Therapeutic Hypothermia after Cardiac Arrest (Peri-TTM)

Therapeutic Hypothermia Post-Cardiac Arrest (Peri-TTM)

An elderly man was resuscitated from out-of-hospital VF cardiac arrest. He remained deeply comatose post ROSC and was ventilated on the intensive care. His temperature control was not actively managed unless hyperthermia developed. 24 hours post admission he started to have myoclonic jerks and his pupils were fixed and dilated. CT brain showed evidence of severe hypoxic ischaemic injury. Treatment was withdrawn at 72 hours after discussion with family.

What is the rationale for the use of therapeutic hypothermia after cardiac arrest?

Prad Shanmugasundaram


Therapeutic hypothermia after cardiac arrest has been under investigation for decades. However, two randomised controlled trials published in 2002 probably acted as the main trigger for the subsequent changes that have taken place.

The HACA study was a multicentre randomised controlled trial of patients suffering out-of-hospital VF arrest (1). Patients in the intervention arm were cooled to 32-34oC over 4 hours for a period of 24 hours, and then rewarmed over 8 hours. Normothermia was the aim for patients in the control arm. The primary outcome was a favourable neurological outcome within 6 months, with secondary end-points of mortality at 6 months and complications in the first week post cardiac arrest. The outcome assessors were blinded with respect to the treatments received. The results showed that 75/136 (55%) of patients in the treatment arm had a favourable neurological outcome compared to 54/137 (39%) in the control group: risk ratio 1.4, 95% confidence intervals 1.08-1.81. Mortality was also reduced in the treatment group: 56/137 (41%) versus 76/138 (55%) giving a RR 0.74 (95% CI 0.58-0.95). This implied a number needed to treat of 6 to prevent one unfavourable neurological outcome. The main criticism of this study was that the temperatures observed in the control group was not normothermia, in fact, these patients developed temperatures in excess of 37oC within 8 hours and remained so until 48 hours later (no further temperature measurements shown).

In the same issue of the New England Journal, Bernard et al. reported the results of a pseudorandomised controlled trial of moderate hypothermia in comatose survivors of out-of-hospital cardiac arrest (2). The intervention group was cooled to 33oC within 2 hours of ROSC for a period of 12 hours versus normothermia. Primary outcome neurological recovery at hospital discharge: home or rehabilitation facility (good outcome) vs nursing home or death (bad outcome). Their results showed that 21/43 (49%) patients in the hypothermia arm had a good outcome versus 9/34 (26%) patients in the normothermia arm (p=0.046). The main criticisms levelled at this study was a lack of blinding, and that the method of randomisation used for enrolment used odd versus even numbered days. The investigators cited difficulties with pre-hospital randomisation by large numbers of ambulance and emergency department staff. This introduced a opportunity for bias, although the investigators note that this seems unlikely given the similarity between the groups.

In response to the results of these two trials the International Liaison Committee on Resuscitation (ILCOR) produced an advisory statement recommending the use of therapeutic hypothermia in adults after out-of-hospital VF arrest (3). They also made the statement that ‘such cooling may also be beneficial for other rhythms or in-hospital cardiac arrests’ despite there being no high-quality evidence to support this recommendation.

The Resuscitation Council (UK) updated their Advanced Life Support guidelines in 2005 to include a similar recommendation in favour of cooling after VF arrest (4), as did the Australian Resuscitation Council in 2006 (5) and the American Heart Association in 2010 (6). NICE took this a step further in March 2011 issuing Interventional procedure guidance 386 recommending therapeutic hypothermia for patients after cardiac arrest from any cause. Surprisingly this was despite no new high-quality randomised controlled trials that showed a benefit in favour of cooling for non-VF cardiac arrest.

A Cochrane review of 481 patients reported a significantly higher proportion of patients in the hypothermia group survived to hospital discharge and had better neurological outcomes compared to patients receiving standard care (7). However, because of the quality of the studies included in the review an overestimation of the treatment effect may have occurred. Another systematic review of the same trials with more rigorous evaluation of the quality of evidence (using GRADE-methodology) found that the evidence regarding therapeutic hypothermia after out-of-hospital cardiac arrest was inconclusive and that clinical equipoise exists (8).

Despite a dearth of new randomised controlled trials, a retrospective, registry-based observational study does provide some further evidence in favour of the benefit of induced hypothermia. These investigators were able to look at the outcomes of 1547 patients before introduction of therapeutic hypothermia, and 3770 patients after implementation of therapeutic hypothermia using the Dutch National Intensive Care Evaluation database (9). They found a 20% relative reduction of hospital mortality in cardiac arrest patients (95% confidence interval 0.65-0.98) after the introduction of therapeutic hypothermia. Encouragingly, this study included cardiac arrest from all rhythms and occurring in- or out-of-hospital.

Most recently, the international multicentre ‘Target Temperature Management after Cardiac Arrest’ – TTM trial compared outcomes after cooling to 33oC versus controlled temperature maintenance at 36oC (preventing the known deleterious effect of hyperthermia) (10). This was the biggest therapeutic hypothermia trial by some distance and found no difference in outcome between the temperature groups. It is too early to say what the full impact of this trial will be, but there is now considerable doubt as to the benefit of cooling after cardiac arrest in adults.


1. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med2002;346:549-56.

2. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med2002;346:557-63.

3. Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW. Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation. Resuscitation2003;57:231-5.

4. Resuscitation Council (UK) (2005) Adult Advanced Life Support. Resuscitation guidelines 2005 Resuscitation Council UK]

5. Australian RC. (2006) Adult advanced life support: Australian Resuscitation Council Guidelines 2006. Emergency Medicine Australasia 18: 337–56

6. Peberdy MA, Callaway CW, Neumar RW et al. (2010) Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 122: Suppl. 86.

7. Arrich J, Holzer M, Herkner H et al. (2012) Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. [Review] [69 refs]. Cochrane Database of Systematic Reviews CD004128

8. Nielsen N, Friberg H, Gluud C, Herlitz J, Wetterslev J. Hypothermia after cardiac arrest should be further evaluated: a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol2011;151:333-41.

9. Van der Wal G, Brinkman S, Bisschops LL, Hoedemaekers CW, van der Hoeven JG, de Lange DW, et al. Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality. Crit Care Med2011;39:84-8

10. TTM Trial Investigators. Target temperature management after out-of-hospital cardiac arrest.


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