In the past two decades, the critical care field has witnessed the development of new concepts and interventions aiming at improving neurological outcome and survival rate of patients after cardiac arrest. Targeted Temperature Management (TTM) has been the standard of care over the past 19 years. However, recent randomized trials have raised several important questions, and the field still remains intensively debated.
The first study showing a benefit of hypothermia after cardiac arrest is dated back to 1959 and included total of 19 patients of perioperative cardiac arrest. The survival rate was 14% in the hypothermia group (31–32°C) compared to 50% in the control group [1]. Despite multiple other small studies, the evidence for mild hypothermia after cardiac arrest was lacking a sufficient power and advisory panel support to recommend its use in common practice.
It was not until the year 2002 where two studies were published in the NEJM demonstrating neurological outcomes and survival with TTM for comatose survivors of out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation. The Hypothermia after Cardiac Arrest Study Group trial included nine centers in five European countries and showed that mild hypothermia (32–34°C for 24 h) in 274 OHCA patients with return of spontaneous circulation (ROSC) provided not only a significant improvement in functional recovery after hospital discharge (55% vs. 39%) but also a lower 6-month mortality rate when compared with patients who were not cooled (41% vs. 55%) [2]. At the same time, an Australian group of investigators showed a hospital survival rate of 49% in the hypothermia group (33°C for 12 h) compared to 26% in the normothermic group in a study that included a total of 77 patients [3].
Since that time, published international guidelines strongly recommended TTM after OHCA and its use has been extended to cardiac arrest of other causes and with other presenting rhythms as well as to the in-hospital setting [4]. However, challenges and controversies continued in relation to the level of evidence, method of cooling, degree of temperature, and duration of hypothermia.
In 2013, a large international trial (TTM trial) randomized a total of 950 unconscious adults after OHCA to either 33°C or 36°C. Lower targeted temperature of 33°C did not confer a mortality benefit as compared with 36°C at the end of the trial (50% vs 48%) or after 180 days (54% vs 52%). The composite endpoint of poor neurologic function or death at 180 days did not differ between the two groups [5].
A study with a limited power was published in JAMA in 2017 comparing 24 hours to 48 hours of TTM at 33°C in unconscious survivors of OHCA. The 6-month neurologic outcome was not statistically different between the two groups [6].
In 2019, a study was published in NEJM that involved 584 patients who had cardiac arrest with nonshockable rhythm and showed better neurologic outcomes with TTM at 33°C compared with 37°C. In this trial, a total of 29 of 284 patients (10.2%) in the hypothermia group were alive with a Cerebral Performance Category (CPC) score of 1 or 2 on day 90, compared to 17 of 297 (5.7%) in the normothermia group [7].
More recently, an open-label, blinded outcome study (known at TTM2) was published in NEJM comparing TTM at 33°C versus ≤37.5°C. Death rate at 6 month was not different between the two groups (50% vs. 48%) and Modified Rankin Scale Score of ≥4 was similar in the two groups (55%) [8].
Clinicians should not misinterpret the results of TTM that a targeted temperature management protocol was without benefit and that normothermia could be achieved with acetaminophen alone. In all TTM trials including TTM2, the targeted temperatures (whether it is hypothermia or normothermia) were achieved with cooling devices (surface of intravascular) and use of sedation. The cohort of patients in TTM2 included patients with shockable rhythm who had witnessed arrest and started CPR by a bystander and cannot be generalized yet to other population. In addition, passive temperature management may lead to fever and possible worse outcome. These observations underscore that targeted temperature management is required in all patients regardless of the target temperature chosen.
It is important to note that real-word experience may be different than the results of the published studies. In a retrospective, before-and-after, cohort study (TTM of 33°C changed to 36°C), targeted temperature management 33°C was associated with increased odds of neurologically intact survival to discharge (odds ratio, 1.79; 95% CI, 1.09-2.94). However, targeted temperature management 33°C was not associated with significantly improved hospital mortality [9].
In conclusion, we still recommend that the targeted temperature of 33-36°C should be maintained for 24 hours using a cooling device (lower temperature in more severe cases), followed by a 12-hour period of rewarming and sedation. Patients who remain comatose should receive sedation and a targeted temperature management protocol with a normothermic target of 36.5°C to 37.7°C to complete 72 hours after ROSC before determining prognosis and initiating end-of life discussion.
REFERENCES
Benson DW, Williams GR, Spencer FC. The use of hypothermia after cardiac arrest. Anesth Analg. 1959;38:423–8. [PubMed] [Google Scholar]
Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–56. [PubMed] [Google Scholar]
Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–63. [PubMed] [Google Scholar]
Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: adult basic and advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2020;142(16_suppl_2):S366-S468.[Google Scholar]
Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369:2197–206. [PubMed] [Google Scholar]
Kirkegaard H, Søreide E, de Haas I, et al. Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial. JAMA 2017;318:341-350.
Lascarrou J-B, Merdji H, Le Gouge A, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med 2019;381:2327-2337. [Google Scholar]
Dankiewicz J et al. Hypothermia versus Normothermia after Out-of-Hospital Cardia Arrest. NEJM 2021; 384:2283-2294. DOI: 10.1056/NEJMoa210059.
Johnson NJ, Danielson KR, Counts CR, Ruark K, Scruggs S, Hough CL, Maynard C, Sayre MR, Carlbom DJ. Targeted Temperature Management at 33 Versus 36 Degrees: A Retrospective Cohort Study. Crit Care Med. 2020 Mar;48(3):362-369. doi: 10.1097/CCM.0000000000004159. PMID: 31809279.