Elsevier

Pediatric Neurology

Volume 32, Issue 1, January 2005, Pages 11-17
Pediatric Neurology

Original articles
Moderate hypothermia in neonatal encephalopathy: Efficacy outcomes

https://doi.org/10.1016/j.pediatrneurol.2004.06.014Get rights and content

Therapeutic hypothermia holds promise as a rescue neuroprotective strategy for hypoxic-ischemic injury, but the incidence of severe neurologic sequelae with hypothermia is unknown in encephalopathic neonates who present shortly after birth. This study reports a multicenter, randomized, controlled, pilot trial of moderate systemic hypothermia (33°C) vs normothermia (37°C) for 48 hours in neonates initiated within 6 hours of birth or hypoxic-ischemic event. The trial tested the ability to initiate systemic hypothermia in outlying hospitals and participating tertiary care centers, and determined the incidence of adverse neurologic outcomes of death and developmental scores at 12 months by Bayley II or Vineland tests between normothermic and hypothermic groups. Thirty-two hypothermic and 33 normothermic neonates were enrolled. The entry criteria selected a severely affected group of neonates, with 77% Sarnat stage III. Ten hypothermia (10/32, 31%) and 14 normothermia (14/33, 42%) patients expired. Controlling for treatment group, outborn infants were significantly more likely to die than hypoxic-ischemic infants born in participating tertiary care centers (odds ratio 10.7, 95% confidence interval 1.3–90). Severely abnormal motor scores (Psychomotor Development Index < 70) were recorded in 64% of normothermia patients and in 24% of hypothermia patients. The combined outcome of death or severe motor scores yielded fewer bad outcomes in the hypothermia group (52%) than the normothermia group (84%) (P = 0.019). Although these results need to be validated in a large clinical trial, this pilot trial provides important data for clinical trial design of hypothermia treatment in neonatal hypoxic-ischemic injury.

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.

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