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Hypothermia for Neonatal Encephalopathy Lowers Death Rate Without Raising Disability

Fitzgerald, Susan

doi: 10.1097/01.NT.0000417964.70149.e6
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INFANTS WITH neonatal encephalopathy who were treated with whole-body hypothermia had a lower mortality rate without increasing severe disability among survivors when monitored through ages 6 to 7 years

INFANTS WITH neonatal encephalopathy who were treated with whole-body hypothermia had a lower mortality rate without increasing severe disability among survivors when monitored through ages 6 to 7 years

Investigators found that that the protective effects of cooling of the brains of term babies who survived hypoxic-ischemic encephalopathy extended into childhood at 6 to 7 years of age.

Longer-term data confirms that whole-body hypothermia reduces the rate of death stemming from neonatal encephalopathy without increasing the rate of low IQ scores or severe disability among babies who survive.

A May 31 report in the New England Journal of Medicine (NEJM) provided seven-year follow-up results from a study that compared infants who underwent whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy with comparable infants who received usual care.

“Whole-body hypothermia did not significantly reduce the rate of a composite end point of death or an IQ score below 70 at 6 to 7 years of age,” the researchers reported. “However, whole-body hypothermia did reduce the rate of death and did not increase the rates of low IQ score or severe disability among survivors. These data extend our previous support for the use of hypothermia in term and near-term infants with hypoxic-ischemic encephalopathy.”

Seetha Shankaran, MD, lead study author and professor of pediatrics at Wayne State University, told Neurology Today that “the same protective effects we saw at 18 months of age continued into childhood.” She said these findings on the sustained benefits of hypothermia therapy should allow clinicians to better inform parents about what to anticipate as their children grow.

Dr. Shankaran said that before the emergence of hypothermia as a therapeutic option the death rate for babies who were moderately to severely affected by hypoxic-ischemic encephalopathy ranged from 30–70 percent. Hypothermia therapy became standard in neonatal units in the US and some other countries in recent years after research showed that cooling has a protective effect on the brains of term babies with hypoxic-ischemic encephalopathy. But there has been a lingering concern that the technology might be saving babies only to have them face a lifetime of significant disability.



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The current report is based on a study carried out from June 2000 to May 2003 at sites participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, which funded the study. Infants were eligible for the study if they had either moderate or severe encephalopathy within six hours after birth, with severe acidosis or resuscitation at birth after an acute perinatal event. Infants were randomly assigned to usual care or to hypothermia at 33.5 degrees Celsius for 72 hours.

Researchers reported in NEJM in 2005 that babies who were given hypothermia therapy tended to fare better than the others as they neared their second birthdays.

“The rate of death or moderate or severe disability at 18 to 22 months was 62% in the control group versus 44% in the hypothermia group, with mortality of 37% and 24% respectively. As compared with the control group, there was no significant increase in major disability among survivors in the hypothermia group,” according to background information in the follow-up report. Rates of moderate or severe cerebral palsy, blindness and hearing impairment were all lower.

For the follow-up, researchers evaluated all available babies at 6 to 7 years of age. Their data included information on 190 of the 208 infants in the original study, including 97 children in the hypothermia group and the 93 children in the control group.

The primary outcome was death or an IQ score below 70 for children at 6 to 7 years of age. The secondary outcomes included death or severe disability, components of disability, motor function, higher cognitive function, severe cognitive delay and psycho-social health, as measured by commonly used assessment tests.

The primary outcome occurred in 46 of the 97 children (47 percent) in the hypothermia group and 58 of the 93 (62 percent) in the control group, the researchers reported. The difference was not statistically significant.

Twenty-seven (28 percent) of the hypothermia infants had died, most early on, compared with 41 (44 percent) of those in the control group. Among the survivors, 19 of 70 children (27 percent) in the hypothermia group and 17 of 52 (33 percent) in the control group had an IQ score below 70.

The rates of cerebral palsy were 17 percent (hypothermia) and 29 percent (controls). There were no differences between the two groups in level of disability of survivors, motor function among the nondisabled children or parent assessment of their children.

“All the children who had moderate-to-severe cerebral palsy at 18 months continued to be affected at 6 to 7 years in both groups,” the researchers reported.



The researchers noted that the main limitation of the study was that it was not large enough to pick up differences in the secondary outcomes. They said the loss of babies to follow-up may also have had a modest effect on the results.

The study received funding from the NIH and the NICHD.

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Dr. Shankaran is continuing to study the hypothermia therapy. In a study submitted for publication that involves the same two groups of babies, MRIs tend to be more favorable for the hypothermia group, she said. Her team is also looking at variations on how best to use hypothermia. For instance, they are studying whether more time — 120 hours instead of 72 — and a lower temperature — 32 degrees instead of 33.5 — might deliver better results.

Donna Ferriero, MD, the W.H. and Marie Wattis Distinguished Professor and chair of the department of pediatrics at the University of California, San Francisco, said it is not fully understood why hypothermia therapy helps prevent brain injury in babies.

“We still don't know the true mechanism at work,” she told Neurology Today. “We think we are slowing the metabolism and thus ultimately preventing cell death.”

Dr. Ferriero was part of a research team that investigated the use of Cool-Cap, a brain-cooling cap that works on the same principle as whole-body hypothermia. The analysis, which was summarized along with other trials involving hypothermia in a meta-analysis published in the British Medical Journal in 2010, showed that treatment was consistently associated with an increased rate of normal survival, defined as survival without cerebral palsy and with a mental developmental index score of more than 84, a psychomotor development index score of more than 84, and normal vision and hearing.

She said doctors tend to prefer the whole-body approach because they are able to apply EEG and amplitude-integrated EEG.

Her research is now focusing on adjuvant therapies that might help prevent brain injury in babies with hypoxic-ischemic encephalopathy, in particular the drug erythropoietin (EPO). She said the thought is that a combination of treatment may work better than one approach alone. For EPO, a phase 1 trial has been completed under the direction of Dr. Ferriero's UCSF colleague, Yvonne Wu, MD, and the goal now is to move the research into a phase 3 trial, Dr. Ferriero said.

Stephen Ashwal, MD, Distinguished Professor of Pediatrics and Neurology at Loma Linda University School of Medicine, said the latest results on the longer-term prognosis of babies who underwent hypothermia were encouraging because they confirm that “we're not saving children only to end up with equal or more severe disabilities.” He said the results also support the recommendations of several professional organizations on the use of hypothermia therapy.

Dr. Ashwal said further research is needed to determine if certain subsets of babies might benefit more than others from the therapy. He also agreed that combination treatment will likely be the preferred approach down the road.

“The question is whether pediatric neurologists and neonatologists can develop better criteria for the use of this kind of treatment,” he said.

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• Shankaran S, Pappas A, Higgin RD, et al, for the Eunice Kennedy Shriver NICHD Neonatal Research Network. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:2085–2092.
    • Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. N Engl J Med 2005;353: 1574–84.
      • Edwards AD, Brocklehurst P, Azzopardi D, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: Synthesis and meta-analysis of trial data. BMJ 2010; 340:c363.
        ©2012 American Academy of Neurology