Cooling down the body as a therapeutic modality has been prevalent since ancient times. The Edwin Smith Papyrus (Fig. 1), an Egyptian medical treatise dating back to 3,500 B.C.E, describes the use of hypothermia as a treatment for various ailments (1). Temple Fay reinvigorated interest in hypothermia in modern-day practice in the 1930s with his experiments on whole-body refrigeration and localized cryotherapy for brain lesions. He invented the cooling blanket, circulating cold fluids through a rubber tube (2). During the second world war, hypothermia fell into disrepute following Nazi experiments on prisoners at the Dachau concentration camp, in gross violation of basic human rights (3). There was a resurgence of interest in the 1950s with the intraoperative use of hypothermia as a brain-protective strategy (4).
Case reports from Baltimore
In 1958, Williams Jr et al. reported four patients who underwent hypothermia following in-hospital cardiac arrest at the Johns Hopkins University School of Medicine and Hospital, Baltimore, Maryland. Chest compression was performed within 4–6 minutes, followed by induced hypothermia to 30–34°C and maintained for 72 hours. All the patients had evidence of severe neurological injury. Three of these patients made a complete neurological recovery. The authors observed that patients with similar neurological injury following cardiac arrest had rarely survived previously (5). They attributed the apparent neuroprotective effect of hypothermia to alleviation of brain swelling following cardiac arrest.
The boy who rose from the dead after being struck by lightning
On the afternoon of July 24, 1958, a 10-year-old boy was brought to the Baltimore City Hospital following a lightning strike. A boy scout had found the victim slumped over his bike at the scene. He thought that he could feel a pulse and performed artificial respiration on the victim using the back thrust-arm lift technique in vogue during those days. There was no sign of life when the boy was seen in the accident room 22 minutes after the event. He lay pulseless, with no respiratory efforts, looking pale, his lips cyanotic, and pupils widely dilated. Those were the days of open-chest cardiac massage, three years before external chest compression was first proposed by Kouwenhoven and Knickerbocker (6). The boy’s chest was opened rapidly; the heart was found to be motionless. Following the administration of epinephrine into the heart and massage, spontaneous cardiac activity returned. He was ventilated initially through an oropharyngeal airway and thereafter through an endotracheal tube. He was packed in crushed ice to induce hypothermia down to a temperature of 31.5°C. Over the next few days, he developed status epilepticus and hemiparesis. He began showing signs of neurological improvement after remaining in a coma for six days. After nearly a month of hospitalization, he was discharged home with no significant neurological deficits. The authors concluded that the timely performance of artificial respiration, open cardiac massage, and expeditious induction of hypothermia likely contributed to his miraculous recovery (7).
In 1961, Benson et al. reported 27 patients who suffered in-hospital cardiac arrest. Among them, there were 19 patients with neurological injury, of whom 12 had undergone induced hypothermia to 31–32°C using a cooling blanket. There were six survivors in the hypothermia group, compared to just a lone survivor among seven patients who did not undergo induced hypothermia. The authors concluded that induced hypothermia in patients with a demonstrable neurological injury following cardiac arrest conferred a significant survival advantage (8).
Peter Safar – the concept of cardiopulmonary-cerebral resuscitation
Peter Safar (Fig. 2) pioneered the use of therapeutic hypothermia in patients who remained comatose after resuscitation from cardiac arrest. In his 1964 publication on the “ABCs” of resuscitation, he recommended initiation of hypothermia within 30 minutes of resuscitation if there were no signs of neurological recovery (9). He espoused the concept of cardiopulmonary-cerebral resuscitation, advocating hypothermia as a brain-protective strategy. Widely regarded as the father of cardiopulmonary resuscitation, Safar was thrice nominated for the Nobel Prize.
