Therapeutic hypothermia: Not so hot for cerebral protection after cardiac arrest or traumatic brain injury
The role of therapeutic hypothermia in the management of traumatic brain injury and cardiac arrest has been called into question. Mehnaz Khan and Simon Stacey review the evidence of recent trials to determine what can be perceived as best practice.
Therapeutic hypothermia (TH) has played a major role in the management of out-of-hospital cardiac arrest (OOHCA) and often in-hospital cardiac arrest following seminal publications in the New England Journal of Medicine which led to its incorporation into the ESC guidelines in 2002 [1,2]. Similarly, TH has been a part of the recommendations issued by the Brain Trauma Foundation (BTF) for the management of traumatic brain injury (TBI) since 2007 [3]; however, since then, a systematic review published in the British Journal of Anaesthesia in 2013 [4], did not support these recommendations, and now the role of TH in the management of cardiac arrests has also come into question. In this review we look at the evidence of previous and more recent trials in order to determine what can currently be perceived as best practice.
The theory
It is clear how, theoretically, TH may benefit patients following cardiac arrest, despite its significant negative physiological effects. The use of induced hypothermia can be traced as far back as 1937 when patients were cooled in an attempt to alleviate symptoms of metastatic cancer. It has routinely been used for a number of years in certain cardiothoracic surgical procedures, and recently some neurosurgical procedures. Physiologically, hypothermia reduces the metabolic rate such that a one degree Celcius drop in core temperature is thought to decrease cerebral metabolic rate by 6–7%. As a result of this, the cerebral blood flow, and therefore (potentially) intracranial pressure (ICP) are also reduced. Due to improved regional cerebral perfusion, it is also thought that ischaemic areas are better perfused, and there may be some anticonvulsant effects of this therapy. At a molecular level, it is thought that there is suppression of a number of chemical actions associated with reperfusion injury, such as excitatory amino acid production, free radical release and calcium shifts causing mitochondrial damage [5].
In TBI, animal models have pointed to multiple pathways involved in neuronal injury which may be influenced by the use of TH positively [4].
Evidence leading to previous guidelines
In 2002 the advanced life support task force (ALS) of the internal liaison committee on resuscitation (ILCOR) recommended that unconscious adults with a ROSC following OOHCA should be cooled to 32–34°C for 12–24 hours post VF arrest. In 2010, the same group went further, suggesting that primary therapeutic hypothermia (PTH) may be useful in initial non-shockable rhythms also [5]. These guidelines largely followed two major trials published in the New England Journal of Medicine in 2002. The first was a multicentre European trial with 273 patients with OOHCA due to ventricular fibrillation (VF) or ventricular tachycardia (VT) [1]. They found improved survival in 59% of patients at six months, compared with 45% after standard care, as well as more favourable neurologic outcome (55% vs 39%). The second trial was smaller, with only 77 patients from four hospitals in Melbourne, Australia [2]. In this trial, they looked at survival to hospital discharge with good neurologic outcome, and found that 49% in the hypothermia group had a good outcome, compared with 26% of the non-hypothermia group. It is worth noting that the particular recommended range of 32–34°C used in both trials has been extrapolated from experiments in animals.
Similarly, following the results of animal models of TBI as well as a number of clinical trials, the BTF issued a level III recommendation for the use of PTH in TBI management in 2007 [3]. Between 2000 and 2007, three trials followed up patients for over 12 months and found the benefit of PTH on neurological outcome. Ten very different trials over the period of 1993–2007 found reduction in ICP associated with PTH (adults and children). Of these, two found improvement in mortality and six in neurologic morbidity.
What’s changed? Current evidence
A recent trial published in the New England Journal of Medicine in December 2013, was conducted looking at 939 patients who had an out-of-hospital cardiac arrest (between November 2010 and January 2013), and received targeted temperature management of either 33°C or 36°C. Results showed no difference in mortality rates in either group, or even any difference in neurologic function at the 180 day follow-up (evaluated by the cerebral performance category scale and modified Rankin scale) [6]. Not only was there no statistical significance, there wasn’t even a non-statistical trend that might suggest inadequate power of the study to detect a difference. This particular randomised controlled trial (RCT) recruited patients from 36 ICUs in Europe and Australia, and the targeted temperature management period was 36 hours from randomisation, with gradual re-warming from 28 hours. Following the intervention period, temperature was still maintained at below 37.5°C until 72 hours post-arrest. This factor may have been the key difference between the previous and current trials. Neurologic evaluat