Elsevier

The Lancet

Volume 365, Issue 9460, 19–25 February 2005, Pages 663-670
The Lancet

Articles
Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial

https://doi.org/10.1016/S0140-6736(05)17946-XGet rights and content

Summary

Background

Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy.

Methods

234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34–35°C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation—ie, severe loss of background amplitude, and seizures—and those with less severe changes.

Findings

In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0·61; 95% CI 0·34–1·09, p=0·1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0·57 (0·32–1·01, p=0·05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1·8; 0·49–6·4, p=0·51), but was beneficial in infants with less severe aEEG changes (n= 172, 0·42; 0·22–0·80, p=0·009).

Interpretation

These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.

Introduction

Hypoxic-ischaemic encephalopathy is an important cause of acute neurological injury at birth, occurring in about one to two babies per 1000 term livebirths.1 No specific clinical intervention has been shown to alter outcome. Experiments have shown that a reduction in brain temperature of 2–5°C applied after perinatal hypoxia-ischaemia can improve neuropathological,2, 3, 4, 5, 6 cerebral energetic,7, 8 electrophysiological,1, 2 and functional outcomes.5, 9

The neuroprotective effects of experimental cooling are dependent on both a sufficient duration of cooling and on the timing of initiation of cooling.1 Extended cooling for 24–72 h, started as late as 6 h after injury, has been associated with persistent protection.3, 5, 8, 9, 10 However, there is rapid loss of effect as treatment delay is increased,1 and cooling does not seem to be protective if started after the onset of delayed seizures.1, 11 Furthermore, hypothermia seems to be less protective in those with the most severe cerebral injuries than in those with less severe injuries.5, 8, 11 These issues could restrict the application of hypothermia to neonatal encephalopathy, in which there is much variation both in the apparent timing of the insult and in the severity. Nevertheless, early induction of moderate hypothermia in adult patients after cardiac arrest improves neurological recovery,12, 13 and moderate hypothermia is generally safe in an intensive-care setting.14, 15, 16, 17, 18

Our aim was to investigate whether 72 h of selective head cooling with mild systemic hypothermia,14, 17 started within 6 h of birth, improves neurodevelopmental outcome at 18 months in infants with moderate or severe neonatal encephalopathy.

Section snippets

Methods

This study was done in 25 perinatal centres in accordance with a trial design registered with the US Food and Drug Administration under the investigational device exemption/premarket approval programme. The institutional review board of every centre approved the protocol, and written informed consent was obtained from parents before randomisation.

Results

Figure 1 shows the trial profile. 234 infants were randomly allocated cooling (n=116) or control treatment (n=118). The prerandomisation aEEG recordings had moderate to severe suppressed background in 105 (91%) cooled and 108 (92%) control infants, with seizures occurring in more than half the infants in both groups (table 1). The age of the infants at randomisation and the numbers of recruitment and protocol violations at study entry (14 cooled vs 13 controls) were closely similar for both

Discussion

Although head cooling with mild systemic hypothermia started within 6 h of birth was of some benefit in a mixed population of infants with moderate to severe encephalopathy, the effect was not significant. These results lend support to our a-priori hypothesis that hypothermia would not be protective in infants with the most severe aEEG abnormalities before randomisation, although there were few infants in this group.

Previous data on the effectiveness of hypothermia in newborn babies are scarce.1

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