ArticlesSelective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial
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
References (30)
- et al.
Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia
Biochem Biophys Res Commun
(1995) - et al.
School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term
J Pediatr
(1989) Cerebral hypothermia for prevention of brain injury following perinatal asphyxia
Curr Opin Pediatr
(2000)- et al.
Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs
J Clin Invest
(1997) - et al.
The effect of prolonged modification of cerebral temperature on outcome after hypoxic–ischemic brain injury in the infant rat
Pediatr Res
(1996) - et al.
Protective effects of moderate hypothermia after neonatal hypoxia- ischemia: short- and long-term outcome
Pediatr Res
(1998) - et al.
Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective
Ann Neurol
(2003) - et al.
Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet
Pediatr Res
(1995) - et al.
Resuscitative hypothermia protects the neonatal rat brain from hypoxic-ischemic injury
Brain Pathol
(2000) - et al.
Delayed postischemic hypothermia improves long-term behavioral outcome after cerebral hypoxia-ischemia in neonatal rats
Pediatr Res
(2002)