The Dandenong Hospital studies
The first prospective clinical trial using hypothermia in survivors of out-of-hospital cardiac arrest was conducted at the Dandenong Hospital in Australia. Twenty-two patients, who remained unconscious after return of spontaneous circulation (ROSC), underwent therapeutic hypothermia to 33°C. Hypothermia was maintained for 12 hours, followed by rewarming. These patients were compared with a historical control group of 22 patients. Hypothermia was associated with significantly more patients with a favorable neurological recovery compared to the control group. No incidence in clinically significant complications were noted with hypothermia (10). The same group carried out a later RCT of 77 patients comparing hypothermia to 33°C with normothermia. In this RCT, significantly more patients randomized to hypothermia were discharged home or to a rehabilitation facility compared to the normothermia group. This RCT (11) and the landmark HACA trial (12), were published in the February 21, 2002 edition of The New England Journal of Medicine. These epoch-making trials marked an important breakthrough in the history cardiopulmonary resuscitation, providing strong evidence that hypothermia may improve outcomes in out-of-hospital survivors of cardiac arrest.
The landmark HACA trial
Population and design
The HACA trial enrolled patients from nine centers in Europe over a 4-year period between March 1996 and July 2000. It compared the impact of mild hypothermia with normothermia in patients between 18–75 years who had sustained out-of-hospital cardiac arrest. The cardiac arrest was witnessed, with ventricular fibrillation or pulseless ventricular tachycardia as the presenting rhythm. The underlying etiology was presumed to be of cardiac origin. The time to commencement of resuscitation attempts by emergency personnel was 5–15 min. The time to ROSC was no more than 60 minutes. Patients who responded to commands after ROSC were excluded.
Patients who were randomized to receive induced hypothermia were cooled to 32–34°C using an external cooling device, within 4 hours of ROSC. The temperature was maintained in the target range for 24 hours, followed by passive rewarming. Normothermia was targeted in the control group. In both groups of patients, sedation was maintained with intravenous infusions of fentanyl and midazolam. In case of shivering, muscle relaxants were administered as appropriate.
A total of 275 patients were enrolled; 137 were randomized to undergo induced hypothermia while 138 were assigned to receive standard care. There were marginal differences in patient characteristics between the two groups at baseline. In the normothermia group, more patients had diabetes mellitus and coronary artery disease. Bystander-administered cardiopulmonary resuscitation was performed more often in the normothermia group.
The primary outcome was based on the neurologic status at six months, evaluated using the Pittsburgh cerebral-performance scale. A score of 1 or 2 represented a favorable neurological outcome. Significantly more patients in the hypothermia group, experienced a favorable neurological outcome 75/136 (55%) compared with patients in the normothermia group 54/137 (39%). The risk ratio was 1.4, with a 95 percent confidence interval of 1.08 to 1.81, in favorof induced hypothermia. Six patients treated with induced hypothermia was estimated to prevent one unfavorable neurologic outcome.
Among the secondary outcomes, the 6-month mortality was also significantly lower in the hypothermia group (41% vs. 55%, p = 0.02). Seven patients treated with induced hypothermia was estimated to prevent one death at 6 months.
Overall, the incidence of complications was not significantly different between the two groups (93/132 vs. 98/135, p = 0.70). However, septic complications occurred more commonly with hypothermia (13% vs. 7%), although the difference was not statistically significant. The incidence of arrythmias, a known complication of hypothermia, was similar in both groups.
The study was unblinded, which may have resulted in bias. Of the 3551 patients screened, only 275 (7.7%) were enrolled, raising the possibility of selection bias and limited generalizability. The neurological status prior to cooling was not evaluated in detail; hence it is questionable whether the two groups of patients had suffered similar neurological injury at baseline. Diabetes mellitus and coronary artery disease were more common in the normothermia group; however, the difference in the primary outcome remained significant on multivariate regression analysis. The target temperature was attained at a median of 8 hours after ROSC, although the study aimed to attain the target temperature at 4 hours of ROSC. Many patients in the control group developed fever that could have potentially caused harm and confounded the results. The trial did not calculate a prospective sample size based on the expected difference in the primary outcome; nor did it report any interim analysis or stopping rules.
