Hypothermic treatment saves baby brain cells
Normally, hypothermia, an unnatural drop in body temperature, is thought of as a bad thing. And for good reason: it is more or less the scientific term for freezing to death. But in at least one specific condition, hypothermia has therapeutic value. First demonstrated in the late 1950s and then dismissed, deliberate cooling has been rediscovered and shown to prevent damaged oxygen-starved brain tissues from dying, giving them time to heal.
The condition in question is hypoxic ischemic encephalopathy (HIE) in the newborn infant, a condition caused by inadequate delivery of oxygen to the brain during labour, and during and immediately following birth.
"We used to just support the organs and treat the symptoms but the damage was a done deal," says Patrick McNamara, Staff Neonatologist at The Hospital for Sick Children (SickKids), of taking care of newborns with HIE. "All we could do was assess the injury and speak to the parents." Which would not be a very pleasant conversation: under those circumstances, most parents would be told their infant had suffered brain damage, that cerebral palsy and/or other negatively life-altering conditions were likely to develop, and nothing could be done to prevent it.
Happily, in the last few years, things have changed. Therapeutic hypothermia, the deliberate lowering of core body temperature, has shown to be effective in reducing the effects of HIE and the technique is now being used in more and more hospitals.
Although the process is not completely understood, it is rather like the cold in your refrigerator slowing down the decay of perishable foods allowing them to be safely eaten next Friday instead of tomorrow.
Slowing down cell metabolism
HIE occurs during or immediately following birth. A lack of blood flow, and therefore oxygen, to specific parts of the brain, kills cells. This hypoxia in turn triggers a cascade of negative effects: within hours seizures may occur, within months permanent neurodevelopmental disorders may become apparent.
HIE is often the result of some kind of fetal distress. For example, the umbilical cord may be pinched too long and too tight, restricting fetal circulation. However, when cells run out of oxygen, they can switch to a kind of emergency mode whereby they continue to sustain themselves with an abnormal metabolic process that does not use oxygen. This anaerobic metabolism can only be sustained for a short period of time. If the cell does not switch back to metabolizing oxygen to survive, it dies.
The problem is that simply restoring circulation and providing the normal amount of oxygen for the newborn at the earliest opportunity which is a standard treatment, is not enough to get the cells to immediately switch back to processing oxygen. The result is that many of the cells continue to die hours after the trauma is over. Lowering the newborn's temperature buys those cells the extra time they need to return to a normal metabolic process.
"It's not freezing, it's making them cool," explains Michael Vincer, neonatologist at IWK Health Centre in Halifax , Nova Scotia . "A normal temperature is 37 [Celsius], we cool them to 33.5 degrees so it's 3 and a half degrees centigrade below normal body temperature." That small drop in temperature can make an enormous difference. Eight trials have now shown the therapy not only reduces mortality and neurodevelopmental conditions, the cooling has no detrimental side effect. It is, in effect, the first and only treatment for HIE yet developed.
Lowering core body temperature
While the target of the cooling is the cells of the brain, both IWK and SickKids lower the body's core temperature with a cooling blanket; other hospitals just cool an infant's head with a special cap. "There has been no comparative trial yet but the benefit seems greater for whole body," says McNamara, adding the blanket is easier for "direct EEG monitoring of the baby's brain function." The infant may be cooled for as long as 72 hours. In general, the technique is relatively simple, cheap, and best of all, effective.
Despite this extremely positive news, there is much that remains unknown. "I'll be following up these infants to age three," says Vincer, who has so far treated two infants with hypothermic therapy. As medical director of IWK's perinatal follow-up program, which tracks the longer-term progress of many high-risk infants, Vincer knows what to look for. "When newborns are asphyxiated, down the road we look for cerebral palsy, cognitive and language delays, and vision and hearing problems. Severely asphyxiated infants more characteristically have bad outcomes." The hope is that this will become far less frequent.
How much and how often HIE induced brain damage is avoided is a question that does not yet have an answer. While hypothermia has been shown to work, identifying on which individuals and under what circumstances it works best has not. "The eligibility criteria is moderate insult in the first six hours," says McNamara, explaining that in general it is the serious and immediate cases of HIE who get the treatment. "But we know there are babies that don't look bad and the injury evolves and they have seizures 14 hours later." McNamara says the data is lacking at both ends of the extremes of HIE. "We don't know how well the therapy works in very severe cases or if patients with milder injury might benefit from the intervention." He adds, "there are probably a whole range of subpopulation questions that need to be asked and answered."
Moreover, there may be reason to believe the benefit is being overestimated. Dr. Vincer notes it is not uncommon to withdraw treatment in severely asphyxiated infants when no benefit is seen or expected. "As with any treatment that is failing, at some point the parents are approached to withdraw treatment. If more cases like this are from the control group, that may 'stack the deck', overestimating the result." Still, despite not knowing for sure which patient will benefit and which one won't, Dr. Vincer says he offers the treatment in part because the complications from cooling are low and controllable. In other words, there is little to lose in trying.
Past and future
While medicine further defines who the best candidates are for hypothermic treatment, people should be grateful that therapy exists at all in modern medicine. The story of how the value of hypothermia as a treatment was found, lost and found again illustrates how science and medicine progress, often in improbable fits and starts.
The history of cooling as a treatment is long. Hippocrates, the ancient world's most famous doctor, is said to have recommended packing wounded soldiers in ice. One of Napoleon's generals also noticed that wounded soldiers had a poorer chance of survival the nearer they were allowed to recover next to the fireplace. However, real progress did not occur until the 1950s when Drs. Bjorn Westin and James Miller demonstrated hypothermia's effectiveness in treating brain injuries in animal studies. This progressed to trials in human infants who would not spontaneously breathe following birth. The results were striking: of 65 treated infants, 52 survived -- many more than would normally be expected at that time. A ten-year follow up also showed none of the surviving children had any sign of cerebral palsy, again an outcome much better than would normally be expected.
As incredible as these results were, the technique did not catch on, partly due to another medical study. In 1958, another paper concerning the importance of proper thermoregulation was published. The difference was that this paper showed how important maintaining a normal body temperature was in premature newborns. The two studies do not actually have contradictory conclusions - one showing that normal temperature to be important for premature babies, the other showing the benefit of cooling in asphyxiated newborns - but they were interpreted that way. "Despite the fact one was about a deliberate intervention and one was about maintaining normal temperature, it was the death of all the research," says McNamara. As unfortunate as this event is, it is perhaps more understandable when one considers that while the studies concentrated on different subsets of infants, many babies who suffer HIE at birth are also premature. "It wasn't until the 1980s they started again with animals."
It was only in 2007 that national health agencies began to approve the use of the technique.
In addition to studies aimed at better selecting HIE patients for treatment, other studies are looking into other possible uses for therapeutic hypothermia. "In children, the sole purpose for now is for the brain," says McNamara, citing types of encephalopathy, metabolic problems, and brain infections such as meningitis as areas likely to produce some positive results. "However, whenever the body has suffered an insult, tissues die. Theoretically, hypothermia should be translatable to other organs," he says.
Indeed, the treatment is already being used with some success in certain cardiac conditions in adults.