Ericalyn Kasdorf, Jeffrey M. Perlman Infant was a 3200 g, 38-week gestation male infant born to a 28-year-old G2P1 (gravida 2, para 1) mother following an uncomplicated pregnancy. Labor was complicated by a maternal temperature of 38.5°C and fetal tachycardia for which the mother received antibiotics, a prolonged second stage of labor associated with variable decelerations, and a bradycardic episode that resulted in an emergency cesarean section. Meconium staining of the amniotic fluid was noted. The infant was hypotonic at delivery and without respiratory effort. Resuscitation included intubation and positive-pressure ventilation (PPV). The initial heart rate was 50 beats/min but increased rapidly to >100 beats/min within 30 seconds of the start of PPV. The infant’s color improved, and he took a first gasp at 4 minutes and made a first respiratory effort at 8 minutes. Rectal temperature in the delivery room was 38.2°C. The Apgar scores were 1, 4, and 7 at 1, 5, and 10 minutes, respectively. The infant was transferred to the neonatal intensive care unit (NICU) for further management. The cord arterial blood gas analysis revealed a partial pressure of carbon dioxide (PCO2) of 101 mm Hg, pH of 6.78, and base deficit of −23 mEq/L. The initial arterial blood gas analysis at 30 minutes revealed a PaO2 of 146 mm Hg (on 50% oxygen), PCO2 of 30 mm Hg, and pH of 7.12. The initial blood glucose level was 32 mg/dL. The hypoglycemia was treated with a 2 mL/kg bolus of dextrose 10% in water (D10W), and subsequent glucose concentration was 84 mg/dL. The initial clinical assessment revealed a lethargic infant with a low-level sensory response. The anterior fontanel was soft. The capillary refill time was approximately 2 seconds. Pertinent cardiovascular findings were a heart rate of 134 beats/min and blood pressure of 44/24 mm Hg with a mean of 34 mm Hg. The infant was intubated and placed on modest ventilator support with equal but coarse breath sounds. The central nervous examination revealed pupils that were 3 mm and reactive. There were weak gag and suck reflexes, along with central hypotonia with proximal weakness. The reflexes were present and symmetric. The encephalopathy at this stage was categorized as Sarnat Stage 2. Because of the history and clinical findings, the infant underwent an amplitude-integrated electroencephalography (aEEG) examination that revealed a moderately suppressed pattern without seizure activity. The infant met criteria for therapeutic hypothermia, which was initiated at approximately 4 hours of age. At 12 hours of age the infant began to exhibit subtle seizure activity with blinking of the eyes, mouth smacking, and horizontal eye deviation associated with desaturation episodes. A clinical diagnosis of seizures was made, and the infant was treated with a total of 40 mg/kg phenobarbital. The seizures persisted over the next 12 hours and the infant was started on a midazolam infusion and treated with one additional dose of phenobarbital before control of the clinical as well as the electrographic seizures was achieved. The encephalopathy peaked on day of life (DOL) 2, and the infant remained in Sarnat Stage 2 encephalopathy. The initial urine output was less than 1 mL/kg/hour for the first 24 hours but increased thereafter, and by DOL 3 the infant was in a diuretic phase. Sodium was initially 136 mEq/L, reached a nadir of 128 mEq/L on DOL 3, but corrected over the next 36 hours. The initial serum bicarbonate level was 18 mEq/L with an anion gap of 16. Both resolved spontaneously by DOL 3. The infant received assisted ventilation until DOL 3, and the PCO2 values ranged between 40 and 50 mm Hg. Additional abnormalities included low calcium and magnesium levels (DOL 2) and mildly elevated liver enzymes. Low-dose dopamine treatment was started for approximately 24 hours for a low mean blood pressure. The infant was treated with antibiotics for 48 hours, with subsequent negative blood cultures. Parenteral nutrition was initiated on DOL 3, and the infant was able to achieve full oral feedings by DOL 14. The neurologic findings improved, although they were still abnormal with central hypotonia and increased deep tendon reflexes at the time of discharge. Magnetic resonance imaging (MRI) on DOL 7 revealed marked hyperintensity on the diffusion-weighted images within the putamen and thalamus bilaterally. Findings of repeat electroencephalography (EEG) were pertinent for mild background slowing. Finally, the placental pathology was consistent with acute chorioamnionitis. The infant was discharged to home on DOL 16. This case illustrates typical evolving encephalopathy following intrapartum hypoxia-ischemia against the background of placental inflammation. The brain injury that develops is an evolving process that is initiated during the insult and extends into a recovery period, the latter being referred to as the “reperfusion phase” of injury.1–3 Management of such an infant should be initiated in the delivery room with effective resuscitation and continued throughout their entire stay including planning of discharge services, such as therapy services. Management consists of the early identification of the infant being at high risk for brain injury, supportive therapy to facilitate adequate perfusion and nutrients to the brain, and neuroprotective strategies, including therapeutic hypothermia as well as therapy targeted at the cellular level to ameliorate the processes that may exacerbate ongoing brain injury (see Chapter 4). These management components