Targeted Hypothermia Provides No Mortality Benefit at 6 Months Compared to Normothermia after Cardiac Arrest

Niklas Nielsen, MD, PhD

Results of a randomized trial from investigator in Sweden could have practice-changing implications in regard to care of patients in unconscious cardiac arrest.

"These results will affect the current guidelines,” said senior investigator Niklas Nielsen, MD, PhD, Researcher at Lund University and Consultant in Anesthesiology and Intensive Care at Helsingborg Hospital, in a statement.

Published in the New England Journal of Medicine, the 1900-patient, open-label trial demonstrates targeted hypothermia provided no benefit versus normothermia, with results suggesting there were no major differences in incidence of death of 6 months between the approaches.

"It is important to set high standards for clinical studies, partly to determine what should be introduced in healthcare, partly to challenge the practices that are already in use—to ensure that we have got it right and that healthcare is evidence-based. The results produced strongly indicate that normal temperature should be recommended, not hypothermia,” continued Nielsen.

With international guidelines recommending unconscious cardiac arrest patients undergo targeted hypothermia to preserve neurologic function, investigators sought to determine whether the previously purported relationship between fever and adverse neurological outcomes was modifiable. To do so, they designed and conducted the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial to evaluate the effects of hypothermia versus normothermia and early treatment of fever in patients after cardiac arrest.

TTM2 randomized 1900 adults with coma who had experienced an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming or targeted normothermia with early treatment of fever. The intervention period of the study lasted 40 hours and began at the time of randomization.

The primary outcome of interest for the trial was incidence of death from any cause at 6 months. The secondary outcome of interest included functional outcome at 6 months, which was measured using the modified Rankin scale. Investigators pointed out plans to assess these outcomes in prespecified subgroups defined by sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission were planned. Adverse events of interest for the trial included pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to temperate management device.

Of the 1900 patients who underwent randomization, 1850 were evaluated for the trial’s primary outcome. Upon analysis, results indicated the primary outcome occurred in 50% of the hypothermia group and 48% of the normothermia group (RR for hypothermia, 1.04; 95% CI, 0.94-1.14; P=.37). The secondary outcome of interest for the trial was assessed in 1747 patients. Results of this analysis indicated 55% of the hypothermia group and 55% of the normothermia group had moderately assure disability or worse, which was defined as a score of 4 or greater using the modified Rankin scale (RR for hypothermia, 1.00; 95% CI, 0.92-1.09).

Results of subgroup analyses indicated outcomes were consistent across prespecified subgroups. Investigators noted that arrhythmia resulting in hemodynamic compromise appeared to be more common among patients in the hypothermia group than those in the normothermia group (24% vs 17%; P <.001). Additionally, assessments of other adverse events indicated incidence did not differ significantly between the hypothermia and normothermia groups.

"The results are important, but not unexpected. For 20 years, we have applied and believed in these practices which we now see do not make a difference for survival. Now, we can use the resources on other things and prioritize other aspects of the acute phase of cardiac arrest,” said lead investigator Josef Dankiewicz, MD, PhD researcher at Lund University and resident physician at Skåne University Hospital, in the aforementioned statement.

This study, “Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest,” was published in the New England Journal of Medicine.