Clin Perinatol 29 (2002) 675 692

The postnatal management of the asphyxiated term infant

Seetha Shankaran, MD *
Neonatal-Perinatal Medicine, Wayne State University School of Medicine, 3901 Beaubien Blvd, Detroit, MI 48201, USA

This article provides an overview of the management of the post asphyxiated term infant. This will include systemic (blood pressure, fluid management, respiratory stabilization, and so forth), as well as cerebral management. The initial focus will be on the immediate delivery room resuscitation, followed by postresuscitation management of term infants with asphyxia. The management of the post asphyxiated infant begins at the time of the delivery and extends into the neonatal period. Failure to initiate appropriate therapy at any stage may exacerbate ongoing injury. This article focuses on specific delivery room and postnatal interventions to minimize or ameliorate ongoing injury.

Delivery room management The delivery room management of term infants following asphyxial injury will focus on the following:
 

Oxygen requirement during resuscitation, Management of the asphyxiated meconium stained infant,  Temperature in the delivery room,  Medications in the delivery room. Oxygen requirement during resuscitation There is considerable debate whether infants should be resuscitated with 100% or lower concentrations of oxygen. This is highly relevant given the importance of oxygen free radicals in the genesis of ongoing injury following

* Childrens Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201, USA. E-mail address: sshankar@med.wayne.edu (S. Shankaran). 0095-5108/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 9 5 - 5 1 0 8 ( 0 2 ) 0 0 0 5 6 - 8

676

S. Shankaran / Clin Perinatol 29 (2002) 675692

hypoxia-ischemia. Three studies have been conducted to address this question. The preliminary trial evaluated response to resuscitation in preterm and term infants. It compared 42 infants who were resuscitated with room air with 42 infants who were resuscitated with 100% oxygen. Median Apgar scores at 5 minutes were higher in the group that was resuscitated with room air; median time to first breath, first cry, and need for assisted ventilation were similar in both groups. Thus room air resuscitation was as effective as resuscitation with 100% oxygen [1]. This study was followed by an international, randomized, controlled trial to test whether room air resuscitation was superior to 100% oxygen for resuscitating asphyxiated newborns [2]. In this trial, 213 of 288 infants who were resuscitated with room air, and 241 of 321 infants who were resuscitated with 100% oxygen were term ( > 37 week gestation). The primary outcome measures, death within 7 days, or moderate or severe encephalopathy, were seen with equal frequency (21.2% and 23.7% for room air and 100% oxygen, respectively). The findings suggested that infants can be resuscitated with room air as effectively as with 100% oxygen. Further evidence suggested that resuscitation with room air prevents oxidative stress in moderately-asphyxiated, term infants [3]. A group of aphyxiated, term infants who were resuscitated with 100% oxygen or room air were compared with a control group of infants who did not requiring resuscitation. The ratio of reduced:oxidized glutathione, which is an accurate index of oxidative stress, was similar in the room air resuscitated and control infants and lower in the 100% oxygen resuscitated group at 72 hours. The low ratio persisted, however, at 28 days in the group that was resuscitated with 100% oxygen; this was indicative of a protracted oxidative stress. In addition, the activities of superoxide dismutase and catalase in erythrocytes were significantly higher in the group that was resuscitated with oxygen compared with the control group at 28 days; this indicated that antioxidant enzymes could not cope with ongoing generation of free radicals in the group that was resuscitated with oxygen. Otherwise, these infants had a normal neurologic assessment. Vento et al [4] recently reported on 6 consecutive years of using room air as an alternative to 100% oxygen in the resuscitation of asphyxiated, term infants. Of 830 asphyxiated infants, 304 were resuscitated with room air and 526 were resuscitated with 100% oxygen; no significant differences in morbidity or mortality were found. The hyperoxemia in the group that was resuscitated with oxygen was associated with increased oxidized glutathione concentrations. At 28 days, significant oxidative stress was found in the group that was resuscitated with oxygen compared with the group that was resuscitated with room air and healthy controls. As a result of these studies, the recommended use of 100% oxygen for resuscitation that is currently stated in the International Guidelines for Neonatal Resuscitation [5] may need to be re-evaluated. The meconium-stained, asphyxiated infant Passage of meconium may be normal or caused by hypoxia, acidemia, or infection. Approximately 20% to 30% of meconium-stained infants are

S. Shankaran / Clin Perinatol 29 (2002) 675692

677

depressed at birth and require resuscitation in the delivery room [6]. When meconium is observed in amniotic fluid, suctioning from the hypopharynx should commence after delivery of the head and before delivery of the shoulder [5]. Direct laryngeal suctioning to remove meconium from the airway should be conducted on any infant who is depressed, with absent respirations, a heart rate less than 100 beats per minute, or with poor muscle tone. By contrast, intubation and suctioning of the vigorous, meconium-stained infant does not decrease the incidence of meconium aspiration syndrome, irrespective of the thickness of the meconium [7]. Meta-analysis of four randomized, controlled trials of endotracheal intubation in vigorous, meconium-stained infants does not support the use of endotracheal intubation at birth. Event rates are low in the reported trials, however, which makes reliable estimates of treatment effects impossible [8]. Saline lavage, administered to loosen intrapulmonary meconium and improve retrieval from the airway, may be detrimental because the procedure can wash out meconium as well as surfactant. Tracheal lavage with dilute surfactant may be of benefit in infants with meconium aspiration syndrome [9 11]. Temperature in the delivery room in the management of the asphyxiated infant Hyperthermia during resuscitation and reperfusion caused increased neuronal injury and release of oxygen free radicals and excitatory amino acids, such as glutamate, in the animal model [12 14]. In the clinical setting, case control studies suggested that maternal fever is associated with an increased risk for newborn encephalopathy [15,16], as well as an increased risk for cerebral palsy [17]. There is no documented benefit to keeping core temperature above normal at birth for asphyxiated infants [18]. Maternal temperature should be monitored and fever should be treated. Perinatal hyperthermia should be avoided in the delivery room and during transport to a perinatal center [5]. Medications in the delivery room in the management of the asphyxiated infant There are very little data that justify the use of medications in the delivery room in the resuscitation of neonates [19]. Medications should be administered only if severe fetal acidemia is accompanied by respiratory depression that is unresponsive to adequate ventilation and chest compressions. Medications that are administered include epinephrine, sodium bicarbonate, and volume expanders. Epinephrine Epinephrine is indicated if the heart rate remains less than 60 bpm after a minimum of 30 seconds of adequate ventilation and chest compressions [5]. Epinephrine is an effective vasoconstrictor with activity mediated through a adrenergic receptor stimulation. The resulting elevation in systemic blood pressure improves coronary perfusion pressure. The dosage to be used is 0.01

