Targeted temperature management, sometimes conflated with therapeutic hypothermia, is part of modern resuscitation guidelines in post-arrest care. There are, however, many aspects of this therapy for which the details remain hazy, including: how long? 24 hours? 48 hours? Or, as in neonates, 72 hours?
This is the “Time-Differentiated Therapeutic Hypothermia” trial, a randomized, single-blind comparison between TTM – in this case, TH at 33°C – treatment for 24 hours versus 48 hours following resuscitation from cardiac arrest. These authors randomized 355 eligible survivors to ICU admission into two generally similar arms, most of whom received their assigned treatment without protocol violations. A great deal of data on survival, adverse events, and other secondary features are presented, and the short of it is: probably no difference. Similar proportions of patients in each arm had cerebral performance scores of 1 or 2 at six months, which was the primary outcome. Mortality at six months was also similar, as was, generally speaking, adverse events. Confidence intervals, however, were quite wide – for example, the relative risk for CPC 1 or 2 was 1.08 with 95% CI of 0.93 to 1.25, the top end of which represents a fairly meaningful difference. However, given the Bayesian pre-test likelihood of such an advantage, the null hypothesis is the clear winner. One clear loser: ICU length-of-stay, and by association, healthcare costs, which will obviously favor the group with a shorter period of TTM.
Some comments on Twitter were overjoyed at six-month survival figures approaching 70% as indicative of advances in post-arrest care. Unfortunately, these are more reflective of their exclusion criteria – which entailed non-cardiac causes of arrest, asystole rhythms, vasopressor-resistant shock, extended pre-ROSC resuscitation times, and a host of other items representing dire prognoses. These are the “best of the best”, which is reasonable to try and reduce heterogeneity and other random effects on outcome measures.
Lastly, it is reasonable to note one of the elements of causality generally entails a dose-response relationship, in which the magnitude of exposure to a beneficial therapy relates in some fashion a continuum of outcomes. Lacking such an apparent relationship, as in this trial, does not refute an association between TTM/TH and improved outcomes, but certainly continues to raise points regarding the precise elements of post-arrest care resulting in improved outcomes. Cooling to 33°C does not appear to confer an advantage to 36°C, nor does an extended exposure to the treatment. What is it really, then, that helps achieve the greater proportion of CPC 1 and 2 survivors?
“Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest”