Therapeutic and Prophylactic Hypothermia for Traumatic Brain Injury

Created on Thu, 01/14/2016 - 23:18
Last updated on Thu, 11/09/2017 - 19:12

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Therapeutic and prophylactic hypothermia are effective methods of controlling number-induced panic in the depressing setting of severe traumatic brain injury. To some extent ICP is regulated by the cerebral metabolic rate, and metabolic rate is affected by temperature: ergo, with the reduction of temperature one should be able to reduce the ICP. There are also seductive theoretical benefits, suspected influence on the cellular damage, inflammation,  oxudative injury, etc. More importantly, the intensivist feels better. With control of temperature comes a reduction in the ICP, and the anxiety-provoking monitor begins to display more pleasing values. Also, the use of muscle relaxant to reduce shivering has a calming effect on the nursing staff (a paralysed sedated patient is easy to look after). However, there may be no benefit in this technique as far as patient-centered outcomes are concerned.

The specific question of therapeutic hypothermia in brain injury has never come up in the fellowship exam. Question 9 from the first paper of 2015 touched on the issue by exploring hypothermia in a broader sense   (i.e. asking the candidates "what indications can you think of for therapeutic hypothermia?") However, with the EUROTHERM 3235 trial (2015) and the recent publication of the new (2016) BTF guidelines one might expect this topic to come up.

History and evolution of this technique

Hypothermia has become very popular for the management of cardiac arrest patients, and these days it is mainly known from that context. However the use of this technique for brain injury is older. Back in the day before post-arrest hypothermia, all the injured heads ended up getting cooled. This was driven by animal studies and physiological concepts rather than anything like what we now call "Level 1 evidence". 

The first application of the techniques to humans actually pre-dated the abovementioned animal experiments. Fay (1943) published his observations on "generalised refrigeration" in severe brain injury. He cooled cooled a series of patients to as low as 28°C for 4–7 days and reported results which (in his view) were better than what he might have otherwise expected from such patients.

Detailed studies of hypothermia in brain injury followed. For instance, in 1959 Hubert Rosomoff found that mongrel dogs with brain injury survived much longer if they were cooled to 25° C for up to 18 hours. On the basis of this, Sedizmir (1959) recommended its use in brain injured humans should become more widespread. Lundberg et al (1956) were already using it for neuroprotection in neurosurgical patients (14 cases were cooled to as low as 24.8°C) and so the transition of this practice into neurotrauma seemed very reasonable.

The technique seemed to have become very popular in the 1960s, in spite of disappointing real-life efficacy. For instance, Drake and Jory (1962) presented their experience with it in 21 patients. "Six of the 12 survivors are chronic nursing problems with severe dementia", the authors complained. The others died of multiple complications, some of which can be associated with the hypothermia itself (and the rest with the grim reality of critical care in this heroic age). The authors present wonderful graphs of the patients' temperature, punctuated with significant events (eg. "tracheotomy", "talked to wife", "GI bleeding", and ultimately "DEATH"). The technique lost popularity, presumably because many others were disappointed with the results. Jennett et al (1980) described it as a passing fad in their review of management strategies.

Rationale for hypothermia in traumatic brain injury

 Most of these points have been scavenged from the excellent articles by Kees H. Polderman (2001) and Schmutzhard et al (2012). Additionally, the a priori trial protocol for Eurotherm 3235 goes into some sirgnificant detail about it. If the exam question invites one to "Critically evaluate therapeutic hypothermia", one would be expected to list a few of the points mentioned below. 

Decreased cellular injury

Decreased inflammatory response and oedema

  • Impairment of neutrophil and macrophage function should decrease the size of the injury and mitigate the oedema (Siesjö et al, 1989)
  • Decreased permeability of the blood-brain barrier, also decreasing the oedema (Fischer et al, 1999)

Decreased cerebral metabolic rate, with many benefits:

  • Decrease oxygen and glucose consumption by the oedematous brain tissue (by 6-10% per 1°C - Polderman, 2001 )
  • Decreased intracranial pressure (thus, improved perfusion of the healthy brain)

Arguments against the use of hypothermia

  • The studies exploring its benefits have been either human case series or animal data
  • The technique is not without risk (i.e. even mild hypothermia has a rate of significant complications)
  • The rate of complications is relatively high, eg. pneumonia
  • The deeper the hypothermia, the greater the risk of complications
  • Haemodynamic instability in hypothermia may decrease CPP
  • Catecholamine responsiveness is diminished at low temperature, making CPP more difficult to achieve with noradrenaline
  • Decreased platelet function may lead to expansion of conservatively managed haemorrhages or contusions

Evidence for and against hypothermia in traumatic brain injury

Pre-Eurotherm era

Georgiou et al (2013): the meta-analysis mentioned by the college in Question 9 from the first paper of 2015. Eighteen trials were found, with 1851 patients in total. There was no benefit in mortality when only high quality trial were included. A risk of pneumonia was noted among a series of six low quality trials (this is where the whole pneumonia thing comes from).

