798 SECTION VI Pediatric Critical Care Neurologic cerebral metabolism Rather, it represents secondary ischemia given the critical values of PbtO2 that are observed In contrast to the cortical hypoxia[.]
798 S E C T I O N V I Pediatric Critical Care: Neurologic BRAIN VULNERABILITY PRIMARY INSULT – SECONDARY INSULT Cardiac arrest Asphyxia % normal PaCO2 CBF 100 PaO2 Reperfusion Repair R E S U S C I T A T I O N Remodeling Hyperemia Hypoperfusion Brain death Minutes Hours Days Weeks Time after insult • Fig 65.4 Hypothetical diagram illustrating the patterns of global cerebral blood flow (CBF) during and after cardiac arrest of moderate duration in humans. Immediately after resuscitation, early postischemic hyperemia occurs for about 15 minutes in subcortical brain regions This is followed by patchy multifocal delayed postischemic hypoperfusion in cortical brain regions lasting from a few hours to days Progressive return of CBF to normal is seen in patients with intact neurologic outcome In contrast, delayed postischemic hyperemia can be observed hours to days postarrest in patients with more severe insults.176,179 This delayed hyperemia appears to be associated with disabled or vegetative outcome (in which CBF gradually decreases to near normal or below normal) or brain death (in which CBF decreases to no flow) However, it is unclear whether all patients with vegetative outcome or eventual brain death develop delayed hyperemia Paco2, Partial pressure of arterial carbon dioxide; Pao2, partial pressure of arterial oxygen cerebral metabolism Rather, it represents secondary ischemia given the critical values of PbtO2 that are observed In contrast to the cortical hypoxia seen after pediatric asphyxia cardiac arrest, cortical PbtO2 was increased in a swine model of VF arrest,172 suggesting that the CBF response after cardiac arrest may depend on arrest phenotype.173 The PbtO2 changes parallel the early cortical hyperemia after VF and highlight the age and insult type reperfusion differences Marked hyperoxia was observed in the cortex at 15 minutes after ROSC using an Fio2 of 1.0 and at hour after ROSC, even when the Fio2 was reduced to 0.5.172 At the level of the microcirculation, earlier studies described capillary stasis, classically described as the no-reflow phenomenon, as discrete areas of the brain with absent perfusion after ROSC Recently, in vivo microscopy in animal models of cardiac arrest allowed examination of microcirculatory disturbances and both confirmed and provided a detailed description of the no-reflow phenomenon After pediatric asphyxial cardiac arrest, vasoconstriction of the pial arterioles was also observed early after the insult, along with capillary stasis in 25% of the capillaries The no-reflow phenomenon was observed to be a dynamic process, with some capillaries with no reflow early after ROSC regaining flow at later time points and other patent capillaries developing no reflow at a later time point.174 In patients with favorable outcomes, global CBF recovers over the subsequent 24 to 72 hours, and carbon dioxide (CO2) reactivity remains intact Patients who not regain consciousness or progress to brain death may develop absolute or relative CBF hyperemia with impaired CO2 reactivity, although the delayed patterns of CBF after cardiac arrest in children merit additional exploration, particularly with regard to their relationship to regional brain injury and overall prognosis.175,176 A theoretic scheme of postarrest global CBF and its relation to neurologic outcome is presented in Fig 65.4, and the existing clinical literature is summarized later Most studies in experimental animal models of asphyxial arrest suggest a similar pattern of CBF and cerebral metabolic rate for oxygen (CMRO2) to that observed after VF cardiac arrest and global ischemia in the early postresuscitation period in humans.166,175 However, there are some exceptions.177 Results from clinical studies of pediatric asphyxial arrest are scarce and somewhat conflicting regarding the prognostic implications of high or low values of postarrest CBF based on a single measurement However, loss of CO2 reactivity appears to be associated with poor outcome in all studies In studies of children between 24 and 48 hours after drowning, Ashwal and colleagues178 observed low CBF in the seven nonsurvivors and no relationship between CBF and partial pressure of arterial carbon dioxide (Paco2) in these patients—again suggesting loss of CBF reactivity to changes in Paco2 In this study, hyperemia was not routinely observed in either survivors in a persistent vegetative state or children who died, but only a single CBF measurement was made in these patients Beyda179 obtained serial measurements of postarrest137 xenon in a series of children who suffered asphyxial arrest from drowning Children with favorable neurologic outcomes had slightly decreased CBF values at 12 hours that increased to normal during the subsequent 24 to 60 hours