The journey of hope to improve the lives of infants born with oxygen deprivation has taken 65 years. Loss of oxygen to the brain may result in death or a lifetime of blindness, mental retardation, or cerebral palsy. In October 2005, Seetha Shankaran and her colleagues in the NICHD Neonatal Research Network reported that lowering a newborn’s body temperature a few degrees could reduce the likelihood of death or disability associated with depleted oxygen.
Oxygen deprivation, or hypoxia, typically occurs as a complication of birth. For example, if the umbilical cord becomes trapped between a baby’s head and the wall of the uterus, pressure on the cord may cut off the baby’s oxygen supply. Hypoxia may also result from blood loss, perhaps when the placenta tears free of the uterine wall, or the uterus ruptures. Blood loss or hypoxia at birth may lead to hypoxic ischemic encephalopathy (HIE), a condition experienced by up to 1 in every 1,000 newborns.
In 1949, James A. Miller first reported in Science that lowering body temperature could increase survival in newborn animals deprived of oxygen. He cooled newborn guinea pigs by wetting them with rubbing alcohol and placing them in front of an electric fan. When deprived of oxygen, the guinea pigs whose body temperatures had been lowered by as few as 4 degrees survived significantly longer than did littermates that had not been cooled. Miller undertook the study because he questioned the then routine practice of warming babies who were deprived of oxygen at birth. Chemical reactions, including those needed to sustain life, occur progressively faster as temperature increases. Miller hypothesized that reducing the speed of those reactions by reducing body temperature could increase survival. Between 1959 and 1972, several reports appeared about using a cooling treatment—by then known as hypothermia—for infants who had not responded within five minutes to standard resuscitation techniques.
Typically, an infant was placed in a cold-water bath, with only its nose, eyes, and mouth above water. Although infants treated with hypothermia appeared to be more likely to survive and less likely to have permanent disabilities, most of these early studies were too small to allow statistically valid conclusions. By the early 1970s, however, several research teams had shown that preterm infants were more likely to survive if they were cared for in warmer environments, and clinical interest in hypothermia waned.
It took 17 years before researchers began to reconsider hypothermia as a potential treatment for HIE. In 1987, Raul Busto and his coworkers found that lowering body temperatures in adult rats that had undergone a surgical technique designed to mimic stroke could lessen brain damage. Encouraged by this finding, researchers resumed testing hypothermia in oxygen-deprived newborn animals. Most of these studies conducted in the mid-1990s showed that cooling immediately after hypoxia reduced the severity of brain damage. Earlier research showed that while the loss of oxygen damaged brain tissue, the initial damage started a chain of reactions that worsened the original injury with each passing hour. It seemed that early cooling might blunt the secondary damage and preserve brain tissue.
Immediate cooling, however, was often impractical in the delivery room. Efforts to stabilize the heart rate and other vital functions of newborns could take several hours, delaying when cooling could begin. Thus, researchers sought to discover whether benefits could still be gained if cooling the infant was delayed. Working with lambs, researcher Alistair Gunn and his coworkers found that the cooling treatment could be delayed for 5 ½ hours and still effectively reduce the extent of brain injury. In their research, the scientists used a special cooling cap, which circulates water around the head, lowering brain temperature while maintaining normal temperatures in the rest of the body. After showing that the cold cap was safe for newborn infants with HIE, the researchers later found that it could reduce the effects of moderate brain injury in newborns.
At the same time, Abbot Laptook was also searching for a more effective means to provide cooling therapy. An earlier study of adult stroke patients demonstrated that a cooling blanket could lower brain temperature. Like the cold cap, the blanket’s temperature was controlled by circulating water and was used to effectively lower body temperature. However, when comparing head cooling to the cooling blanket in newborn swine, Laptook and his coworkers found that head cooling most effectively lowered temperatures in brain areas nearest the skull, while inner brain areas remained warm. By comparison, the blanket cooled the entire brain uniformly. Shortly thereafter, the researchers demonstrated the blanket’s safety in newborns with oxygen loss.
In July of 2000, Laptook, Shankaran, and other colleagues in the NICHD Neonatal Research Network began enrolling oxygen-deprived term newborns in a large-scale study of the cooling blanket. In October 2005, the researchers published their findings, showing that using the blanket to lower body temperature to about 92°F within the first six hours of life reduced the chance for disability and death among full-term infants with HIE. Unlike earlier cold cap findings, however, this study showed that the blanket’s more uniform cooling could reduce the extent of death and disability resulting from both severe and moderate brain injury.
Currently, the NICHD is consulting with the American Academy of Pediatrics as the organization develops practice recommendations to treat hypoxia at birth. Three ongoing hypothermia treatment studies will provide additional information on the most effective ways to provide the treatment. These continuing refinements should accelerate access to the therapy for all infants who could benefit from its use.