are briefly discussed in this chapter. Hypoxic-ischemic encephalopathy (HIE) is an infrequent event with a range of reported incidences, with a rate of 1.5 per 1000 live births in one report.4 HIE secondary to intrapartum asphyxia is a widely recognized cause of long-term neurologic sequelae, including cerebral palsy.5 Severe and prolonged interruption of placental blood flow will ultimately lead to asphyxia, the biochemical process characterized by worsening hypoxia, hypercarbia, and acidosis (in the more severe cases defined as an umbilical arterial cord pH ≤7.00).6 During the acute phase of asphyxia, the ability to autoregulate cerebral blood flow (CBF) to maintain cerebral perfusion is lost. When this state occurs, CBF becomes entirely dependent on blood pressure to maintain perfusion pressure, a term known as a pressure-passive cerebral circulation.3 With interruption of placental blood flow the fetus will attempt to maintain CBF by redistributing cardiac output not only to the brain but also to the adrenal glands and myocardium. This redistribution occurs at the expense of blood flow to kidneys, intestine, and skin.6 Despite such redistribution efforts, even a moderate decrease in blood pressure at this stage could lead to severely compromised CBF. With ongoing hypoxia-ischemia, CBF declines, leading to deleterious cellular effects. With oxygen depletion, a number of cellular alterations occur including replacement of oxidative phosphorylation with anaerobic metabolism, diminution of adenosine triphosphate (ATP), intracellular acidosis, and accumulation particularly of calcium. The ultimate deleterious effects include the release of excitatory neurotransmitters, such as glutamate, free radical production from fatty acid peroxidation, and nitric oxide (NO)–mediated neurotoxicity, all resulting in cell death.5,6 Following resuscitation and the reestablishment of CBF and oxygenation, a phase of secondary energy failure occurs. In the experimental paradigm this phase transpires from 6 to 48 hours after the initial insult and is thought to be related to extension of the preceding mechanisms, leading to mitochondrial dysfunction.1 It is clear that during asphyxia, not only the brain but also many other vital organs are at risk for injury. For this reason, postresuscitation management of the infant who has suffered intrapartum hypoxia-ischemia must also focus on supporting those systemic organs that may have been injured. Future therapies must also target the cellular injury that occurs following asphyxia. The use of room air or supplemental oxygen in the delivery room has been previously identified as a gap in knowledge that is crucial to resolve. Resuscitation of the depressed newborn infant is aimed at restoring blood flow and oxygen delivery to the tissues. The most current international guidelines continue to recommend initiation of resuscitation with room air for term and late preterm infants ≥35 weeks’ gestation and to avoid use of 100% oxygen in this population as it has been associated with excess mortality.7,8 The exception to this, is the recommendation to increase to 100% oxygen if the infant’s heart rate remains less than 60 beats/min after at least 30 seconds of PPV that moves the chest, and as chest compressions are initiated.9 Monitoring should take place via pulse oximeter, with the goal of achieving oxygen saturations in the interquartile range of preductal saturations measured in healthy term babies born vaginally at sea level (Table 8.1).10,11 Notably, a 2019 meta-analysis of five randomized controlled trials (RCTs) and five quasi-RCTs showed a decrease in short-term mortality when using room air versus 100% oxygen for resuscitation of infants ≥35 weeks’ gestation (risk ratio [RR] = 0.73, 95% confidence interval [CI] 0.57–0.94).12 Two of these aforementioned RCTs showed no difference in neurodevelopmental impairment in survivors at 1 to 3 years of age, and five RCTs showed no significant difference in rates of Sarnat Stage 2–3 HIE.12 The mechanisms contributing to mortality in the oxygen group are unclear and important to determine. Interestingly, use of 100% oxygen has been associated with increased biochemical markers of oxidative stress in asphyxiated term neonates, as well as delay to first cry and sustained respiration.13 Adapted from Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: neonatal resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Reprinted with permission. Circulation. 2015;132:S543-S560. ©2015 American Heart Association, Inc. There have been few studies comparing room air with 100% oxygen, specifically during resuscitation of infants with HIE. One study performed in the era before cooling demonstrated increased risk of adverse outcome, defined as death or severe neurodevelopmental disability, by 24 months of age in infants diagnosed with asphyxia and exposed to severe hyperoxemia in the first 2 hours of life (defined as arterial partial pressure of oxygen [PaO2] >200 mm Hg).14 Another study of infants with perinatal acidemia or an acute perinatal event, in addition to a 10-minute Apgar score of five or less or ongoing need for assisted ventilation at 10 minutes and hyperoxemia on admission (defined as a PaO2 >100 mm Hg), demonstrated an association with moderate-severe HIE and abnormal brain MRI. This population included both infants treated with whole-body hypothermia as well as controls, and importantly more infants in the hyperoxemia group developed signs of moderate-severe encephalopathy, qualifying them for