In these children, CBF reactivity to CO2 was intact Children with eventual vegetative outcome or brain death exhibited hyperemia with loss or attenuation of CO2 reactivity This hyperemia progressed to low or normal flow over the following 12 to 72 hours in children with vegetative outcome (minimally conscious state) CHAPTER 65 Hypoxic-Ischemic Encephalopathy and progressed to low and then no flow with the development of brain death A pilot pediatric study found that time spent under the optimal mean arterial pressure range in which autoregulation was present, based on an infrared cerebral oximetry-arterial pressure– based system, was predictive of poor outcomes.180 ASL-MRI techniques have been developed that not require contrast material injections In a small study that included both adults and children, global hyperemia was demonstrated after cardiac arrest at varying time points.181 In neonates with HIE, hyperperfusion occurred in regions with concurrent water diffusion abnormalities, implying a potential pathophysiologic linkage between the two observations, but patient outcomes were not reported.182 Brain metabolism, as assessed by CMRO2, is reduced during the early postischemic period in preclinical models and then progressively recovers to a level that varies depending on the model used and duration of ischemia.168,183 In some models, including VF arrest in dogs, significant recovery of CMRO2 may occur during the first few hours, despite persistent postischemic hypoperfusion—creating the potential for a secondary ischemic insult during reperfusion Whether this increase in CMRO2 represents appropriate synaptic activity, seizures, or basal metabolism is not certain In other models and in descriptions of adult cardiac arrest, global CBF and CMRO2 were matched during the first few hours after ischemia with delayed relative global hyperperfusion.175 Cerebral microdialysis has been used in pilot studies to assess for alterations in metabolism after cardiac arrest Using microdialysis in a porcine model of cardiac arrest, increased lactate/pyruvate ratios were found during arrest and again in a delayed fashion, especially if the animals were maintained normothermic versus hypothermic.184 This same group found increased lactate/pyruvate ratios and glutamate using microdialysis in adult survivors after cardiac arrest, all of whom were treated with hypothermia.185 Prolonged increases in brain lactate detected using proton MRS after global hypoxiaischemia in children have also been reported.37,186,187 Oxidative stress decreases the function of the pyruvate dehydrogenase, a key enzyme complex in oxidative metabolism, possibly contributing to the shift to anaerobic metabolism.188 Although routine monitoring of CBF, CMRO2, or PbtO2 has not been applied extensively to the postarrest setting in children, their routine assessment using contemporary methods may possibly lead to an improved understanding of pathophysiology and serve as a potential target for the titration of brain-directed therapy (see Chapter 60) Histopathology of Hypoxic-Ischemic Encephalopathy Ischemic neuronal change, as first described by Sommer in 1880 and later by Spielmeyer, involves a progression from extensive cellular microvacuolation to a cell that resembles a naked shrunken nucleus.27 As described by Brierley and colleagues,50 “this type of neuronal damage is neither ubiquitous nor randomly distributed but is found in regions which exhibit selective vulnerability to hypoxic stress.” As discussed previously, death of selectively vulnerable neurons (e.g., hippocampal CA1) cannot be explained by vascular distribution Remarkably, these clinical descriptions of cell shrinkage were consistent with apoptosis rather than necrosis However, the connection between selective vulnerability and apoptosis was made 100 years later.64 Neuronal death after cardiac arrest is seen not only in the selectively vulnerable neurons but also as a subtle histopathologic finding in the arterial boundary zones These neurons (not otherwise selectively vulnerable) are in the most poorly perfused areas during or after resuscitation.45 799 Neuronal death in the arterial boundary zones was elegantly described by Nemoto and associates in a monkey model of 16 minutes of complete global brain ischemia followed by days of intensive care.189 Maximal damage appeared to be in the classically described selectively vulnerable zones, but neuronal death was also observed in the most distal distribution of the posterior cerebral artery and in the watershed zones of the anterior and middle cerebral arteries With sufficient injury in the arterial boundary zone, more severe findings can be seen, such as microinfarction or laminar necrosis.28,189 As previously discussed, even in stroke, neuronal death in an ischemic penumbra can occur either by necrosis, apoptosis, or, potentially, some of the other aforementioned neuronal death pathways, such as necroptosis, ferroptosis, pyroptosis, or