After more than 20 years of research on the best treatment for full-term infants affected by oxygen deprivation during the birthing process, Seetha Shankaran, M.D., neonatologist at DMC's Children's Hospital of Michigan and Hutzel Women's Hospital, served as the lead investigator in a definitive Journal of the American Medical Association study that documented the safest depth and duration of body-cooling to minimize injury from hypoxic ischemic encephalopathy (HIE) in newborns.
The multi-center study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, was led by a nationally recognized pediatric researcher at the Detroit Medical Center (DMC) and Wayne State University School of Medicine on the treatment of injuries caused by oxygen deprivation ("hypoxia") during birth. The published study in the Journal of the American Medical Association (JAMA) has determined the safest temperature and duration for body-cooling ("hypothermia") of newborns in order to minimize the injuries during the first few days of life.
The study, which involved 364 infants over a six year period, showed the results of the randomized clinical trial that the safest depth and duration of hypothermia treatment – using a specially designed "cooling blanket" – consists of lowering the oxygen-starved newborns' body temperature to 33.5 degrees Celsius for a period of 72 hours.
"Neither longer cooling nor deeper cooling nor both were more superior to cooling for 72 hours at 33.5 degrees Celsius in reducing death or survival with disability at 18 months of age," says Dr. Shankaran.
The finding is significant and surprising according to Dr. Shankaran because earlier studies using animal models had suggested that lowering the temperature to 32 degrees Celsius and for a longer period (120 hours) might provide better injury protection for the oxygen-deprived newborns.
The study, was conducted at 18 U.S. neonatal centers by the Neonatal Research Network of the National Institute of Child Health and Human Development (NICHD) – and with Dr. Shankaran as lead investigator. The study reports the safety outcomes assessed during the neonates stay in the NICU. The neonates who survived were followed up to 18 months of age to examine the effect of longer or deeper cooling on overall rate of death or disability, which was the primary outcome of the study.
HIE occurs in approximately one in 1,000 full-term infants in the United States each year, as a result of interrupted blood-flow and lack of oxygen at birth. The condition can be caused by such problems as umbilical cord strangulation in the newborn, placental abruption, cardiac or respiratory arrest in the mother during delivery or other disorders that decrease delivery of blood-borne oxygen to the neonate. About 4,000 of the 4 million babies born in this country each year are affected by HIE. Between 15 percent and 20 percent will die in infancy or early childhood from the ailment, and another 25 percent will develop severe and permanent neuropsychological deficits, including mental retardation, visual or motor dysfunction, epilepsy and cerebral palsy.
For Dr. Shankaran, a pioneer in finding effective methods for protecting HIE-affected newborns whose landmark 2005 study in the New England Journal of Medicine helped to make the 72-hour "cooling blanket" procedure the standard of care in treating this condition, the publication of the new clinical trial was "a very encouraging step forward.
"I think we have shown clearly and with a great deal of accuracy [in the new study] that using whole-body cooling in the neonatal period at 33.5 C for 72 hours is safer than either longer cooling, deeper cooling or both."
During the trial, Dr. Shankaran and her colleagues in the NICHD's Neonatal Research Network, randomly assigned full-term infants with moderate or severe encephalopathy within six hours of birth to four different hypothermia groups, 33.5C for 72 hours, 33.5 for 120 hours, 32.0C for 72 hours and 32.0C for 120 hours.
Mortality was 9 percent for the HIE-group that had been cooled at 33.5C for 72 hours, compared to 19 percent, 18 percent and 19 percent in the other groups.
The results should have an immediate positive impact on clinicians who treat HIE-affected newborns in neonatal intensive care units by providing assurance that cooling at 33.5C for 72 hours has now been demonstrated to be the treatment of choice. Clinicians should avoid cooling for either longer duration of time or for a greater depth.
"In this trial we saw that the rate of death or disability was 29.3% with cooling for 72 hours at 33.5 C. This is even lower than the 44% rate we achieved with cooling for 72 hours at 33.5 C with our first trial published in the New England Journal of Medicine in 2005. The reason for this reduced rate could be that the number of infants with severe encephalopathy was lower in this trial than our first trial, but other changes in care practices may also have helped to reduce this rate," Dr. Shankaran says.
Investigators are now planning to examine adding additional therapies to hypothermia therapy. "They need to enroll larger numbers of study participants since the rate of death or survival with disability is 29% as shown in this trial," she adds.
Dr. Shankaran, says the latest research breakthrough could not have occurred without "the tremendous amount of work that was done by all of the researchers in the Neonatal Research Network, or without the public dollars provided for this effort over the years by the NICHD.
Children's Hospital of Michigan CEO Luanne Thomas Ewald noted, "Dr. Shankaran has devoted her career to improving the lives of high-risk newborns. This latest research is the latest example of how her leadership has paved the way for providing the best treatment and outcomes for pediatric patients affected with HIE throughout the world."