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A quick update on an TTM2 trial published in the NEJM last month. As part of the chain of survival it’s important to optimise the post resuscitation phase, primarily to preserve neurological function as this is an important determinant of outcome. Arguably (and in or opinion) neurological outcome is more important than survival as our aim is to return our patients to as close to full functional health as possible.
Hypothermia as a treatment for a range of conditions where neurological outcomes are important has a strong theoretical basis, and in lab based experiments it certainly seems to have an effect, but thus far those effects have not translated to the real world.
In the post cardiac arrest situation interest in hypothermia was originally very strong following a series of small trials that appeared to show benefit, but that was questioned when the TTM trial showed no benefit to a lower temperature of 33C vs. 36C. So why are we now looking at a second randomised controlled trial of temperature management of post cardiac arrest patients? The answer is that past studies were at risk of bias and also there was a lack of clarity in early trials of whether the treatment benefit resulted from a target temperature or from the avoidance of fever.
The Targeted Temperature Management 2 trial (TTM2) is designed to answer this question. You can read the abstract below, but as always we strongly recommend you read the full paper yourself and look at some of the other blogs reviewing the paper at the end of the page.
What type of trial is this?
It’s a randomised trial which is the best way to test a therapy. Interestingly this trial was co-enrolled with another post cardiac arrest trial TAME which examines mild hypercapnia in the same patients. That makes the randomisation process slightly more complex, so a block randomisation technique was used to ensure equal numbers of both trials in a 1:1 ratio.
Tell me about the patients.
Interestingly the original hypothermia trials post cardiac arrest focused on those patients with shockable rhythms. That’s fine from a research design, but arguably focuses on those patients most likely to have a positive outcome. In principal there is nothing wrong with that approach but it does mean that such trials have limited generalisability when the results hit the real world. In this trial. In this TTM2 trial they did not exclude non-shockable rhythms as shown below (from the TBC site)
- Out-of-hospital cardiac arrest of presumed cardiac or unknown cause
- Sustained ROSC: >20 minutes of circulation without need for chest compressions
- Unconscious: as defined by the FOUR score motor response <4 and not able to obey verbal command
- No limitations to management in place
- Inclusion must be no later than 180 minutes after ROSC
- Unwitnessed cardiac arrest with initial rhythm asystole
- Temperature on admission < 30°C
- On ECMO prior to ROSC
- Suspected pregnancy
- Intracranial bleed
- Severe COPD with long-term home O2
In fact, roughly 3/4 of patients in the trial had a shockable rhythm which is not really surprising as those patients predominate in those who get ROSC (return of spontaneous circulation).
What did they do?
In TTM2, the normothermia group focused on keeping body temperature below 37.8C (the patients had an alarm fitted for when the patient temperature rose above 35C). The temperature was maintained with pharmacological and external cooling methods. The point here is that the temperature in these patients was very actively managed and in this study 46% of patients in this group needed active external cooling. It’s really important to recognise that this arm of the trials was temperature controlled and not just left to do their own thing.
In the hypothermia group attempts were made to get patients to the target temperature of 33C as soon as possible. This involved the use of cold fluids, external cooling devices and/or intravascular cooling devices. Temperature was controlled using a feedback system linked to an indwelling bladder thermometer.
What about the outcome?
As we said earlier, at St Emlyn’s we are most interested in neuro-disability outcomes. In this study the primary outcome was mortality at 6 months, but they have included neurodisability outcomes as secondary outcomes. Like many similar studies they used the Modified Rankin Scale (MRS) with a score of 4-6 defining a poor outcome (that’s moderate severe disability or worse).
Tell me the results.
Before we get onto the primary outcome it’s worth checking whether they actually did what they intended to do as this has been a problem in past trials. In TTM2 there was an emphasis on getting people in the intervention arms to the required temperature quickly and in keeping them there (we were a recruiting site in Virchester). Despite this being a real driver in the study the median time to gaining a temperature of 34C in the hypothermia group was 3 hours. That’s quite a long time, but is perhaps a realistic real world result (and not as we might achieve in small animals in lab settings which is where hypothermia has often shown benefits). As the graph shows below, following randomisation they did keep the patients temperature in range during the trial.
1800 patients were included in the final analysis.
The headline figures are that there was no statistically significant difference in the primary outcome of death at 6 month (50% (465/925) for normothermia vs 48% (446/925) for hypothermia RR 1.04 (95% CI 0.94-1.14, p = 0.37)).
In terms of functional outcome at 6 months, there was again no statistically significant difference. 488 of 881 patients (55%) in the hypothermia group and 479 of 866 patients (55%) in the normothermia group had a modified Rankin scale score of 4 to 6 (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Other secondary outcomes were similarly unremarkable.
In terms of adverse events, there were more (24 vs. 17%) in the hypothermia group, with the difference mostly attributed to increased arrhythmias.
So we just stick to 36C then?
On the basis of this and previous trials that seems the right thing to do at this time. The question of whether hypothermia works post cardiac arrest seems unlikely but it’s important to note the quite long delay to achieve hypothermia. We still don’t know whether hypothermia might work if done very early in the patient journey, though logistically this would be very difficult to achieve.
The study was also disrupted by COVID and so some of the patient outcome data was acquired in different ways (face to face or online). That may have had an effect for some of the secondary outcomes. This may be resolved when we get the 24 month outcome data which in itself is important as many clinicians would say that 6 months is too early to truly determine a neurological outcome.
We also need to await the results of the TAME trial as that may influence the results.
Justin Morgenstern at First10EM makes a good point that we still don’t really know whether avoidance of fever really makes a difference as that’s not been tested. So we will have to decide whether to go for not controlling temperature at all vs. fever control as in this trial. It’s a good point and a perfectly reasonable conclusion. I think people will come down on different sides of that debate (and others will still want to use hypothermia as there are some strong advocates out there). As is almost always the case in EBM this new data helps clarify our knowledge but it does not tell us everything. My thoughts are below, but I’d be interested to hear your thoughts too.
Active temperature management to target a body temperature below 37.8C is indicated for post cardiac arrest patients on the ICU.
Read more here
- Modified Rankin Score https://en.wikipedia.org/wiki/Modified_Rankin_Scale
- Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest N Engl J Med 2021; 384:2283-2294 DOI: 10.1056/NEJMoa2100591
- Bernard SA, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002 Feb 21; PMID: 11856794
- Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 Feb PMID: 11856793
- Nielsen N, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013 Dec 5. PMID: 24237006