excitatory DREADD lines for singular excitation or inhibition of either the whole 5-HT or whole NA systems. These models were then uniquely combined to further enable 1) concurrent excitation or inhibition of both systems in the same neonate or 2) inhibition of one system while exciting the other system in the same neonate. In total, we developed 8 distinct sets of conditional genetic mouse models for singular and combined 5-HT and NA system perturbation paradigms. The 8 experimental groups and 2 control groups were repeatedly assayed for the autoresuscitation reflex using a robotic neonate cardiorespiratory assessment platform, Looper. Neonates are repeatedly tested until they succumb. Resulting data were analyzed with our recently published waveform analysis software, Breathe Easy, to calculate operant outcomes. In 320 mice total, we found 4 groups with decreased autoresuscitation success: NA activation, NA activation + 5-HT activation, NA activation + 5-HT inhibition, and 5-HT activation. There was no change in survival in any of the other groups including 5-HT inhibition. Preliminary results suggest a potential cardiovascular mechanism of autoresuscitation failure independent of respiratory outcomes. At baseline, all 4 groups with decreased survival showed increased heart rate (HR) whereas the other groups either had the same HR or a decreased HR. During early recovery, defined as beginning at the 10th breath following the primary gasp until recovery, the 4 groups with decreased survival show higher HR than the other groups following the 1st bout of autoresuscitation. As recovery progressed in these groups, HR continued to increase as well until the next autoresuscitation test. Ventilatory frequency, tidal volume, and ventilation all increased in the 3 groups where NA was activated either in isolation or in combination, but there were decreases in all other groups, including 5-HT activation. As the underlying genetic and environmental mechanisms driving SIDS are likely to have pleiotropic effects across multiple neural systems, our first-of-its-kind dual 5-HT and NA system modulations set the stage to more comprehensively model key aspects of SIDS neuropathology that reveal a previously uncharacterized dynamic functional interplay between the NA and 5-HT systems in protective respiratory reflexes. NIH: 1F32HL160073-01A1, R01HL130249 44617-S4. BCM McNair Scholar Program, March of Dimes Basil O'Connor Research Award, Parker B. Francis Fellowship, CJ Foundation for SIDS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Concurrent, dual perturbations of the 5-HT and NA systems reveal dynamic interplay in regulating the neonate autoresuscitation reflex

Sudden Infant Death Syndrome (SIDS) is a leading cause of infant mortality worldwide. Postmortem studies indicate abnormalities in the serotonergic (5-HT) and noradrenergic (NA) systems of the respiratory network. To better understand the relative and potential combined contributions and interactions of these two neurotransmitter systems to SIDS pathology, we developed a novel series of conditionally expressed inhibitory (hM4De) and excitatory (hM3D) DREADD models that allows for singular excitation or inhibition of either the whole 5-HT or whole NA systems as defined by cre- and FLPo- drivers. These models were then uniquely combined to further enable 1) concurrent stimulation or inhibition of both the NA and 5-HT systems in the same animal or 2) inhibition of one system while exciting the other system in the same animal. In total, after two years of complex breeding combining 3 loci and 6 alleles, we developed 8 distinct sets of conditional genetic mouse models for various singular and combined 5-HT and NA system perturbation paradigms.Failure of the neonate auto-resuscitation reflex is hypothesized to be a common endpoint in many SIDS cases. The autoresuscitation reflex can be readily assayed in neonate mice by repeated bouts of exposure to an anoxic gas to induce bradycardia and apnea followed by restoration of room air to observe successful or failed autoresuscitation. The 8 experimental groups and 2 control groups were repeatedly assayed for the autoresuscitation reflex using a new closed loop robotic neonate cardiorespiratory assessment platform and outcomes were analyzed with our recently developed comprehensive respiratory analysis platform, Breathe Easy, to calculate operant outcomes. In >170 mouse pups (≈17 pups per group) assayed over three months, we found that singular DREADD-mediated activation or inhibition of the NA system results in decreased survival. Interestingly, we found that DREADD-mediated 5-HT activation decreases survival. In contrast to previous studies, we found that DREADD-mediated 5-HT inhibition does not impact survival, particularly when all neonates are challenged to autoresuscitation failure. Furthermore, we show survival is restored to control levels when NA inhibition is combined with 5-HT inhibition; however, failure via NA activation is not rescued by 5-HT inhibition. Controls used for comparison were CNO-injected controls as we also show an effect of CNO on survival that cannot be attributed to time of day, rig, experimenter, weight, background genotype, etc. As the underlying genetic and environmental mechanisms driving SIDS are likely to have pleiotropic effects across multiple neural systems, our first-of-its-kind dual 5-HT and NA system modulations sets the stage to more comprehensively model key aspects of SIDS neuropathology that reveal a previously uncharacterized dynamic functional interplay between the NA and 5-HT systems in protective respiratory reflexes. NIH: 1F32HL160073-01A1, R01HL130249 44617-S4. BCM McNair Scholar Program, March of Dimes Basil O'Connor Research Award, Parker B. Francis Fellowship, CJ Foundation for SIDS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pre- and early postnatal nicotine exposure exacerbates autoresuscitation failure in serotonin-deficient rat neonates.

