Hypoxic-ischemic encephalopachy (HIE) is not a discrete entity hut rather refers to the clinical and neuropathologic findings that occur in the full term infant following a significant episode of either intrapartum or neonatal asphyxia. It represents the single most important perinatal cause of neurologic morbidity in the full term infant. The frequency of HlE is approximately 4%, an incidence that has remained fairly constant over the past ten years. In order to confirm a diagnosis of HlE two criteria must he met: there needs to be a history of perinatal distress and the infant must have an abnormal neurologic examination shortly after birth. In the past the clinical management of the infant with HIE has focused on the treatment of central nervous system dysfunction. It is now recognized that the infant with HIE may have variable injury to multiple organ systerns, particularly pulmonary, cardiovascular, renal, and metabolic.1,2 In fact, the majority of neonatal deaths can be attributed to complications arising from the severe compromise of organ systems other than the central nervous system.1
Initial management of the infant with HIE includes an assessment of the infant's ventilation and perfusion status. If the infant has a spontaneous respiratory rate of 40 breaths/minute or more, adequate breath sounds, a PaO2 greater than 50 torr and a PaCO2 less than 45 torr, no action may be necessary. Ventilatory assistance and/or an enriched oxygen environment may be required for infants not meeting these criteria. A chest x-ray is of major importance in assessing the nature and extent of the problem. Discontinuation of ventilatory assistance should be entertained once the infant establishes adequate spontaneous respiratory activity. The continued need for supplemental oxygen can be assessed by the continuous measurement of oxygen saturation with pulse oximetry.
The assessment and improvement of preload is the most overlooked aspect of the management of the infant with asphyxia. Perfusion status is most readily assessed by the measurement of mean arterial pressure and capillary filling time. If the mean arterial pressure is low or capillary filling time is prolonged, the administration of a 10 cc/kg fluid bolus over 20 to 30 minutes may improve cardiac output. A repeat bolus 10 cc/kg may be given cautiously if low mean arterial pressure or poor capillary perfusion persist. The agents most useful for improving preload include fresh frozen plasma, normal saline, whole blood, and packed red blood cells.
MANAGEMENT OF MULTIPLE ORGAN SYSTEMS FAILURE
Because myocardial dysfunction has been noted frequently in infants with HIE, an assessment of cardiac function is recommended for infants who manifest a persistent peripheral hypoperfusion or a refractory hypoxemia. If there is evidence of impaired cardiac output the use of a cardiotonic agent can be considered. Inotropic agents, particularly dopamine and dobutamine, are the agents most commonly used in the newborn. Although the effective dose for each infant differs, a recommended starting point is 2 u,g/ kg/minute. Depending upon the clinical response, the dose can be increased in increments to 20 µ-g/kg/ minute. Treatment of hypovolemia, hypoxemia, hypercarbia, and acidosis must accompany drug therapy in order to assure optimal drug effect.
During asphyxia, energy requirements are met by anaerobic glycolysis, an inefficient mechanism that results in a rapid depletion of glycogen stores. If the asphyxia is prolonged or glycogen stores are marginal, the infant with HIE will manifest hypoglycemia within hours after birth. To prevent hypoglycemia it is recommended that intravenous glucose supplementation be initiated shortly after birth. The rate of glucose infusion needs to be monitored with Dextrostix* and blood glucose determinations to maintain a blood glucose level between 50 and 90 mg/dL.
Persistent hypocalcemia over the first few postnatal days has been documented in infants with HIE. For this reason serum calcium levels need to be monitored frequently. Because hypocalcemia may adversely affect myocardial contractility, calcium replacement with a 10% calcium gluconate solution may be warranted.
Transient renal insufficiency manifested by oliguria and azotemia has been observed frequently in infants with HIE.1 It is vital to determine whether the cause of oliguria is prerenal or renal in origin. If an infant has a prompt increase in urinary output when an intravenous fluid bolus of 10 to 20 cc/kg is administered, it can be presumed that the renal failure is secondary to inadequate renal perfusion. Conversely, a poor response to the rapid administration of intravenous fluid may indicate that renal impairment exists. In such infants there is a diminished clearance of free water and salt and a diminished excretion of hydrogen ions. Fluid retention may ensue causing hyponatremia. Clinical management includes maintenance of the balance of water, electrolytes, and hydrogen ions. Fluid intake should be equal to insensible water loss (40 mL/kg/day) plus urinary output. Initially a glucose solution without electrolytes is preferred. The concentration of glucose needs to be adequate to maintain a blood glucose level between 50 and 90 mg/ dL. Measurements of serum blood urea nitrogen, creatinine, and electrolytes every 12 hours are helpful in determining when to add electrolytes to the intravenous solution.
Central Nervous System
The goal of therapy in the management of neurologic dysfunction is to mitigate further brain injury. Because HIE encompasses a wide range of cerebral injury, treatment of an individual infant must be based on the evolution of specific neurologic findings over1 the first few postnatal days. In an attempt to ascertain the extent of neurologic injury, three clinical stages of HIE have been described (Table).1-4 Frequent clinical assessment of the infant with HIE is required to ascertain whether the encephalopathy is improving or worsening.
An infant with mild HIE probably requires no specific treatment. Although it has been suggested that infants with mild HIE may benefit from the prophylactic administration of anticonvulsant agents, particularly barbiturates,5 data from a recent randomized clinical trial do not support this recommendation.6
For infants with moderate or severe HIE, specific treatment has been directed toward the control of seizures and the prevention of cerebral edema. The usual pattern of clinical .seizure activity is one in which seizures begin at 12 to 24 hours of age and stop at five to seven days as the underlying acute encephalopathy resolves. Often the seizures are intractable to anticonvulsant therapy. Recent data suggest that the failure of anticonvulsant therapy in controlling seizures may be because many neonatal seizures have a subcortical origin, representing a lack of cortical inhibition rather than excessive cortical activity.' Until more data are available, anticonvulsant treatment ot clinical seizures is recommended.
