A 55 year old presented to ED following a witnessed VF arrest. He received bystander CPR and several shocks from the ambulance crew. He was intubated at the scene, and transferred to ED with return of spontaneous circulation. He had primary PCI to LAD and was transferred to the ICU for therapeutic hypothermia. He was kept at 33 degrees for 24 hours, and rewarmed over 8 hours. He extubated 2 days late with no cognitive impairment, and mild weakness in one arm.

What is the evidence for and against Targeted Temperature Management (TTM) post cardiac arrest?

Sam Clark

Patients, who have suffered out of hospital cardiac arrest and who remain unconscious despite ROSC remain at high risk of death and severe neurological impairment(1). It has been postulated that a lack of cerebral blood flow leading to the development of free radicals and other cytokine mediators result in a reperfusion to the ischaemic tissue and subsequent neurological impairment(2). Evidence from dogs suggested that mild hypothermia might be of some benefit in the management of this significant problem(3).

This led to two seminal papers that both were prospective randomised control trials investigating the effects of induced hypothermia on out of hospital cardiac arrest patients. Both these studies demonstrated both a reduction in mortality and an improved neurological benefit(4,5).

Holzer et al performed a multicentred study across 9 centres in 5 European countries for patients who had been resuscitated after cardiac arrest due to ventricular fibrillation(4). They randomized 273 patients to either TTM with a bladder temperature of 32-34oC as rapidly as possible, maintained for a period of 24 hours prior to rewarming or no specific temperature control in the normothermia group. The results demonstrated a 14% drop in mortality at six months and 16% increase in favourable neurological outcomes for the hypothermia group compared to the control group (risk ratio 0.74 ; CI 0.58-0.95 and risk ratio 1.40; 1.08-1.81, respectively). Bernard et al’s Australian four centred study conducted at the same time demonstrated similar results in further 77 patients(5). This time patients were randomized by day of the month to either a mild hypothermia group cooled in the field to 32-34oC for 12 hours prior rewarming or a normothermia group. In addition to this both groups received intravenous thrombolysis if their post ROSC ECG suggested acute myocardial infarction. They found that 49% of the hypothermia group survived and had a good neurological outcome as opposed to on 23% percent of the control group (odds ratio 5.25; CI 1.47-18.76).

This combined with a further 40 non-randomised trials suggesting improved outcomes with TTM(6); patient registries from the Netherlands(7) (over 5,000 patients, which showed 6.6% reduction in mortality) and Scandinavia(8) (986 patients reported 61% survival in witnessed VF/VT arrests and 92% of those with good neurological outcome); and finally, a meta-analysis demonstrated a number needed to treat to prevent one death of seven and of six for a good neurological outcome(9) led to changing of International Resuscitation Guidelines to include TTM for witnessed out of hospital VF/VT arrests. A Cochrane review and its subsequent update reinforced these findings(10).

However, TTM to 33oC was not without its critics, who suggested that there was a (non significant) trend towards severe sepsis in the treatment groups in both trials and, that in one of the studies(4), there was high degree of fever in the control group. Fever has been associated with a poor outcome and therefore it has been questioned whether the beneficial effects of cooling to 33oC were responsible the improvement in the two groups or the deleterious effects of the fevers were to blame. This criticism lead to the study that become known as TTM(11), a multi-centered RCT comparing Targeted Temperature Management at 33oC versus 36oC after Cardiac arrest. It involved 36 ICUs in Europe and Australia using a modified intention to treat analysis. 950 patients were enrolled and 939 were included in the primary analysis. Inclusion criteria included all out of hospital cardiac arrests with a sustained ROSC for 20 minutes and GCS<8 despite ROSC. Both groups were cooled to their targets, maintained for 36 hours and then re warmed at 0.25oC per hour. Additionally, fever was actively managed for 72 hours. The results showed no difference in mortality with 50% of T33 and 48% of T36 (hazard ratio 1.06; CI 0.89-1.28, p=0.51). There was also no difference in neurological outcomes 54% of T33 either died or had a poor neurological outcome compared to 52% of T36 (RR= 1.02, CI 0.88 to 1.16). Severe adverse effects were common in both groups, but there was a trend for this to be marginally higher in the T33 group (93% vs 90%, p=0.09).

The findings of TTM have resulted in a sea change in the management of patients post cardiac arrest. There has been a shift away from cooling to 33oC with some units avoiding fever and others cooling to 36oC. However, there have been criticism of this change including Australian Resuscitation Council, who suggested caution in their statement from December 2013. Critics attacked the rate of rewarming, and a suggestion that T36 group patients had better profiles (more shockable rhythms and more bystander CPR) (12). However, possibly the most important points made post TTM are that: both groups used active temperature management and not normothermia avoiding fevers; at the time of TTM, cooling to 33oC was considered best practice in ICU and TTM showed no advantage over that best practice; though the TTM trial is the largest trial thus far, it was designed for a reasonably substantial effect size and differences in cooling to 33oC to 36oC is likely to a small effect and therefore difficult to prove any superiority without unrealistically large sample sizes.

Finally, there has been interest in the idea of cooling in the prehospital setting, however, Kim et al (13) demonstrated no advantage to prehospital cooling compared to standard regimes in 1369 patients. Though it is notable that the standard regime for VF/VT included cooling to 33oC on arrival at their destination hospital. Further trials on cooling are still ongoing.

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References:

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4) Hypothermia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002, 346:549-556.
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