Readers of this blog may know that I harbor measured skepticism for HACA even though I recognize that it may be beneficial. From a pragmatic perspective, it makes sense to use it, since the outcome of hypoxic-ischemic encephalopathy (HIE) and ABI (Anoxic Brain Injury) is so dismal. But what did the original two studies actually show?
- The HACA group multicenter trial randomized 273 patients to hypothermia versus control and found that the hypothermia group had higher rates of "favorable neurological outcome" (a cerebral performance category of 1 or 2 - the primary endpoint) with RR of 1.40 and 95% CI 1.08-1.81; moreover, mortality was lower in the hypothermia group, with RR 0.74 and 95% CI 0.58-0.95
- The Bernard et al study randomized 77 patients to hypothermia versus control and found that survival (the primary outcome) was 49% and 26% in the hypothermia and control groups, respectively, with P=0.046
So it was welcome news today when the results of the Targeted Temperature Management study were published on-line in the NEJM, to help us determine if we have been on the right track or not since 2002. Reasoning that, among other considerations, fever after cardiac arrest is associated with a poor prognosis (but is it causal or an association?), it may have been the prevention/treatment of fever in the 2002 studies that drove their findings, the TTM investigators randomized 950 patients who were unconscious after OOH cardiac arrest to a target temperature of 33 degrees versus 36 degrees.
The first concern I had, before even reading the results, is that we may have a problem of separation here. If there is an effect of temperature on outcomes, it is reasonable to expect that the greater the difference in temperature between the groups, the greater will be the difference in outcomes (and the more likely we will find a statistically significant result). In the original trials, the hypothermia target was 32-34 degrees, but in the control group, the sky was the limit - they could be normothermic at 37 degrees or higher if some of the cohort was febrile some of the time. Now we're restricting our separation to 3 degrees. This could make it harder to show a significant result.
Another problem is that the TTM trial enrolled all patients with OOH cardiac arrest of presumed cardiac cause, not just patients with VT of VF. I have never actually seen explicated why the 2002 trials excluded cardiac rhythms other than VT and VF but I always assumed it was because the prognosis is so dreadfully poor with other rhythms that their inclusion would just dilute the sample with patients in whom there was little hope of a treatment effect, thus reducing effective sample size. In the TTM trial, 20% of patients had rhythms other than VT of VF, so the effective sample size may have been 20% lower.
In TTM, the mortality (primary endpoint) was 50% in the 33 degree group and 48% in the 36 degree group with P=0.51. At 180 days, the endpoint of death or poor neurological function had been met in 54% of the 33 degree patients and 52% in the 36 degree patients with P=0.78. There are several ways of looking at these results. Below is a logic matrix of sorts with the main possibilities:
- there is a dose-response relationship for HACA; treating the control group to 36 degrees reduced separation (difference between study groups was approximately 3 degrees during intervention period based on Figure 1 in the article) and led to a negative result; targeting a temperature lower than 33 degrees or higher than 36 degrees or both would have increased separation and allowed for a positive result (original HACA study group separation 4.5 degrees and Bernard et al group separation 4 degrees)
- 36 degrees is the floor for the net beneficial effect of hypothermia (for whatever reason); further reductions in temperature do not confer additional net benefit
- TTM was underpowered (Type II error)
- The 2002 results represent Type I errors or bias due to study shortcomings