Sudden infant death syndrome (SIDS) is one of the leading causes of death during the first year of life and abnormalities linked to serotonin (5-HT) have been identified in many SIDS cases. Cigarette smoking and associated exogenous stressors, e.g. developmental nicotine exposure, may compound these serotonergic defects and any associated defects in cardiorespiratory function. Using neonatal rodent pups subjected to medullary 5-HT deficiency and perinatal nicotine exposure, we examined the impact of this interplay of factors on the neonates' ability to autoresuscitate at specific ages. In perinatal nicotine-exposed 5-HT deficient pups, impaired autoresuscitation along with significantly delayed post-anoxic recovery of normal breathing and heart rate was observed at postnatal day 10 (P10). We found that the interaction between 5-HT deficiency and perinatal nicotine exposure can significantly increase pups' vulnerability to environmental stressors and exacerbate defects in cardiorespiratory protective reflexes to repetitive anoxia during the development period. Cigarette smoking during pregnancy increases the risk of sudden infant death syndrome (SIDS), and nicotine replacements, a key ingredient of cigarettes, have been recently prescribed to women who wish to quit smoking during their pregnancy. Serotonin (5-HT) abnormalities have been consistently identified in many SIDS cases. Here we investigated the effects of perinatal nicotine exposure in mild 5-HT deficiency rat neonates on autoresuscitation, a protective cardiorespiratory reflex. The mild 5-HT deficiency was induced by a maternal tryptophan-deficient diet, and nicotine was delivered from embryonic day (E) 4 to postnatal day (P) 10 at 6mg kg-1 day-1 through an osmotic pump. In P10 rats, nicotine exposure exacerbates autoresuscitation failure (mortality) in mildly 5-HT-deficient rats to a greater extent than in controls (P=0.029). The recovery of eupnoea and heart rate to baseline values following repetitive anoxic events (which elicit an apnoea accompanied by a bradycardia) is significantly delayed in 5-HT-deficient rats treated with nicotine, making them more susceptible to failure of autoresuscitation (eupnoea recovery: P=0.0053; heart rate recovery: P=<0.0001). Neither 5-HT deficiency nor nicotine exposure alone appears to affect the ability to autoresuscitate significantly when compared among the four treatments. The increased vulnerability to environmental stressors, e.g. severe hypoxia, asphyxia, or anoxia, in these nicotine-exposed 5-HT-deficient neonates during postnatal developmental period is evident.

Caffeine improves survival in autoresuscitation‐impaired serotonin deficient rats

