Pulse
Keeping a Cool Head
An experimental treatment offers a ray of hope for babies who suffer brain damage caused by oxygen deprivation at birth.
The infant pictured on Robert Couser’s laptop wears a football-style helmet designed to protect a network of plastic tubing that covers the scalp. Through the tubing runs water cool enough to lower the brain’s temperature by 4 degrees C.
The device, known as CoolCap, was used in a multicenter, prospective, randomized clinical study that tested the effects of brain cooling on babies who were deprived of oxygen at birth. Couser, a neonatologist at Children’s Hospitals and Clinics of Minnesota in Minneapolis, was the local principal investigator for the study, which involved 28 institutions in the United States, New Zealand, Canada, and the United Kingdom. Altogether, the study involved more than 230 full-term infants with hypoxic-ischemic encephalopathy (HIE), including 16 at Children’s in Minneapolis, between July 1999 and January 2002. Findings from the study were published in The Lancet in February of 2005.
Helpful Hypothermia?
Hypoxic-ischemic encephalopathy is caused by oxygen deprivation, or asphyxia, from several mechanisms including placental insufficiency or compression of the umbilical cord. It occurs in one to three babies per 1,000 full-term live births, and it results in damage to cells in the brain and may contribute to death or developmental delays in newborns.
The idea behind CoolCap is to induce hypothermia in an affected infant’s brain in order to decrease or inhibit a destructive chain of events that leads to permanent brain damage.
Until recently, general supportive care was believed to be the only option for babies with HIE. This might include an array of interventions such as respiratory, cardiac, and circulatory support, as well as treatment for organ failure, seizures, and chemical imbalances. Even with such intervention, many infants die. Survivors are often left with disabling conditions such as cerebral palsy, seizure disorders, or long-term mental impairment.
Couser says the CoolCap study provides the first evidence in humans that brain damage caused by asphyxia during birth can be reversed with cerebral hypothermia and mild systemic cooling—at least in some babies.
A Matter of Degrees
Half the infants in the study were randomly assigned to wear the CoolCap. (Both their brain and core body temperature were cooled during treatment.) The other half received general supportive care, which the CoolCap babies also received. The premise behind the study was to shift the focus of treatment from damage control to neuroprotection.
Here’s the theory behind it: A hypoxic ischemic event triggers a process with two distinct phases. In the acute phase, cardiac output decreases, blood flow slows, and the risk of brain damage from asphyxia increases. During the second phase, blood flow has been re-established and oxygen is traveling to the brain. But by then a destructive, and often life-threatening, cascade of events that includes the production of neurotoxins has been set in motion.
Researchers have proposed disrupting the cascade with chemicals, pharmacologic agents, or brain cooling, Couser says.
In the CoolCap study, the brain temperature was lowered to an estimated 32 to 33.5 degrees C. Core body temperature was reduced to 34.5 degrees C (plus or minus 0.5 degree C). The CoolCap system regulated the brain temperature, while an overhead radiant warmer kept core body temperature in the desired range. Brain cooling began prior to 6 hours of age (average, 4.6 hours of age). Couser says it is critical to intervene before harmful neurotoxic substances are produced following resuscitation.
The babies wore the cap for 72 hours because it is believed that this is the length of time the body produces substances that are toxic to the central nervous system. At 18 months of age, the surviving infants had a neurological exam as well as auditory, visual, and neurodevelopmental assessments.
Couser and the other investigators found that brain cooling benefited 80 percent of the infants—those who presented with mild or moderate encephalopathy at the beginning of the study. The remaining 20 percent—those with evidence of severe encephalopathy—received no discernable benefit.
Fifteen cooled and 19 control infants died during the initial 76-hour monitoring period. Over the next four days, 12 cooled and 7 control infants died. However, of the 108 cooled infants, about half had an unfavorable primary outcome, compared with two-thirds of the control infants.
Findings Raise New Questions
Clearly, brain cooling isn’t a cure for all oxygen-deprived babies with brain damage. But because cooling was shown to have a positive impact on some, Children’s in Minneapolis continues to offer the treatment to all eligible infants.
Still, questions abound. How long should treatment last? Do all babies require the same amount of cooling? Should cooling be combined with pharmacologic agents? Is whole-body cooling better than selective brain cooling? What is the optimal cooling temperature? “If you cool the brain too much, it’s harmful. If not enough, there’s no beneficial effect,” Couser says, adding that the treatment is likely to change over time as more basic research determines its role.
In the meantime, the CoolCap study has helped researchers hone their diagnostic skills. “It’s giving us all more education about how to better assess, in a systematic way, a baby born following asphyxia,” Couser says. As a result of the study, physicians have a more thorough protocol for assessing the severity of encephalopathy as well as a better understanding of how to use tools such as the amplitude-integrated EEG for quicker screening and evaluation.
Olympic Medical in Seattle, which manufactures the device and funded the study, is awaiting FDA approval for the CoolCap system. Once approved, Couser hopes that other Minnesota neonatal intensive care units (NICUs) with the resources and patient volume will offer the treatment. “We would like to work with any other NICU in developing it, if they’re interested,” he says.
Couser says that if a baby is born following asphyxia but is not yet known to have an encephalopathy, it’s important to consult with a center that has the capability to give advice on the medical evaluation and treatment options.
“What we need to do now is educate the entire community about the fact that babies born with this problem need to undergo a quick evaluation to understand the significance of the asphyxial event,” he says. “Once identified, get the babies into a center where they can be evaluated as quickly as possible because the window is very short.”—Miriam Karmel