whole-body hypothermia.15 These data support ongoing judicious use of oxygen during resuscitation. The initial step in management is early identification of those infants at greatest risk for progression to HIE. This is a highly relevant issue because the therapeutic window, the interval following hypoxia-ischemia during which interventions might be efficacious in reducing the severity of ultimate brain injury, is likely to be short. It is estimated on the basis of experimental studies to vary from soon after the insult to approximately 6 hours.16–18 Given this presumed short window of opportunity, infants must be identified as soon as possible after delivery to facilitate the implementation of early interventions as described in the case history. Studies exploring initiation of treatment between 6 and 24 hours following birth suggest there may be some benefit to this strategy; however, uncertainty remains regarding its effectiveness and more research is needed in this area.19 What put the infant presented in this case at high risk for neurologic injury? There was clinical evidence of chorioamnionitis, fetal bradycardia, and perinatal depression with need for resuscitation in the delivery room, including intubation and PPV, and there was evidence of severe fetal acidemia, followed by evidence of early abnormal neurologic findings and abnormal cerebral function as demonstrated by amplitude-integrated EEG.20–22 Indeed, the infant progressed to stage 2 encephalopathy with seizures. A summary of supportive management is given in Fig. 8.1. Assessment of adequate respiratory function is critical in the infant with HIE. Inadequate ventilation and frequent apneic episodes are not uncommon in severely affected infants, necessitating assisted ventilation. Changes in carbon dioxide (CO2) are important to monitor carefully as hypercarbia increases and hypocarbia decreases CBF.23 Some experimental animal studies had previously suggested that a modest elevation in PaCO2 (50–55 mm Hg) at the time of hypoxia-ischemia was associated with better outcome than when the PaCO2 is within the normal (mid-30s) range.24 However, this is a complex issue as it has been shown that progressive hypercarbia in ventilated premature infants, for example, is associated with loss of autoregulation.25 Moreover, in the management of preterm infants with respiratory distress syndrome (RDS), the presence of hypocarbia, particularly when prolonged, has been associated with periventricular leukomalacia (PVL) (see Chapter 2). In term infants, there is also evidence that hypocarbia is associated with adverse outcome, especially in the setting of HIE. In a study of term infants diagnosed with intrapartum asphyxia, severe hypocapnia (defined as PaCO2 <20 mm Hg) increased risk of adverse outcome defined as death or severe neurodevelopmental disability at 12 months of age.14 A secondary study of the National Institute of Child Health and Human Development (NICHD) whole-body hypothermia trial demonstrated an association of minimum PaCO2 and cumulative exposure to PaCO2 less than 35 mm Hg with adverse neurodevelopmental outcome at 18 to 22 months of age.26 A post hoc analysis of the Cool Cap Study showed similar results, with hypocapnia in the first 72 hours after randomization (defined as PaCO2 <30 mm Hg) associated with an increased risk of death or severe neurodevelopmental disability at 18 months of age.27 The authors of this study speculated that the etiology for frequent hypocapnia is unclear; it may be related to less CO2 production in the setting of severe brain injury versus excessive support with mechanical ventilation and/or resuscitation. Additionally, a retrospective cohort study of 198 term infants with moderate to severe HIE treated with therapeutic hypothermia showed an association of lowest PCO2 averaged over days 1 to 4 of life with identification of brain injury on MRI (odds ratio [95% CI] 1.07 [1.00–1.14]; P = 0.04).28 With these data in mind, it is recommended that CO2 be maintained in the normal range in mechanically ventilated infants at risk for HIE. This goal may be difficult to achieve in clinical practice as infants with HIE often demonstrate hypocapnia. In a study of 52 term infants with HIE, only 11.5% of infants were normocapnic through the first 3 days of life; 29% were moderately hypocapnic and 5.8% were severely hypocapnic.29 Given the presence of a pressure-passive cerebral circulation, as discussed earlier, management strategy should aim to maintain the arterial blood pressure within a normal range for age and gestation. It is not uncommon for infants with hypoxia-ischemia to exhibit hypotension which may be related to myocardial dysfunction, endothelial cell damage, or rarely to volume loss. The treatment should be directed toward the cause—that is, inotropic support should be given for myocardial dysfunction, and volume replacement for intravascular depletion.30 Hemodynamics may also be affected by treatment with therapeutic hypothermia and subsequent rewarming. One small observational study of infants with HIE treated with hypothermia demonstrated an increase in mean arterial blood pressure by median of 8 mm Hg and a decline in heart rate by 32 beats/min during the cooling process.31 Another observational study of 20 infants with HIE treated with therapeutic hypothermia demonstrated that both heart rate and cardiac output increased during the rewarming process following hypothermia.32 Interestingly, in this study while mean arterial blood pressure was noted to decline with