WHOLE-BODY HYPOTHERMIA FOR HYPOXIC NEWBORNS MAY PROVE NEUROPROTECTIVE
In an experimental protocol, whole-body-hypothermia reduced the rate of disability in full-term newborns with hypoxic ischemic encephalopathy, according to a report in the New England Journal of Medicine (2005;353:1574–1584).
The finding is important, experts said, because other than palliative care, there is nothing to offer infants with moderate-to-severe hypoxic ischemic encephalopathy, and many infants die. Among those who survive, many have severe disabilities, including cerebral palsy, with deficits in fine motor skills, memory, and auditory development.
Forty-four percent of the hypothermia group developed a moderate to severe disability or died, compared with 62 percent in the standard care group, the study demonstrated; 24 in the hypothermia group died compared with 38 in the control group. Seetha Shankaran, MD, Professor of Pediatrics and Division Director of Neonatal-Perinatal Medicine at Wayne State University's Children's Hospital of Michigan, led the study.
In an interview with Neurology Today, Dr. Shankaran said: “There's a lot more we need to learn about cooling. This is certainly not the standard of care.” Before we can conclude that a hypothermic protocol is neuroprotective, trials must document outcomes not just at 18 to 24 months, but also at school age.
The study, which was conducted through the 16-site Neonatal Research Network, part of the National Institute of Child Health and Human Development, randomized 208 infants who experienced oxygen deprivation during birth to two treatment arms: 102 to the experimental hypothermia protocol and 106 to standard care (ventilator assistance, blood pressure monitoring, IV hydration, and other newborn intensive care supportive therapies). The hypothermia group also received supportive care.
To be included in the trial, infants had to be at full-term (36 weeks or more) gestation, have had treatment no later than six hours after birth, sustained either severe acidosis or perinatal complications and resuscitation at birth; and had moderate or severe encephalopathy at birth.
TECHNIQUE REMAINS INVESTIGATIONAL
Whole-body hypothermia was done by esophageal cooling to 33.5 degrees Celsius for 72 hours. A blanket that circulated water to 5 degrees Celsius was used to cool the baby down. A computer measured temperature with a probe in the baby's esophagus. Once the infant's temperature was lowered to the target of 33.5 degrees Celsius, the baby remained on the cool blanket for 72 hours. Then, the baby was slowly warmed until esophageal and skin temperatures rose to 36.5 degrees Celsius. Temperatures were monitored by esophageal and skin probes, at first every 15 minutes for four hours; then every hour for eight hours; and finally every four hours for the remainder of the cooling period.
Duane Alexander, MD, Director of the National Institute of Child Health and Development, acknowledged in a published statement that even though the results are “extremely promising … the potential for serious harm exists if the conditions followed in this protocol are not carried out precisely as they were during the study, by personnel skilled in their use.”
Dr. Shankaran agreed, adding that important neurodevelopment outcomes have yet to be examined. “We worked hard to develop a protocol to use when these kids enter school,” she said. “It is detailed and we've worked with the other trial groups [namely the COOLCAPS investigators] so that our follow-up will be similar.”
Earlier this year, the COOLCAPS trial demonstrated that selective hypothermia was technically feasible (Lancet 2005;365:663–670). According to Donna M. Ferriero, MD, COOLCAPS co-investigator, the outcomes improved only when we excluded the severely damaged infants. “When we looked at all babies, the data approached significance,” added Dr. Ferriero, Professor of Neurology and Pediatrics at the University of California-San Francisco.
MORE DATA NEEDED
Lu-Ann Papile, MD, a neonatologist and Professor of Pediatrics at the University of New Mexico in Albuquerque, wrote a companion editorial (N Engl J Med 2005;353(15):1619–1624). She told Neurology Today that clinicians should not use the experimental treatment without informed consent. “We don't know who this treatment would benefit; when it is best to treat; and how long to use it … we'll get the best information from a meta-analysis of all of the trials.”
Terrie Inder, MD, PhD, Associate Professor of Pediatrics in the Department of Newborn Medicine and Neurology at Washington University in St. Louis, MO, told Neurology Today: “We need to know who would benefit; when the injury occurred; what kind of injury – whether it was deeper, superficial, or involved all of the brain, and when is the best time to do it. We still don't know what temperature to use.”
Dr. Inder, also a principal investigator on the multi-institutional ICE trial with centers in Australia, Canada, and the US, explained that a sport-type, ice pack is being used rather than a cap or blanket. The ICE trial is about half way through, she explained. Researchers are also awaiting results from The UK's Medical Research Council TOBY (Total Body Hypothermia) trial, a whole body-hypothermia for the treatment of perinatal asphyxial encephalopathy. As of November 11, 2005, 184 newborns have been enrolled (www.npeu.ox.ac.uk/toby). The trial design requires 236 infants to demonstrate a 30 percent reduction in the relative risk of mortality or serious disability at 18 months.
So far, outcomes data have been published only for children up to 18 to 24 months. Yet to come is a follow-up neurodevelopmental analysis at school age. Follow-up studies at school age of cognitive and cortical function have been incorporated into all the trial study designs. Investigators will also be assessing long-term neurodevelopmental outcomes to school age.
Based on the research to date, Dr. Ferriero concluded: “We're getting closer to a rational therapy.” Asked if she had an idea of what that would look like, she said that she thought: “We are most likely headed towards using cooling in conjunction with other growth factor therapies, such as erythropoietin [now being tested in a stroke trial].”