Concise Critical Appraisal: Moderate Therapeutic Hypothermia in Patients with Nonshockable Rhythms

Targeted temperature management (TTM) and moderate therapeutic hypothermia (MTH) have become staples of post-cardiac arrest management and are recommended by both the American Heart Association and European Resuscitation Council in post-cardiac arrest comatose patients who have achieved return of spontaneous circulation (Callaway et al. Circulation. 2015;132:S465-482; Nolan et al. Resuscitation. 2015;95:202-222). Landmark trials during the past two decades have shown benefit for both TTM and MTH in cardiac arrest due to ventricular fibrillation and ventricular tachycardia (Bernard et al. N Engl J Med. 202;346:557-563; Hyperthermia after Cardiac Arrest Study Group. N Engl J Med. 2002;346:549-556; Nielsen et al. N Engl J Med. 2013;369:2197-2206). The optimal strategy for post-cardiac arrest temperature management in nonshockable rhythms is less clear.
 
Lascarrou et al (N Engl J Med. 2019. Epub ahead of print) set out to test the effectiveness of MTH in patients with nonshockable rhythms by conducting an open-label randomized controlled trial of 584 patients who had cardiac arrest with an initial nonshockable rhythm that compared MTH with normothermia TTM. The primary end point was favorable neurologic outcome, defined as a cerebral performance category (CPC) score of 1 or 2 at 90 days. Patients were randomized to either MTH (33°C [91.4°F] for 24 hours, followed by 12 hours of rewarming and 24 hours of normothermia) or normothermia (37°C [98.6°F] for 48 hours). The study included patients aged 18 years and older with both in-hospital and out-of-hospital cardiac arrests, who had Glasgow Coma Scale scores of ≤ 8 post-cardiac arrest. Patients were excluded for a no-flow time ≥ 10 minutes, a low-flow time > 60 minutes, time from arrest to screening > 300 minutes, hemodynamic instability, severe hepatic dysfunction, or other standard exclusion criteria. CPC score was determined at 90 days via semistructured phone interview.
 
A total of 584 patients were randomized. Three from the hypothermia group withdrew consent, leaving 581 (284 in the hypothermia group and 297 in the normothermia group). The groups were evenly matched with regard to age; gender; baseline comorbidities; and type, location, and etiology of arrest. Roughly one-fourth of patients sustained an in-hospital cardiac arrest, three-fourths had an out-of-hospital arrest, and two-thirds had a cardiac etiology for their cardiac arrest. The rate of witnessed cardiac arrest was over 90%, and bystander CPR was close to 70% in both groups. At 90 days, 10.2% of the hypothermia group versus 5.7% of the normothermia group had a CPC score of 1 or 2 (CI, 0.1 to 8.9; p = 0.04). Mortality at 90 days was similar between the groups (81.3% vs. 83.2.%; 95% CI, –8.0 to 4.4), and there was no difference in adverse events, mechanical ventilation, or intensive care unit stay.
 
While the results of this study demonstrate a positive effect on neurologically intact survival in MTH versus normothermia, it has several limitations. The fragility index is 1, meaning that a difference in outcome of a single patient would have changed the results. A total of 2723 patients were assessed for eligibility and 2139 were not enrolled, so the patient population was highly selected. Almost one-fourth of the patients were not randomized because of a no-flow time greater than 10 minutes, and 628 either had vasopressor requirements that were too high or were too sick at baseline to be randomized. The rates of witnessed arrest and bystander CPR were also high, suggesting a selected patient population. This limits the generalizability to a smaller subset of post-cardiac arrest patients.
 
This study is an important work in exploring a crucial part of post-cardiac arrest care in patients with nonshockable rhythms. Overall, this study supports the use of a TTM strategy of 33°C (91.4°F) over normothermia targeting 37°C (98.6°F) in nonshockable rhythms in a certain subset of patients. Further research is needed to validate these findings, given the small fragility index, and to determine whether this strategy is beneficial for sicker patients with cardiac arrest and an initial nonshockable rhythm.
 