rewarming, middle cerebral artery systolic flow velocity increased during this time. Additionally, a recent systematic review and meta-analysis of the effect of hypothermia on renal and myocardial function suggests possible short-term myocardial benefits of cooling as measured by level of brain natriuretic peptide, cardiac troponin, and creatine kinase MB as well as less frequent evidence of myocardial dysfunction on EKG, echocardiogram, and tissue doppler measurements.33 It is unclear whether these short-term cardioprotective effects will confer long-term benefit. Hypoxic-ischemic infants often progress to a fluid overload state. The fluid overload seen after delivery may be related to renal failure secondary to acute tubular necrosis or to the syndrome of inappropriate antidiuretic hormone release (SIADH). Clinically such infants present with an increase in weight, low urine output, and hyponatremia. Indeed, in our case example, all these findings were present until diuresis was achieved. While fluid restriction is common practice for treatment of infants with HIE, the most recent Cochrane review of this subject highlights the need for further studies to assess whether this practice impacts morbidity and mortality in infants with HIE.34 A 2018 randomized controlled trial of 80 neonates with HIE treated with whole-body cooling showed no difference in death or neurodevelopmental disability at 6 months of life between infants randomized to normal fluid intake and those to restricted fluid intake (defined as 2/3 of normal intake) in the first 4 days of life.35 Fluid and electrolyte administration should be individualized to the need of each patient. A 2021 meta-analysis assessing renal function in term and near-term infants with asphyxia showed a significant difference between the incidence of acute kidney injury in infants treated with therapeutic hypothermia compared to controls (RR = 0.81; 95% CI 0.67–0.98, P = 0.03).33 In one randomized controlled trial included in this meta-analysis, the incidence of acute kidney injury was 32% in the group of term infants with encephalopathy treated with therapeutic hypothermia, compared to 60% of those infants randomized to standard treatment and not treated with therapeutic hypothermia (P < 0.05).36 The mechanism of this potential protective effect is not entirely understood and warrants further investigation. Renal perfusion does appear to be dynamic during the cooling and rewarming process, with renal saturation (Rsat) increasing and renal oxygen extraction levels decreasing in one study, as measured by near-infrared spectroscopy, after rewarming in infants with HIE treated with hypothermia.37 The authors noted that Rsat started to increase even before the rewarming process, which they hypothesize may be in part due to the natural evolution of renal reperfusion following asphyxia, followed by an increase in cardiac output and vasodilation, which occurs after rewarming. Past studies have assessed the treatment of oliguria, which often occurs in encephalopathic infants with theophylline, on the theory that adenosine acts as a vasoconstrictive metabolite following hypoxia-ischemia, which contributes to a decreased glomerular filtration rate. In two randomized controlled studies, asphyxiated infants received a single 8 mg/kg dose of theophylline within the first hour of life in an attempt to block this vasoconstriction. Theophylline was associated with a decrease in serum creatinine and urinary β2-microglobulin concentrations as well as enhancement of creatinine clearance.38,39 A meta-analysis of four studies, including these two, assessing the use of prophylactic theophylline for the prevention of renal dysfunction in term infants with asphyxia showed a reduced incidence of severe renal dysfunction.40 These studies, however, were conducted before the era of therapeutic hypothermia and theophylline levels were not measured in two of the four studies. One recent pharmacokinetic study in term infants with HIE treated with therapeutic hypothermia demonstrated low clearance of theophylline, with a 50% longer half-life compared to full-term infants without HIE and normothermia.41 A 2018 systematic review and meta-analysis including six trials with a total of 436 term infants with birth asphyxia showed a 60% reduction in the risk of acute kidney injury treated with a single dose of aminophylline, albeit with only moderate quality of evidence.42 Cleary more data are needed to better assess pharmacokinetics and potential side effects, as well as to understand the drugs’ effects in conjunction with therapeutic hypothermia. In the context of cerebral hypoxia-ischemia, experimental studies suggest that both hyperglycemia and hypoglycemia may exacerbate brain damage. In adult experimental models as well as in humans, hyperglycemia accentuates brain damage, whereas in immature animals subjected to cerebral hypoxia-ischemia, significant hyperglycemia to a blood glucose concentration of 600 mg/dL entirely prevented brain damage.43 Conversely, the effects of hypoglycemia in experimental neonatal models vary, as do the mechanisms of the hypoglycemia. Thus insulin-induced hypoglycemia is detrimental to immature rat brain subjected to hypoxia-ischemia. However, if fasting induces hypoglycemia, a high degree of protection is noted.44 This protective effect is thought to be secondary to the increased concentrations of ketone bodies, which presumably serve as alternative substrates to the immature brain. In the clinical setting, hypoglycemia when