by: david warmflash
Therapeutic hypothermia (TH), intentional cooling of a patient to a selected core body temperature, is coming online for an increasing number of indications. Induction of mild hypothermia at 32–36° C, and maintenance of the low temperature for at least 24 hours (“targeted temperature management”), is routine after cardiac arrest, if a patient is comatose upon resuscitation. Researchers are also investigating TH at 32° C for cerebral protection in settings of stroke and to reduce intracranial pressure after traumatic brain injury . Patients are cooled into the low end of the moderate hypothermia range (28–32° C), or below, for aortic arch surgery or certain other procedures where cardiopulmonary bypass (when blood is diverted from the heart and lungs through pumping and oxygenating equipment) is not an option.
In one of the most dramatic applications of cooling, several North American trauma surgery centers, led by the University of Pittsburgh, are running a phase 2 clinical trial of a profound hypothermia treatment called Emergency Preservation and Resuscitation for Cardiac Arrest From Trauma (EPR-CAT). That’s a mouthful, but essentially it’s suspended animation—like what you’ve seen in science fiction films, like Interstellar (2014), or Planet of the Apes (1968), that enables people to “sleep” through a space voyage lasting months, years, or centuries, except that it’s very short-term. Patients’ life processes are suspended for an hour or so; this is achieved by reduction of core body temperature to just a few degrees above freezing point. It is being tested on victims of severe blood loss trauma. The idea is that reduced metabolism from the hypothermia will eliminate the brain’s need for oxygen, thereby stalling death, until surgeons can repair the injuries and replace lost fluids. It works in dogs and pigs, so there’s really no reason why it shouldn’t work in humans too.
Hypothermia is what happens in hibernating animals in winter, and it’s the reason why their need for oxygen goes down substantially. But forcing low body temperature on non-hibernators like humans is risky. Especially as the temperature gets very low, hypothermic patients are subject to electrocardiographic abnormalities (prolonged P-R and Q-T intervals and QRS widening), leading to life-threatening arrhythmias, coagulopathies, electrolyte disturbances, insulin resistance, and infection. Therefore, EPR-CAT is only coming into use in humans now when medical technology enables all sorts of intervention and monitoring of body systems in an intensive care setting, rather than say 75 or 100 years ago.
But hibernating animals don’t have those complications, because their electrolyte, clotting, and all body systems adjust appropriately to the hibernation state. Furthermore, inducing and controlling a drop in body temperature, holding the patient at a desired temperature, and then warming up the body again is a sloppy process compared with how hibernating animals do it. With injured humans, one has to lower the shivering threshold by inhibiting the temperature control in the hypothalamus with drugs, such as an opioid-like meperidine. Then, the patient is subjected to cooling, either from the outside with cooling blankets or internally through infusion of cold fluids. All this takes care of the need for oxygen, but places strain on the various body systems that natural hibernators automatically adjust.
Over the past several years, researchers have elucidated regions, pathways, and receptors in the brains of hibernators that trigger hibernation, not simply by resetting the body thermostat in the hypothalamus, but by signaling organs and tissues throughout the body to reset to a hibernation mode. One brain area under intense study by Matteo Cerri and colleagues at the University of Bologna,in Italy is the raphe pallidus. With microinjections of the GABAA agonist muscimol, the team was able to induce suspended animation/hibernation in rats, animals that do not hibernate naturally. Meanwhile, Domenico Tupone has produced the same effect at Oregon Health Sciences University, also in rats, but using an adenosine (A1AR receptor) agonist, N6-cyclohexyladenosine (CHA) administered into the cerebroventricular system.
Rather than just resetting the body thermostat, these treatments are activating hibernation pathways that affect body systems universally. Further understanding of the pathways and elucidation of others, and development of relevant pharmacologic agents and administration routes, potentially can improve precision of TH, allowing lower temperatures and application to a broader range of conditions.