autophagy Thus, it appears that there may be a continuum between apoptosis, alternative neuronal death pathways, and both programmed and “unprogrammed” necrosis that may depend on a large number of factors, such as duration of the insult and brain region in question.83 Recently, ferroptosis has emerged as potentially playing a key role in ischemia reperfusion injury.190 Ferroptotic cell death is regulated by numerous biological processes, such as fatty acid metabolism and glutathione synthesis, including induction of the selenoprotein glutathione peroxidase-4 (GPX4).191 Pharmacologic selenium injection inhibits ferroptotic cell death after both hemorrhagic and ischemic stroke in a GPX4-dependent manner.191 Importantly, glutathione depletion is thought to be one factor contributing to the pathology of HIE after experimental pediatric asphyxial cardiac arrest, and this appears to be sex dependent.69 Whereas programmed modes of cell death in a given area often affect only a select percentage of neurons, infarction affects all neurons and all other cell types, including glia and cerebrovascular endothelium Obviously, if the arrest time is long or if the postischemic conditions are sufficiently poor, infarction of the entire brain can occur Vaagenes and colleagues studied neuropathology after primary VF arrest of 10 minutes in dogs.28 Despite vegetative outcome at 96 hours, only scattered ischemic neuronal changes in the selectively vulnerable neurons and to a much lesser extent in the vascular watersheds were observed Microinfarct formation was seen in only of 18 dogs, suggesting that patchy ischemic neuronal change is sufficient for vegetative outcome They then compared this 10-minute VF arrest with an asphyxial episode (airway occlusion) resulting in cardiac arrest with minutes of no flow Related either to differences in the initial insult or to postischemic events, asphyxial arrest resulted not only in ischemic neuronal change in the selectively vulnerable regions but also in marked microinfarct formation (30 of 32 dogs) and scattered petechial hemorrhages This more severe histologic injury was seen despite significantly easier ROSC in the asphyxial arrest group (Fig 65.5) In addition, unlike VF arrest, asphyxial arrest caused some ischemic neuronal changes even after no flow of only minutes Similarly, worse neurologic injury and neuronal loss was observed in adult rats subjected to asphyxial versus VF cardiac arrest of identical duration (5 minutes) in contemporary studies Greater neuronal loss was observed after asphyxial cardiac arrest in the hippocampus and cerebellar cortex, despite greater myocardial dysfunction and higher serum lactate after VF of an equal insult duration.173 These findings may explain the poor outcome generally observed after cardiac arrest in children (usually, asphyxial arrest) compared with that in adult series (often, VF arrest) Indeed, the contemporary report comparing asphyxial versus VF cardiac arrest in rats also included a human observational study in 500 adults that demonstrated similar findings—worse brain injury after asphyxial 800 S E C T I O N V I Pediatric Critical Care: Neurologic Clinical Outcome and Prognostication After Pediatric Cardiac Arrest VF arrest Asphyxial arrest Resuscitation Resuscitation Neuronal injury in selectively vulnerable zones Neuronal injury in selectively vulnerable zones Watershed infarcts Marked microinfarct formation and petechial hemorrhages • Fig 65.5 Schematic diagram based on the work of Vaagenes and col- leagues28 comparing the histologic outcome of ventricular fibrillation (VF) cardiac (adult) and asphyxial (pediatric) arrest (From Kochanek PM Novel pharmacologic approaches to brain resuscitation after cardiorespiratory arrest in the pediatric patient In Holbrook P, ed Critical Care Clinics Philadelphia: WB Saunders; 1988:661–777.) versus VF cardiac arrest—even when adjusting for insult severity and other confounders.173 After asphyxial cardiac arrest that results in long-term survival in both adult and pediatric-aged animals,192–194 the pattern of neuronal death produced is similar to that reported in human studies,195 including that of the young victim of asphyxial cardiac arrest, Karen Ann Quinlan,196 in which a predilection for basal ganglia injury resulting in a persistent minimally conscious state was observed Finally, studies by Hogler and associates197 demonstrated the expansion of damage comparing versus 10 minutes of VF cardiac arrest in pigs Substantial expansion of neuronal death across multiple brain structures—such as the cortex, caudate, and cerebellum—was seen between the 7- and 10-minute durations, and edema appeared in the 10-minute group These studies shed additional light on the impact of cardiac arrest duration on the extent of neuronal damage given the challenges of defining arrest duration in the human condition Advances in magnetic resonance imaging (MRI) during the last decade allow