PEDIATRICS Vol. 120 No. 1 July 2007, pp. 171-172 (doi:10.1542/peds.2007-0602)
COMMENTARY |
Determinants of Outcome After Head Cooling for Neonatal Encephalopathy
Obstetrics and Gynaecology, Hornsby Hospital, Hornsby, New South Wales, Australia
Abbreviations: HIE, hypoxic-ischemic encephalopathy
If the inhabitants of Olympus were to set 10 tasks for Hercules in perinatology, then the prevention and limitation of neurologic injury would be high on the list, along with the prevention of preeclampsia, prematurity, postpartum hemorrhage, and the impact of poverty on pregnancy outcome.
The Cool Cap (Olympic Medical, Seattle, WA)1 Trial is a step along this path. The role of this technology is as-yet uncertain, its long-term benefits are unclear, and its safety profile is still incompletely defined. However, given the frequency of adverse outcomes in this group (>60% in the whole cohort), the promising outcomes of the original randomized trials strongly suggest that cooling will be an important part of our armamentarium in the years ahead.
The latest article2 from the group presents an exploratory posthoc analysis of the data from the Cool-Cap Trial for the purpose of hypothesis generation to inform additional studies of factors that may influence the outcome of treatment.
The original study (and, therefore, the conclusions drawn from it) was, to some extent, held hostage by the difficulties inherent in the prospective diagnosis of hypoxic-ischemic encephalopathy (HIE). This subgroup of infants with newborn encephalopathy is of particular interest because of the association with acute intrapartum problems. A pathology that is in evolution at the time of birth may be reversible. Unfortunately, the criteria used to demonstrate a hypoxic-ischemic etiology as set out in the study's inclusion criteria (ie, Apgar score of 
5 at 10 minutes, need for resuscitation at 10 minutes, cord pH <7.00, or base deficit of 
16 mmol/L) were particularly nonspecific. The most specific characteristic, the cord gases, were available, even with this research subgroup, in only a minority of cases. Perhaps this accounts for the high prevalence figure for HIE quoted of 2 to 3 in 1000. In the population-based case-control study by Badawi et al,3,4 newborn encephalopathy (of all etiologies) occurred in 3.75 in 1000 births, only 29% of which were thought to have possible intrapartum hypoxia when using very inclusive criteria. Pure HIE was calculated to occur in 1.6 in 10000 term births.
Of course, the difficulty is that by the time the underlying etiology is identified, the chance for intervention in the subgroup that may respond is lost. As yet, no reliable test exists to identify those who have had a severe insult in the hours before birth. Therefore, because potentially reversible pathologies are diluted by those in which the injury is distant to the birth, studies that seek to accurately identify subgroups that may benefit from or be harmed by treatment need to be large and are difficult to mount.
Even with these reservations, this analysis raises some interesting possibilities. The authors confirmed the prognostic significance of grade of encephalopathy and severity of electroencephalographic abnormality as predictors of outcome. They demonstrated that selective head cooling was effective in the management of both moderate and severe encephalopathy. They also identified an intriguing association between birth weight and outcome. Although the division of birth weight into those below and above the 25th centile seems a little arbitrary, given the sample size, it is probably not unreasonable. In the analysis presented, larger infants were both more likely to have an adverse outcome, in terms of death or severe disability at 18 months of age, and more likely to show a greater therapeutic response to treatment. The authors put forward several possible explanations for these results. However, it remains an unexpected finding. In the Badawi et al study of newborn encephalopathy,3,4 infants >4 kg had the lowest incidence of newborn encephalopathy of any group, whereas birth weight of <3rd centile was the risk factor with the greatest magnitude of effect.
So what other possible explanations may help explain this association with birth weight? It is possible that, compared with growth-restricted fat-depleted fetuses, larger infants may respond to episodes of profound hypoxia by metabolizing fat with the production of ketone bodies and free radicals. Larger infants in the face of hypoxia still have to meet the metabolic demands of the large placenta and body, thus diverting precious oxygen and blood flow from central organs. Interestingly, the only group of large infants who were at increased risk of newborn encephalopathy in the Badawi et al3,4 study were those infants >4 kg who had an acute onset of severe preeclampsia with its associated placental ischemia but no time to decrease their metabolic demands by growth restricting. These infants were more likely to develop signs of intrapartum hypoxia and were at a 14-fold increased risk of newborn encephalopathy. Larger infants also have greater head volumes and greater volumes of cerebral blood flow. This may lead to differential cooling of superficial and deep cerebral structures, which might confer a benefit. Finally, because larger infants, in general, seem to be protected from newborn encephalopathy, it is quite possible that encephalopathy in such an infant is indicative of a more severe insult, especially when it is thought to follow an acute insult. This may help to explain the trend to worse outcomes with increasing birth weight, and it would be interesting to see the analysis for those infants >90th centile for birth weight.
The findings in relation to fever are, I believe, of great interest given the link between intrapartum fever and adverse neurologic outcome (such as cerebral palsy) demonstrated by Grether and Nelson,5 among others. Although it is not yet known whether control of fever changes the outcome, it is a tempting proposition. In the cooling group there were 11 infants with a temperature >38°C either before cooling or at rewarming. Nine of these infants had an adverse outcome compared with 50 of 97 in the cooling group who did not experience fever (odds ratio: 4.2 [95% confidence interval: 0.97–18]). In this analysis, the contribution of birth weight dominated that of fever; however, given the constancy of this association, it seems likely that fever is an independent risk factor for adverse outcome.
Although there was no statistically significant difference, there was a trend toward poorer outcomes in smaller infants who were cooled compared with those in the control group: 24 of 39 in the intervention group compared with 14 of 33 in the controls (odds ratio: 2.17 [95% CI: 0.85–5.54]). This may well be from chance alone; however, given the small numbers in this subgroup analysis, it is quite possible that it represents a true effect. Additional studies will need to address this question. Certainly no benefit has been shown in these smaller infants. In future studies, it may also be of value to differentiate between infants who are small for gestational age and those who are growth restricted. The pathways that lead to growth restriction may well have affected the ability of the neonate to cope with acute injury and not necessarily in a negative manner.
Cooling, either selective or whole-body, is one of the few therapies shown in randomized studies to have a definite neuroprotective effect.1,6 It is in its infancy, but it is here to stay. In time we will know more about how to optimally apply it and to whom. It is an exciting time to be alive.
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FOOTNOTES |
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Accepted Mar 1, 2007.
Address correspondence to John M. Keogh, FRANZCOG, Obstetrics and Gynaecology, Hornsby Hospital, Palmerston Road, Hornsby, New South Wales 2077, Australia. E-mail: keoghj1{at}optushome.com.au
The author has indicated he has no financial relationships relevant to this article to disclose.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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