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evident
Original paper
2005NEJMPediatrics

NICHD neonatal hypothermia trial

Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy

RCTNeonatal encephalopathy

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Overview

Whole-body cooling to 33.5 degrees C for 72 hours reduced the composite of death or moderate or severe disability in infants of at least 36 weeks with HIE.

Clinical takeaway

In infants of at least 36 weeks' gestation with moderate or severe encephalopathy treated by 6 hours of age, whole-body hypothermia reduced the composite of death or moderate or severe disability. Death alone and cerebral palsy among survivors did not differ significantly.

Key result

Death or moderate or severe disability: 45 of 102 (44%) with hypothermia vs 64 of 103 (62%) with usual care (RR 0.72, 95% CI 0.54-0.95; P=0.01).

Practice impact

Offer whole-body hypothermia to eligible term or late-preterm infants with moderate or severe HIE who can start cooling by 6 hours of age.

Evidence

Study design

Randomized trial of whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours followed by slow rewarming, versus usual care.

Enrollment

208

Follow-up

Neurodevelopmental outcome assessed at 18 to 22 months of age.

Geography

Not listed

Clinical question

Does whole-body hypothermia reduce death or moderate or severe disability in infants with moderate or severe hypoxic-ischemic encephalopathy?

Population

  • Infants with gestational age of at least 36 weeks, admitted at or before 6 hours of age, with either severe acidosis or perinatal complications and resuscitation at birth, and with moderate or severe encephalopathy.

Intervention

Whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming.

Comparator

Usual care (control group).

Primary outcome

Combined end point of death or moderate or severe disability.

Among infants with primary outcome data, death or moderate or severe disability occurred in 45 of 102 (44%) with hypothermia vs 64 of 103 (62%) with usual care (RR 0.72, 95% CI 0.54-0.95; P=0.01).

Risk ratio / 0.72 / 95% CI 0.54-0.95 / p=0.01

Key results

  • Of 239 eligible infants, 102 were assigned to hypothermia and 106 to control. Primary outcome data were available for 205 infants.
  • Death or moderate or severe disability: 45 of 102 (44%) with hypothermia vs 64 of 103 (62%) with control (RR 0.72, 95% CI 0.54-0.95; P=0.01).
  • Death: 24 (24%) with hypothermia vs 38 (37%) with control (RR 0.68, 95% CI 0.44-1.05; P=0.08); this comparison was not statistically significant.
  • Among survivors, cerebral palsy occurred in 15 of 77 (19%) with hypothermia vs 19 of 64 (30%) with control (RR 0.68, 95% CI 0.38-1.22; P=0.20); there was no increase in major disability among survivors.

Harms

  • Adverse events were similar in the two groups during the 72 hours of cooling.
  • Death alone was not significantly lower with hypothermia (RR 0.68, 95% CI 0.44-1.05; P=0.08).

Clinical Use

Practice impact

  • Start whole-body hypothermia by 6 hours of age in infants of at least 36 weeks' gestation with moderate or severe HIE who meet the trial's acidosis or resuscitation criteria.

Applicability

  • Most applicable to infants of at least 36 weeks' gestation with moderate or severe encephalopathy who can be admitted and randomized by 6 hours of age.

Limitations

  • 239 infants were eligible, 208 were randomized (102 hypothermia, 106 control), and 205 had primary outcome data (102 vs 103).
  • Death and cerebral palsy among survivors had confidence intervals that included no effect.
  • The abstract does not describe how usual care managed temperature.

Common misinterpretations

  • Do not say hypothermia significantly reduced death; the death comparison was not statistically significant (95% CI 0.44-1.05).
  • Do not say hypothermia significantly reduced cerebral palsy among survivors; that secondary comparison was not statistically significant (P=0.20).

Related evidence

TTM - Context

Citation

Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584. doi:10.1056/NEJMcps050929

Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.