TTM/Hypothermia trials
This is my second and last post while being in San Diego, CA. Will continue once I head back to my NYC apartment! The famous TTM 2 Trial was just published in the NEJM on June 17, 2021 and is a follow up to the TTM 1 Trial. I’m a little behind on the ball so let’s get straight into it. The data I present is directly from the papers along with info from smarter people who are better at analyzing and challenging this stuff than I am.
Briefly, TTM 1 in 2014 compared cooling patients to 33C versus 36C. 950 patients were enrolled. 50% in the 33C arm had died. 48% in the 36C arm had died. 53% had a modified Rankin score of ≥4 in the 33C group and 51% in the 36C group. The trial concluded that there was no added mortality beneift from cooling to 33C vs 36C.
TTM 2: Hypothermia versus Normothermia after Out-Of-Hospital Cardiac Arrest
Very similarly TTM 2 sought out to see how many patients who suffered from OSH cardiac arrest died at 6 months (primary outcome) using normothermia vs hypothermia at 33C. 1850 patients were enrolled. At 6 months, 50% in the hypothermia group had died and 48% in the normothermia (37.5C) group.
Secondary outcome was functional ability at 6 months using the modified Rankin Scale (used to determine neurologic disability). At 6 months, 55% had moderate to severe disability (Rankin≥4) and the same, 55%, in the normothermia group.
Rankin scale is as follows: 0-no symptoms, 1-no significant disability despite symptoms; 2-slight disability, unable to carry out past activities but w/o assistance; 3-moderate disability, walk w/o assistance; 4-moderate severe disability, unable to walk or attend bodily needs w/o assistance; 5-severe disability, bedridden, incontinent, constant nursing care; 6-dead
As an aside, I see many patients in my ICU with >4 on the scale and it’s very difficult to manage for a family — the constant need for care and observation seems endless and the quality of life suffers tremendously.
24% of patients in cooling arm had more arrhythmias resulting in hemodynamic compromise vs 17% in 37.5C group.
66% in cooling had to be paralyzed vs 45%. Paralytics are also not the most favorable thing to use. And cooled patients had almost an additional day of mechanical ventilation than normothermic patients.
So that being said, there is not much evidence that inducing body to 33C vs maintaining normothermia provides any changes in terms of living and preserving neurological/physical functional ability. And there’s data that shows cooling to 33C causes more harm too. This was a large trial as well with around 1800 patients!
Some critics of the trial who standby hypothermia might argue that if time to cooling was faster, it may work (but looking at graphs that compare TTM2 to “positive cooling trials” like HYPERION and HACA (hypothermia after cardiac arrest).
There is always a discussion brought up in my ICU group though about type of cardiac arrest PTA. 79% of the arrests were shockable rhythms (VF, pulseless VT), 12% were asystole, 8% were PEA. I have to follow up with them why they were discussing that.
The HACA trial (mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest) concluded that cooling from 32–34C showed improved neurological outcomes and mortality benefits in patients who suffered from VF (41% vs 55%). Timeline matters though as this was published in 2001. 137 patients were enrolled — not a lot. A limitation to this trial was that a lot patients who were in the control group of normothermia developed fevers as shown in the T-graph below (taken from NEJM HACA paper).
The HYPERION trial published in 2019 by Lascarrou, et al had 584 patients who suffered from non-shockable rhythms and showed that cooling to 33C had a favorable neurological outcome compared to normothermia using CPC. But similarly to HACA trial, a number of patients in the control group had fevers >38C as well (>5%) — there was 294 patients in the control group. I don’t know if this is statistically important or not.
Anyhow, my institution currently utilizing cooling to 33C. I wonder when that will change. Trials pop up here and there so I think it’s prudent not to change things too quickly. TTM 3 should aim to question whether avoidance of fevers 37.7C is crucial to neurological and mortality benefits. But it seems like the direction is heading towards not cooling as these methodical trials are being designed better and better.
Dk