678

S. Shankaran / Clin Perinatol 29 (2002) 675692

to 0.03 mg/kg (ie, 0.1 to 0.3 ml/kg of a 1:10,000 solution given intravenously and repeated in 3 5 minutes). If access is available, the intravenous route is the most efficacious. If the intravenous route is not available, the endotracheal route may be used. Effects of endotracheal epinephrine are delayed and less consistent. There is a possibility that endotracheal epinephrine accumulates in the lower airways. When pulmonary circulation improves, more epinephrine is absorbed and the potential for side effects, such as hypertension, increases. The efficacy of epinephrine has not been evaluated in a randomized, controlled trial in neonates. The efficacy of doses of epinephrine that are higher than the one recommended have not been proven in animal models nor in pediatric or neonatal patients. It should be noted that severe metabolic acidosis inhibits the hemodynamic response to epinephrine. Sodium bicarbonate Bicarbonate functions as an effective buffer when CO2 can be eliminated from the lungs. If bicarbonate is administered in the absence of adequate ventilation, CO2 will increase with resultant respiratory acidosis [20 22]. A decrease in cerebral blood flow is another possible adverse effect in depressed neonates [23]. Current guidelines recommend a dosage of 1 to 2 mEq/kg of a 0.5 mEq/mL solution by slow intravenous administration only after adequate ventilation and circulation are established [5]. Acidemia should be corrected if it is persistent despite adequate ventilation and oxygenation and blood gas values are available to monitor the response to bicarbonate therapy. There are no randomized controlled trials that evaluated the efficacy of bicarbonate in neonatal resuscitation. Volume expanders Volume expanders are rarely indicated in the delivery room. If volume expansion is needed emergently in the delivery room, an isotonic crystalloid solution, such as normal saline or Ringers lactate, should be administered [5]. O-negative blood may be used if there is evidence of intrapartum blood loss. Albumin is no longer recommended for initial volume expansion because of limited availability, risk for introducing infectious diseases, and a strong association between its use and increased mortality in a meta-analysis of adult and pediatric trials [24,25]. It is also important to identify the cause of hypovolemic shock in the depressed or asphyxiated infant. Examples include placenta previa, ruptured cord, or tight nuchal cord that results in fetal hypovolemia. Slow intravenous administration of 10 ml/kg of crystalloid solution is the recommended initial dose. Acutely asphyxiated infants may develop severe myocardial depression, cardiomegaly, tricuspid regurgitation, reduced cardiac output, and hypotension [26 28]. Volume load is contraindicated in such infants; a further increase in preload may further compromise cardiac function [25]. If hypotension is present and there is evidence of myocardial compromise, dopamine should be initiated [25,29].

S. Shankaran / Clin Perinatol 29 (2002) 675692

679

Post resuscitation management Acute hypoxic-ischemic injury causes multi-organ dysfunction; hence, the infant should be monitored for multi-organ failure [26 28]. Monitoring of mean arterial blood pressure, and, in some infants, central venous pressure, is needed. Electrolyte imbalance and hypocalcemia or hypomagnesemia are not uncommon and should be monitored. The coagulation status of these infants may be impaired and should be evaluated if clinically indicated; disseminated intravascular coagulopathy should be treated with fresh, frozen plasma or platelets, as needed. More specific interventions are fluid management, including renal support, ventilation, and neuroprotection. Each is reviewed in more detail. Fluid management The kidney is one of the most frequently damaged organs in the asphyxiated, full-term infant [26 28]. The asphyxiated newborn is prone to develop vasomotor nephropathy (prerenal) or acute renal failure. Vasomotor nephropathy refers to renal dysfunction with or without parenchymal damage caused by reduced renal perfusion. Continued vasomotor nephropathy can lead to irreversible renal damage. Hypertension, hypoxemia, hypovolemia, activation of the renin-angiotensin-aldosterone system, and intra-renal adenosine system, as well as stimulation of catecholamines and increased vasopressin, all contribute to disturbances of glomerular hemodynamics [30]. Urine output should be measured with a urine collection bag or with an indwelling catheter (which may increase the risk for ascending urinary tract infection). A decrease in urine output with oliguria ( < 1ml /kg/h) or anuria indicates incipient acute renal failure. However, 60% percent of infants with acute renal failure following severe asphyxia [31] have normal urine output. When hypovolemia is the primary cause of oligo-anuria, the urinary flow rate should normalize within a few hours, after rapid volume replacement with crystalloid solution. When no diuresis occurs, fluid administration should be repeated, unless the neonate has signs of myocardial dysfunction. The administration of dopaminegic agents may be beneficial in infants with myocardial dysfunction; however, the effects of dopamine are dose dependent. The renal vasodilator and diuretic response to dopamine result from stimulation of dopaminergic receptors and are seen with low doses (0.5 2 mg/kg/min). Medium (2 6 mg/kg/min) or high doses (6 10 mg/kg/min) that are often needed to sustain systemic cardiovascular effects by way of q- and b-adrenergic receptors will increase renal vascular resistance [30]. After hypoxia or ischemia, renal adenosine acts as a vasoconstrictive metabolite that contributes to a decrease in the glomecular filtration rate. The vasoconstriction that is caused by adenosine can be inhibited by the nonspecific adenosine receptor antagonist, theophylline. In a recent, randomized, controlled trial of 51 asphyxiated, term infants, a single dose of 8 mg/kg

