Each year, more than 650,000 adult patients experience a cardiac arrest in the United States (US) alone.¹ Although survival rates for both in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) have improved in recent years, overall survival rates remain low.^2,3 Among survivors, there is a substantial risk of neurological injury and disability which is due to a combination of whole body anoxia, ischemia/reperfusion injury, inflammation, and excitotoxicity.⁴ We provide a review of the key randomized controlled trials (RCT) of targeted temperature management (TTM) (Table 1).

Table 1: Randomized Control Trials Evaluating Targeted Temperature Management for Cardiac Arrest

Authors	N	Design	Year	Population	Intervention vs. control	Primary Outcome	Major Findings
The Hypothermia after Cardiac Arrest Study Group	275	RCT	2002	OHCA due to a shockable rhythm	TTM 33°C vs. normothermia (37°C)	Favorable neurologic outcome at 90 days	Significantly higher survival and survival with favorable neurological outcome in hypothermia group
Bernard et al.	77	RCT	2002	OHCA due to ventricular fibrillation	TTM at 33°C  vs. 37°C	Survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility	Significantly higher survival with favorable neurological outcome in hypothermia group
Bernard et al. [RICH trial]	234	RCT	2010	OHCA due to ventricular fibrillation	Cool IV fluids en-route to hospital vs. standard of care	Survival to discharge	No significant difference in survival to discharge
Nielsen et al. [TTM trial]	939	RCT	2013	OHCA with a presumed cardiac cause	TTM at 33°C vs. 36°C	All-cause mortality through the end of the trial (mean period of 256 days)	No significant differences between the groups
Kim et al.	1359	RCT	2014	OHCA with either VF or non-shockable rhythms	Pre-hospital cooling with 2 L of 4°C normal saline vs. standard care	Survival to hospital discharge and neurological status at discharge	No improvement in survival or neurological outcomes
Lopez et al. [FROST-I trial]	150	RCT	2018	Witnessed OHCA with shockable rhythms	TTM at 32°C, 33°C, and 34°C	Favorable neurologic outcome at 90 days	No significant difference in primary outcome between study groups
Lascarrou et al. [HYPERION trial]	581	RCT	2019	OHCA and IHCA with non-shockable rhythms	TTM at 33°C vs. normothermia 37.5°C	Survival with a CPC of 1 or 2 at 90 days	Significantly improved survival with a CPC of 1 or 2 in hypothermia group but no difference in overall mortality
Dankiewicz et al. [TTM2 trial]	1861	RCT	2021	OHCA with a presumed cardiac cause	TTM at 33°C vs. targeted normothermia 37.5°C	Death from any cause at 6 months	No significant differences between groups

In 2002, two landmark RCTs were published simultaneously that found therapeutic hypothermia (TH) to be effective in reducing the risk of neurological disability in patients with OHCA due to an initial shockable rhythm who were comatose post-arrest.^5,6 These trials led to a rapid adoption of TH into clinical practice for prevention of neurological injury in post-arrest patients. TH also received a class I recommendation in resuscitation guidelines⁷ which has since expanded to include patients with non-shockable rhythms and patients with IHCA.⁸ However, there are key limitations of the earlier RCTs that merit discussion. First, both trials were small and included a total of 352 patients, raising the possibility of chance findings. Second, temperature was not actively managed in the control arm such that a substantial number of patients randomized to normothermia became febrile. Due to this, it is difficult to discern whether the positive findings were due to a true benefit of TH or due to the deleterious effects of fever on neurological recovery in the normothermia group. Importantly, treatment was not blinded and protocols for neuro-prognostication were not standardized between the treatment groups. Therefore, it is possible that worse survival in the normothermia group may have been driven, at least in part, by premature withdrawal of care. Finally, post-resuscitation care over the years has evolved with development of comprehensive treatment protocols across centers. Whether the large effect of TH seen in the earlier trials is consistent in contemporary practice remains unclear.

Recent trials have attempted to address the above limitations. The Targeted Temperature Management (TTM) trial randomized 950 subjects with an OHCA to two different temperature targets: 33°C versus 36°C, with active temperature management in both groups.⁹ Unlike the earlier RCTs, no significant difference in mortality (50% vs. 48%; P = 0.51), or a composite of mortality and poor neurological outcome at 6 months (54% vs. 52%; P = 0.78) between the two treatment arms was observed. Other trials, although smaller than the TTM trial, corroborated the findings of the TTM trial.¹⁰ Collectively, these trials suggest that a strategy of intense cooling may not provide any additional benefit when compared to mild TH with avoidance of fever. However, neither of these studies included a normothermia group. Moreover, non-shockable rhythms were underrepresented in these trials; in the TTM trial non-shockable rhythms comprised only 20%. This is despite >75% of all cardiac arrests are due to asystole or pulseless electrical activity.

The HYPERION trial studied the efficacy of TH (33°C) versus targeted normothermia (37°C) in 584 comatose patients admitted to an intensive care unit (ICU) after a cardiac arrest due to an initial non-shockable rhythm and included both OHCA and IHCA patients. The trial found a significant benefit in favor of TH for the primary end point of 90-day survival with a favorable neurological outcome (10.2% vs. 5.7%; 95% [CI], 0.1 to 8.9, P = 0.04), but no difference in overall mortality.¹¹ While the trial demonstrated a benefit of TH compared to normothermia and is the only RCT to include IHCA patients, the effect estimate had a large confidence interval such that the occurrence of one additional primary endpoint in the normothermia group would have eliminated the statistical significance (i.e., a fragility index of the trial was 1).¹²

Accordingly, the recently published TTM2 trial is highly relevant as it compares TH with targeted normothermia in a large and diverse cohort of OHCA patients.¹³ The trial included 1,861 patients with OHCA at 61 sites across Australia, Europe and the US who were comatose post-arrest. Patients were randomized to TH of 33°C versus targeted normothermia (goal temperature: <37.5°C). Overall, there was no difference in survival at 6 months (50% vs. 48%, P = 0.37) and no difference in survival with severe disability on the modified Rankin scale (55% vs. 55%; RR 1.00; 95% CI, 0.92-1.09). There was also no difference in health-related quality of life between the groups, but a higher incidence of arrhythmias with the use of hypothermia. These findings are in direct contrast to the original RCTs published in 2002 and the HYPERION trial,^5,6 but do align with the findings reported in the TTM trial.

