Ancient societies figured out that hypothermia was useful for hemorrhage control, but it was Hippocrates who realized that body heat could be a diagnostic tool. He caked his patients in mud, deducing that warmer areas dried first.
Typhoid fever, the plague of Athens in 400 BC and the demise of the Jamestown Colony in the early 1600s, led Robert Boyle to attempt to cure it around 1650 by dunking patients in ice-cold brine. This is likely the first application of therapeutic hypothermia, but it failed to lower the 30 to 40 percent mortality rate. One hundred years later, James Currie tried to treat fevers by applying hot, cold, and warm to the surface and having the patients drink liquids at those temperatures. These innovations were not any more successful than the brine, however.
Hydropaths, popular in the early 1800s, were referred to by Sir William Osler as “hermaphrodite practitioners who look upon water as a cure-all.” He realized, however, the therapeutic effects of using water for compresses and baths. One hydropath taught Osler that a rigid protocol of cold baths for typhoid fever could save lives, and Osler implemented this at Johns Hopkins. He published this protocol in the article, “The Cold-Bath Treatment of Typhoid Fever” in 1892, and physicians everywhere saw a drop in mortality.
Physicians had come to believe by the 1930s that cold was incompatible with life. All clinical thermometers of the time were calibrated only to 94°F, and this thermal barrier was so deeply ingrained in medical techniques that subnormal temperatures were combatted at all costs. Electrical heating devices or hot water bottles and warm blankets were considered necessary emergency equipment in every hospital, but this was about to change.
Therapeutic hypothermia’s father was Temple Fay, MD, a neurosurgeon at Temple University. As a medical student, he was unable to come up with a response when his mentor asked why tumors were less common in the extremities. This ultimately led him to experimental cancer study. He published work in 1937 on how hypothermia suspended cancer cell growth but normal temperatures allowed their growth to resume.
He treated his first patient with hypothermia in 1938 to prevent cancer cells from multiplying. Chloral hydrate and sodium bromide (sedatives) were given by rectum the night before. Paraldehyde, another sedative, was given immediately before hypothermia induction. The patient was cooled to 32°C for 24 hours.
He described it like this: “The first attempt at general refrigeration was made on November 28, 1938…. I … shut off the heat … and opened the windows [to aid] the cracked ice. … For many reasons, chiefly because of the prejudice on the part of the nurses, we had not dared submerge the entire patient in a bed of cracked ice. … The nurses’ home, interns’ quarters, and [other services] were alive with dubious comment….”
A series of patients were treated, but the nurses detested working on the “refrigeration service,” as they called it. “Frankly, the nurses were scared. They could not get the patients’ temperature with the clinical thermometers. The long-stem laboratory thermometers might break in getting a rectal reading. The ice and ice water were always in the way, even when the patient was turned. The pulse was weak. The breathing was shallow. They couldn’t get the patient’s blood pressure. … The entire project of general refrigeration had snowballed into a vast issue of distortions of truth, and even my friendly colleagues began to look askance, and asked how long this absurd experiment was going to be permitted.”
The program was almost shut down, but Dr. Fay and the hospital engineers made blankets from rubber tubes to carry a cold solution from a special “beer cooler.” Commercially available machine pumps were found useful in this technique, and they also developed electric thermocouples for 24-hour charting of rectal temperatures.
“What we learned after breaking the human thermal barrier on the hypothermic side was that human survival was possible under proper supervision. When total body refrigeration was established above 24℃, that hypothermic state could be maintained for 10 days (probably longer if required) when temperature levels of 29.4-32.3℃ were maintained,” he wrote. Dr. Fay also developed refrigeration techniques to reduce pain, and in 1945, was first to publish on using hypothermia for cerebral trauma.
During World War II, Germans confiscated one of Dr. Fay’s manuscripts that had been sent to Belgium for publication. German pilots downed in frigid waters would succumb to freezing temperatures, even if rescued quickly. This led to hypothermia recovery experiments on concentration camp victims in one of the most grotesque, unethical distortions of medicine ever. When the German atrocities were discovered, it set back the field by 10 years, but by the 1950s, research in hypothermia expanded and great strides were made.