680

S. Shankaran / Clin Perinatol 29 (2002) 675692

theophylline administered prophylactically in the first hour was associated with a decrease in serum creatinine and urinary b2-microglobulin and improvement in creatinine clearance [32]. Further studies are needed to evaluate this promising intervention. In the presence of acute, tubular necrosis, fluid restriction is recommended. If there is persistent oliguria/anuria, azotemia and other complications ( ie, hyperkalemia), temporary dialysis treatment (preferably peritoneal dialysis) may be needed. Fluid restriction is also recommended when inappropriate antidiuretic hormone release is suggested based on an increase in body weight, decrease in serum sodium, and increase in urine osmolarity. Blood pressure, and, in some infants, central venous pressure should be monitored. Hypotension should be treated with fluid resuscitation or inotropes as clinically indicated. The cardiovascular effects of dopamine [33] are mediated through q- and b-adrenegic activity; this may result in significant adverse effects if metabolic clearance is delayed. These include cardiac arrhythmia, depression of peripheral chemoreceptor activity, and increase in peripheral vascular resistance, particularly in the pulmonary vascular bed [34]. Dobutamine is an inotropic agent devoid of q- and b-adrenergic activities, and does not have the chronotropic and hypertensive effects of other catecholamines. Hypotension that is unresponsive to inotropic agents may respond to steroid therapy [35]. It is important to maintain systemic blood pressure in the normal range because cerebral autoregulation is often absent in term infants after a major hypoxic-ischemic insult [36,37]. Ventilation In the mature animal model, gentle ventilation with permissive hypercapnia is neuroprotective and acts, at least in part, by decreasing energy use. Cerebral blood flow during hypoxia-ischemia is better preserved in the normocapnic and hypercapnic immature rat model. Glucose is better utilized, ATP and phosphocreatinine are better preserved, and CSF glutamate is lower in hypercapnic rats [38,39]. Currently no data are available about the role of hypercapnia in term infants after a hypoxic-ischemic insult. Although not directly applicable, a metaanalysis of permissive hypercapnia in the prevention of morbidity and mortality of mechanically-ventilated, newborn, preterm infants did not show any benefit from this strategy [40]. The post asphyxiated infant with respiratory failure should be monitored for the development of pulmonary hypertension by clinical and echocardiographic studies. A recent meta-analysis noted that inhaled nitric oxide improved the outcome in term and near term infants with hypoxia, by reducing the incidence of death or need for extra corporeal membrane oxygenation [41]. Inhaled nitric oxide can be used during inter-hospital transport of newborns with hypoxic respiratory failure [42]. Therapy with inhaled nitric oxide should be initiated when the oxygenation index rises above 25; recommended guidelines for monitoring nitric oxide therapy should be followed [43]. Infants with acute, perinatal asphyxia are at risk for developing meconium aspiration syndrome and

S. Shankaran / Clin Perinatol 29 (2002) 675692

681

pulmonary hypertension. A recent meta-analysis showed that surfactant administration decreased the number of infants treated with extracorporeal membrane oxygenation in those with meconium aspiration syndrome that led to moderate to severe respiratory failure [44].

Neuroprotection The neurologic status of the asphyxiated infant should be monitored immediately following birth and then daily. Encephalopathy, which generally evolves over the initial 2 to 3 days, is the best predictor of long-term outcome. Early predictors (ie, within the first hours of life) of long-term outcome were recently described and include an abnormal amplitude integrated EEG [45,46] and an abnormal urinary lactate to creatinine ratio [47]. Neuroprotection of the acute, post asphyxiated infant is critical because the brain is the one organ that is less likely to recover after hypoxia-ischemia [28]. Pharmacologic strategies Neuroprotection can be broadly classified into: (1) approaches to reduce cerebral edema, (2) glucose, (3) use of anticonvulsants and (4) cerebral resuscitation. Reducing cerebral edema. Cerebral edema occurs in asphyxiated infants during the first 72 hours. Measures to reduce cerebral edema have included hyperventilation, the use of hypertonic saline, mannitol, and furosemide; none has been evaluated in term infants in clinical trials. There is no evidence to support the use of hyperventilation to reduce the increase in intracranial pressure that may occur following acute, asphyxial injury. Decreasing the serum levels of carbon dioxide (paCO2) results in cerebral hypoperfusion that may further aggravate the ischemic injury. The use of hypertonic saline solution to decrease the intracranial pressure was successful in adults [48], but has not been examined in term infants. Other agents that can be used to reduce edema or elevated intracranial pressure, such as mannitol, furosemide, or phenobarbital, have not been useful in neonates [49 51]. Dexamethasone or glucocorticoids may be neuroprotective when used prophylactically in the animal model [52,53]. There is no evidence to support its use in the neonate, however. Role of glucose. Hyperglycemia and hypoglycemia may aggravate neuronal injury [54,55]. Hyperglycemia may contribute to elevated levels of cerebral lactate and compound the effects of acidosis. The goal of glucose therapy is to maintain normoglycemia with a continuous infusion of glucose at a rate of 4 to 6 mg/kg/min until enteral feeds are initiated [56]. Anticonvulsant therapy. Approximately 50% of infants with hypoxic-ischemic encephalopathy have seizures that can be detected clinically; an additional number of infants only have EEG seizures. Seizure activity should be treated

682

S. Shankaran / Clin Perinatol 29 (2002) 675692

with phenobarbital. Additional anticonvulsant medications can be added if breakthrough seizures occur despite therapeutic serum levels of phenobarbital. Strategies aimed at cerebral protection. The pathophysiology of asphyxial brain injury was studied in neonatal and adult animal models and was described in recent reviews [56 58]. Oxygen deprivation and ischemic injury lead to anaerobic metabolism that result in the depletion of ATP and high energy reserves. Failure of energy-dependent reuptake pumps, that normally move the excitatory neurotransmitters glutamate out of synapses and into glial cells, results in overstimulation of glutamate receptors and opening of the N-Methyl-D-Aspartate (NMDA) channels; this allows calcium to enter cells. The cascade of events that follows involves accumulation of cytosolic calcium and calcium-mediated deleterious effects. Post resuscitative reoxygenation results in free radical formation (superoxide anion, hydroxyl radical) and activation of lipases, protease, endonucleases, and cytokines, all of which cause additional damage to the neuron and result in cell necrosis and apoptosis. The goal of cerebral neuroprotection is to interrupt any step or steps in this cascade of events. In term infants, hypoxic-ischemic brain injury leads to neuronal injury; in the premature infant, oligodendroglial injury predominates [58]. Many studies were performed in animal models to evaluate timed injury and therapies with agents given before, during, and after a hypoxic-ischemic insult. Translating preclinical to clinical studies is challenging because of many factors including: (1) postinjury rescue treatment seems to be the only feasible approach with acute perinatal asphyxia; (2) the animal models vary in cortical, white matter, and deep gray matter structural development when compared with the human neonate; (3) the potential window of rescue neuroprotection in perinatal animal models seems to be close to 6 hours after a timed injury [59], however; in the human neonate, neither the timing nor the severity of the hypoxic-ischemic injury is known; and (4) a single therapeutic agent or approach may impact only one step or steps in the cascade of events after the hypoxic-ischemic injury; therefore, a multi treatment approach may be needed. The following section focuses on supportive therapies for neuroprotection that may be used in the clinical setting (whether proven or unproven). Only the preclinical studies that may translate to a clinical setting will be reviewed. The reader is also referred to several recent reviews of neuroprotection [56 58,60]. NMDA receptor antagonists In animal models, blockade of glutamate receptors had neuroprotective effects. Kynurenic acid, a glutamate antagonist, ameliorated injury when administered after hypoxic-ischemic injury in the neonatal rat [61]. Similarly, posthypoxic treatment with the NMDA receptor antagonist MK-801 decreased focal injury in rats [62,63]. In fetal sheep, neuronal outcome was improved by suppression of postischemic epileptiform activity with MK-801. In human adults, the efficacy of a antagonist of the glycine site of the NMDA receptor was evaluated in a randomized, controlled trial of patients with acute stroke who had no improve-

S. Shankaran / Clin Perinatol 29 (2002) 675692

683

ment in outcome noted [64]. Because of possible cardiovascular and neurobehavioral side effects and potential for teratogenic effects, NMDA receptor antagonists are not recommended in the clinical setting in neonates with asphyxial injury [65 67]. Calcium channel blockers Calcium is a central mediator of the cascade of events to neuronal death; the calcium channel antagonist flunarazine was found to be partially neuroprotective when used prophylactically in fetal sheep [68] or rats [52] but not in the posttreatment model [69]. Cardiovascular side effects were noted; hence low dose flunarizine was subsequently used in fetal sheep pretreated before ischemic injury [70]. Fetal cardiovascular effects were minimal and neuronal cell damage was reduced significantly in many cerebral areas; probably by inhibition of glutamate release. There was a human study of the use of the calcium channel blocker nicardapine in four severely asphyxiated, newborn infants [71]. Continuous infusion of nicardapine was administered at 5 to 10 mg/kg/h with incremental increases to a total of 40 mg/kg/h for total duration of 12 hours. There was marked hypotension in three infants concurrent with a decrease in cerebral blood flow velocity. Calcium channel blockers may cause systemic hypotension and cerebral hypoperfusion because cerebral autoregulation is impaired in these infants [36]. Barbiturates Studies in perinatal animals suggested that high dose phenobarbital may be beneficial when used before the perinatal insult [72,73]. Barbiturates decrease energy depletion after injury. Studies have not been performed in animal models when barbiturates were administered after a perinatal insult. Thiopentone-induced coma after severe birth asphyxia is associated with complications, as was seen in a study of six severely asphyxiated infants [74]. Moderately high doses of prophylactic phenobarbital was beneficial when administered to 14 infants, compared with 16 infants who were not given phenobarbital. A lower mortality rate was noted among infants who received phenobarbital and more survivors had normal examinations [75]. A subsequent randomized, controlled study was performed in 32 severely asphyxiated neonates assigned to a thiopental treatment or a control group [76]. Incidence of seizures was similar in the two groups; however, more infants who received thiopental infusion had systemic hypotension. At 1 year of age there were no significant differences in neurodevelopmental outcome among survivors. A more recent randomized study with an adequate sample size to detect a 50% reduction in the incidence of neonatal seizures, evaluated a 40 mg/kg dose of phenobarbital in severely asphyxiated infants [77]. There were no adverse events from phenobarbital on blood pressure or other vital signs, nor was there a decrease in seizures. There was, however, a significant improvement in neurologic outcome at 3 years in the group that was treated with phenobarbital. A current review of the literature revealed that prophylactic anticonvulsants cannot be recommended in term infants with acute

684

S. Shankaran / Clin Perinatol 29 (2002) 675692

asphyxial injury [78]. Thus, the potential role of phenobarbital or other anticonvulsants should be studied with adequate sample size, minimal attrition, and with adequate power to detect clinically important reductions in death and disability as the primary outcome measures. Magnesium Magnesium may be protective because of activity at different levels of the cascade of events following experimental injury. In the newborn piglet, a protective effect by magnesium was demonstrated on NMDA receptor binding characteristics during cerebral hypoxia [79]. Magnesium prevents neuronal death from excitatory amino acids [80,81] or from oxidative injury [82]. Pretreatment with magnesium may be protective; therapy during asphyxia or post injury did not reduce cerebral injury in the animal models evaluated [83 85]. In term infants, a phase I study was initiated to evaluate two doses of magnesium sulphate (250 mg/kg and 400 mg/kg) in 15 full-term infants with severe, acute asphyxial injury. The lower dose was not associated with hypotension, but was associated with respiratory depression. The higher dose was followed by an unacceptable risk for hypotension [86]. Xanthine oxidase inhibition and free radical scavenger: allopurinol Reperfusion of ischemic brain leads to formation of cytotoxic free radicals when posthypoxic, ischemic reoxygenation occurs. Metabolism of hypoxanthine that accumulates in the brain during hypoxia-ischemia leads to additional production of superoxide and hydroxyl radicals. Allopurinol, a xanthine oxidase inhibitor and free radical scavenger, is protective with pretreatment and after the experimental injury. Pretreatment with allopurinol prevented modification of NMDA receptor-ion channel binding characteristics that were induced by repeated episodes of asphyxia [87]. Neuroprotection with pretreatment may be partly attributed to preservation of energy metabolites [88]. Cerebral edema and neuropathologic changes were reduced in the rat pups who were pretreated with allopurino. [89]. Allopurinol was as effective as a neuroprotective agent in the postischemic state. High-dose allopurinol in the rat pup was protective when administered immediately after the injury; decreases in cerebral edema, neuronal necrosis and cystic infarction occurred [90]. Allopurinol was investigated in a pilot study in term infants with asphyxia by Van Bel et al [91]. High-dose allopurinol (40 mg/kg ) was administered intravenously to 11 infants; 11 others served as controls. Free radical status was assessed by serial plasma determinations of nonprotein-bound iron, antioxidant capacity, and malondrildehyde. Cerebral perfusion was assessed by near infrared spectroscopy and brain electrocortical activity examined by cerebral function monitoring. Six control and two infants who were treated with allopurinol died. No adverse effects of allopurinol treatment were noted. In the infants who were treated with allopurinol, free radical formation decreased whereas cerebral blood volume and electrical brain activity was more stable than in the control infants. The number of infants who were evaluated in this study are limited. There were

