A Rediscovered Way to Save Lives Cooling the Brain for its Own Good
Doctors have known for centuries that controlled cooling can save certain patients from death or brain damage -- during heart operations, after strokes, even after spinal injuries. German surgeons have found success in cooling some at-risk patients to alarmingly low temperatures. For some pharmaceutical companies, though, it's too low-tech.
Leonhardt's breastbone is soft and barely thicker than a match, but surgeon Michael Hübler has experience cutting through infants' bones and directs the delicate bone saw with great care.
Finally, the heart lies exposed, hardly bigger than a plum, beating inside the infant's open ribcage. Hübler connects it to the heart-lung machine using two tubes. "Twenty-eight degrees?" asks Wolfgang Böttcher, the perfusionist who operates the machine. "Yes," Hübler confirms.
Böttcher types in the desired temperature. A heat exchanger in the quietly humming heart-lung machine starts up. The temperature shown on the anaesthetic monitor plummets -- 35.5 degrees Celsius (95.9 degrees Fahrenheit), 33.4 (92.1), then 31.7 (89). Finally, 14 minutes later, it reaches 28.0 (82.4), nearly 10 degrees Celsius (18 degrees Fahrenheit) below normal body temperature.
The patient here in OR 5 at the German Heart Institute Berlin (DHZB) is three days old and weighs seven pounds. His umbilical cord hasn't sloughed off yet. But Leonhardt was born with a serious heart defect. The connections to his aorta and pulmonary artery are reversed and his blood flows in two separate circulatory systems. If doctors had not kept the prenatal connection between the two systems artificially open for the past three days, the baby would likely be dead. Now it's high time for the operation.
The cooling has slowed Leonhardt's heart rate to 45 beats per minute. Hübler gives the command for "cardioplegia," and a solution containing potassium slips into the patient's tiny heart, which stops beating seconds later.
Cold, but Oxygenated
Now only the heart-lung machine is still working. Hübler can begin detaching the aorta and pulmonary artery from the heart and reattaching them in the correct position. It's a protracted, complicated procedure, and the reason for the radical body cooling.
"We've known for a long time, from avalanche victims and people who fell through ice, that cold can protect the brain from oxygen deficiency," Hübler explains. "We hope for precisely this effect from the cooling done during surgery as well."
Low temperatures protect better against oxygen deficiencies than any other method. The brain reacts sensitively when its oxygen supply grows short, triggering a cascade of harmful reactions. Dangerous free radicals and toxic metabolites flood tissues, while the blood grows over-acidic and the brain swells. Any single drug can prevent a few isolated reactions, but body cooling can regulate nearly all of them. "It's unique," declares Katharina Schmitt, who directs a research laboratory here at the DHZB.
'It Can Tip the Balance'
The idea of "therapeutic hypothermia," as the cooling treatment is called, is not new. During Napoleon's time it was known that injured soldiers survived better in the snow than when they were carried close to fire. For the first major heart surgeries in the 1950s, doctors packed patients in ice until the heart stopped, then operated without the help of a heart-lung machine. After the procedure, they warmed the patient until the heart began to beat again.
Doctors in Siberian clinics still operate this way now and report astonishingly low mortality rates. But in the Western world, therapeutic hypothermia lost importance after the invention of the heart-lung machine. Now the treatment is seeing a sudden and widespread boom, finding use in more and more areas of medicine. It's being tried with babies who have suffered oxygen deprivation during birth, as well as for victims of strokes, heart attacks and head injuries. The technique is especially prevalent in pediatric heart surgery.
Not long ago, simple survival was the main objective in major operations on infants like Leonhardt. Today, mortality rates for even the most complicated procedures have dropped to around one percent. "Now," says Felix Berger, director of the DHZB's Department of Congenital Heart Defects and Pediatric Cardiology, "it's about the children surviving the surgery without damage."
Long-term studies show that patients who undergo such operations often suffer later from poor concentration, minor motor abnormalities, trouble finding the right words, or other impairments -- probably consequences of lowered oxygen supply to the brain during surgery, among other factors. "These children can lead a normal life, and can learn to compensate for much of it," Berger says. "But when it comes to studying at university or not, it can tip the balance."
Surgeons now see protecting the brain more effectively as a primary goal. Ten members of Berger's department study the topic. It is now standard at the DHZB, for example, to monitor the oxygen saturation of cerebral tissue constantly during surgery with the help of optical sensors.
Still, bringing body temperatures so low is a risky practice. "Hypothermia doesn't just provide protection, it can also cause damage," Schmitt warns. "Clinical results as well as our research show this."
