October 12, 2005
Lowering infants' body temperature to about 92 degrees Fahrenheit within the first 6 hours of life reduces the chances of disability and death among full term infants who failed to receive enough oxygen or blood to the brain during birth. This finding was reported by researchers in the Neonatal Research Network of the National Institute of Child Health and Human Development, one of the National Institutes of Health.
The study appears in the October 13, 2005 New England Journal of Medicine.
"The experimental cooling of newborns to prevent death and injury from oxygen deprivation during birth is extremely promising," said NICHD Director Duane Alexander, M.D. "Yet it would be premature to implement the study results under any but the most carefully controlled and monitored circumstances. 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."
The study was led by Seetha Shankaran, M.D., of the Division of Neonatal-Perinatal Medicine, at Wayne State University School of Medicine in Detroit, one of the participating NICHD Neonatal Research Network study sites.
Hypoxic ischemic encephalopathy (HIE) occurs when an infant's brain fails to receive sufficient oxygen or sufficient blood before birth. HIE may occur hours before birth, or, in some cases, during labor and delivery. The condition may result from a variety of causes. These include compression of the placenta, tearing of the placenta from the uterine wall before birth, compression of the umbilical cord, and rupture of the uterus. Dr. Shankaran explained that HIE is estimated to occur from 0.5 to 1 times per every thousand births.
The study authors wrote that 10 percent of infants with moderate HIE die, as do 60 percent of infants with severe HIE. "Many, if not all," survivors of severe HIE experience major disability, they added.
Previous studies, conducted in laboratory animals, suggested that cooling the brain from 2 to 5 degrees Celsius after HIE could reduce the chances for the death and disability that often result from HIE, the authors wrote.
To conduct the study, researchers enrolled infants from the 15 centers making up the NICHD neonatal network. All the infants had experienced oxygen deprivation during the birth process. A total of 208 infants took part in the study. They were assigned at random to 1 of 2 groups, with 102 infants undergoing the experimental cooling (hypothermia) treatment and 106 receiving standard care. Standard care for HIE may involve placing the infant on a ventilator to assist breathing monitoring blood pressure, and providing fluids intravenously, and other newborn intensive care supportive therapies.
The infants were cooled by placing them on a soft plastic blanket through which water circulates. The blanket's temperature is regulated by computer. For the study, the blankets were set at 5 degrees Celsius (41 degrees Fahrenheit). The infant's temperatures were lowered to 33.5 degrees Celsius (92.3 degrees Fahrenheit), as measured by a temperature probe placed in an infant's esophagus. The infants in the hypothermia group were enrolled within the first 6 hours of birth, and remained on the cooled blanket for 72 hours. After 72 hours had passed, they were gradually warmed to a normal body temperature.
Infants in both the hypothermia group and the control group received standard newborn intensive care including monitoring of vital signs and were watched carefully for signs of organ dysfunction.
When the infants were examined at 18 to 22 months of age, 44 percent of those in the hypothermia group developed a moderate to severe disability or had died, as compared to 62 percent in the control group.
Dr. Shankaran explained that when the study's three principal outcomes--death, moderate disability, and severe disability--were considered as one unit, the difference between the two groups of infants was statistically significant. However, when these three adverse outcomes were analyzed as separate categories, the difference between the two groups of infants for any individual outcome was not statistically significant.
Dr. Shankaran explained that it was not possible to recruit enough infants to arrive at statistically significant measures for the differences in the various outcomes between the two groups. Because HIE occurs infrequently, it took 3 years to enroll enough infants to conduct the current study from the 15 participating NICHD Neonatal Research Network sites.
In terms of the actual number of infants affected, fewer infants in the hypothermia group died or experienced moderate or severe disability than was experienced by infants in the control group. For example, 24 infants in the hypothermia group died, as compared to 38 in the control group. Similarly, 15 infants in the hypothermia group experienced disabling cerebral palsy, compared to 19 infants in the control group. Blindness occurred in 5 infants in the hypothermia group and in 9 infants in the control group. Infants in the hypothermia group also averaged higher on measures of infant mental and physical development than did infants in the control group.
"A concern with any therapy that reduces mortality among infants at high risk of death and disability is the possibility of an increase in the number of infants who survive with disabilities," the study authors wrote. "In our study there was no evidence of increased rates of moderate or severe disability at 18 to 22 months of age among infants treated with hypothermia."
Side effects of the treatment consisted of a temporary hardening and drying of the skin where the skin came in contact with the cooling blanket, Dr. Shankaran said.
"Physicians need to exercise extreme caution in putting the study's results into practice,"said Rose Higgins, M.D., program scientist for the NICHD Neonatal Research Network and an author of the study. "Most newborn intensive care units don't have the resources or experienced personnel to duplicate the carefully controlled conditions of the study."
Dr. Higgins added that comparatively minor fluctuations in an infant's body temperature—perhaps by as little as a few degrees—could result in serious harm if not closely monitored by trained personnel.
During the 72 hours of the hypothermia treatment, personnel trained in life support and use of the cooling blanket monitored all infants continuously. Fluctuations in the infant's temperature were compensated for immediately by adjustments to the cooling blanket.
Moreover, only full-term infants took part in the study, Dr. Higgins said. It is not known whether preterm infants with HIE would benefit or be harmed from hypothermia treatment.
Dr. Higgins said that the NICHD is currently advising the American Academy of Pediatrics to develop practice recommendations for treating infants with HIE. Moreover, three ongoing studies of hypothermia treatment are expected to provide additional information on the most effective ways to carry out the treatment.
Dr. Higgins added that the NICHD Neonatal Research Network will also follow both groups of children until they reach the ages of 6 or 7, to compare the incidence of health problems or learning difficulties.
The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.