S. Shankaran / Clin Perinatol 29 (2002) 675692

685

differences in baseline characteristics between the two groups, and no neurologic outcome data are available. The data are very promising, however, and support the investigation of allopurinol as a neuroprotective agent in a large, multicenter trial. Pharmacologic protection with allopurinol was also examined in infants who underwent cardiac surgery using deep hypothermic circulatory arrest [92]. Allopurinol or placebo was administered before, during, and after surgery in 348 infants. Clinical efficacy end points of death, seizures, coma, and cardiac events were monitored until hospital discharge. Allopurinol provided significant neurocardiac protection in the higher-risk infants with hypoplastic left heart syndrome but had no benefit in the lower risk infants who had other congenital cardiac defects. No significant adverse events were associated with allopurinol treatment. Because prophylactic treatment is the most desirable approach to neuroprotection, the transplacental kinetics of allopurinol, that was administered before the onset of labor in experimental animals, was examined by Boda et al [93]. In the newborn piglet, allopurinol levels were lower than maternal values but still high enough to ensure effective inhibition of xanthine oxidase activity. The investigators later treated pregnant women with a single dose of allopurinol or placebo, that was administered immediately after the onset of labor. There were 24 women with term gestation in the study. Allopurinol was rapidly transferred to the fetus, even when time to delivery was short; fetal allopurinol and oxy-purinol levels correlated with maternal levels. This study raised the possibility of investigating an intrapartum approach in the management of acute perinatal asphyxia in a large, clinical trial. Hypothermia Modest reductions of brain temperature, on the order of 2 to 4C, seem to be the most promising of the specific, neuroprotective therapies that have emerged over the past 10 to 15 years. In animal models, the extent of neuroprotection associated with brain cooling was related to the duration and depth of cooling [94 96]. Gunn et al [59] demonstrated the presence of a therapeutic window in near-term, fetal sheep that allowed modest hypothermia to be initiated up to 5.5 hours after ischemia. Three small pilot studies examined modest hypothermia for newborns with encephalopathy following acute perinatal asphyxia [97 99]. Methods of inducing modest hypothermia for the brain included head cooling, head cooling combined with body cooling, and body cooling alone [97 100]. Gunn [98] published the first clinical study where infants with clinical evidence of encephalopathy were randomized to no cooling or sequentially either minimal (rectal temperature 36.3 0.2C) or mild systemic cooling (rectal temperature 35.7 0.2C). Head cooling was accomplished by circulating water at 10C through a coil of tubing wrapped around the head for 72 hours. All infants were warmed by servo controlled overhead heaters to maintain an allocated rectal temperature. No infants developed cardiac arrhythmia, hypotension, or bradycardia during cooling.

686

S. Shankaran / Clin Perinatol 29 (2002) 675692

In 1999, Simbruner and colleagues [100] examined the physiological effects of hypothermia in a retrospective analysis with historical controls. Hypothermia was induced in 21 asphyxiated infants by placing a cap formed from cooled packs around the head at a temperature of 10C to maintain nasopharyngeal temperature of between 34C and 35C for 3 days. The investigators found that heart rate, respiratory rate, and abdominal skin temperature were lowered during the period of hypothermia. There were no differences in episodes of bradycardia, arrhythmia, bleeding, or organ failure between the cooled infants and 15 asphyxiated infants who received standard care during the preceding 6-month period. Cardiovascular changes during mild hypothermia and rewarming were reported by Thoresen and Whitelaw in 2000 [99]. Infants with clinical evidence of encephalopathy and an abnormal electroencephalogram were cooled by surface cooling of the trunk (n = 3, target rectal temperature 33C to 34C) or by applying a cap perfused with cooled water for 72 hours (n = 6, target temperature 34C to 35C). Maintenance heating and rewarming were provided by an overhead heater. Mean arterial pressure increased and heart rate decreased during cooling, and reversed during rewarming. The investigators report that in five infants, mean arterial blood pressure decreased because of a large increase in output of the overhead heater. Administration of anticonvulsants or sedatives, or intercurrent hypoxemia also produced drops in target temperature. In two infants, inspirated oxygen concentration had to be increased to maintain adequate oxygenation during cooling; the investigators attributed this to pulmonary hypertension. Thus, the investigators recommended careful monitoring in anticipation of the cardiovascular changes in the planning and execution of clinical trials. Azzopardi and coworkers [97] recently published their results on the safety and feasibility of whole body hypothermia for neonatal encephalopathy. Sixteen infants with birth asphyxia were assessed by amplitude integrated electroencephalography (aEEG); cooling was initiated in the 10 infants with an aEEG that was prognostic of poor outcome. Hypothermia was induced by blowing cool air, using a commercial cooling system, through a translucent, perforated, paper blanket that was placed over the infant. Rectal temperature was maintained at 33.3 0.6C for 48 hours. During hypothermia a lower heart rate and higher mean blood pressure were noted without any clinical effects. None of these studies of modest hypothermia used an automatic control mechanism to regulate the temperature at a desired value but depended upon investigators making frequent changes at the bedside. The efficacy of modest hypothermia may depend, in part, upon the stability of the lowered temperature; an automatic control mechanism may avoid large fluctuations in brain temperature. The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network recently evaluated, in newborn animals, a commercially available cooling system (Blanketrol II 7Hyperthermia-Hypothermia system) to control brain temperature during whole body hypothermia. They used the results of the animal experiments to perform a pilot study that evaluated the

