General Supportive Management of the Term Infant With Neonatal Encephalopathy Following Intrapartum Hypoxia-Ischemia

Abstract

Hypoxic-ischemic encephalopathy (HIE) is an infrequent event with a potentially neurologically devastating outcome. Severe and prolonged interruption of placental blood flow will ultimately lead to asphyxia, the biochemical process characterized by worsening hypoxia, hypercarbia, and acidosis. 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 with 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. Treatment should focus on early identification of the infant at risk for evolving HIE and initiation of therapeutic hypothermia in appropriate patients. Supportive care should include checking the glucose level shortly after birth and correcting it promptly as needed, maintaining the carbon dioxide level in a normal range, and avoiding hyperthermia as adverse outcome has been reported with derangements in all of these parameters. Judicious fluid management is also necessary in this population at risk for renal injury and oliguria. Many adjunctive therapies to hypothermia are currently undergoing investigation, including xenon or erythropoietin administration, for example. Investigators must determine if it is clinically feasible to administer these treatments. Early results of erythropoietin trials specifically are promising, but larger clinical studies are needed.

Keywords

anticonvulsants, cerebral hypoxia-ischemia, erythropoietin, hypothermia, induced, infant, magnesium, newborn, xenon

•

Early identification of the infant at risk for evolving hypoxic-ischemic encephalopathy 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 renal 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 to therapeutic hypothermia, such as xenon or erythropoietin administration, are promising but larger clinical studies are needed.

Case History

HI was a 3200-g, 38-week 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 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. A 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 ₂of 146 mm Hg (on 50% oxygen), P co ₂of 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 ₁₀W), 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 abdomen was soft and without masses. 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 cooling, 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 received a loading dose of phenobarbital (40 mg/kg). The seizures persisted over the next 12 hours and the infant was given phosphenytoin and additional phenobarbital and a midazolam drip was started 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 supportive management included fluid restriction; the initial urine output was less than 1 mL/kg per 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 ₂values 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 7 days for presumed sepsis, although the blood culture results remained negative. Parenteral nutrition was initiated on DOL 3, tube feedings were started on DOL 4, and the infant was able to achieve full nipple feedings on 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 on DOL 16.

This case illustrates typical evolving neonatal encephalopathy following intrapartum hypoxia-ischemia against the background of placental infection/inflammation. The brain injury that develops is an evolving process that is initiated during the insult and extends into a recovery period, the latter 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 through the evolving process. Management consists of identification of the infant as at high risk for developing evolving 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 of 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 but likely occurring in less than 1 of 1000 live term deliveries in the developed world. 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. 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 neonate 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 or blended oxygen in term infants, 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 5.1 ). This concept is based in part on meta-analyses of five studies. The 2005 Cochrane meta-analysis showed a significant reduction in the rate of death in infants resuscitated with room air in comparison with 100% oxygen (relative risk [RR] 0.71, 95% confidence interval [CI] 0.54–0.94). Of note, there was no significant difference in incidence of grade II or III HIE (based on Sarnat staging) between groups. A subsequent meta-analysis, performed by Rabi and colleagues, included two additional studies and also demonstrated lower mortality in the room air group than in the 100% oxygen resuscitation group in the first week of life (odds ratio [OR] 0.7, 95% CI 0.5–0.98), and at 1 month (OR 0.63, 95% CI 0.42–0.94). Again, there was no difference between groups in incidence of grade II or III HIE. It remains unclear why this discordance exists as more severe encephalopathy may have been anticipated in the oxygen-treated group if brain injury and mortality are linked. Clearly the mechanisms contributing to death 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 and delay to first cry and sustained respiration.

Table 5.1

Targeted Preductual Sp o ₂After Birth

Time After Birth (min)	SP o ₂Level (%)
1	60–65
2	65–70
3	70–75
4	75–80
5	80–85
10	85–95

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.

In relation to long-term follow-up, Saugstad et al. had previously shown no difference in neurologic handicap at 18 to 24 months of life (albeit with a high dropout rate) between term and preterm infants resuscitated with room air versus those resuscitated with 100% oxygen. Importantly, most of the patients were from a low-resource limited setting, which combined with the high dropout rate, limits the generalizability of these data. A more recent meta-analysis by Saugstad et al. that included the aforementioned study with an additional two follow-up studies again showed no significant difference in neurodevelopmental outcome at follow-up ranging from 11 to 24 months.

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 more recent study of infants with perinatal acidemia or an acute perinatal event in addition to a 10-minute Apgar score of 5 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 scans. This population included both infants treated with whole-body hypothermia as well as controls.

Some experimental studies do suggest benefit associated with oxygen use over room air as it relates to the brain and systemic circulation. Thus resuscitation with 100% oxygen is associated with more rapid restoration of hypoxia-depressed CBF, improved cerebral perfusion, and significantly lower levels of excitatory amino acid levels in striatum, as well as more favorable short- and long-term outcomes in surviving adult mice. Additionally, in mice exposed to hypoxia-ischemia associated with circulatory arrest, resuscitation with 100% oxygen resulted in significantly greater rates of return of spontaneous circulation than that with room air. These observations may be important to consider in resuscitation of the neonate with sustained bradycardia in the delivery room that is reflective of circulatory hypoperfusion.

There is a critical need for ongoing studies with long-term follow-up assessing the use of room air versus supplemental oxygen, especially in the setting of HIE. Three of the largest studies that have driven the international guidelines and recommendations were conducted in developing countries where antenatal and peripartum care and neonatal mortality rates differ from those in the developed world.