Phenobarbital is the most widely used anticonvulsant agent. Beyond its anticonvulsant properties, phenobarbital also may beneficially reduce catecholamine secretion, toxic tree radicals, cerebral edema, and general metabolic activity. There is no consensus regarding the recommended loading dose of phenobarbital; the range varies from 10 mg/kg to 40 mg/kg. Ir is administered in increments of 10 mg/kg at 15 minute intervals. The therapeutic range is a serum level of 20 to 40 µg/mL, Because the half life of phenoharhital in infants with HIE can ho as long as 100 hours,8 it is recommended that maintenance therapy (3 to 4 mg/ kg/day) he delayed until the serum level falls to the lower end of the therapeutic range in order to avoid toxicity. Electroencephalogram evidence of seizure activity should he sought before maintenance therapy is initiated.
Clinical Stages of Hypoxlc-lschemfc Encephalopathy
If seizure activity persists despite phenobarbital therapy, the addition of another anticonvulsant agent has been advocated. Currently, phenytoin and lorazepam are the most popular second drugs of choice (RA Ehrenkranz, unpublished questionnaire). An intravenous loading dose of 15 to 20 mg/kg of phenytoin infused over 15 minutes will achieve a therapeutic blood level of 20 to 30 µg/mL. Maintenance therapy of 3 to 4 mg/kg/day must be given intravenously because oral phenytoin may be absorbed erratically. Published studies on the use of lorazepam for the treatment of neonatal seizures are scant and at present the optimal dosing schedule is unknown.1'
There are no clear-cut guidelines for the duration of anticonvulsant therapy. Ingenerai, it is recommended that anticonvulsants should be discontinued prior to discharge it clinical seizures have stopped and epileptiform activity is not evident on an electroencephalogram study.10 For infants with persistent seizures, king term phenobarbital therapy is advocated. Because infants who manifested neonatal seizures are at risk for subsequent epilepsy, parents need to be educated about the clinical manifestations of seizures.
At present, the role of brain edema in the genesis of brain injury in infants with HIE is not well delineated. It is not clear whether the ederna is a cause of brain injury or whether it is a phenomenon secondary to prior tissue necrosis. Moreover, there have been no controlled clinical studies that have demonstrated that the use ot therapy aimed at the prevention or reduction of brain edema mitigates brain injury in infants with HlE. For these reasons, the management of brain edema remains controversial. Potential therapies include fluid restriction, dexamethasone, and mannitol. Because excessive fluid intake may aggravate brain edema and further compromise cerebral perfusion, fluid restriction may be beneficial. There are no compelling data that warrant the recommendation to use dexamethasone therapy. A recent preliminary study demonstrated that the administration of marinimi led to a reduction in intracranial pressure and an improvement in cerebral perfusion pressure in a small group of severely asphyxiated newborn infants." Further observations are needed to determine if mannitol therapy will lessen the extent of brain injury.
Experimental methods of brain preservation in animal models of hypoxia-ischemia have been studied extensively. Agents that appear promising include prostaglandin inhibitors,12 calcium blockers, n and glutamate antagonists.14 As more insight is gained into the pathophysiology of hypoxic-ischemic brain injury, new clinical therapies will emerge.
1. Sexson WR, Sexson SB, Rawson JE, et al: The multisystem involvement of the asphyxiated newborn. Pediatr Res 1976;10432.
2. Tack E, Perlman JM, Hausel C, et al: Systemic manifestations of perinatal asphyxia in the newborn. Pediatr Res 1986; 20:362A.
3. Samat HB, Samat MS: Neonatal encephalopthy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33:696.
4. Amiel-Tison C, Ellison P: Birth asphyxia in the full-term newborn: Early assessment and outcome. Dev Med Child Neurol 1986; 28;371.
5 Volpe JJ: Hypoxic-ischemic encephalopathy: Clinical aspects, in Neurology of the Newborn. Philadelphia, WB Saunders, 1987; p 236.
6. Goldberg R, Moscoso R, Bauer C, et al: Use of barbiturate theraphy in severe perinatal asphyxia: A ramdomized controlled trial. J Pediatr 1986; 109:851.
7. Kellaway P, Mizrahi E: Neonatal seizures, in Luders H, Lesser RP (eds): Epilepsy: Electroclinical Syndromes. New York, Springer-Verlag, 1987, p 13.
8. Gal P, Toback J, Erkan NV, et al: The influence of asphyxia on phenobarbital dosing requirements in neonates. Dev Pharmacol Ther 1984; 7:145.
9. Deshmukh A, Wittert W, Schnitzler E, et al: Lorazepam in the treatment of refractory neonatal seizures. Am J Dis Child 1986; 140:1042.
10. Vining E, Freeman J: Seizures which are not epilepsy. Pediatr Ann 1985; 14:716.
11. Levene MI, Evans DH: Medical management of raised intracranial pressure after severe birth asphyxia. Arch Dis Child 1985; 60:12.
12. Hallenbeck JM, Leitch DR, Dutka AJ, et al: Prostagladin I^sub 2^, indomethacin, and heparin promote post-ischemic neotonal recovery in dogs. Ann Neurol 1982; 12:145.
13. Wiernsperger N, Gygax P, Hofman A: Calcium antagonist P4 108-068: Demonstration of its efficacy in various types of experimental brain ischemia. Stroke 1984;15:679.
14. Meldrum B, Evans M, Griffiths T, et al: Ischaemic brain damge: The role of excitatory activity and of calcium entry. Br J Anaesth 1985; 57:44.
Clinical Stages of Hypoxlc-lschemfc Encephalopathy