The post-HACA era
Following the HACA and the Australian trial, observational studies and a meta-analysis (13) also echoed similar findings, with favorable neurological outcomes among patients treated with hypothermia following cardiac arrest. This prompted the International Liaison Committee on Resuscitation (ILCOR) recommendation for therapeutic hypothermia to 32–34°C in survivors of out-of-hospital cardiac arrest (14). Although the strategy of cooling gained widespread acceptance, several questions remained unanswered, opening the door for further studies across larger, more generalizable populations and using different target temperatures.
The targeted temperature management -1 (TTM-1) trial
Conducted across 36 centers in Europe and Australia, the TTM-1 trial included out-of-hospital cardiac arrest survivors (15). Patients remained unconscious with a GCS of <8 on arrival to hospital. In contrast to the HACA and the Australian trial that only included patients with ventricular fibrillation as the presenting rhythm, this study included patients with any arrest rhythm. In the intervention arm, the target temperature of 36 C, compared to 33°C in the control group. The target temperature was maintained for 28 hours in both groups followed by rewarming. Following the intervention period, the temperature was maintained below 37.5°C among patients who remained unconscious in both groups.
Clinical outcomes in the TTM-1 trial contrasted with the findings of the HACA and Australian trials. The all-cause mortality through the study period was similar between the two groups. Among patients in the 33°C group, the mortality was 50% compared with 48% in the 36°C group (hazard ratio: 1.06; 95% confidence interval, 0.89 to 1.28; P = 0.51). At 180 days, 54% of patients randomized to 33°C had died or experienced poor neurological outcomes assessed using the cerebral performance category scale, compared with 52% of patients in the 36°C group; the difference was not statistically significant.
The TTM-2 trial
In light of the TTM-1 results, the question remained whether fever control alone would provide equivalent clinical outcomes compared to active reduction of temperature below the normal range. The TTM-2 trial included 2000 patients, randomized to hypothermia to 33°C or fever control alone (16). In the latter group, if the temperature reached 37.8°C, a temperature control device was used to maintain the temperature at 37.5°C. The target temperatures were maintained for a 40-hour period in both groups, followed by maintenance of normothermia (36.5°C – 37.7°C) from 40 to 72 hours. No difference in mortality was observed between the two groups at 6 months. Besides, the functional outcomes based on the modified Rankin scale and the health-related quality of life at 6 months were also similar. This well-conducted study strongly suggested that in contrast to previous studies, maintenance of normal temperature alone would result in similar outcomes compared to therapeutic hypothermia.
The HYPERION trial
The effect of moderate hypothermia in out-of-hospital cardiac arrest with non-shockable rhythms was evaluated in the HYPERION trial (17). Patients were randomized to moderate hypothermia of 33°C in the first 24 hours compared with targeted temperature management of 37°C. At 90 days, a significantly larger number of patients randomized to moderate hypothermia survived with a favorable neurological outcome (CPC score of 1or 2) compared with patients who underwent targeted normothermia (10.2% vs. 5.7%, p = 0.04). The 90-day mortality was similar between the two groups.
During the period that the HACA trial was conducted, clinical outcomes from out-of-hospital cardiac arrest had remained dismal, despite advances in the field of resuscitation. Induced hypothermia was presumed to the brain through reduced metabolism and oxygen consumption at lower temperatures. Although intraoperative cooling was employed from the 1950s, reports of hypothermia following cardiac arrest were few and far between and remained dormant for several decades. The HACA trial represented a landmark and triggered a radical change in the management of survivors of out-of-hospital cardiac arrest. The study held the promise of improving the dismal outcomes following out-of-hospital cardiac arrest, despite several limitations. More recent trials, including the TTM 1 and 2 trials, have not corroborated the beneficial effects observed in the HACA trial; they suggest that control of fever alone may lead to improved clinical outcomes. However, questions regarding the optimal timing and duration of cooling, and specifically, the possible beneficial effects in more severe cardiac arrest syndromes, especially following non-shockable rhythms, remain unanswered.
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