S. Shankaran / Clin Perinatol 29 (2002) 675692

687

feasibility of whole body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth. In the animal investigation, three miniature swine were instrumented, ventilated, and temperature probes were placed in the esophagus and the brain. Body cooling was achieved using the automatic control mode of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of the esophageal temperature to 34.5C for 72 hours, followed by slow rewarming. In the animal experiments, body cooling was achieved rapidly within 90 minutes; esophageal temperature was a good marker of deep brain temperature. In the human investigation, infants were randomized at 4.11.3 hours and cooling was initiated by 5.3 hours. Target temperature was achieved within 30 minutes and remained constant throughout the intervention period. No adverse events occurred during the 72 hours of cooling [101]. Modest hypothermia seems to be a safe and promising therapy for acute hypoxic-ischemic brain injury. Efficacy of therapy with hypothermia needs to be examined with follow-up of treated infants; only one study has reported outcome on a small group of infants [102]. The challenge to clinicians is to select the infants who are at highest risk for death and disability, and initiate the cooling within the therapeutic window. There are several, ongoing, randomized, controlled trials of hypothermia for hypoxic-ischemic encephalopathy that are using different entry criteria and cooling strategies. Within the next 2 years, two major trials will report their results on whether induced hypothermia, initiated within 6 hours of birth, and continued for 72 hours in term infants with encephalopathy, will reduce the incidence of death or disability at 18 months of age. In the interim, therapeutic hypothermia should not be used outside of stringent, randomized, multicenter trials. The outcome measures to be used to look at the effectiveness of hypothermia should be sensitive enough to detect meaningful effects.

Summary Investigations in animal models of hypoxic-ischemic injury have not translated into clinical trials of success because of the complex pathology of hypoxicischemic brain injury in neonates, the difficulty in defining the onset and duration and severity of the injury, the underlying predisposing disorders of the mothers or the infant, the side effects of many of the investigational drugs precluded clinical use, and many of the investigational agents interfered with only one step of the cascade of events that lead to brain injury. It is possible that a combination of therapeutic agents, including those that affect different levels of the cascade to cell death, will have the greatest neuroprotective effects. Modest hypothermia postpones secondary energy failure and can prolong the window while pharmacotherapeutic agents can be used. It is possible that in the future, sequential administration of agents or strategies that are initiated in the intrapartum period

688

S. Shankaran / Clin Perinatol 29 (2002) 675692

and continued postnatally will be the optimum method for treating infants who are at highest risk for brain injury following acute hypoxic-ischemic asphyxia.

References
[1] Ramji S, Ahuja S, Thirupuram S, et al. Resuscitation of asphyxic newborn infants with room air or 100% oxygen. Pediatr Res 1993;34:809 12. [2] Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: The Resair 2 Study. Pediatrics 1998;102:e1. [3] Vento M, Asensi M, Sastre J, et al. Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics 2001;107:642 7. [4] Vento M, Asensi M, Sastre J, et al. Six years of experience with the use of room air for the resuscitation of asphyxiated newly born term infants. Biol Neonate 2001;79:261 7. [5] International guidelines for neonatal resuscitation. An excerpt from the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Pediatrics 2000;106:e29. [6] Wiswell TE, Gannon CM, Jacob J, et al. Delivery room management of the apparently vigorous meconium-stained infant: results of the multicenter, international collaborative trial. Pediatrics 2000;105:1 7. [7] Wiswell TE. Handling the meconium-stained infant. Semin Neonatol 2001;6:225 31. [8] Halliday HL. Endotracheal intubation at birth for preventing morbidity and mortality in vigorous, meconium-stained infants born at term. Cochrane Library Disk Issue 1 2000. [9] Ibara S, Ikenoue T, Murata Y, et al. Management of meconium aspiration syndrome by tracheobronchial lavage and replacement of surfactant TA. ACTA Paediatr Japonica 1995;37: 64 7. [10] Lam BCC, Yeung CY. Surfactant lavage for meconium aspiration syndrome: a pilot study. Pediatrics 1999;103:1014 8. [11] Ogawa Y, Ohara Y, Itakura Y, et al. Bronchial lavage with surfactant solution for the treatment of meconium aspiration syndrome. J Jpn Med Soc Biol Interface 1996;26(Suppl):179 87. [12] Chen H, Chopp M, Welsch KM. Effect of mild hyperthermia on the ischemic infarct volume after middle cerebral artery occlusion in the rat. Neurology 1991;41:1133 5. [13] Kuroiwa T, Bonnekoh P, Hossmann KA. Prevention of postischemic hyperthermia prevents ischemic injury of CA1 neurons in gerbils. J Cereb Blood Flow Metab 1990;10:550 6. [14] Suehiro E, Fujisawa H, Ito H, et al. Brain temperature modifies glutamate neurotoxicity in vivo. J Neurotrauma 1999;16:285 97. [15] Adamson SJ, Alessandri LM, Badawi N, et al. Predictors of neonatal encephalopathy in fullterm infants. BMJ 1995;311:598 602. [16] Badawi N, Kurinczuk JJ, Koegh JM, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998;317:1554 8. [17] Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997;278:207 11. [18] Gunn AJ, Bennet L. Is temperature important in delivery room resuscitation? Semin Neonatol 2001;6:241 9. [19] Wyckoff MH, Perlman J, Niermeyer S. Medications during resuscitation - what is the evidence? Semin Neonatol 2001;6:251 9. [20] Hein HA. The use of sodium bicarbonate in neonatal resuscitation: help or harm? Pediatrics 1993;91:496 7. [21] Kette F, Weil MH, Gazmuri RJ. Buffer solutions may compromise cardiac resuscitation by reducing coronary perfusion pressure [published correction appears in JAMA 1991;266: 3286] [see comments]. JAMA 1991;266:2121 6. [22] Ostrea EM, Odell GB. The influence of bicarbonate administration on blood pH in a closed system: clinical implications. J Pediatr 1972;80:671 80.