Our previous investigation demonstrated that an existing underlying vulnerability in rat neonates (i.e. brainstem 5‐HT deficiency) in combination with a stressor (i.e. pre‐ and early post‐natal nicotine exposure) exacerbates autoresuscitation failure from an anoxic event at a critical developmental period (P10 rats). During this critical period, we hypothesize that caffeine, a respiratory stimulant, will improve successful autoresuscitation rates in the 5‐HT deficient, nicotine exposed P10 neonates and reduce mortality. Preliminary data demonstrate that an intraperitoneal injection of 10mg kg−1 caffeine prior to anoxic challenge improves autoresuscitation rates (survival rate approximately 40%) in the 5‐HT deficient, nicotine exposed P10 rats in comparison to the rats who received IP saline vehicle injections (survival rate of 25%). Prior investigation suggests that eupnea and heart rate recovery following an anoxic event (which elicits an apnea accompanied by a bradycardia) is significantly delayed in 5‐HT deficient rats treated with nicotine, making them more susceptible to failure of autoresuscitation (p&lt;0.05). Presence of caffeine is likely facilitating successful autoresuscitation by shortening apnea duration and promoting an early onset of gasping post‐apnea for a faster eupnea and heart rate recovery.Support or Funding InformationResearch is supported by the NIH Program Project Grant HD036379 (NICHD, PI, Dymecki, S. M.; Project PI, Nattie, E. E.). The authors would also like to acknowledge the generous support of the Tenney Fund and the Ryan Fellowship (awarded to S. Lee).

Adenosine A1-receptor blockade impairs the ability of rat pups to autoresuscitate from primary apnea during repeated exposure to hypoxia.

Failure of gasping to bring about autoresuscitation from hypoxia-induced apnea has been suggested to play a role in sudden unexpected infant death. Little is known, however, about factors that influence the ability of gasping to restore life during severe hypoxia in newborns. Given that adenosine modulates cardiac function during hypoxia-induced apnea and that cardiac dysfunction plays a role in mediating autoresuscitation failure, the present experiments were carried out on 34, 5- to 6-, and 10- to 11-day-old rat pups to investigate their ability to autoresuscitate from hypoxia-induced apnea during repeated exposure to hypoxia after adenosine A1-receptor blockade. Each pup was placed into a temperature-controlled chamber regulated to 37 ± 1°C and repeatedly exposed to an anoxic gas mixture (97% N2 and 3% CO2) until the occurrence of autoresuscitation failure. One group was studied following administration of the selective adenosine A1-receptor antagonist 8-Cyclopentyl-1,3,-dipropylxanthine (DPCPX) and one group was studied following vehicle. DPCPX significantly attenuated bradycardia during hypoxia-induced apnea and impaired the ability of both age groups of pups to autoresuscitate during repeated exposure to hypoxia (5–6 days tolerated – vehicle 17 ± 4 vs. DPCPX 10 ± 2 hypoxia exposures [P < 0.05]; 10–11 days tolerated – vehicle 10 ± 2 vs. DPCPX 7 ± 2 hypoxia exposures [P < 0.05]). Death in all pups resulted from the inability of gasping to restore cardiovascular function during hypoxia-induced apnea although the mechanism of cardiovascular dysfunction/failure was influenced and the occurrence hastened by DPCPX. Thus, our data provide evidence that adenosine acting via adenosine A1-receptors enhances the ability of rat pups to tolerate repeated exposure to severe hypoxia during early postnatal maturation.

Prenatal and early postnatal nicotine exposure adversely affects autoresuscitation in serotonin deficient rats

We investigated the effects of prenatal and early postnatal nicotine exposure in rat neonates treated with control vs. tryptophan deficient diets, the latter known to induce a brainstem 5-HT deficiency. In P10 neonates, nicotine exposurefrom E4 to P10 at 6mg kg-1 day-1 exacerbates autoresuscitation failure in 5-HT deficient rats (p<0.05) to a greater extent than in controls. Exposure to nicotine compounds the effects of 5-HT deficiency whereas neither 5-HT deficiency nor nicotine alone appears to affect the ability to autoresuscitate significantly. Furthermore, the recovery of eupnea and heart rate to baseline values following an anoxic event (which elicits an apnea accompanied by a bradycardia) is significantly delayed in 5-HT deficient rats treated with nicotine, making them more susceptible to failure of autoresuscitation (p<0.05). In younger (P5) and older (P12 – 13) pups, neither 5-HT deficiency nor nicotine exposure alone affects the ability to autoresuscitate; interestingly, the two factors combine...