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—that is, 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 following 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. What put this infant at high risk for neurologic injury? There was clinical evidence to suggest chorioamnionitis, there was fetal bradycardia before delivery, the infant was severely depressed, there was the need for resuscitation in the delivery room (i.e., intubation and positive-pressure ventilation), 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. 5.1 .

Ventilation

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 Pa co ₂are important to monitor carefully as hypercarbia increases and hypocarbia decreases CBF. Some experimental animal studies had previously suggested that a modest elevation in Pa co ₂(50–55 mm Hg) at the time of hypoxia-ischemia was associated with better outcome than when the Pa co ₂is within the normal (mid-30s) range. However, this is a complex issue because progressive hypercarbia in ventilated premature infants is associated with loss of autoregulation. Moreover, in the management of preterm infants with respiratory distress syndrome (RDS), the presence of hypocarbia has been associated with periventricular leukomalacia (PVL) (see Chapter 2 ). In term infants, there is increasing 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 Pa co ₂<20 mm Hg) led to increased risk of adverse outcome defined as death or severe neurodevelopmental disability at 12 months of age. A secondary study of the National Institute of Child Health and Human Development (NICHD) whole-body hypothermia trial demonstrated an association of minimum Pa co ₂and cumulative exposure to Pa co ₂less than 35 mm Hg with adverse neurodevelopmental outcome at 18 to 22 months of age. A post hoc analysis of the Cool Cap Study showed similar results, with hypocapnia in the first 72 hours after randomization (defined as Pa co ₂<30 mm Hg) associated with an increased risk of death or severe neurodevelopmental disability at 18 months of age. The authors of this study appropriately speculated that the etiology for frequent hypocapnia is unclear, it may be related to less carbon dioxide (CO ₂) production in the setting of severe brain injury versus excessive support with mechanical ventilation and/or resuscitation. With these data in mind, it is recommended that the Pa co ₂be 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 term infants with HIE, with only 11.5% of infants were normocapnic through the first 3 days of life; 29% were moderately hypocapnic and 5.8% were severely hypocapnic.

Maintenance of Adequate Perfusion

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. The hypotension may be related to myocardial dysfunction, to 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. On rare occasions infants may be hypertensive, though this may be observed in association with seizures.

Fluid Status

Hypoxic-ischemic infants often progress to a fluid overload state. Delivery room management may contribute to this problem as many infants receive fluid volume as part of the resuscitation process. Animal studies have suggested that fluid volume infusion at time of resuscitation may be detrimental in some cases. Thus in the asphyxiated neonatal piglet model, animals that received volume infusion during resuscitation demonstrated increased pulmonary edema and decreased lung compliance 2 hours after resuscitation. 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 and treatment consisted of fluid restriction until diuresis was achieved and the gradual introduction of sodium supplementation on DOL 2. Others have treated the oliguria 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 dose of theophylline (8 mg/kg) within the first hour of life in an attempt to block this vasoconstriction. Theophylline was associated with a decrease in serum creatinine and urinary β ₂-microglobulin concentrations as well as enhancement of creatinine clearance. 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. These studies, however, were conducted before the era of therapeutic hypothermia. Additionally, theophylline levels were not measured in two of the four studies. Cleary more data are needed to better assess potential side effects, as well as to understand the drugs’ effects in conjunction with therapeutic hypothermia.

Control of Blood Glucose Concentration

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. 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. 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. 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. Interestingly, multiorgan dysfunction, as measured by liver and renal function, and hematologic studies, was more severely abnormal in the hypoglycemic population. 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.

Temperature

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 ). The potential risks associated with an elevated temperature were highlighted in an observational secondary study of the NICHD whole-body cooling trial. 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 ). 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. 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. 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. 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. Given these results, transport teams travelling long distances with infants to a cooling center should develop protocols for the transfer of such infants, so as to avoid a delay in cooling and to improve temperature stability.

Seizures

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. 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. 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. 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. This conflicting evidence, along with the observation that not all clinical seizures have an electrographic correlate, highlights that the optimal management of seizures in the neonatal period in the setting of HIE remains unclear (see also Chapter 7 ). In many centers clinical and/or electrographic seizures are treated with an anticonvulsant, usually phenobarbital, and treatment is continued if seizures persist until the anticonvulsant therapy (e.g., phenobarbital, phosphenytoin, or midazolam) has been optimized. Large randomized controlled trials are warranted to guide evidence-based management for monitoring and management of seizures associated with HIE.

Prophylactic Barbiturates

Experimental studies lend support to the potential role of prophylactic phenobarbital in combination with hypothermia. In the neonatal rat model of HIE, rats treated with both 40 mg/kg phenobarbital and hypothermia had better early and late outcomes than hypothermia-only treatment. Early outcomes included better sensorimotor performance and less cortical damage in the phenobarbital-treated group. Late beneficial outcomes included better sensorimotor performance and lower neuropathology scores. 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. 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 < .05) demonstrated normal neurodevelopmental outcome at 3-year follow-up. No adverse effect of phenobarbital administration was observed. 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 = .01). Mortality and neurologic outcome at discharge were not statistically different between the two groups. Similarly, in a second 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 < .0001). There was, however, no reduction in neurodevelopmental impairment at latest follow-up (range 18–49 months). The most recent Cochrane review of prophylactic barbiturate administration following perinatal asphyxia demonstrated an overall reduction in seizures with treatment but no significant change in mortality. This review also highlights the paucity of data regarding long-term outcome. It is clear more studies are needed with long-term follow-up to assess the potential protective effect of prophylactic phenobarbital when used in combination with hypothermia.