S. Shankaran / Clin Perinatol 29 (2002) 675692

689

[23] Lou HC, Lassen NA, Friss-Hansen B. Decreased cerebral blood flow after administration of sodium bicarbonate in the distressed newborn infant. Acta Neurol Scand 1978;57:239 47. [24] Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998;317:235 40. [25] Roberton NRC. Use of albumin in neonatal resuscitation. Eur J Pediatr 1997;156:428 31. [26] Martin-Ancel A, Garcia-Alix A, Cabanas FGF, et al. Multiple organ involvement in perinatal asphyxia. J Pediatr 1995;127:786 93. [27] Perlman JM, Tack ED, Martin T, et al. Acute systemic organ injury in term infants after asphyxia. Am J Dis Child 1989;143:617 20. [28] Shankaran S, Woldt E, Koepke T, et al. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 1991;25:135 48. [29] Walther FJ, Siassi B, Ramadan NA, et al. Cardiac output in newborn infants with transient myocardial dysfunction. J Pediatr 1985;107:781 5. [30] Toth-Heyn P, Drukker A, Guignard JP. The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy. Pediatr Nephrol 2000;14:227 39. [31] Karlowicz MG, Adelman RD. Nonoliguric and oliguric acute renal failure in asphyxiated term neonates. Pediatr Nephrol 1995;9:718 22. [32] Jenik AG, Cernadas JMC, Gorenstein A, et al. A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatrics 2000;105:e45. [33] DiSessa TG, Leitner M, Ti CC, et al. The cardiovascular effects of dopamine in the severely asphyxiated neonate. J Pediatr 1981;99:772 6. [34] Seri I. Cardiovascular, renal and endocrine actions of dopamine in neonates and children. J Pediatr 1995;126:333 44. [35] Tantivit P, Subramanian N, Garg M, et al. Low serum cortisol in term newborns with refractory hypotension. J Perinato 1999;19:352 7. [36] Boylan GB, Young K, Panerai RB, et al. Dynamic cerebral autoregulation in sick newborn infants. Pediatr Res 2000;48:12 7. [37] Pryds O, Greisen G, Lou H, et al. Vasoparalysis associated with brain damage in asphyxiated term infants. J Pediatr 1990;117:119 25. [38] Vannucci RC, Brucklacher RM, Vannucci SJ. Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat. Pediatr Res 1997;42:24 9. [39] Vannucci RC, Towfighi J, Heitjan DF, et al. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Pediatrics 1995;95:868 74. [40] Woodgate PG, Davies MW. Permissive hypercapnia for the prevention of morbidity and mortality in mechanically ventilated newborn infants. Cochrane Library Disk Issue 200l. [41] Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Library Disk Issue 2001. [42] Kinsella JP, Griebel J, Schmidt JM, et al. Use of inhaled nitric oxide during interhospital transport of newborns with hypoxemic respiratory failure. Pediatrics 2002;109:158 61. [43] American Academy of Pediatrics Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics 2000;106:344 5. [44] Soll RF, Dargaville P. Surfactant for meconium aspiration syndrome in full term infants. Cochrane Library Disk Issue 2000. [45] al Naqeeb N, Edwards AD, Cowan FM, et al. Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography. Pediatrics 1999;103:1263 71. [46] Hellstrom-Westas L, Rosen I, Svenningsen NW. Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants. Arch Dis Child 1995;72:F34 8. [47] Huang C, Wang S, Change Y, et al. Measurement of the urinary lactate: creatinine ratio for early identification of newborn infants at risk for hypoxia-ischemic encephalopathy. N Engl J Med 1999;341:328 35.

690

S. Shankaran / Clin Perinatol 29 (2002) 675692

[48] Qureshi AI, Suarez JI. Use of hypertonic sale solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med 2000;28:3301 13. [49] Levene MI, Evans D. Medical management of raised intracranial pressure after severe birth asphyxia. Arch Dis Child 1985;60:12 6. [50] Levene MI, Evans DH, Forde A, et al. Value of intracranial pressure monitoring of asphyxiated infants. Devel Med Child Neurol 1987;29:311 9. [51] Shankaran S, Woldt E, Bedard MP, et al. Feasibility of invasive monitoring of intracranial pressure in term neonates. Brain Dev 1994;16:121 5. [52] Chumas PD, Del Bigio MR, Drake JM, et al. A comparison of the protective effect of dexamethasone to other potential prophylactic agents in a neonatal rat model of cerebral hypoxicischemia. J Neurosurg 1993;79:414 20. [53] Tuor UI, Chumas PD, De Bigio MR. Prevention of hypoxic/ischemic damage with dexamethasone is dependent on age and not influenced by fasting. Exper Neurol 1995;132:116 22. [54] Sheldon RA, Partridge JC, Ferriero DM. Postischemic hyperglycemia is not protective to the neonatal rat brain. Pediatr Res 1992;32:489 93. [55] Yager JY, Heitjan DF, Towfighi J, et al. Effect of insulin-induced and fasting hypoglycemia on perinatal hypoxic-ischemic brain damage. Pediatr Res 1992;31:138 42. [56] Cornette L, Levene MI. Post-resuscitative management of the asphyxiated term and preterm infant. Semin Neonatol 2001;6:271 82. [57] Gluckman PD, Pinal CS, Gunn AJ. Hypoxic-ischemic brain injury in the newborn: pathophysiology and potential strategies for intervention. Semin Neonatol 2001;6:109 20. [58] Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. MRDD Research Reviews 2001;7:56 64. [59] Gunn AJ, Gunn TR, Gunning MI, et al. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998;102:1098 106. [60] Peeters C, van Bel F. Pharmacotherapeutical reduction of post-hypoxic-ischemic brain injury in the newborn. Biol Neonate 2001;79:274 80. [61] Andine P, Lehmann A, Ellren K, et al. The excitatory amino acid antagonist kynurenic acid administered after hypoxic-ischemia in neonatal rat offers neuroprotection. Neurosci Lett 1988;90:208 12. [62] Hattori H, Morin AM, Schwatz PH, et al. Posthypoxic treatment with MK-801 reduces hypoxic/ischemic damage in the neonatal rat. Neurology 1989;39:713 8. [63] Park CK, Nehls DG, Graham DI, et al. The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol 1998;24:543 51. [64] Sacco RL, DeRosa JT, Haley EC, et al. Glycine antagonist in neuroprotection for patients with acute stroke. GAIN Americas: a randomized controlled trial. JAMA 2001;285:1719 61. [65] Andaloro VJ, Monaghan DT, Rosenquist TH. Dextromethorphan and other N-Methyl-DAspartate receptor antagonists are teratogenic in the avian embryo model. Pediatr Res 1998; 43:1 7. [66] Bokesch PM, Kapural M, Drummond-Webb J, et al. Neuroprotective, anesthetic, and cardiovascular effects of the NMDA antagonist, CNS 5161A, in isoflurane-anesthetized lambs. Anesthesiology 2000;93:202 8. [67] Hustveit O, Maurset A, Oye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, and muscarinic receptors. Pharmacol Toxicol 1995;77:355 9. [68] Gunn AJ, Williams CE, Mallard C, et al. Flunarizine, a calcium channel antagonist, is partially prophylactically neuroprotective in hypoxic-ischemic encephalopathy in the fetal sheep. Pediatr Res 1994;35:657 63. [69] Gunn AJ, Gluckman PD. Flunarizine, a calcium channel antagonist, is not neuroprotective when given after hypoxia-ischemia in the infant rat. Dev Pharmacol Ther 1991;17:205 9. [70] Berger R, Lehmann T, Karcher J, et al. Low dose flunarizine protects the fetal brain from ischemic injury in sheep. Pediatr Res 1998;44:277 82. [71] Levene MI, Gibson NA, Fenton AC, et al. The use of a calcium-channel blocker, nicardipine, for severely asphyxiated newborn infants. Developmental Med Child Neuro 1990;32:567 74.