Anoxia‐induced respiratory arrest and autoresuscitation in rat pups exposed to dietary tryptophan deficiency

Many Sudden Infant Death Syndrome cases are associated with abnormalities in the medullary serotonergic system. We hypothesize that these abnormalities impair infants from adequately responding to stresses, such as hypoxia and hypercapnia (asphyxia), which may be a consequence of rebreathing exhaled gases when in the prone positition. Asphyxia initiates a series of events that lead to a reflex known as autoresuscitation. To examine the role of a moderate depletion of serotonin (5HT) on autoresuscitation, we studied pups born from Sprague‐Dawley dams fed a diet partially deficient in tryptophan (~45%). Using head‐out plethysmography, we identified the cardiorespiratory responses to repeated episodes of anoxia (97% N2:3% CO2) and the ability to autoresuscitate from anoxia‐induced respiratory arrest. At each age studied (P5, P8, P12) tryptophan deficient pups had a similar level of autoresuscitation failure as control. We then examined the effect of “pretreatment” with prior post‐natal chronic intermittent hypoxia (CIH) on the ability to autoresuscitate. CIH increased the ability of control pups to autoresuscitate but had no effect on survival in tryptophan deficient pups (P=0.042; Chi‐square). This suggests that CIH improves the ability to autoresuscitate from anoxia‐induced respiratory arrest, likely through a 5HT dependent mechanism. (NIH National Institute of Child Health and Development HD36379)

Heart Glycogen Influences Protective Responses of Rat Pups to Hypoxia during Early Postnatal Maturation

Failure to auto resuscitate from hypoxic-induced apnea by gasping has been suggested to play a role in sudden infant death. Little is known, however, about factors that influence gasping and its ability to sustain life during acute hypoxia in the newborn. Given that cardiac dysfunction and circulatory failure likely play a role in mediating auto resuscitation failure, the present experiments were carried out on 206 rat pups to investigate the influence of heart glycogen -- a metabolic substrate that supports cardiac function during acute hypoxia -- on the time to last gasp (TLG) during a single period of unrelenting hypoxia, and on the ability to auto resuscitate (AR) from primary apnea during repeated hypoxic challenge. On days 1-2, 5-6, and 10-11 postpartum, each pup was placed into a temperature controlled chamber regulated to 37 ± 1° C and exposed either to a single period of unrelenting hypoxia produced by breathing an anoxic gas mixture (97% N2 and 3% CO2) and the TLG determined, or repeatedly exposed to hypoxia and the ability to AR from primary apnea determined. Pups were studied with normal heart glycogen concentrations and with decreased heart glycogen concentrations effected by prior isoproterenol-induced transient tachycardia. A decrease in heart glycogen concentration did not significantly alter the TLG upon exposure to a single period of unrelenting hypoxia. It did, however, significantly decrease the number of successful AR from primary apnea during repeated hypoxic exposures in 1-2, 5-6, and 10-11 day-old pups. Thus, heart glycogen concentration influences the ability of rat pups to AR from hypoxic-induced primary apnea during early postnatal life.

Postnatal loss of brainstem serotonin neurones compromises the ability of neonatal rats to survive episodic severe hypoxia

Pet-1(-/-) mice with a prenatal, genetically induced loss of 5-hydroxytryptamine (5-HT, serotonin) neurones are compromised in their ability to withstand episodic environmental anoxia via autoresuscitation. Given the prenatal role of 5-HT neurones in the development of neural networks, here we ask if a postnatal loss of 5-HT neurones also compromises autoresuscitation. We treated neonatal rat pups at postnatal day (P)2-3 with an intra-cisternal injection of 5,7-dihydroxytryptamine (5,7-DHT; ~40 μg; n = 8) to pharmacologically lesion the 5-HT system, or vehicle (control; n = 14). At P7-10 we exposed unanaesthetized treated and control pups to 15 episodes of environmental anoxia (97% N(2), 3% CO(2)). Medullary 5-HT content was reduced 80% by 5,7-DHT treatment (P < 0.001). Baseline ventilation (V(E)), metabolic rate (V(O(2))), ventilatory equivalent (V(E)/V(O(2))), heart rate (HR), heart rate variability (HRV) and arterial haemoglobin saturation (S(aO(2))) were no different in 5-HT-deficient pups compared to controls. However, only 25% of 5-HT-deficient pups survived all 15 episodes of environmental anoxia, compared to 79% of control littermates (P = 0.007). High mortality of 5,7-DHT-treated pups was associated with delayed onset of gasping (P < 0.001), delayed recovery of HR from hypoxic-induced bradycardia (P < 0.001), and delayed recovery of eupnoea from hypoxic-induced apnoea (P < 0.001). Treatment with 5,7-DHT affected neither the gasping pattern once initiated, nor HR, V(E)/V(O(2)) or S(aO(2)) during the intervening episodes of room air. A significant increase in HRV occurred in all animals with repeated exposure, and in 5-HT-deficient pups this increase occurred immediately prior to death. We conclude that a postnatal loss of brainstem 5-HT content compromises autoresuscitation in response to environmental anoxia. This report provides new evidence in rat pups that 5-HT neurones serve a physiological role in autoresuscitation. Our data may be relevant to understanding the aetiology of the sudden infant death syndrome (SIDS), in which there is medullary 5-HT deficiency and in some cases evidence of severe hypoxia and failed autoresuscitation.