Oxygenated, but Cold
Body temperatures below 30 degrees Celsius (86 degrees Fahrenheit) can lead to dangerous cardiac arrhythmia, or abnormality in the heartbeat. Blood vessels become permeable, which increases the danger of capillary leak syndrome, in which fluid leaks out of the veins until the body becomes grotesquely swollen. Schmitt's colleague Antje Diestel has shown that even a minor degree of cooling causes long cells to shrink into spheres, which can cause tiny cuts in blood vessels or increase inflammation. "Cooling is a major intrusion into the body," Schmitt says.
This raises questions of how far a body should be cooled and for how long -- and how quickly the patient can be warmed up again. Schmitt and her team are looking to shed light on all these questions. They have also discovered a combination of two common drugs that could help prevent capillary leak syndrome.
Heart surgeons also stand to learn a few lessons from emergency physicians. Standard ambulance equipment in many cases will include a refrigerator stocked with infusions of a cold saline solution -- maintained at four degrees Celsius (39 degrees Fahrenheit). Alex Lechleuthner, head of Cologne's emergency medical services, explains, "Each year, just in Cologne, we use this technique to cool around 400 people we have resuscitated after a cardiac arrest." Barely two liters (0.5 gallons) of the ice-cold infusion liquid are enough to reduce body temperature by around one degree Celsius (1.8 degrees Fahrenheit) during the trip to the hospital. In the intensive care unit, a special catheter inserted into the femoral vein then acts like the heat exchanger in a refrigerator, further cooling the unconscious patient down to 33 degrees Celsius (91 degrees Fahrenheit) over the course of 24 hours. Afterward, the patient is warmed again very gradually.
Not Just to Protect the Brain
The emergency method has improved survival rates. "One in six fatalities can be prevented this way," says Bernd Böttiger, director of the Department of Anaesthesiology and Postoperative Intensive Care at the University of Cologne. Böttiger saw to it that hypothermia was added to EU medical guidelines for resuscitation after cardiac arrest. German health insurance also started covering the procedure in January.
It has been shown, again and again, that even slight body cooling can tip the scales. Long before the technique became established, an emergency physician in Bonn named Markus Födisch saved the life of a 37-year-old man who suffered a heart attack and collapsed in a supermarket. Födisch resuscitated the man, then heaped bags of frozen French fries on his unconscious form. "That was the only way," Födisch remains convinced, "he could survive the cardiac arrest without neurological damage."
Body cooling is often routine in neonatal units, too, where staff reduce the body temperatures of infants who have suffered oxygen deficiency during birth to 33.5 degrees Celsius (92 degrees Fahrenheit) for three days. Doctors believe this improves the infants' outlook considerably.
Hypothermia is even being tested for its usefulness in preventing paraplegia caused by spinal injuries. There have been spectacular success stories. In one high-profile case, Kevin Everett, an American football player for the Buffalo Bills, injured his spine while trying to tackle an opposing player. The team's doctor had the presence of mind to give Everett an ice-cold infusion while still on the playing field. Everett surprised his doctors with an extensive recovery.
The treatment may also be given to stroke and heart attack patients in the future. "We've tried more than a thousand different substances to protect the brain from oxygen deficiency after a stroke, all without success," says Rainer Kollmar, a neurologist at Erlangen University. "The single promising method is body cooling." Kollmar plans to test the technique on stroke patients in a larger study.
Here too, there are signs that a slight degree of cooling -- or even just consistently reducing the fever that often accompanies a stroke -- can have an astonishing effect.
Low-Cost Treatment? Nein Danke
Still, funding for research is lacking. Cooling a patient's body temperature is a simple and low-cost process, but this, paradoxically, is precisely the cause of Kollmar's funding shortage. The pharmaceutical industry, which generally funds clinical studies, has little interest in a treatment that costs next to nothing. "It's a crazy situation," Kollmar says. "We've got the weapon in our hands, but somehow we lack the ammunition."
Böttiger, Kollmar's colleague in Cologne, is familiar with the problem. It wasn't until he began testing possible new drugs that could help reduce a patient's body temperature by several degrees within the space of minutes that potential financial backers suddenly took an interest. But so far these substances -- a hormone that controls hibernation in animals, for example -- are only being used in animal testing.
In OR 5, meanwhile, Leonhardt's heart has begun beating again of its own volition. The defect is fully repaired and the infant officially has a healthy heart. His incubator is waiting for him just outside.
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