S. Shankaran / Clin Perinatol 29 (2002) 675692

691

[72] Myers RE, Williams MV. Lost opportunities for the prevention of fetal asphyxia: sedation, analgesia, and general anaesthesia. Clin Obstet Gynaecol 1982;9:369 414. [73] Richter JA, Holtmas Jr JR Barbiturates: their in vivo effects and potential biochemical mechanisms. Prog Neurobiol 1982;18:275 319. [74] Eyre JA, Wilkinson AR. Thiopentone induced coma after severe birth asphyxia. Arch Dis Child 1986;61:1084 9. [75] Svenningsen NW, Blennow G, Lindroth M, et al. Brain-orientated intensive care treatment in severe neonatal asphyxia. Arch Dis Child 1982;57:176 83. [76] Goldberg RN, Moscoso P, Bauer CR, et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr 1986;109:851 6. [77] Hall RT, Hall FK, Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998;132:345 8. [78] Evans DJ, Levene MI. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Library 2001. [79] Hoffman DJ, Marro PJ, McGowan JE, et al. Protective effect of MgS04 infusion on NMDA receptor biding characteristics during cerebral cortical hypoxia in the newborn piglet. Brain Res 1994;644:144 9. [80] Marret S, Gressens P, Gadisseux JF, et al. Prevention by magnesium of excitotoxic neuronal death in the developing brain: an animal model for clinical intervention studies. Dev Med Child Neurol 1995;37:473 84. [81] Puza S, Goel R, Hoffman D, et al. Pretreatment with magnesium protects NMDA receptor in fetal guinea pig brain during hypoxia. Prenatal Neonatal Med 1996;1:349 54. [82] Regan RF, Jasper E, Guo YP, et al. The effect of magnesium on oxidative neuronal injury in vivo effects. J Neurochem 1998;70:77 85. [83] de Haan HH, Gunn AJ, Williams CE, et al. Magnesium sulfate therapy during asphyxia in nearterm fetal lambs does not compromise the fetus but does not reduce cerebral injury. Am J Obstet Gynecol 1997;176:18 27. [84] Galvin KA, Oorschot DE. Postinjury magnesium sulfate treatment is not markedly neuroprotective for striatal medium spiny neurons after perinatal hypoxia/ischemia in the rat. Pediatr Res 1998;44:740 5. [85] Penrice J, Ames PN, Punwani S, et al. Magnesium sulfate after transient hypoxia-ischemia fails to prevent delayed cerebral energy failure in the newborn piglet. Pediatr Res 1997;41:443 7. [86] Levene M, Blennow M, Whitelaw A, et al. Acute effects of two different does of magnesium sulphate in infants with birth asphyxia. Arch Dis Child 1995;73:F174 7. [87] Marro PJ, Hoffman D, Schneiderman R, et al. Effect of allopurinol on NMDA receptor modification following recurrent asphyxia in newborn piglets. Brain Res 1998;787:71 7. [88] Williams GD, Palmer C, Heitjan DF, et al. Allopurinol preserves cerebral energy metabolism during perinatal hypoxia-ischemia: a 31P NMR study in unanesthetized immature rats. Neurosci Lett 1992;144:103 6. [89] Palmer C, Vannucci RC, Towfighi J. Reduction of perinatal hypoxic-ischemic brain damage with allopurinol. Pediatr Res 1990;27:332 6. [90] Palmer C, Towfighi J, Roberts RL, et al. Allopurinol administered after inducing hypoxiaischemia reduces brain injury in 7-day-old rats. Pediatr Res 1993;33:405 11. [91] Van Bel F, Shadid M, Moison RMW, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 1998;101:185 93. [92] Clancy RR, McGaurn SA, Goin JE, et al. Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest. Pediatrics 2001;108: 61 70. [93] Boda D, Nemeth I, Kiss P, et al. Treatment of mothers with allopurinol to produce therapeutic blood levels in newborns. Prenat Neonat Med 1994;4:130 4. [94] Carroll M, Beck O. Protection against hippocampal CA1 cell loss by post-ischemic hypothermia is dependent on delay of initiation and duration. Med Brain Dis 1992;7:45 50.

692

S. Shankaran / Clin Perinatol 29 (2002) 675692

[95] Colbourne F, Corbett D. Delayed post-ischemic hypothermia: a six-month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995; 15:7250 60. [96] Sirimanne ES, Blumberg RM, Bossano D, et al. The effect of prolonged modification of cerebral temperature on the outcome after hypoxic-ischemic brain injury in the infant rat. Pediatr Res 1996;39:591 7. [97] Azzopardi D, Robertson NJ, Gowan FM, et al. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics 2000;106:684 94. [98] Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102:885 92. [99] Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics 2000;106:92 9. [100] Simbruner G, Haberi C, Harrison V, et al. Induced brain hypothermia in asphyxiated human newborn infants: a retrospective chart analysis of physiological and adverse effects. Intensive Care Med 1999;25:1111 7. [101] Shankaran S, Laptook A, Wright LL, et al. Whole body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized controlled pilot study in term infants. Pediatrics 2002;110:377 85. [102] Battin MR, Dezoete JA, Gunn TR, et al. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics 2001;107:480 4.