Genesis of gasping is independent of levels of serotonin in the Pet-1 knockout mouse

Eupnea is normal breathing. If eupnea fails, as in severe hypoxia or ischemia, gasping is recruited. Gasping can serve as a powerful mechanism for autoresuscitation. A failure of autoresuscitation has been proposed as a basis of the sudden infant death syndrome. In an in vitro preparation, endogenous serotonin is reported to be essential for expression of gasping. Using an in situ preparation of the Pet-1 knockout mouse, we evaluated such a critical role for serotonin. In this mouse, the number of serotonergic neurons is reduced by 85-90% compared with animals without this homozygous genetic defect. Despite this reduction in the number of serotonergic neurons, phrenic discharge in eupnea and gasping of Pet-1 knockout mice was not different from that of wild-type mice. Indeed, gasping continued unabated, even after administration of methysergide, a blocker of many types of receptors for serotonin, to Pet-1 knockout mice. We conclude that serotonin is not critical for expression of gasping. The proposal for such a critical role, on the basis of observations in the in vitro slice preparation, may reflect the minimal functional neuronal tissue and neurotransmitters in this preparation, such that the role of any remaining neurotransmitters is magnified. Also, rhythmic activity of the in vitro slice preparation has been characterized as eupnea or gasping solely on the basis of activity of the hypoglossal nerve or massed neuronal activities of the ventrolateral medulla. The accuracy of this method of classification has not been established.

Maintenance of convective requirement during recovery from moderate heat stress in newborn mice

Hypothermia often provides a regulated protective mechanism that improves survival. In contrast, overheating may result in disruption of cerebral function, impacting upon respiratory/thermal control centers. Hyperthermia in newborns, particularly if accompanied by hypoxia, is associated with diminished arousals, increased apneas and failure of autoresuscitation. Recovery from hyperthermia is associated with an induced hypothermia which is believed to be a thermoregulatory phenomenon. Whether a hyperthermia induced hypothermia following heat stress occurs in newborn mice with limited thermoregulatory ability is unknown, and whether this affects the tight linkage between ventilation and metabolic rate normally maintained in hypothermic newborns remains to be elucidated. Newborn (day 2 and 7) pepN mice fitted with a small face mask and placed in an open flow respirometer were exposed to normoxia and initial ambient temperatures (Ta) of either 30°C, 32°C or 34°C for 40 min, after which Ta was decreased to and subsequently increased from 18°C at a rate of 0.5°C/min. Metabolic rate (rates of oxygen consumption and CO2 production), ventilation (VE) and body temperature (Tb) were measured continuously. For both ages, nest Tb was ~30°C and the Tb-Ta difference at day 2 and 7 was ~1°C or 2°C, respectively. In response to cooling from Ta = 30°C or 32°C both ages were capable of limited thermogenesis; in response to cooling from Ta = 34°C thermogenic effort was ablated. Irrespective of the initial Ta, the convective requirement (i.e. VE/metabolic rate) was maintained during heating and cooling for a given Ta; though the convective requirement tended to be higher in mice initially exposed to 34°C. The results support the notion that following moderate overheating and during recovery hypothermia the mechanisms that couple ventilation to metabolic rate are not impaired.