associated with hypoxia-ischemia is detrimental to the brain. Thus term infants delivered in the presence of severe fetal acidemia (umbilical arterial pH <7.0) who presented with an initial blood glucose concentration lower than 40 mg/dL were 18 times more likely to progress to moderate or severe encephalopathy compared with infants with a glucose greater than 40 mg/dL.45 In another post hoc analysis of the Cool Cap Study, unfavorable outcome at 18 months was seen more commonly in infants with hypoglycemia (≤40 mg/dL) and hyperglycemia (≥150 mg/dL) within the first 12 hours following randomization.46 Interestingly, multiorgan dysfunction, as measured by liver and renal function and hematologic studies, was more severely abnormal in the hypoglycemic population.46 Additionally, after adjusting for Sarnat stage and 5-minute Apgar score, only hyperglycemic infants randomized to hypothermia had a reduced risk of death and/or severe disability at 18 months of age (adjusted RR = 0.8, 95% CI: 0.66–0.99), infants with hypoglycemia or normoglycemia did not benefit significantly from treatment.47 Derangements in glucose levels have also been associated with varying patterns of brain injury on MRI. Thus a prospective study of 179 infants with moderate-to-severe HIE treated with therapeutic hypothermia showed that infants with hypoglycemia and labile glucoses had higher adjusted odds of watershed or focal-multifocal strokes, as well as basal ganglia or watershed injury on MRI obtained at a median of 9 days of life, compared with infants with normal glucose values.48 Hypoglycemia was another risk factor for adverse outcome in our case as the infant presented with an initial blood glucose concentration of 32 mg/dL. In the ongoing management of hypoxia-ischemia, a glucose level should be screened shortly after birth, corrected promptly as needed, and monitored closely. In both animal and human studies, ischemic brain injury has been shown to be influenced by temperature; elevation either during or following the insult exacerbates brain injury, whereas a modest reduction in temperature reduces the extent of injury (see Chapter 4).49 The potential risks associated with an elevated temperature were highlighted in an observational secondary study of the NICHD whole-body cooling trial.50 This study found that an increased temperature in the control group following hypoxia-ischemia was associated with a higher risk of adverse outcome. The odds ratio of death or disability at 18 to 22 months of age was increased 3.6- to 4-fold for each 1°C increase in the highest quartile of skin or esophageal temperatures (see also Chapter 4).50 In this same cohort, this effect persisted into childhood, with an increased odds of death or IQ less than 70 at age 6 to 7 years for infants with an average esophageal or skin temperature in the upper quartile in the first 3 days of life.51 Therefore it is important to pay close attention to temperature in the infant with a hypoxic-ischemic event. At the time of delivery, the infant’s temperature may be in the normal range or may be elevated in the context of clinical chorioamnionitis with maternal fever, making temperature a highly relevant issue. This raises the important question of how to manage temperature immediately following resuscitation of a near-term or term infant. Should the goal be to maintain the temperature in a normal range until it is evident that the neonate is a potential candidate for therapeutic hypothermia? On the other hand, the clinician could consider initiating passive cooling even at the time of delivery, with discontinuation of use of the radiant warmer in the delivery room. In a study of passive cooling initiated before and during transport to a referral center for evaluation for therapeutic hypothermia, passive cooling resulted in initiation of therapy 4.6 hours earlier than if therapy had been started at the cooling center.52 This concept is especially relevant because many infants who may be treated with therapeutic hypothermia are born at referring centers. Thus in a study of 45 term infants with moderate or severe HIE treated at a single center with selective head cooling, 96% were outborn, and the time to initiate cooling was 4.69 ± 0.79 hours.53 Another study comparing active cooling with a servo-controlled mattress to passive cooling during transport demonstrated a later age at cooling and greater temperature instability in the passively cooled group; 27% of infants in the passive group did not achieve the target temperature and 34% of infants were overcooled.54 An additional study comparing passive cooling to active cooling with a servo-controlled device showed a significantly lower heart rate in the actively cooled group (140 vs. 124 beats/min on admission), without any significant differences in coagulation profiles, rate of pulmonary artery hypertension, or other vital sign changes.55 Given these results, transport teams traveling long distances with infants to a cooling center may consider development of protocols for the transfer of such infants, so as to avoid a delay in cooling and to improve temperature stability.54 Hypoxic-ischemic cerebral injury is one of the most common causes of early-onset neonatal seizures. Although seizures are a consequence of the underlying brain injury, seizure activity in itself may also contribute to ongoing injury. Experimental evidence strongly suggests that repetitive seizures disturb brain growth and development as well as increase the risk for subsequent epilepsy.56,57 Human