The much anticipated results of the Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM 2) trial were finally published in the New England Journal of Medicine on June 17th, to the fanfare that tends to surround trials of this magnitude and importance.
Let’s dive right into the nuts and bolts of it: TTM 2 follows in the wake of the original TTM trial (Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest – TTM 1) published in 2013. The latter study on temperature management in patients with coma after out-of-hospital cardiac arrest (OHCA) found no difference between targeted temperature management (TTM) at 33°C vs. 36°C in terms of survival and neurological function at 6 months. With moderate hypothermia (just a degree and a half shy of normothermia) having been found to be non-inferior to the traditional, lower temperature target, researchers quickly came to ask whether normothermia would be just as reasonable a temperature target post-ROSC.
This formed the basis for the TTM 2 trial. In an international, multicentre trial the investigators enrolled 1900 adult patients with ROSC after OHCA (of whom 1850 were evaluated for the primary outcome) and randomised them to receive either TTM at 33°C (Intervention group: 925 pts.) or normothermia with fever control for temperatures above 37,7°C (Control group: 925 pts.).
For the primary outcome measure of all-cause mortality at 6 months, there was no difference between the intervention group and the controls (50% vs. 48%, respectively). The secondary outcome was poor neurological function at 6 months, as measured by the modified Rankin scale. No difference here either. The two arms of the study seem well balanced in baseline characteristics and the other treatments undertaken (sedation regimens, coronary interventions etc). There was a significantly increased rate of haemodynamically important dysrhythmias in the hypothermia group (24% vs. 16%), but otherwise no difference in adverse events.
So all in all a negative trial, suggesting quite strongly that there is no benefit to therapeutic hypothermia in comatose OHCA patients.
I suspect most clinicians were expecting a negative trial result. Since the original TTM trial demonstrated no benefit to 33°C over 36°C, and given the fact that, as temperature targets, normothermia and 36°C are so close as to be nearly inseparable from one another in real-world clinical practice, it is no great surprise that there was no demonstrable between-group difference in TTM 2 either.
There is no doubting the scientific quality and high standards of TTM 2. The trial was brilliantly executed by a superbly experienced research team. The results, nonetheless, need to be interpreted with a few caveats, before we all start chucking the cooling devices out of our ICUs.
First a bit of TTM history: The original TTM trial very quickly engendered a paradigm shift in temperature management, with many centres targeting higher temperatures almost immediately afterwards, as evidenced by an excellent retrospective cohort study by Ryan Salter and colleagues. Alarmingly, this paper also demonstrated a significantly increased incidence of frank hyperthermia after the publication of TTM 1, suggesting that many clinicians took the trial results to mean that post-ROSC temperature is largely irrelevant. This is both a misrepresentation of the study, as well as being indicative of a worrisome complacency in the approach to temperature management. To underscore the importance of this observation, the Salter paper further revealed a trend towards increased mortality post-TTM 1, which should be a warning sign that a more permissive policy towards temperature targets may have a significant downside that merits further attention.
While TTM 2 goes very far in undermining the argument for deeper hypothermia, it does not in any way suggest that temperature has no impact on outcomes. It’s worth noting that hyperthermia was assiduously avoided in the normothermia group (judging from the supplementary material [figure S5] the incidence of fever was relatively low in both groups in the first 40 hours), which is in itself a deliberate temperature management strategy. In fact, 46% of the normothermia patients underwent active cooling with a device, and normothermia was maintained for at least 72 hours after enrolment.
Fever is associated with unfavourable neurological outcomes after cardiac arrest, and avoiding it seems physiologically rational for a number of reasons. One potential translatory consequence of TTM 2 could be clinicians moving even further away from temperature control (with emphasis on avoiding fever) as a management priority in the post-ROSC care bundle. That would be a most concerning development, and one that is not supported by the available evidence.
So what does TTM 2 mean for clinical practice? Hypothermia is certainly starting to look dead in the water, but I think it would be a mistake to argue that, by extension, post-ROSC temperature doesn’t matter at all.
Until a robust clinical trial (if ever such a trial comes to pass) fails to demonstrate a difference in outcome between TTM with fever avoidance and no temperature management at all, it seems logical to target temperatures no higher than normothermia as a rule in this patient group, and explicitly avoid hyperthermia. As the authors themselves conclude: “Whether this type of fever control is of benefit must be addressed in a separate trial”.
Dankiewicz et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med 2021; 384:2283-2294.
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;369:2197-2206.
Salter R et al. Changes in Temperature Management of Cardiac Arrest Patients Following Publication of the Target Temperature Management Trial. Crit Care Med. 2018 Nov;46(11):1722-1730.
Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-556.