Bigelow, et al. quickly perfected general hypothermia for intracardiac surgery in 1950, benefiting the brain and the heart. (Ann Surg. 1950;132:849.) Rosomoff and Holaday worked out much of the physiology in 1954, figuring out that therapeutic hypothermia reduced cerebral oxygen consumption, blood flow, and metabolic rate, demonstrating a direct effect between body temperature, intracranial pressure, and brain volume. (Am J Physiol 1954;179:85.)
Niazi and Lewis found in the late 1950s that patients’ temperatures could be lowered to even 9°C and then rewarmed with complete recovery. This would help patients with accidental hypothermia.
Some 20 years later, a landmark paper by G. Rainey Williams, Jr., MD, and Frank Spencer, MD, from Johns Hopkins reviewed four cases where it was used in cardiac arrest. (Ann Surg 1958;148:462; http://1.usa.gov/1BvriDi.) This is an absolutely fascinating report of patients who suffered cardiac arrest, received open chest cardiac massage to achieve return of spontaneous circulation, and were treated with hypothermia. It had some early success, but severe complications overwhelmed the benefits as its use became more widespread. Cardiac irritability and ventricular fibrillation when patients’ temperatures were below 30°C were problems because precisely meeting a target temperature with the available equipment was nearly impossible.
Later, in 1959, Williams and Spencer, now joined by Benson and Yates, published “Use of Hypothermia after Cardiac Arrest.” (Anesth Analg 1959;38:423.) Two of 27 patients failed to achieve ROSC; six had no coma and were excluded from analysis. Twelve of the remaining 19 received hypothermia; seven did not. One of the seven survived in the untreated group, and six of 12 survived in the hypothermia group (14% vs 50%). They treated the patients at 30-32°C from 34 to 84 hours, and stopped based on the patient’s response. By 1959, induced hypothermia was also used for cardiac surgery and by neurosurgeons for head and spinal cord injuries.
Severe complications became apparent as therapeutic hypothermia became more widespread. Cardiac irritability and ventricular fibrillation when patients’ temperatures were below 30°C became problematic because it was nearly impossible to precisely meet a target temperature with the available equipment. There also was a much higher rate of infections, most significantly a decreased clearance rate of staphylococcal bacteremia, and vasospasm, increased plasma viscosity, hyperglycemia, cardiac dysfunction, and coagulopathies. These complications made its use risky and difficult to manage without intensive care, and the technique was essentially abandoned.
The few human papers on therapeutic hypothermia published after this time reinforced hypothermia’s problems. Bohn, et al. published a case series in 1986 of 24 children who remained in persistent coma after being resuscitated from drowning. (Crit Care Med 1986;14:529.) They used therapeutic hypothermia to treat elevated intracranial pressure; those treated had a much higher rate of neutropenia and septicemia than the control group.
Cardiac arrest care, however, advanced during this period. Zoll published a study about counter shocks for ventricular fibrillation (N Engl J Med 1956;254:727), and Kouwenhoven (JAMA 1960;173:1064) and Safar (Anesth Analg 1961;40:609) introduced closed chest massage in 1960. The 1970s and 1980s saw cardiac arrest care systems developed such as defibrillators in 1979. “Accidental Death and Disability: The Neglected Disease of Modern Society” in 1966 by the National Academy of Sciences spurred the development of EMS systems across the country. (http://bit.ly/1BC5XZG.) Richard Cummins, MD; Joseph Ornato, MD; William Thies, PhD; and Paul Pepe, MD published their “chain of survival” concept in 1991. (Circulation 1991;83:1832.) CPR and defibrillators were now available outside the hospital and in the field, and widespread early resuscitation from cardiac arrest became a reality.
Disappointment set in again, though. Patients continued to do poorly despite improvements in cardiac arrest care. Only a tiny fraction was surviving, and they suffered profound neurologic sequelae. Becker, et al. summed up the frustration with the paper, “Outcome of CPR in a Large Metropolitan Area — Where Are the Survivors?” in the Annals of Emergency Medicine. (1991;20:355.)