studies, however, show conflicting evidence. Glass et al. demonstrated that clinical seizures in the setting of HIE in the era before therapeutic hypothermia were associated with worse cognitive and motor outcome at age 4 years.58 The Cool Cap Study also demonstrated that the presence of aEEG seizures at time of enrollment was independently associated with an unfavorable outcome, defined as death or severe disability at 18 months.59 It remains unclear if seizures may be truly damaging to the newborn brain or if they are simply reflective of the degree of brain injury. In contrast, a secondary analysis of the NICHD whole-body cooling trial demonstrated that the presence of clinical seizures at any time during the hospitalization was not associated with death or moderate or severe disability at 18 months of life.60 This conflicting evidence may be secondary to the fact that electrographic seizures frequently do not have a clinical correlate, and some clinical events suspected to be related to seizures may be nonepileptic in origin.61 It is recommended that all infants at risk for seizures, such as the infant in our case or infants undergoing therapeutic hypothermia, undergo continuous EEG to accurately characterize seizures, although this remains challenging in many NICU settings.62 The optimal therapeutic approach for seizures in the neonatal period in the setting of HIE remains unclear (see also Chapter 7).63–65 In many centers clinical and/or electrographic seizures are treated with an anticonvulsant, commonly phenobarbital as a first-line agent, and treatment is continued if seizures persist until the anticonvulsant therapy (e.g., phenobarbital, fosphenytoin, midazolam, or levetiracetam) has been optimized. Wide variation in antiepileptic drug use has been reported between centers treating infants with HIE with therapeutic hypothermia. A review of the Children’s Hospital Neonatal Database and Pediatric Health Information Systems data for 1658 neonates treated with therapeutic hypothermia from 20 NICUs showed that 95% of patients with electrographic seizures received antiepileptic treatment, most commonly phenobarbital (97.6%), followed by levetiracetam (16.9%), and phenytoin/fosphenytoin (15.6%).66 A recent small randomized controlled trial demonstrated phenobarbital to be more effective in neonatal seizure cessation compared to levetiracetam (80% vs. 28%, P < 0.001) due to any cause.67 Large RCTs are still warranted to guide evidence-based management for monitoring and management of seizures associated with HIE. The prophylactic administration of high-dose barbiturates to infants at highest risk for developing HIE was evaluated in small studies before the era of therapeutic hypothermia and the results were conflicting. In one randomized study, the administration of thiopental initiated within 2 hours of birth and infused for 24 hours did not alter the frequency of seizures, intracranial pressure, or short-term neurodevelopmental outcome at 12 months.68 Of importance was the observation that systemic hypotension occurred significantly more often in the treated group. In another randomized study, 40 mg/kg body weight of phenobarbital administered intravenously to asphyxiated infants between 1 and 6 hours of life was associated with subsequent neuroprotection. In this study there was no difference in the frequency of seizures between the two groups in the neonatal period; however, 73% of the pretreated infants compared with 18% of the control group (P < 0.05) demonstrated normal neurodevelopmental outcome at 3-year follow-up. No adverse effect of phenobarbital administration was observed.69 There have been additional studies demonstrating a decrease in the incidence of seizures in infants treated with prophylactic phenobarbital. In one small study of term and near-term asphyxiated infants, phenobarbital administered within 6 hours of life resulted in a seizure frequency of 8% in the treatment group versus 40% in the control group (P = 0.01). Mortality and neurologic outcome at discharge were not different between the two groups.70 Similarly, in another study, infants who were given 40 mg/kg of prophylactic phenobarbital during whole-body cooling had fewer clinical seizures than a control group of infants (15% vs. 82%, P < 0.0001). There was, however, no reduction in neurodevelopmental impairment at follow-up (range 18–49 months).71 The most recent Cochrane review of prophylactic barbiturate administration following perinatal asphyxia demonstrated an overall reduction in seizures with treatment, but with no significant change in mortality.72 This review also highlighted the paucity of data regarding long-term outcome and concluded that prophylactic phenobarbital administration could not be recommended but is a promising area of research. Known adverse effects of therapeutic hypothermia in newborns include a significant increase in thrombocytopenia.73 Infants with prolonged hypoxia often demonstrate a trend toward moderate thrombocytopenia, which may be compounded by alterations in platelet activation and aggregation seen with hypothermia.74 One meta-analysis of a wide spectrum of patients treated with therapeutic hypothermia demonstrated an increased risk of thrombocytopenia and transfusion requirements, without a resultant increased risk of hemorrhage.75 Hematologic parameters should be monitored closely and appropriate blood products administered as needed. In addition to hypothermia (see Chapter 4), the following potential neuroprotective strategies have been