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., recently 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 in newborns.
The study, http://jama.jamanetwork.com/article.aspx?articleid=2084890, showed the results of the randomized clinical trial clearly demonstrate 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. The finding is significant 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, which 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 – found that “among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy (HIE), longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU [neonatal intensive care unit] death.” The study reports the safety outcomes assessed during the neonates stay in the NICU. The neonates who survived are being 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.
The authors of the study concluded: “These results have implications for patient care and design of future trials.”
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 7 percent for the HIE-group that had been cooled at 33.5C for 72 hours, compared to 14 percent, 16 percent and 17 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 a separate editorial, JAMA noted that the research conducted by Dr. Shankaran and her colleagues over many years is essential to finding therapies for HIE in newborns. “Therapeutic hypothermia would not be a safe and effective therapy in neonatal care if not for the willingness and enthusiasm of neonatologists who take on the extra work needed to enter neonates into clinical trials,” said the editors.
“In the trial by Shankaran,” they added, “clinical practice did not bear out preceding preclinical studies [the earlier studies on animal models]. However, the persistent high mortality and morbidity found with perinatal asphyxial encephalopathy encourages continuing efforts to improve the efficacy of treatment and minimize intercurrent and subsequent complications from this unpredictable and often devastating condition. The current focus is on adjunct therapies that can augment 72 hours of hypothermic neuroprotection at 33 degrees C to 34 degrees C.”
Dr. Shankaran, a Wayne State University School of Medicine professor of pediatrics and division director of Neonatal and Perinatal Medicine for both DMC Children’s Hospital of Michigan and DMC Hutzel Women’s Hospital, was quick to point out that this 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.
“All of us have dedicated ourselves to this research,” she added, “because we know how devastating these injuries can be to infants. And when you do research that can help to improve the lives and the care of high-risk children and make a change in the outcomes for them… that is very gratifying indeed. Watching children get better and go on to live healthy lives [after receiving therapy for HIE] is what keeps us going!”
Steven Lipshultz, M.D., pediatrician-in-chief at the Children’s Hospital of Michigan DMC and chair of pediatrics for the Wayne State University School of Medicine, noted, “Dr. Shankaran’s numerous contributions to neonatal research over the years provide “a compelling example of how good scientific research can improve outcomes for all our pediatric patients.
“At the end of the day, providing the best possible care for our patients at the Children’s Hospital of Michigan is the overriding goal,” he said. “Dr. Shankaran has been assisting in that effort for more than two decades, and her pioneering work in neonatal medicine speaks for itself.”
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About the Children’s Hospital of Michigan, www.childrensdmc.org
For more than 125 years, the Children’s Hospital of Michigan is the first hospital in the state dedicated exclusively to the treatment of children. With more than 40 pediatric medical and surgical specialties and services, the hospital is a leader internationally in neurology and neurosurgery, cardiology, oncology, and diagnostic services; it is ranked one of America’s best hospitals for children and sees more children than any hospital in the state. More Michigan pediatricians are trained at the Children’s Hospital of Michigan than at any other facility. Children’s Hospital of Michigan is one of eight hospitals operated by the Detroit Medical Center (DMC).
About Wayne State University, www.wayne.edu
Wayne State University is a premier urban research institution offering more than 400 academic programs through 13 schools and colleges to nearly 32,000 students. Its School of Medicine is the largest single-campus medical school in the nation, with more than 1,200 medical students. In addition to undergraduate medical education, the school offers master’s degree, Ph.D. and M.D.-Ph.D. programs in 14 areas of basic science to about 400 students annually.