evaluation of regional cerebral volumes and provide anatomic details that corroborate preclinical studies Reduced hippocampal volumes were observed in eight patients who sustained a brief (,7 minutes) out-of-hospital cardiac arrest In these patients with favorable neurologic outcome, hippocampi were 10% to 12% smaller at months after cardiac arrest compared with controls.198 In a similar evaluation of 26 survivors of out-of-hospital cardiac arrest with favorable neurologic outcome, both hippocampal and cortical volumes were reduced at months after cardiac arrest.199 Furthermore, at 21 days after cardiac arrest, 11 patients in a minimally conscious state had a 26% to 30% reduction of hippocampal volumes and an 8% reduction in temporal lobe volumes.200 Recent studies attempted to correlate early changes in diffusion-weighted imaging (DWI) with neurologic outcome Extensive cortical signal abnormalities and hippocampal hyperintensities on DWI may be an indicator of poor prognosis after cardiac arrest.201 Survival and neurologic outcome after out-of-hospital pediatric cardiac arrest are remarkably poor, and evidence suggests meager improvement in outcome as compared with in-hospital pediatric cardiac arrest.15,70 Survival to hospital discharge after out-of-hospital arrest ranges from 8% to 25% and after in-patient arrest from 24% to 51%, with an overall survival of 13%.16–18,21,24 The most common cause of death is neurologic injury for out-ofhospital arrests and cardiovascular failure for in-hospital arrests.18 Although survival to hospital discharge is higher in pediatric than adult cardiac arrest (except for infants), the proportion of patients with favorable (defined as minimal to no disability) neurologic outcomes is lower, which may reflect in part lesser limitations of life-sustaining therapies in children compared with adults.24 Favorable neurologic outcome in pediatric patients surviving cardiac arrest is often overestimated using traditional categorical outcome measures such as the Glasgow Outcome Scale score and Pediatric Cerebral Performance Category Scale.202–204 Unlike many other forms of acute brain injury, there is little evidence to support improved functional recovery trajectories between discharge and year postarrest when comparing pediatric205 with adult206 cardiac arrest.207 Late improvements in mobility after cardiac arrest lag those seen after TBI (22% vs 66%) years after the initial event.208 In the two Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) studies, 71% of the 160 surviving children who underwent neuropsychological testing had a favorable outcome on the Vineland Adaptive Behavior Scales–II.209 However, on further testing, one-quarter of those children had global cognitive impairment and 86% had selective neuropsychological deficits year postarrest, highlighting the need for tracking longitudinal outcomes and support for recovery Families from the out-of-hospital THAPCA study had increased evidence of burden during the year following their child’s arrest,210 with burden related to the child’s functional status High mortality and poor outcome after cardiac arrest in children generally represent out-of-hospital or unwitnessed cardiac arrests This is particularly true in infants, for whom the proportion of bystander CPR is the lowest and asphyxial arrests are the highest.25,211 Recovery is much better in children who had witnessed arrests, recovery of pulses prior to hospital arrival, cold water submersion, or isolated respiratory arrest, for whom intact survival rates as high as 44% to 75% have been reported.18,20,212–214 These clinical data seem to reflect the severe neuropathology observed in experimental asphyxia-induced arrest given that asphyxia is the most common mode of cardiac arrest in all of the clinical pediatric series.20,21,202,212–214 Clinical factors—such as initial pH, number of epinephrine doses, and arrest duration—have been examined in both classical and contemporary studies in an attempt to prognosticate outcome from cardiac arrest Although sometimes predictive, this information can be misleading For example, the time delay before analysis of the first blood sample can vary, as can estimates of arrest duration With asphyxial arrest, even controlled experimental animal studies show that the time from asphyxia until cardiac arrest varies considerably Currently, the most powerful individual predictor of neurologic outcome after cardiac arrest is the trajectory of neurologic examination over time in the absence of confounding factors such as sedation, neuromuscular blockade, and impaired recovery of other organ function215 (see Chapter 60) As noted in one review, abnormal pupillary reactivity and motor CHAPTER 65 Hypoxic-Ischemic Encephalopathy response 24 hours postcardiac arrest in the absence of sedation and muscle relaxation medications are useful for prognostication.216 The electroencephalogram (EEG) can also provide prognostic information for