The role of respiratory control disorders in SIDS

Although sudden death in infants resulting from cardiac arrhythmias are well documented these appear to account for no more than 5-10% of SIDS cases. Sudden respiratory failure currently is viewed as the most likely cause of death in the remainder. Accidental asphyxiation appears to have a causal role in less then 50% of deaths diagnosed as SIDS. The rest are most likely do to some form of acute respiratory failure. Although failure of autoresuscitation or failure to arouse from sleep likely contribute to the final sequence of events leading to at least some SIDS deaths, these cannot be regarded as causes of the primary respiratory failure initiating the fatal sequence. Past and current studies provide strong circumstantial evidence that obstructive sleep apnea and/or apnea of prematurity likely account for respiratory failure leading to SIDS in some or many deaths. In drawing conclusions it is well to recognize that mechanisms leading to death in SIDS are heterogeneous and therefore there is room for several plausible theories for respiratory or circulatory abnormalities contributing to SIDS.

Alpha2 receptor binding in the medulla oblongata in the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is the leading cause of postnatal infant mortality in the United States. Its etiology remains unknown. We propose that SIDS, or a subset of SIDS, is due to a failure of autoresuscitation, a protective brainstem response to asphyxia or hypoxia, in a vulnerable infant during a critical developmental period. Gasping is an important component of autoresuscitation that is thought to be mediated by the "gasping center" in the lateral tegmentum of the medulla, a region homologous in its cytoarchitecture and chemical anatomy to the intermediate reticular zone (IRZ) in the human. Since we found that [3H]para-aminoclonidine ([3H]PAC) binding to alpha2-adrenergic receptors localizes to this region in human infants and, thereby provides a neurochemical marker for it, we tested the hypothesis that [3H]PAC binding to alpha2-adrenergic receptors is decreased in the IRZ in SIDS victims. Using quantitative tissue autoradiography with [3H]PAC as the radioligand and phentolamine as the displacer, we analyzed alpha2-receptor binding density in the IRZ, as well as in 7 additional sites for comparison, in 10 SIDS and 10 control medullae. There were no significant differences in alpha2 receptor binding in the IRZ, vagal nuclei, or other medullary sites examined between SIDS and control cases. These results suggest that the putative gasping defect in the IRZ in SIDS victims is not related to [3H]PAC binding to alpha2-adrenergic receptors.

Effects of upper airway stimulation on swallowing, gasping, and autoresuscitation in hypoxic mice.

Severe hypoxia produces a state of neural depression known as hypoxic coma in which reflex activity is believed to be absent but from which spontaneous recovery ("autoresuscitation") still can occur. We evaluated the swallowing reflex during hypoxic coma by employing mechanical and chemosensory stimuli. BALB/c mice were given 97% N2-3% CO2 to breathe. At onset of coma, a 0.05-ml bolus of saline or water was infused into the pharynx. Unlike mechanical stimulation (sham infusion), fluid infusion usually was followed by rapid swallowing, more so with water than with saline. This model allowed examination of interactions among swallowing, hypoxic gasping, airway fluid removal, and autoresuscitation. Compared with sham infusion, saline and water reduced gasping rate equally. Saline, however, prolonged the process of autoresuscitation more than did water, an effect possibly related to an observed increased retention of saline in the airway. Occasionally, mice failed to swallow after infusions, in which case airway obstruction during gasping and autoresuscitation failure was repeatedly observed. These studies suggest that the swallowing component of the laryngeal chemoreflex is present during hypoxic coma and that swallowing facilitates autoresuscitation when upper airway fluid is present.

