Study led by Dr. Shankaran published in New England Journal of Medicine
Lowering an infant's body temperature to about 92 degrees Fahrenheit within the first six hours of life reduces the chances for disability and death among infants who failed to receive enough oxygen or blood to the brain during birth, according to a Wayne State University School of Medicine study published in tomorrow's New England Journal of Medicine .
The study involving 208 infants was led by Seetha Shankaran, M.D., WSU professor of pediatrics and division director of neonatal-perinatal medicine at Children's Hospital of Michigan and Hutzel Women's Hospital. The research was conducted through the 16-site Neonatal Research Network, part of the National Institute of Child Health and Human Development. The NICHD is one of the National Institutes of Health.
During the two-year study, researchers randomly enrolled qualifying infants from the NICHD neonatal sites. All infants had experienced oxygen deprivation during birth. Of the total 208 infants who took part in the study, 102 underwent the experimental cooling, or hypothermia, treatment, and 106 received standard care. Children's Hospital of Michigan and Hutzel Women's Hospital, combined, contributed findings from 34 cases to the study, the most of any site. CHM/Hutzel participants included some infants who were transferred immediately after birth to CHM from other Michigan hospitals.
Hypoxic ischemic encephalopathy occurs when the brain fails to receive sufficient oxygen or sufficient blood before the infant is born. 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.
Standard care for HIE may involve placing the infant on a ventilator to assist breathing, monitoring blood pressure, 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, or 41 degrees Fahrenheit. Each infant's temperature was lowered to 33.5 degrees Celsius, or 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 six 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 from the hypothermia group developed a moderate to severe disability or had died as compared to 62 percent in the control group. This is a statistically significant difference between groups.
“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 institute the study results under any but the most carefully controlled and monitored circumstances.”
HIE is estimated to occur from 0.5 to 1 times per every 1,000 births. The study also indicates 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 are severely disabled,” Dr. Shankaran said.
Previous studies, conducted in laboratory animals, suggested that cooling the brain from 2 degrees Celsius to 5 degrees Celsius after HIE could reduce the chances for the death and disability that often result from HIE, the authors wrote.
Dr. Shankaran noted the study's results are statistically valid only when all of the infants in the study are considered together as one group. When possible outcomes were evaluated separately, the differences between each outcome in the two groups of infants were not statistically significant.
However, in terms of the number of infants affected, trends in these data indicated 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. Five infants in the hypothermia group developed blindness as did nine in the control group. Infants in the hypothermia group also tended to score higher on measures of infant mental and physical development than infants in the control group.
Dr. Shankaran explained that it was not possible to recruit a large enough pool of infants to arrive at statistically significant measures for the differences in the various outcomes between the two groups. Because HIE occurs infrequently, it took three years to enroll a large enough number of infants to conduct the current study from the 16 participating NICHD Neonatal Research Network sites.
"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 hardening and drying of the skin where it 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 probably don't have the resources 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 potentially 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 the 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 on the development of 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 also will follow both groups of children until they reach the ages of six or seven, to learn if either group experiences any health problems or learning difficulties.