August 30, 2017


EJRC Article review

In cardiac arrest management there are a series of targets and recommendations following the chain of survival to ensure the best clinical results. Among these is the restoration of spontaneous circulation and, more importantly, good neurological outcome. One measure to achieve the latter is to include therapeutic hypothermia or  targeted temperature management (TTM) in the initial treatment strategy. The current resuscitation guidelines recommend a target temperature of between 33-36°C for at least 24 hours [1,2].

Have you ever considered why 24 hours is the target duration? If the targeted temperature remained at at 33ºC for 48 hours, could it be better than 24 hours at the same targeted temperature? Fortunately, a group of investigators also asked this question and carried out a randomised clinical trial (RCT).

Aim & Methods

The Time-differentiated Therapeutic Hypothermia trial (TTH48) was an investigator-initiated, blinded-outcome-assessor, RCT conducted in 10 European ICUs and 6 European countries [3]. In this RCT, 48-hour TTM at 33°C was compared with standard 24-hour TTM in comatose patients admitted to the ICU after an out-of-hospital cardiac arrest of presumed cardiac origin. A total of 355 patients were enrolled and randomised to TTM (33±1°C) for 48-hours(n=176) or 24-hour (n = 179), from February 2013, to June 2016.


The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, and the occurrence of adverse events. More patients in the 48-hour group had a favourable outcome (69% vs 64%), but this was not statistically significant (absolute difference, 4.9%; RR, 1.08; 95% CI, 0.93-1.25; P = .33), the mortality at six-months was 27% in the 48-hour group and 34% in the 24-hour group (difference, −6.5%; RR, 0.81; 95% CI, 0.59-1.11; P = .19) Adverse events were more common in the 48-hour group (97%) than in the 24-hour group (91%), Nevertheless, most of them were mild and did not appear to affect neurologic outcome. The median ICU length of stay was longer in the 48-hour than in the 24-hour group (151 hours vs 117 hours; P < .001), but there was no significant difference in hospital length of stay.

Discussion Points

After reading this article it is hard not to think that we have once again fallen into the pit of those RCT with inconsistent or inconclusive results, which is becoming more frequent when carrying out RCT in the critical care setting. But why were these results not what we expected? Perhaps the answer has been solved by the authors themselves, as they proposed an 80% power to show an absolute difference of 15%, and initially a sample size of 338 patients was calculated, which may have increased the risk of a type II error, and added to the reasons for these negative results. There are also some issues directly related with the intervention and its effectivity, including timing of this, using the wrong end point, and perhaps a bad selection of population [4].


Does this mean that we have not been doing things right or simply that we have not asked the right question? This study has shown us that despite obtaining a statistically significant result, we have improved the quality of care of patients with cardiac arrest as the over-all survival rate and proportion of patients with good neurologic outcome at 6 months were higher than in previous TTM studies, and higher than anticipated with sample size calculation.

Article review prepared and submitted by EJRC member Aaron Blandino Ortiz, Intensive Care Medicine, Ramón y Cajal University Hospital, Madrid, Spain.


1-    Callaway CW, Donnino MW, Fink EL, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18) (suppl 2):S465-S482.
2-    Donnino MW, Andersen LW, Berg KM, et al; ILCOR ALS Task Force. Temperature management after cardiac arrest: an advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Circulation. 2015;132(25):2448-2456.
3-    Kirkegaard H, Søreide E, de Haas I, Pettilä V, Taccone FS, Arus U, Storm C, Hassager C, Nielsen JF, Sørensen CA, Ilkjær S, Jeppesen AN, Grejs AM, Duez CHV, Hjort J, Larsen AI, Toome V, Tiainen M, Hästbacka J, Laitio T, Skrifvars MB. Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial. JAMA. 2017;318(4):341–350. doi:10.1001/jama.2017.8978
4-    Vincent JL. We should abandon randomized controlled trials in the intensive care unit. Crit Care Med. 2010;38:S534–S538.

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