patients after cardiac arrest.217 Scollo-Lavizzari and Bassetti218 retrospectively examined the relation between first postarrest EEG and clinical outcome in 408 cases A fivegrade classification was used to categorize EEGs Although permanent severe neurologic damage was observed in some patients with grade I EEG, none of the 208 patients with grade IV or V EEGs had a good neurologic recovery A single-center retrospective case series in children showed that having a burst suppression or electrocerebral silence pattern was associated with poor outcome at hospital discharge, with a positive predictive value of 90% and negative predictive value of 91%.219 In children who were treated with hypothermia postarrest, seizures were common, largely nonconvulsive, and occurred most frequently during the rewarming period.220 Detailed quantitative EEG221 and EEG reactivity may also be important prognostic tools after cardiac arrest in children.217,222 Adjunctive prognostic information also can be obtained from brain-derived protein levels in blood components (i.e., serum, plasma) Serum brain biomarker trajectories, including S100b (from astrocytes), neuron-specific enolase (NSE; from neurons), and myelin basic protein (MBP; from myelin), were noted to differ by brain insult.223 Biomarker trajectories differ by brain injury etiology: levels peaked earlier after accidental TBI, later after hypoxia, and were in between for children with abusive head trauma Two single-center prospective studies in children with cardiac arrest found that serum S100b and NSE had excellent prognostication accuracy.224,225 Brain-based biomarkers glial fibrillary acidic protein (from astrocytes) and ubiquitin carboxylterminal hydrolase L1 (from neurons) showed promise in predicting outcome226 in a small study NSE and other biomarkers may be useful in determining responsiveness to therapeutic interventions in trials and would qualify as pharmacodynamics response biomarkers, using current terminology.227,228 Somatosensory-evoked potentials (SSEPs) have been used in an attempt to provide early prognostic information after cardiac arrest SSEPs have strong positive predictive value for poor outcome as early as 24 hours postarrest in children.229 Auditoryevoked response testing has also been used in children with cardiac arrest after drowning.230 Normal evoked responses were observed in all children who recovered neurologically intact Children who recovered with significant handicaps demonstrated a reduction in wave V amplitude over time and prolonged wave I-V interpeak latencies In adults, bilaterally absent N20 waves at 24 and 48 hours have a reported specificity of 100% in predicting poor outcome after cardiac arrest However, note that in many studies, the SSEP results were used to guide medical decision-making.231 Summary recommendations from Abend and Licht have suggested that the absence of bilateral cortical SSEPs are most reliably predictive of outcome when peripheral SSEP responses are present.215 The prospective utility of computed tomography (CT) of the brain and other neuroimaging modalities232 after cardiac arrest is unknown (Fig 65.6) A head CT scan takes only a few minutes and is useful for ruling out intracranial lesions contributing to the cause of arrest In a large retrospective case series of children who had drowned, children with any abnormal CT finding (e.g., loss of gray-white differentiation, infarction) within the first 24 hours of admission died.233 Of children with an initially normal CT scan on the first day who had a subsequent abnormal CT scan, 801 96% either died or remained in a coma Another single-center retrospective study in children with cardiac arrest and head CT scan within 24 hours found that loss of gray-white differentiation and basilar cistern effacement were associated with unfavorable outcomes.232 Brain MRI can provide excellent regional evidence of brain injury after cardiac arrest without radiation, but it requires longer transport time outside of the ICU It is typically employed for prognostication subacutely after the patient stabilizes, but findings evolve over time In one study that used a novel scoring system, damage seen in the cortex and basal ganglia correlated well with neurologic outcome.234 Cortical abnormalities seen in DWI and injury to the basal ganglia on conventional MRI were predictive of an unfavorable outcome after pediatric cardiac arrest.235 In a small study of children surviving cardiac arrest, increased CBF using ASL and water restriction frequently occurred in similar brain regions in children, with an unfavorable outcome 236 Using brain MRS, decreases in the brain metabolite N-acetylaspartate and increases in lactate in the basal ganglia and cortex can assist in outcome determination in children after drowning and cardiac arrest.186,237,238 However, no particular test or clinical variable will have sufficient accuracy to prognosticate on its own Combining clinical variables