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July 30, 2015

Intensive Care Medicine journal

Review of a randomised controlled trial


For decades, improving survival following out-of-hospital cardiac arrest (OOHCA) has been the target of many experimental studies. However, recently the focus has shifted from just ‘survival’ to ‘survival with favourable neurological recovery’, with hypothermia being proposed in international guidelines [1] as a neuroprotective mechanism. Contrary to these recommendations, a recent study by Nielsen et al [2] did not show any benefit from a targeted temperature of 33°C in mortality and neurological function at 6 months post Intensive Care Unit (ICU) discharge. However, as stated by the authors, the scales assessing neurological function (the Cerebral Performance Category/CPC and the modified Rankin scale/mRS) are crude ones and not designed to detect mild cognitive impairment.  

The study by Cronberg et al. in this June’s JAMA Neurology [3] attempts to shed light on the obscure area of neurological recovery post OOHCA. They report data from the original Targeted Temperature Management (TTM) trial [2], a multicentre, international, parallel group, randomised clinical trial comparing two strict target temperature regimens of 33°C and 36°C. Using the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE) and the Mini-Mental State Examination (MMSE) to evaluate cognition, the Medical Outcomes Study 36-item Short Form Health Survey (SF-36) to measure health-related quality of life, and two simple questions to assess daily function and normal recovery, they concluded that there are no differences between patients receiving TTM at 33°C vs. 36°C. Even though 90% of the survivors returned home and about two-thirds of them reported having made a complete mental recovery, more than 50% of the patients’ relatives or close acquaintances noted some level of cognitive decline, with less than 50% being able to return to their previous state of employment.


One of the study’s strengths is that it tries to address the pertinent question of quality of life after OOHCA, using a robust protocol and a pre-specified analysis plan in order to avoid outcome reporting bias and data-driven results. More than 90% of the patients that were alive at follow-up participated in the structured examination; a noteworthy rate. Acknowledging the absence of a generally accepted neuropsychological test for the assessment of these patients, the authors used ‘a novel approach’ by combining performance outcome, observer-reported and patient-reported measures, in an attempt to increase the sensitivity of the assessment and have elucidated very interesting information as a result.


Although pre-specified in the initial analysis of the TTM trial, the reported study outcomes are a result of a post-hoc analysis. As such, they are exploratory and hypothesis-generating only, since the trial wasn’t powered to detect the differences in cognitive outcomes, quality of life and daily function that it reported. Another reason necessitating caution in the interpretation of the trial’s results is the inherent problem with blinding the body temperature during the patient’s ICU stay. Even though the researchers tried to minimise the risk of bias by blinding the outcome, the administrators and the statisticians, there is always the risk that the patients could have been made aware of the information, a fact that could have influenced their answers. Lastly, as pointed out in the article, the CPC has poor discriminatory value despite its’ wide use, the IQCODE hasn’t been validated in this population and the MMSE is insensitive for the detection of mild cognitive impairment. This notwithstanding, the authors’ combination of the tests has highlighted very interesting differences between what it is reported by patients and observers, that had not previously been detected by standard outcome scales.


This is a well-designed study that attempts to answer a very important question. Even if the results reported need to be interpreted with caution, lower temperatures didn’t seem to translate to better cognitive outcomes, and although cognitive changes are common, the overall 6-month outcome of OOHCA patients who survive at hospital discharge is quite good.

This article review was submitted by ESICM Journal Review Club member Victoria Metaxa on behalf of the Ethics section.


1.    Nolan JP et al. Advancement Life support Task Force of the International Liaison committee on Resuscitation. Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation. Resuscitation 2003; 57:231-5
2.    Nielsen N et al. TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013; 369:2197-206
3.    Cronberg T et al. TTM Trial Investigators. Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C vs 36°C After Out-of-Hospital Cardiac Arrest: A Randomised Clinical Trial. JAMA Neurology 2015; 72:634-41

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