Study1	Patients Included	Number	Protocol	Primary Outcome	Overall Outcomes and Notes
Bernard et al 2002	Shockable rhythms with out-of-hospital cardiac arrest	77	33°C (91.4°F) for 12 hrs vs. normothermia	Neurologic outcome based on discharge disposition, as defined by ability to be discharged home or to a rehab facility.   49% of hypothermia group had good neurologic outcome vs. 9% of normothermia group. (p = 0.046)	Therapeutic hypothermia was effective in patients with shockable rhythms who achieved ROSC within 30 min.
Hypothermia after Cardiac Arrest Study Group 2002	Shockable rhythms with witnessed cardiac arrest	275	32°C (89.6°F) - 34°C (93.2°F) for 12 hrs as measured by bladder temperature, with external cooling vs. normothermia	CPC score 1 or 2 at 6 months.   55% of hypothermia group had good neurologic outcome vs. 39% in normothermia group (RR 1.40; 95% CI, 1.08-1.81).	Therapeutic hypothermia was effective for improving CPC at 6 months in patients with witnessed arrest with shockable rhythms. Time to ROSC was roughly 20 min in each group. Rates of bystander interventions were 49% and 43%. Therapeutic hypothermia showed lower 6-month mortality. Not all normothermia patients stayed fever free.
Nielsen et al 2013	Age > 18, GCS score < 8, any rhythm, as long as not unwitnessed with asystole, with presumed cardiac cause	939	33°C (91.4°F) vs. 36°C (96.8°F) for 28 hrs, followed by rewarming	All-cause mortality at trial end.   50% (33°C [91.4°F]) vs. 48% (36°C [96.8°F]) with no difference in mRS or CPC at 6 months.	Roughly 80% shockable rhythm, with 1 min to start of BLS, roughly 10 min to ACLS, and 25 min to ROSC. Most patients had in-person follow-up.
Frydland et al 2015	Age > 18, GCS < 8, any rhythm, as long as not unwitnessed with asystole, with presumed cardiac cause	178 of initial 939	33°C (91.4°F) vs. 36°C (96.8°F), then 28 hrs of gradual rewarming	All-cause mortality 84% in both groups, much worse than the 50% vs. 48% in the trial overall.	Good neurologic outcome in 15% of the TTM 33°C (91.4°F) group and 15% of the TTM 36°C (96.8°F) group.
Lascarrou et al 2019	Cardiac arrest with initial nonshockable rhythm, with primary end point of favorable neurologic outcome (CPC score 1 or 2) at 90 days. Included both inpatients and outpatients aged ≥ 18 years, with GCS score ≤ 8 post-arrest. Exclusion criteria: no-flow time ≥ 10 min, low-flow time > 60 min, time from arrest to screening > 300 min, hemodynamic instability, severe hepatic dysfunction, or other standard exclusion criteria.	584, with 581 in final analysis	33°C (91.4°F) vs. 37°C (98.6°F) for 24 hrs post-arrest	CPC 1 or 2 at 90 days, 10.2% in hypothermia group vs. 5.7% in normothermia group p = 0.04) with large CI and barely avoiding grossing 0.	No difference in mortality or adverse events. Two-thirds of patents had cardiac etiology, with large number of witnessed arrests and bystander CPR.

Abbreviations: ACLS, advanced cardiac life support; BLS, basic life support; CI, confidence interval; CPC, cerebral performance category; GCS, Glasgow Coma Scale; mRS, modified Rankin Scale; ROSC, return of spontaneous circulation; TTM, targeted temperature management.
 
1. Studies cited in column 1:

• 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 Feb 21;346(8):557-563. https://www.ncbi.nlm.nih.gov/pubmed/11856794
• Hyperthermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 Feb 21;346(8):549-556. https://www.ncbi.nlm.nih.gov/pubmed/11856793
• Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-2206. https://www.ncbi.nlm.nih.gov/pubmed/24237006
• Frydland M, Kjaergaard J, Erlinge D, et al. Targeted temperature management of 33°C and 36°C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm: a TTM sub-study. Resuscitation. 2015 Apr;89:142-148. https://www.ncbi.nlm.nih.gov/pubmed/25629544
• Lascarrou JB, Merdji H, Le Gouge A, et al; CRICS-TRIGGERSEP Group. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019 Oct 2. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31577396

David Gordon, MD, is a critical care fellow at the University of Maryland in Baltimore, Maryland, USA, and a graduate of the Advanced Resuscitation Program at Stony Brook Medicine.
 
Brian J. Wright, MD, MPH, is a clinical assistant professor and the program director for the Advanced Resuscitation Training Program in the Department of Emergency Medicine at Stony Brook Medicine. Dr. Wright is an editor of Concise Critical Appraisal.