SGEM#336: You Can’t Always Get What You Want – TTM2 Trial

Date: July 1st, 2021 Guest Skeptic: Dr. Justin Morgenstern is an emergency physician and the creator of the #FOAMed project called First10EM.com. Reference: Dankiewicz et al: TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. NEJM 2021 Case: A 58-year-old man collapsed in front of his family. When paramedics arrived, they found him to be in cardiac arrest, with ventricular fibrillation on the monitor. Paramedics managed to get return of spontaneous circulation after a single defibrillation, but the patient is still comatose on arrival. The charge nurse turns to you and asks: should I grab the ice packs? Background: Hypothermia has been a mainstay of post-arrest care after the publication of two trials in 2002 that both suggested a benefit. This trial by Bernard and colleagues randomized 77 patients with an initial cardiac rhythm of ventricular fibrillation who had achieved return of spontaneous circulation (ROSC) but were persistently comatose. The trial was not truly randomized, as the groups were based on the day of the month, and they also weren’t blinded. The results of this Australian trial seemed too good to be true. Hypothermia resulted in a large improvement in neurologic outcomes, defined as well enough to be sent home or to a rehab facility. It was 49% of the hypothermia group versus only 26% of the normothermia group. This gives a NNT of 4. The reported p value was borderline at 0.046, and when I re-calculate, it comes out as 0.06 (not statistically significant). The other trial was the Hypothermia After Cardiac Arrest (HACA), also published in NEJM 2002. They randomized 273 comatose adult patients out of 3,551 screened patients. These were witnessed OHCA who had a shockable rhythm, achieved ROSC, and had a short downtime. This trial used an air mattress to cool patients and was also not blinded. This second trial done in Europe also showed impressive results for favorable neurologic outcome. It was 55% in the hypothermia group vs 39% in the normothermia group (NNT 6). They also reported a 14% absolute decrease in mortality with therapeutic hypothermia post-OHCA. As a result of these two-small trials, hypothermia was widely adopted. However, there were many voices in the evidence-based medicine world that reminded us of the significant uncertainty that remained, and the weaknesses of these two trials. The SGEM covered a few  trials looking at therapeutic hypothermia for OCHA in the pre-hospital setting. The bottom line is there is not good evidence that therapeutic hypothermia is superior to usual care and cannot be recommended. SGEM#21: Ice, Ice, Baby (Hypothermia post Cardiac Arrest) SGEM#54: Baby It’s Cold Outside (Pre-Hospital Therapeutic Hypothermia in Out of Hospital Cardiac Arrest) SGEM#183: Don’t RINSE, Don’t Repeat Because of that uncertainty, a much larger, multi-center trial was run. This is the original Target Temperature Management (TTM) trial by Nielson et al NEJM 2013. As almost everyone knows, they compared two difference hypothermia targets, 33C and 36C. The result was no benefit for their primary outcome of mortality at the end of the trial and no benefit Cerebral Performance Category (CPC), modified Rankin Score (mRS) or mortality at 180 days. We did a structured critical appraisal of the TTM trial on SGEM#82. The bottom line was that the trial did not demonstrate a benefit of a targeted temperature of 33C vs. 36C for survival of OHCAs. But both groups in the TTM trial were hypothermic, so although it was the highest quality evidence available, it didn’t tell us whether hypothermia was any better than normothermia. Which is why the TTM2 trial was performed. Clinical Question: Does hypothermia result in improved survival after cardiac arrest as compared to controlled normothermia? Reference: Dankiewicz et al: TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Car...