30th May 2014 The TTM Trial

Presented by Dr Andrew Taylor

Clinical trials which show a benefit from a simple treatment are rare. When two trials in 2002 demonstrated that therapeutic hypothermia (TH) improved outcomes in patients following out of hospital cardiac arrest (OOHCA) the practice was adopted rapidly. These trials, one conducted in Melbourne and one in Europe, exhibited methodological flaws but led to the inclusion of TH in most of the resuscitation guidelines and a recommendation by the Cochrane Group. Furthermore, the basic science of how TH protects the brain was investigated and the use of TH in similar systems, for example pre-hospital medicine, was studied in large trials (The SkepticalEM blog gives an interesting perspective on some of these studies).

As soon the TTM trial was published it led to a reversal of  opinion about the benefit of TH in the treatment of patients following OOHCA and has probably resulted in more editorials, comments, blog posts, and podcasts than any other paper published in intensive care medicine. Some of the more comprehensive and interesting ones are included below. This trial addressed many, if not all, of the methodological flaws of the previous studies and also, importantly, described a clear prognosis and withdrawal algorithm, consistently lacking in previous studies.

This paper clearly has important implications for the management of OOHCA patients, and perhaps all patients with acute brain syndromes, but it does not tell us everything we need to know about temperature management during critical illness. Comment focussed on how both arms avoided pyrexia and this has become the proposed mechanism of improved outcome with TTM. It is not certain, however, that avoidance of pyrexia is the mechanism of benefit, the trial did not set out to answer this question, and the data around pyrexia and acute brain syndromes is not clear cut, have a look at this review.

In common with many other “negative” studies in ICM it forces us to ask questions about the systems in which we care for patients. Does TTM work through a biological mechanism or is the benefit simply because patients are treated within a well constructed system which reduces variations in care and decreases the number of interventions? If this is the case should we be putting more resources into working out how to develop and maintain excellent systems rather than conducting RCTs?

Social medial sources have covered every nuance of the study, Chris Nickson has summarised the trial in an all-you-need-to-know post on LITFL and an EM blog from Manchester covers TTM in a journal club format. There are also a variety of other useful blogs such as the Neuroicudoc blog and the PulmCCM blog. Scott Weingart (EMCrit) interviewed Steve Bernard after the trial was published, these play on loading so open in new windows: part 1 and part 2.

EMCrit also has its own commentary and an interview with Jon Rittenberger who authored the NEJM editorial linked above. This interview is interesting, it is probably the only serious piece of commentary which suggests that different temperatures might be right for different patients. Again, it begins on loading so opens in a new window.

The lead author in the TTM Trial, Niklas Nielsen, has also been interviewed widely:

An interview with Intensive Care Network just after the trial came out:

An interview when the study was presented at the American Stroke Association

An interview with the European Heart Association

Next week we will be discussing stroke mortality and hypoxia.