General supportive management of the term infant with neonatal encephalopathy following intrapartum hypoxia-ischemia

Key points

• Early identification of the infant at risk for evolving hypoxic-ischemic brain injury and initiation of therapeutic hypothermia is critical in overall management.

• Glucose should be checked shortly after birth and corrected promptly as needed.

• Carbon dioxide should be maintained within a normal range to avoid exacerbation of brain injury.

• Judicious fluid management is necessary in this population at risk for acute kidney injury and oliguria.

• Hyperthermia should be avoided, and passive or active cooling may be considered for infants traveling long distances to a cooling center.

• Adjunctive therapies for therapeutic hypothermia are needed.

Case history

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 (P co ₂ ) 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 Pa o ₂ of 146 mm Hg (on 50% oxygen), P co ₂ 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 (D ₁₀ W), 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 P co ₂ 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. 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.

Introduction

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. HIE secondary to intrapartum asphyxia is a widely recognized cause of long-term neurologic sequelae, including cerebral palsy. 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). 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. 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. 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. ^, 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. 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.

Delivery room management

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. ^, 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. 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 ). ^, 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). 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. 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.

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 [Pa o ₂ ] >200 mm Hg). 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 Pa o ₂ >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. These data support ongoing judicious use of oxygen during resuscitation.

Early identification of infants at highest risk for development of hypoxic-ischemic brain injury

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. 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. 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. Indeed, the infant progressed to stage 2 encephalopathy with seizures.

Supportive care

A summary of supportive management is given in Fig. 8.1 .