Targeted Hypothermia for Patients in Coma After Cardiac Arrest Does Not Improve Mortality, Function

Targeted hypothermia in patients experiencing coma after an out-of-hospital cardiac arrest did not lower 6-month mortality rates or improve 6-month functional outcomes compared with normothermia, according to results from the TTM2 study, published in The New England Journal of Medicine.

However, targeted temperature management is still recommended in these patients, according to an accompanying editorial by Laurie J. Morrison, MD, of the University of Toronto, and Brent Thoma, MD, of the University of Saskatchewan, Saskatoon, Canada.

“The key takeaway from the TTM2 trial for clinicians should be that targeted temperature management involving pharmacotherapy, device cooling, and timely neurologic prognostication is a crucial treatment strategy to improve outcomes in patients who have had a cardiac arrest. The target temperature, at the discretion of the clinician, could be 33°C, 36°C, or 37.5°C or less,” they wrote.

Morrison and Thoma provided some perspective on these recent results from TTM2 by reviewing those from the first TTM study, in which researchers found that a targeted temperature of 33°C (hypothermia) was not superior to a targeted temperature of 36°C (normothermia). The effect on clinical practice, however, was not as expected.

“Scientific evidence is often poorly implemented or misinterpreted when it is incorporated into clinical practice. Trends in clinical care after publication of the first TTM (Target Temperature Management 33°C versus 36°C after Out-of-Hospital Cardiac Arrest) trial are illustrative and alarming. Aiming to build on remarkable improvements in outcomes in patients after cardiac arrest, the TTM trial used standardized surface or intravascular temperature-management protocols to test whether a targeted temperature of 33°C (hypothermia) was superior to a targeted temperature of 36°C (normothermia). It was not; mortality and neurologic outcomes were similar,” they wrote.

“After publication of the trial results, surveys from multiple countries indicated that targeted temperature management practices had been relaxed or were no longer adopted by many clinicians. Perhaps clinicians misinterpreted the results as indicating that a targeted temperature management protocol was without benefit and that normothermia could be achieved with acetaminophen alone. The impressive survival and neurologic function outcomes in both the normothermia group and the hypothermia group in the first TTM trial were achieved with a suite of targeted interventions, including the use of sedation and cooling devices in a similar percentage of patients in both groups. The key message from the trial was that targeted temperature management is required, regardless of the target temperature chosen,” the editorialists wrote.

Researchers of the second Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2), led by Josef Dankiewicz, MD, PhD, of Skåne University Hospital Lund, Lund University and Clinical Studies, Sweden, wrote: “International guidelines recommend targeted temperature management to prevent hypoxic–ischemic brain damage in patients with coma after cardiac arrest.

“Although guidelines strongly recommend targeted temperature management with a constant target between 32°C and 36°C, they also state that the overall evidence is of low certainty. A systematic review that included a meta-analysis and trial sequential analysis indicated that the available trials had high risks of bias and random error,” they added.

Dankiewicz and colleagues, therefore, conducted the open-label TTM2 trial, for which they randomized 1,850 patients with coma who had an out-of-hospital cardiac arrest to targeted hypothermia at 33°C, followed by controlled rewarming, or to targeted normothermia with early treatment of fever. In patients undergoing hypothermia, the treatment encompassed 40 hours, during which targeted temperatures were maintained for 28 hours, followed by 12 hours of rewarming and sedation. Those who remained comatose then underwent targeted temperature management with a normothermic target of 36.5°C to 37.7°C for 32 additional hours (total time: 72 hours).

At 6 months, 50% of patients treated with hypothermia had died, compared with 48% of those treated with normothermia (RR with hypothermia: 1.04; 95% CI: 0.94-1.14; P=0.37).

Functional outcome was assessed in 1,747 patients, and was identical in both groups, with 55% of patients in each group having moderately severe disability or worse (modified Rankin scale score: ≥4). Patients in the two groups also had similar health-related quality of life, which was assessed via the EQ-5D-5L visual-analogue scale, both with inclusion of patients who died and with only those who survived (mean between-group difference in patients who survived to 6 months: −0.8 points; 955 CI: −3.6 to 2.0).

Arrhythmia resulting in hemodynamic compromise was more common in patients treated with hypothermia compared with normothermia (24% versus 17%, respectively; P˂0.001). The incidence of other adverse events—including pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complicated related to device used to manage targeted temperatures—were not significantly different.

“Two unexpected serious, possibly intervention-related adverse events occurred in each group: an intravascular device–related thrombosis in one patient in the hypothermia group and two patients in the normothermia group, and bradycardia with worsening hemodynamic function in one patient in the hypothermia group,” noted Dankiewicz and colleagues.

They concluded that targeted hypothermia did not lower 6-month mortality in these patients compared with normothermia.

According to Morrison and Thoma, results from TTM2 are encouraging, and targeted temperature management still plays a vital role in the treatment of these patients.

“In both TTM trials, the overall survival at 6 months among patients who had had out-of-hospital cardiac arrest was approximately 50%. This is a remarkable achievement as compared with the historical value of approximately 25%, and it may be attributed to advances in critical care, the implementation of targeted temperature management, and a uniform approach to neurologic prognostication. The TTM2 trial has the potential to support quality-improvement studies by tracking both compliance with the targeted temperature management protocol and survival as critical process and outcome measures,” they wrote.

Study limitations include that patients from both groups were treated similarly to isolate the effects of hypothermia, and the subsequent use of ICU care was not representative of clinical practice, the use of a conservative protocol for neurologic prognostic assessments and guidance for withdrawal of life support, unblinding of ICU staff members, lack of a control group that underwent no temperature management, use of mechanical fever control, inclusion of only out-of-hospital cardiac arrests, and inclusion of one-fifth of patients in another trial.

1. According to results from the TTM2 trial, targeted hypothermia did not lower 6-month mortality compared with normothermia in patients with coma after out-of-hospital cardiac arrest.

2. According to editorialists, targeted temperature management is still crucial in patients who have suffered cardiac arrest, and helps improve outcomes.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Cat ID: 358

Topic ID: 74,358,254,730,358,5,192,925