The Cooling Effects of Therapeutic Hypothermia

A recent spinal cord injury to Buffalo Bills’ football player Kevin Everett has heightened interest in the use of therapeutic hypothermia for the treatment of neurologic damage resulting from spinal cord and traumatic brain injuries, stroke, and cardiac arrest. However, a number of variables that need additional study, as well as logistical issues, currently stand in the way of the treatment’s potential for wider application, which is backed by highly promising results in clinical studies.

“One of the key issues is that the risks are so low in using [therapeutic hypothermia] that it should be investigated further and utilized in trials on a much wider scale,” said Gary K. Steinberg, MD, PhD, in an interview with Neurology Reviews. “I think hypothermia has a very bright future and really remarkable potential for improving outcome for various types of injury to the nervous system.”

HIGH BENEFITS, LOW RISKS

Dr. Steinberg, Professor and Chairman of the Department of Neurosurgery at the Stanford University School of Medicine in California, has studied therapeutic hypothermia for more than 20 years and has used the treatment clinically since 1991, when he first cooled the body temperature of a patient in the operating room. Since then, Dr. Steinberg has routinely used mild hypothermia in more than 2,500 patients with cerebrovascular problems by cooling those who have a high risk of stroke, without seeing any significant adverse effects.

Although the precise mechanism of mild hypothermia’s protective effect on the brain is unclear, the therapy seems to function by blocking the detrimental cascade of events that occurs during the minutes, hours, and sometimes days after a neurologic event, Dr. Steinberg explained. The benefits that can result from the treatment—improved neurologic function and decreased disability—are complemented by a low adverse event profile.

“The risks, quite frankly, are pretty minimal,” Dr. Steinberg said. “The degree of hypothermia that we’re talking about is mild. You’re taking the spinal cord or body temperature down just 4 degrees, from 37°C to 33°C.”

Temperatures lower than that, however, would increase the risk of cardiac arrhythmias, clotting parameters, electrolyte abnormalities, metabolic problems, and infection, Dr. Steinberg said. “You’re balancing the depth of the hypothermia with the risks,” he added, “but 33°C seems to be very, very benign.”

Daniel L. Herr, MD, Medical Director of the Surgical Intensive Care Unit at the Washington Hospital Center in Washington, DC, organized the Symposium on Therapeutic Temperature Management, held in Breckenridge, Colorado, this March. The meeting examined both clinical research and logistical aspects of normothermia and hypothermia.

“I think the benefits are science-driven,” Dr. Herr told Neurology Reviews. “All the therapies we’ve had for head injuries and neurologic diseases have been looking for the silver bullet. We’ve developed drugs for each individual pathway, while cooling actually decreases all the inflammatory pathways at once... [by] knocking down that inflammatory cascade.”

In 2003, the American Heart Association recommended the use of therapeutic hypothermia for certain out-of-hospital cardiac arrest patients, after two studies showed that survivors who were cooled sustained less neurologic damage and had higher overall survival rates than those who were not cooled. “And the neat thing about all those data is that [they showed] you only have to treat one out of every six patients to have a positive outcome,” Dr. Herr said.

INTERNAL VERSUS EXTERNAL COOLING

Several key modalities of inducing mild hypothermia include cooling the patient externally through the use of ice packs or a thermostatically controlled device, as well as cooling the patient internally via a catheter. Dr. Steinberg uses the intravascular method of cooling his patients, in which a cold solution cools the metallic tip on a specialized catheter, which in turn cools the core body temperature.

“With internal cooling, there is a potential risk of causing clotting and thrombosis in the veins,” Dr. Steinberg said. “That risk seems to be extremely low, based on the studies that have been done that compare the internal cooling to a blanket or no cooling. These catheters have been tested, they’re heparin-coated, and they have a very low risk of causing any clotting abnormalities.”

In contrast, Benjamin Abella, MD, MPhil, Assistant Professor of Emergency Medicine and Clinical Research Director of the Center for Resuscitation Science at the University of Pennsylvania in Philadelphia, uses the external cooling method with a thermostatically controlled device to treat post–cardiac arrest patients. He believes that the technique helps maintain body temperature more effectively than non–thermostatically controlled cooling methods, such as injecting cold saline into the bloodstream or placing ice packs on the body.

