Original articlesModerate hypothermia in neonatal encephalopathy: Efficacy outcomes
Introduction
Neuroprotective strategies that may improve outcomes after hypoxic-ischemic injuries are attracting substantial clinical interest. Many pharmacologic investigations have not consistently improved outcomes in animals and humans, perhaps because of the complexity of secondary processes that extend hypoxic-ischemic injury. Although several therapies have shown promise in a preventative strategy, few have demonstrated merit in a postischemic intervention strategy for hypoxic-ischemic disease.
Rescue treatment of neonatal hypoxic-ischemic injury with induced hypothermia is currently being investigated in several multicenter trials around the globe, after extensive animal research established an impressive and consistent record of neuroprotection [1], [2], [3]. Hypothermia delayed up to 6 hours after hypoxic-ischemic injury has resulted in improvement of secondary energy failure, infarct volume, and functional outcomes in neonatal animals [4], [5], [6], [7]. After performing a feasibility study with five neonates, we conducted this randomized, controlled, multicenter pilot trial of moderate hypothermia in hypoxic-ischemic neonates to determine incidence of adverse neurologic outcomes in neonates who meet entry criteria within 6 hours of birth or hypoxic-ischemic event, randomized to either hypothermia or normothermia; to test uniformity of treatment initiation in different clinical situations; and to provide evidence-based, sample size estimates for a large-scale clinical trial.
Section snippets
Methods
Institutional Review Boards of seven participating institutions approved this study. Informed consent was obtained before enrollment. The National Institute for Neurologic Disorders and Stroke appointed a Data and Safety Monitoring committee, which provided oversight of this multicenter pilot trial. Sixty-five infants were enrolled from January 1998 through January 2001 with a 12-month follow-up period.
Demographics
Six participating sites enrolled 65 infants, 32 randomized to hypothermia, 33 to normothermia. Sixty-three infants were screened but not enrolled for the following reasons: Only one abnormality on neurologic examination (16), gestation <35 weeks (10), maternal chorioamnionitis (8), referral after the 6-hour window (14), in utero growth retardation (1), encephalopathy without clinical sign of hypoxic-ischemic injury (2), chromosomal malformation (2), parental refusal of consent (3), inadequate
Discussion
This pilot trial provides important data for designing large hypothermia trials in neonatal hypoxic-ischemic injury. Using our entry criteria of two neurologic examination abnormalities for neonates who presented within 6 hours of hypoxic-ischemic injury, mainly severely affected Sarnat stage III neonates were enrolled, although Sarnat stage I infants could potentially be enrolled. They are also primarily outborn, and had a higher death rate compared with the inborn hypoxic-ischemic neonates.
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Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, Horgan MJ, Languani S, Bhatia JJ, Givelichian LM, Sankaran K, Yager JY. Moderate hypothermia in neonatal encephalopathy: Efficacy outcomes.