Eurotherm 3235 trial (2015):

This was probably the most interesting thing to happen in this area in recent history. Among the trial collaborators was Kees H. Polderman whose brilliant reviews of hypothermia are an excellent resource for the CICM trainee. St Emlyn's Blog has an excellent article by Dan Horner describing the trial. Anyway, the following analysis probably has some exam importance. In summary:

  • Enrolled 387 patients;
  • Hypothermia was used as a second-line therapy to reduce ICP. 
  • No survival benefit was observed.
  • Recruitment was suspended early owing to safety concerns.
  • ICP control was in fact better in the hypothermia group (they required rescue therapies less frequently) but this seems to have made no difference to mortality.

This trial may be criticised for using hypothermia as a mid-tier therapy (whereas in many places it is used as a rescue therapy for otherwise uncontrollable ICP, as an alternative to decompressive craniectomy). Stage 1 therapies for raised ICP were composed of very basic manoeuvres: elevating the head of the bed, boluses of propofol, adequate analgesia, opening the EVD and keeping a MAP of 80 mHg. Then, if these simple things failed to reduce the ICP, they graduated to Stage 2 and the Eurothermians either started cooling them or use some sort of osmotherapy (for the non-hypothermia group). Barbiturates and decompressive craniectomy were reserved for refractory cases as Stage 3 therapies. This differs from local practice, and some might argue that hypothermia belongs alongside decompressive craniectomy as a last ditch measure. In their response to such criticism, the Eurotherm authors pointed out that it is implausible to expect a mortality benefit from hypothermia when it is used in super-severe cases after all other therapies had failed

Moreover, the trial power calculation yielded 1800 patients, which was reduced to 600 (somehow preserving the same power) but they only ended up enrolling 387 patients before the trial was terminated ("futility", etc). The enrolled patients ended up being cooled late (on average, 12 hours late) and were given 2000ml of cold saline (which probably did not help the brain oedema).

The trial was terminated early "after the steering committee concluded that there were signs of harm with the treatment being evaluated"; there was an almost 10% difference (25.7% vs 36.5%) in disability outcome, and risk of death strongly favoured the control group (OR was 1.45). 

Post-Eurotherm era

POLAR-RCT (awaited): ANZICS plan to entrol about 500 patients and cool half of them to 33 C for three days. The rewarming will be titrated to ICP control (i.e. if their ICP increases, the rewarming stops and cooling is reintroduced). The plan is to finish data collection in 2017.

Society recommendations

The Brain Trauma Foundation does not recommend prophylactic hypothermia. The main reason for their doing so is not safety or futility concerns; instead it seems all the good-quality studies about this intervention have clinically significant differences in the way they use hypothermia, which makes it difficult to perform a meta-analysis (and the BTF people in fact gave up on trying to meta-analyse them). Until better data are available, the BTF has cooled towards hypothermia.



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Rosomoff, Hubert L. "Experimental Brain Injury During Hypothermia*." Journal of neurosurgery 16.2 (1959): 177-187.

Lundberg, Nils, Kai C. Nielsen, and Eric Nilsson. "Deep Hypothermia in Intracranial Surgery*." Journal of neurosurgery 13.3 (1956): 235-247.

Jennett, B., et al. "Treatment for severe head injury." Journal of Neurology, Neurosurgery & Psychiatry 43.4 (1980): 289-295.

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Marion, Donald W., et al. "Treatment of traumatic brain injury with moderate hypothermia." New England Journal of Medicine 336.8 (1997): 540-546.

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Xu, Lijun, et al. "Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade." Journal of Cerebral Blood Flow & Metabolism 22.1 (2002): 21-28.

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Siesjö, Bo K., et al. "Calcium, Excitotoxins, and Neuronal Death in the Brain." Annals of the New York Academy of Sciences 568.1 (1989): 234-251.

Fischer, Silvia, et al. "Hypothermia abolishes hypoxia-induced hyperpermeability in brain microvessel endothelial cells." Molecular brain research 74.1 (1999): 135-144.

Schmutzhard, Erich, et al. "Therapeutic hypothermia: The rationale." Critical Care 16.2 (2012): 1.

Andrews, Peter JD, et al. "Hypothermia for intracranial hypertension after traumatic brain injury." New England Journal of Medicine 373.25 (2015): 2403-2412.