considered. Erythropoietin (Epo) is a glycoprotein hormone most recognized for its role in erythropoiesis. However, it has also been shown to naturally increase during hypoxia-ischemia, along with an increase in Epo receptors. Epo is thought to provide a neuroprotective adaptive response during hypoxia-ischemia because of this effect.3 Suggested protective mechanisms of action include antioxidant and antiinflammatory responses, induction of antiapoptotic factors, and decreased nitric oxide–mediated injury and susceptibility to glutamate toxicity.76 Both stroke and hypoxic-ischemic animal models have demonstrated histologic protection with recombinant human Epo treatment.77–80 In the neonatal rat stroke model, treated animals also performed better in most components of spatial learning and memory performance.77 Epo has also shown a beneficial effect in a study of term infants with moderate-severe HIE who were not treated with therapeutic hypothermia. In this study, infants were randomly assigned to receive recombinant Epo (rEpo) at either 300 U/kg or 500 U/kg every other day for 2 weeks beginning at less than 48 hours after birth. The rate of death or moderate-severe disability at 18 months was significantly reduced, occurring in 43.8% in the control group versus 24.6% in the rEpo group (RR 0.62, 95% CI 0.41–0.94). Benefit was seen in infants with moderate (P = 0.001) but not severe HIE (P = 0.227). There was no difference in primary outcome between doses used in this study and Epo was well tolerated.81 In a multicenter phase 1 study of infants of at least 36 weeks’ gestation with HIE, Epo (1000 U/kg) administered in conjunction with therapeutic hypothermia was safe and resulted in plasma concentrations that were neuroprotective in animal studies.82 Follow-up of infants enrolled in this pharmacokinetics study between 8 and 34 months of age (mean 22 months) reported no deaths and moderate-severe developmental disability in only 1 of 22 patients available for follow-up, though this study was not designed to determine efficacy.83 A larger phase II double-blinded trial of 50 infants treated with hypothermia and randomly assigned to either placebo or five total doses of Epo at 1000 U/kg per dose showed fewer infants treated with Epo with brain injury on MRI performed at 4 to 7 days of age and improved motor outcome at 1 year of life.84 The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial, a phase III randomized, placebo-controlled trial of Epo in infants with moderate to severe HIE treated with therapeutic hypothermia and multiple doses of Epo (1000 U/kg/dose) compared to placebo enrolled 500 infants ≥36 weeks’ gestation, with primary composite outcome of death or mild, moderate or severe neurodevelopmental impairment at 2 years of life.85 There was no significant difference in mortality or two year neurodevelopmental outcomes recently reported, and additionally Epo was associated with a higher number of serious adverse events.86 Another proposed therapeutic approach for the elimination of oxygen free radicals generated during and after hypoxia-ischemia is to administer specific enzymes, such as allopurinol, known to degrade highly reactive radicals to a nonreactive component.3 In a clinical study, asphyxiated infants who received allopurinol demonstrated lower blood concentrations of oxygen free radicals than control infants.87 However, a 2012 Cochrane review of three trials, involving 114 infants with encephalopathy treated with allopurinol, concluded there was no significant difference between treated and control groups in the risk of death during infancy or of neonatal seizures.88 With such a small number of patients included, larger studies may be needed to determine whether there is truly lack of benefit. Follow-up from two of these randomized studies showed no difference in long-term outcomes at 4 to 8 years of age between treated infants and controls.89 Melatonin has also been suggested as a potential adjunctive therapy because of its antioxidant properties. Aly et al. described a small study of 30 term infants with HIE and 15 controls. Half of the infants with HIE were randomly assigned to the 10 mg/kg enteral melatonin plus hypothermia group and the other half to hypothermia alone. The melatonin/hypothermia group had fewer seizures on follow-up EEG at 2 weeks and fewer white matter abnormalities on MRI obtained after 2 weeks of life compared with the hypothermia group alone.90 A more recent small randomized-controlled trial of 25 infants with hypoxia-ischemia randomized 12 infants to hypothermia plus a daily 5 mg/kg IV dose of melatonin and 13 to hypothermia plus placebo. Infants in the hypothermia plus melatonin group were found to score significantly higher on the Bayley III cognitive testing at 18 months of life (101 vs. 85, P = 0.05).91 A 2021 systematic review and meta-analysis of melatonin for neuroprotection in neonatal encephalopathy confirms there is a paucity of data with these small studies, with a total of only 215 infants from five randomized-controlled trials, including the trial just described.92 This meta-analysis highlights the need for larger clinical trials studying melatonin in this population. Given the important role of excessive stimulation of neuronal surface receptors by glutamate in promoting a cascade of events leading to cellular death, it has been logical to identify pharmacologic agents that would either inhibit glutamate release or block its postsynaptic action.3 Glutamate receptor antagonists (i.e., N-methyl-D-aspartate [NMDA] subtypes) have been extensively investigated in experimental animals. Noncompetitive antagonists provided a reduction in brain damage in adult animals even when administered up to 24 hours after the insult. The available NMDA antagonists include dizocilpine (MK-801), magnesium, xenon, phencyclidine (PCP), dextromethorphan, and ketamine.3 Most of the previously mentioned NMDA antagonists are not widely used, however, magnesium and xenon will be discussed further in the following sections. Magnesium is an NMDA antagonist, blocking neuronal influx of Ca2+ within the ion channel, and is also thought to potentially have antioxidant, anticytokine, and antiplatelet effects in the setting of perinatal asphyxia.3 One large multicenter trial of infants born to women treated with magnesium sulfate who were at imminent risk for delivery between 24 and 31 weeks’ gestation demonstrated that moderate or severe cerebral palsy occurred significantly less frequently in the magnesium-treated group (1.9% vs. 3.5%; RR 0.55, 95% CI 0.32–0.95).93 With this promise of neuroprotection with magnesium in preterm infants, there has been additional investigation in term asphyxiated infants. In a study performed by Bhat et al., term infants with severe perinatal asphyxia received three doses of magnesium (250 mg/kg per dose) within 6 hours of birth and at 24-hour intervals. An abnormal neurologic examination at discharge, performed by a clinician blinded to group assignment, was found in 22% of the treatment group compared with 56% of the placebo group (P = 0.04).94 This is an interesting finding and is supported by a clinical study in which low plasma magnesium (<0.76 mmol/L) in the first 3 days of life was associated with impaired brain metabolism as measured by magnetic resonance spectroscopy in 65 term infants with HIE.95 Despite these observations, there is a paucity of data with long-term outcome of magnesium administration to term infants with HIE. A meta-analysis of five clinical studies, including the study by Bhat et al., demonstrated a reduction in adverse short-term outcome with no difference in mortality or seizures.96 There have been several studies assessing feasibility of therapeutic hypothermia administration in addition to magnesium sulfate. One small study of nine neonatal patients with HIE treated infants with therapeutic hypothermia, as well as combination therapy of Epo with magnesium, without any adverse events.97 Clearly larger clinical studies are needed with long-term follow-up assessing the combined effect of magnesium with hypothermia. Xenon, an inhaled anesthetic, has been investigated as another adjunctive therapy with hypothermia, as it acts as a noncompetitive antagonist of the NMDA subtype of the glutamate receptor in the brain and rapidly crosses the blood-brain barrier.3,76 While some preclinical studies of xenon showed great potential, results of the first randomized clinical study in term newborns with HIE have not been as promising. The Total Body hypothermia plus Xenon (TOBY-Xe) trial assessed a total of 92 infants, 46 treated with cooling alone and 46 with cooling plus 30% inhaled xenon administered within 12 hours of life for a duration of 24 hours. There were no differences in biomarkers of cerebral damage, including a lactate-to-N-acetyl aspartate ratio in the thalamus and fractional anisotropy in the posterior limb of the internal capsule. This finding was thought to potentially be related to the late administration of xenon (median 10 hours), the lack of power to detect a difference in the N-acetyl aspartate ratio, or the possibility that infants in this cohort were too severely affected at enrollment.98 Larger clinical studies are still needed to determine the time window in which xenon could be administered with hypothermia, the dose and duration of treatment needed, and xenon’s effect on long-term neurodevelopmental outcomes. The discovery of the benefits of therapeutic hypothermia has been one of the greatest advancements in newborn neuroprotection over the past 2 decades. There are many aspects of care the clinician can tailor to their individualized patient to optimize outcome, including judicious oxygen and fluid administration. There are many adjunctive therapies on the horizon that may also provide benefit and continue to be investigated on an ongoing basis (Fig. 8.2).
Chapter 8: General supportive management of the term infant with neonatal encephalopathy following intrapartum hypoxia-ischemia
Key points
Case history
Introduction
Delivery room management
Time After Birth (min)
Spo2 Level (%)
1
60–65
2
65–70
3
70–75
4
75–80
5
80–85
10
85–95
Early identification of infants at highest risk for development of hypoxic-ischemic brain injury
Supportive care
Ventilation
Maintenance of adequate perfusion
Fluid status
Renal function
Control of blood glucose concentration
Temperature
Seizures
Prophylactic barbiturates
Coagulopathy
Potential neuroprotective strategies aimed at ameliorating secondary brain injury
Erythropoietin
Oxygen free radical inhibitors and scavengers
Excitatory amino acid antagonists
Magnesium
Xenon
Conclusions
Related posts:
Intraventricular hemorrhage in the premature infant
Neurodevelopmental outcomes following very preterm birth: What clinicians need to know
Neurological and neurobehavioral evaluation
Diagnosis and management of acute symptomatic seizures in neonates
Pediatric Spinal Cord Injury
Multiple Sclerosis Pain
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Neupsy Key
Fastest Neupsy Insight Engine
