Thread by @stephanamayer

1/ So now it's the cataclysmic TTM -2 trial, just published in @NEJM. How can a world changing trial like HACA published in 2002 now be effectively reversed almost 20 years later? I will explain.

nejm.org/doi/full/10.10…

2/ Lots of head scratching. Hard to understand. But I am not surprised. It's a pattern that we have seen before with goal directed therapy for sepsis and intensive insulin therapy for hyperglycemia. The answer is that a trial's results depend very much on the clinical milieu

3/ When Manny Rivers published his EGDT classic in the @nejm in 2001, the milieu was bad sepsis therapy. The control group was neglected, under-resuscitated, anemic nursing home patients. I remember these shocky patients in the in ER those days, waiting for hours for an ICU bed.

4/ By the time Derek Angus countered with PROCESS and finally PRISM in 2017, supposedly disproving that EGDT works, the world had changed. The isolated study intervention was now being applied in a world where everyone was much more cognizant of fluid resuscitation in sepsis.

5/ So the world was a better place because of Rivers. The milieu had much improved and sepsis protocols were everywhere. In that setting the randomized intervention "no longer works." But actually Manny Rivers won, because he changed the world.

6/ In 2001 Van den Berghe published her @nejm classic on IIT, targeting glucose levels of 80-110 mg/dl, with a shocking mortality reduction. The control group got q6H insulin IVP. In those days, looking at BG levels of 300 mg/dl was fine, and insulin drips were only for DKA

7/ .So new trials started to repeat the experiment. Except the milieu had changed, because using insulin drips for non-ketotic patients had normalized. The nurses stopped pushing back, and every hospital had an updated IIT protocols.

8/ in 2009 NICE-SUGAR "disproved" that it was necessary to achieve true normoglycemia. But by that point all patients were on insulin drips and we were comparing higher versus lower targets. Van den Bergh won, because she changed the world and proved the folly of q6H coverage.

9/ So now comes TTM-2. When the groundbreaking HACA trial was published in 2002 the milieu for OHCA patients was worse than terrible. This was untreatable, no one could even imagine recovery, advanced support was withheld, and we actively pushed families to withdraw.

10/ How the world has changed. Survival with good recovery after OHCA has been improving over the past 20 years. The rates of good outcome in TTM-1 and TTM-2 are drastically better than the <2% survival rates from the 90's. All boats have been lifted, and the nihilism is gone.

11/ Once again, Fritz Sterz won, because he changed the world. And in this drastically changed milieu, in which we have seen recovery and fight for it, the core body temperature target in isolation doesn't matter. It's the milieu that matters.

12/ So I still will use TTM for my OHCA patients and go for mild hypothermia 36° C. And keep trying to think of another new crazy idea that might change the world.
/FIN

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