There are several strengths of the TTM2 trial that merit discussion. First, it is the largest study of targeted temperature management to date and had 90% power to detect an absolute 7.5% difference in mortality. For context, the observed mortality difference in the Bernard and HACA study was 17% and 14%, respectively. Aside from the randomized treatment, both groups were treated similarly including use of mechanical ventilation, sedation, and neuromuscular blockers. Importantly, neuro-prognostication was performed using a standardized protocol and withdrawal of care before 96 hours was strongly discouraged, unless further treatment was deemed unethical or if there was evidence of brain death. Furthermore, while patients and physicians were not blinded, outcome assessors were blinded thereby reducing bias. Finally, follow up was nearly 100% and there were few protocol deviations.

A few limitations of the TTM2 trial also deserve mention. First, >90% of cardiac arrests were witnessed and approximately 80% received bystander cardiopulmonary resuscitation (CPR). Moreover, a high proportion of patients had an initial shockable rhythm, suggesting that the study findings may not be generalizable to all OHCA patients. Despite this, survival rates in this study were similar to survival reported in the earlier trials. Similarly, only OHCA patients were included and therefore findings may not apply to patients with IHCA. However, data supporting a benefit of TH in IHCA patients is limited given the limitations of the HYPERION trial noted above.¹⁴ Second, active cooling was used in 46% of patients in the normothermia group which highlights the high prevalence of fever and underscores the importance of active temperature management in the post-arrest setting. Therefore, the TTM2 trial should not be interpreted as no benefit of any temperature management. Third, although hypothermia was initiated quickly with a median time to achieve 34°C of 3 hours after randomization, it remains to be seen whether more rapid cooling would have demonstrated a benefit of TH. However, prior RCTs have not shown pre-hospital cooling to improve survival in OHCA.^15,16 Finally, it should be noted that there were on average 136 minutes from patient contact until randomization, which increased the total time from patient contact to temperature goal to over 5 hours. This likely represents the real-world experience of cardiac arrest survivors, but future RCTs should test whether more rapid time-to-cooling will confer neuroprotection.

In summary, based on the findings of TTM2 trial, TH is not superior to targeted normothermia for neuroprotection in OHCA patients. It is possible that the time window during which TH may provide patient benefit is narrow, and unrealistic to achieve using current cooling protocols. However, until future RCTs studies such as those evaluating intra-arrest cooling and selective cerebral hypothermia are completed, we believe that routine use of TH for neuroprotection may no longer be necessary. We recommend active temperature management to maintain normothermia in post-cardiac arrest patients.

References

1. Holmberg MJ, Ross CE, Fitzmaurice GM, et al. Annual incidence of adult and pediatric in-hospital cardiac arrest in the United States. Circ Cardiovasc Qual Outcomes 2019;12:e005580.
2. Girotra S, Nallamothu BK, Spertus JA, et al. Trends in survival after in-hospital cardiac arrest. N Engl J Med 2012;367:1912-20.
3. Chan PS, McNally B, Tang F, Kellermann A, Group CS. Recent trends in survival from out-of-hospital cardiac arrest in the United States. Circulation 2014;130:1876-82.
4. Katz A, Brosnahan SB, Papadopoulos J, Parnia S, Lam JQ. Pharmacologic neuroprotection in ischemic brain injury after cardiac arrest. Ann N Y Acad Sci 2021;May 31:[Epub ahead of print].
5. 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.
6. 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.
7. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S768-86.
8. Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132:S465-82.
9. 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.
10. Lopez-de-Sa E, Juarez M, Armada E, et al. A multicentre randomized pilot trial on the effectiveness of different levels of cooling in comatose survivors of out-of-hospital cardiac arrest: the FROST-I trial. Intensive Care Med 2018;44:1807-15.
11. Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med 2019;381:2327-37.
12. Tignanelli CJ, Napolitano LM. The fragility index in randomized clinical trials as a means of optimizing patient care. JAMA Surg 2019;154:74-79.
13. Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med 2021;384:2283-94.
14. Chan PS, Berg RA, Tang Y, Curtis LH, Spertus JA. Association between therapeutic hypothermia and survival after in-hospital cardiac arrest. JAMA 2016;316:1375-82.
15. Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation 2010;122:737-42.
16. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA 2014;311:45-52.

Clinical Topics: Arrhythmias and Clinical EP, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Coronary Syndromes

Keywords: Quality of Life, Out-of-Hospital Cardiac Arrest, Hypothermia, Survival Rate, Coma, Respiration, Artificial, Brain Death, Neuroprotection, Confidence Intervals, Temperature, Follow-Up Studies, Goals, Random Allocation, Cardiopulmonary Resuscitation, Hypothermia, Induced, Arrhythmias, Cardiac, Intensive Care Units, Survivors, Clinical Protocols, Neuromuscular Blocking Agents, Hospitals, Physicians, Hypoxia, Brain, Inflammation, Reperfusion Injury

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