“Evidence seems to suggest that [physicians should keep cardiac arrest patients] cold from 12 to 24 hours,” Dr. Abella said in an interview with Neurology Reviews. “This is a tricky thing if you’re just using ice bags and cold saline, because body temperatures tend to fluctuate quite a bit, whereas a thermostatically controlled device seems to hold body temperature very nicely.”

At the Washington Hospital Center, Dr. Herr and his fellow clinicians prefer to use the thermostatically controlled device “only because you don’t need a doctor to do it,” Dr. Herr said. “The only thing doctors need to do is order the blanket; they [instruct a nurse to] put it on, and the treatment starts immediately.... So for us the advantage [of external cooling] is speed of application, not so much speed to cooling.”

In addition, he noted, “The first initial line of treatment, no matter what, is 2 liters of ice-cold saline, which doesn’t require any piece of equipment. The purpose of the equipment is to maintain the hypothermia.”

COOLING PATIENTS WITH SPINAL CORD INJURY

Dr. Steinberg’s success in intravascularly treating stroke patients with mild hypothermia could parlay into clinical use for patients with spinal cord injuries—thus far, a novel and relatively untested application for this therapy.

“In the field of stroke, mild hypothermia is by far the most protective agent and is the gold standard in the laboratory, in many ways, for protecting the brain against stroke,” Dr. Steinberg said. “That’s been extended to protecting the brain against traumatic injury and protecting the spinal cord. So in the laboratory, it’s highly protective against spinal cord injury.”

In terms of protecting CNS tissue, the benefits and risks for treating patients with spinal cord injury would be similar to those seen in patients who have had stroke, traumatic brain injury, or cardiac arrest, Dr. Steinberg said. However, there needs to be more clinical data showing that therapeutic hypothermia improves outcomes for spinal cord injuries before the therapy can see wider clinical use, he added.

“Therapeutic hypothermia for spinal cord injuries is experimental, in the sense that it hasn’t been proved in the most rigorous kinds of studies that patients with spinal cord injuries treated with hypothermia do better,” Dr. Steinberg said. “There doesn’t seem to be much downside, but I would argue that we still need to do the proper trials to prove that it’s beneficial in large numbers of patients.... So that’s the problem with the field right now.”

UNKNOWN VARIABLES

While current data indicate that cooling a patient with mild hypothermia should be initiated as soon as possible, defining other variables that affect how the treatment is administered is less clear. Chief among these unknown factors are the timing and duration of cooling, as well as the rate of rewarming the body.

“It takes several hours to cool someone down [externally], given current technology,” Dr. Abella said. “If you start to cool someone six hours after resuscitation, he or she will really be cold at nine or 10 hours. Although it’s not entirely clear, the benefit may diminish at that point.”

Dr. Steinberg pointed out that the duration of cooling patients is another unresolved issue.

“In surgery we often warm them immediately [after cooling],” he said. “But there are some patients who have been cooled for 48 hours and then rewarmed slowly. In the laboratory, we’ve done experiments showing that two hours of cooling and one hour of cooling are actually equivalent [in terms of efficacy], but it depends on the model and the disease, so duration is an unknown that needs to be investigated further.”

Dr. Steinberg noted the rate of rewarming the body may also be important, in that rewarming the body too quickly may diminish the benefits associated with cooling. “But you can cool at a very fast rate, and there doesn’t seem to be any downside of that,” Dr. Steinberg said.

LOGISTIC AND FINANCIAL BARRIERS

In addition to the challenges presented by unknown variables, the complexity of instituting a hypothermia protocol in hospitals, as well as financial obstacles, stand in the way of wider application of this treatment.

“There really needs to be consensus within a hospital about equipment, cooling methods, and whether to cool at all, since there are a variety of reasons one might or might not want to cool someone,” Dr. Abella said. “These kinds of institutional logistic barriers loom large.

“Thermostatically controlled cooling devices are [also] expensive,” Dr. Abella pointed out. “To my knowledge, there’s no specific billing code for instituting hypothermia as of now. So the reimbursement is not commensurate with the cost [of using] one of these devices,” he added.

Despite these challenges, researchers hope to see more clinical data that support inducing mild hypothermia for the treatment of neurologic conditions before the therapy becomes more widely used.

“There’s certainly enthusiasm, and I think a lot of us believe that there is definitely a therapeutic value,” Dr. Herr said. “But there are a lot of studies that need to be done, and a lot of studies that need to be done well.”       

NR