Mechanism of failure of recovery from hypoxic apnea by gasping in 17- to 23-day-old mice

The mechanism of failure of autoresuscitation from hypoxic apnea in 17- to 23-day-old (weanling) Swiss Webster related/J mice was investigated by recording electrocardiogram (ECG) and ventilation in adult, weanling, and 11-day-old mice. Hypoxic apnea was induced with 97% N2-3% CO2. O2 (21% or 50% O2) or 97% N2-3% CO2 was given at the onset of apnea. The ECG showed no arrhythmias predictive of failure of autoresuscitation. The first indication of failure was a progressive fall in gasp volume ("run down"). This pattern also occurred in animals given continuous 97% N2-3% CO2 and was significantly different from that in mice that survived. Gasping duration in 97% N2 was longer in weanlings than adults but shorter than in 11 day olds. Respiratory and heart rate recovery were more rapid in adults than in weanlings. Although recovery in high O2 was more rapid, the survival rate was not increased. The lack of effect of high O2 on survival and the virtually identical pattern of gasping in mice dying in 97% N2 and air leads us to conclude that in mice that fail to autoresuscitate little or no O2 reaches the medullary respiratory centers. We speculate that this may be due to increased vulnerability of cardiac muscle to anoxia in 17- to 23-day-old mice, resulting in early and severe heart failure.

Gasping Patterns of the Isolated Respiratory Centers of Birds and Mammals during Anoxia, Their Phylogenetic Significance, and Implication in Hibernation

Previous articleNext article No AccessGasping Patterns of the Isolated Respiratory Centers of Birds and Mammals during Anoxia, Their Phylogenetic Significance, and Implication in HibernationWilliam A. Hiestand, Fred W. Stemler, and Jacob E. WiebersWilliam A. Hiestand Search for more articles by this author , Fred W. Stemler Search for more articles by this author , and Jacob E. Wiebers Search for more articles by this author PDFPDF PLUS Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by Volume 26, Number 2Apr., 1953 Article DOIhttps://doi.org/10.1086/physzool.26.2.30154513 Views: 6Total views on this site Citations: 9Citations are reported from Crossref Journal History This article was published in Physiological Zoology (1928-1998), which is continued by Physiological and Biochemical Zoology (1999-present). PDF download Crossref reports the following articles citing this article:Yvonne A. Dzal, William K. Milsom Effects of hypoxia on the respiratory and metabolic responses to progressive cooling in newborn rodents that range in heterothermic expression, Experimental Physiology 106, no.44 (Mar 2021): 1005–1023.https://doi.org/10.1113/EP089085Angelina Y. Fong Postnatal changes in the cardiorespiratory response and ability to autoresuscitate from hypoxic and hypothermic exposure in mammals, Respiratory Physiology & Neurobiology 174, no.1-21-2 (Nov 2010): 146–155.https://doi.org/10.1016/j.resp.2010.08.012Prashant Deshpande, Atul Khurana, Polly Hansen, Davida Wilkins, Bradley T. Thach Failure of autoresuscitation in weanling mice: significance of cardiac glycogen and heart rate regulation, Journal of Applied Physiology 87, no.11 (Jul 1999): 203–210.https://doi.org/10.1152/jappl.1999.87.1.203Teresa Gonya-Magee, Robert C. Vannucci Ontogeny of Cerebral Oxidative Metabolism in the Chick Embryo, Journal of Neurochemistry 38, no.55 (May 1982): 1387–1392.https://doi.org/10.1111/j.1471-4159.1982.tb07917.xL.M Lutton The effect of hypoxia on the physical performance of the thirteen-lined ground squirrel, the eastern chipmunk and the albino norway rat, Comparative Biochemistry and Physiology Part A: Physiology 71, no.11 (Jan 1982): 85–91.https://doi.org/10.1016/0300-9629(82)90371-1E.F. Adolph Regulations during survival without oxygen in infant mammals, Respiration Physiology 7, no.33 (Oct 1969): 356–368.https://doi.org/10.1016/0034-5687(69)90019-XRoy F. Bulington, George J. Klain Effect of hypoxia on gluconeogenesis in the albino rat and thirteen-lined ground squirrel (Citellus tridecemlineatus), Comparative Biochemistry and Physiology 20, no.11 (Jan 1967): 275–283.https://doi.org/10.1016/0010-406X(67)90740-2RAYMOND J. HOCK The Care and Use of Hibernating Mammals, (Jan 1965): 273–331.https://doi.org/10.1016/B978-1-4832-3221-8.50013-4G.W. SALT, ERIK ZEUTHEN The Respiratory System, (Jan 1960): 363–409.https://doi.org/10.1016/B978-1-4832-3142-6.50015-X