Sterz, et al. published a 1991 animal study showing mild hypothermia initiated immediately after ROSC improved neurologic outcomes. (Crit Care Med 1991;19:379) The target of 34-36°C temperature target was unique and several degrees warmer than much of the earlier literature. More than that, they maintained the target temperature only for one hour post-resuscitation, and then let the temperature climb passively. Therapeutic hypothermia was back in fashion.
Bernard, et al. from Monash Medical Centre in Australia published the paper, “Clinical trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest,” in Annals of Emergency Medicine in 1997. The pilot study prospectively followed 22 comatose resuscitated patients treated at 33°C for 12 hours, and compared them with 22 retrospectively matched controls. Mortality was 10 vs 17, and CPC 1 or 2 was 11 vs 3.
Bernard and his colleagues expanded on their paper in 2002 in the New England Journal of Medicine article, “Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia.” (N Engl J Med 2002;346:557.) They prospectively randomized 77 patients with resuscitated VF with persistent coma. They excluded pregnancy and persistent cardiogenic shock despite epinephrine. All received lidocaine. The MAPs were maintained between 90-100 mm Hg, pO2 > 100, and pCO2 of 40. Patients were cooled to 33°C for 12 hours before being allowed to rewarm passively. Mortality was similar in both groups, but patients with CPC 1 or 2 were 21 vs 9 if they had been treated with hypothermia.
Another study, “Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest,” enrolled 237 patients with resuscitated ventricular fibrillation arrest treated with therapeutic hypothermia to 32-34°C for 24 hours and compared them with normothermic patients. Median time to starting cooling was 105 minutes post-arrest, but the patients did not reach target temperature until nearly eight hours after the arrest. There was a 14 percent absolute risk reduction in mortality and a 16 percent improvement in CPC 1 and 2 scores for patients treated with hypothermia.
Hypothermia was then endorsed by the American Heart Association in 2002 and by the Advance Life Support Task Force of the International Liaison Committee on Resuscitation in 2003. Its use in post-resuscitation care spread widely and quickly as a standard of care. But other controversies developed as the practice became more widespread. Treatment was expanded to resuscitated rhythms other than the ventricular fibrillation and ventricular tachycardia under the assumption that brain ischemia from any source would benefit from hypothermia. Guidelines had adopted 32-24°C, but the optimal temperature target was uncertain.
Work at the Safar Center for Resuscitation in Pittsburgh led to the paper by Logue and Callaway, “Comparison of the Effects of Hypothermia at 33°C or 35°C after Cardiac Arrest in Rats.” They were able to demonstrate that minimal hypothermia at 35°C was as good as cooling to 33°C in mortality and neurologic outcomes, and both were better than normothermia. (Acad Emerg Med 2007;14:293.)
Zeiner, et al. published data that a fever in the post-cardiac arrest period had adverse neurologic outcomes, so researchers postulated that the neurologic benefit had little to do with hypothermia and is more the result of preventing hyperthermia. (Arch Intern Med 2001;161:2007.)
Then came a paper by Nielsen, et al. that enrolled 950 patients in 36 centers remained unconscious after being resuscitated from out-of-hospital cardiac arrest. (N Engl J Med 2013;369:2197.) Any initial rhythm was allowed, which is in line with current practice. They were randomized to temperatures of 33°C or 36°C for 28 hours and rewarmed. Normothermia was maintained until 72 hours post-arrest. There was a non-significant two percent mortality difference at the end of the treatment protocol and 180 days later. Patients with a CPC score 3-5 were 54% vs 52%; this was not statistically significant.
Critics, however, said patients in this study had short no-flow times that may not have been valid for a wider population. The study was designed as a non-inferiority study powered to find an 11% absolute risk reduction between 36°C and 33°C, which would be a NNT of 9. That is asking a lot of any cardiac arrest treatment besides chest compressions and defibrillation.
The adoption of higher temperatures is widespread but not complete. The critical care involved in maintaining a patient at 33°C compared with 36°C is much larger but not significantly so. The risks and complications are higher but, again, not significantly. Hypothermia seems to convey a mortality and neurologic benefit compared with normothermia, but preventing hyperthermia may be the greatest benefit.
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