with testing results improves accuracy of outcome prediction.229,239 Development and prospective validation of tests and panels of tests obtained early after cardiac arrest that reliably predict ultimate outcome would be valuable Response of the Immature Brain to Cardiac Arrest Clinical and laboratory studies suggest that the neurologic outcome of newborn animals after a hypoxic-ischemic insult is favorable compared with that of adults, although this may be related to the ability of newborn animals to tolerate asphyxia systemically This is most evident when neonatal and adult experimental models are compared In newborn monkeys, even 12 minutes of asphyxia did not result in cardiac arrest.240 In beagle pups, 15 minutes of asphyxia produced hypotension but not cardiac arrest.241 By comparison, cardiac arrest due to asphyxia in mature large-animal models generally occurs within to minutes.28,165,242 Kirsch and associates243 showed that newborn piglets had better recovery of SSEP and less postarrest hypoperfusion than young adult pigs in the initial hours after global cerebral ischemia Thus, not only does the cardiovascular response during asphyxia appear to be more robust in immature animals but also the intrinsic sensitivity of the brain to a hypoxic-ischemic insult may be lower Studies suggest a selective vulnerability of the neonatal brainstem sensory nuclei to asphyxia.240,244 This selective vulnerability may more correctly represent a relative lack of vulnerability of the neonatal cerebral cortex to asphyxia because anoxic perfusion was tolerated for over 12 minutes in immature monkeys, most of which demonstrated no ischemic neuronal change.240 However, some mechanisms of secondary damage, such as excitotoxicity, appear to be more injurious in the immature brain.245,246 Further complexity is added to processes such as excitotoxicity when the immature brain is involved, as some degree of excitatory stimulation is essential for neuronal survival and normal development.247 That fact may underscore the recognized vulnerability of developing neurons to sustained (6–8 hours or longer) exposure to certain anesthetics—a process that occurs in developing primates.248 802 S E C T I O N V I Pediatric Critical Care: Neurologic A B C Cho Cr NAA D • Fig 65.6 Neuroimaging after asphyxial cardiac arrest in children (A) Computed tomography scan of the head on day showing decreased gray-white differentiation, consistent with cerebral edema (B) T2weighted magnetic resonance image using a 3-T magnet on day 10 showing enhancement of the basal ganglia, thalamus, and parietal lobes (arrows) (C) Diffusion-weighted imaging shows corresponding edema of the globus pallidus (arrow) (D) Multivoxel magnetic resonance spectroscopy showing the whole-brain chemical analysis of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) A regional color map for NAA is shown Finally, greater plasticity in the immature brain may also allow for improved long-term recovery of function, although this may be more important in focal insults.249,250 The poor clinical outcome of infants and children presenting in cardiac arrest may be related to specific mechanisms operating in the setting of the asphyxia As the asphyxial arrest is developing, cardiac standstill is preceded by a variable period of severe hypoxia with increased CBF During this period, severely hypoxic perfusion—a form of incomplete ischemia—is produced, which can markedly increase cerebral lactate production.251 The initial phase of asphyxia can also be accompanied by extreme stress during struggling, which could increase CMRO2 and may be accompanied by systemic hyperglycemia.178 The combination of hypoxic perfusion or incomplete hypoxia-ischemia and hyperglycemia can increase cerebral lactate concentration to 30 to 35 mmol/g and decrease tissue pH to levels as low as 6.05.252–254 These lactate levels are much higher than those observed during even 30 minutes of complete ischemia (11–14 mmol/g) and are above the threshold of 20 to 25 mmol/g, at which lactic acid can produce local coagulation necrosis.255 In addition, it has been shown that a veritable storm of neurotransmitters is released to extremely high levels during asphyxia prior to reperfusion.23 Thus the no-flow period that ultimately develops in asphyxial cardiac arrest—in contrast to VF—is occurring in a brain that ... numerous biological processes, such as fatty acid metabolism and glutathione synthesis, including induction of the selenoprotein glutathione peroxidase-4 (GPX4).191 Pharmacologic selenium injection... manner.191 Importantly, glutathione depletion is thought to be one factor contributing to the pathology of HIE after experimental pediatric asphyxial cardiac arrest, and this appears to be sex dependent.69... is favorable compared with that of adults, although this may be related to the ability of newborn animals to tolerate asphyxia systemically This is most evident when neonatal and adult experimental