Critically evaluate the role of induced hypothermia in the management of traumatic brain injury.

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College answer

Induced hypothermia refers to the use of techniques to intentionally lower the core body temperature  below a physiological level (i.e. <36 degrees), in this case, in a patient with a traumatic brain injury.

Rationale
• Reduction in metabolic rate
• Reduction in oedema
• Modification of the inflammatory response

Indications
Prophylactic (early)
Therapeutic (for the management of elevated intracranial pressure)

Advantages
• Reduction in core body temperature is associated with a reduction in cerebral metabolic 
rate and reduction in cerebral blood flow
• Will be associated with a reduction in intracranial pressure
• Noted cerebral protective effect in animal models and in case reports of survival with good 
neurological recovery in hypoxic ischaemic encephalopathy in patients with severe 
accidental hypothermia
• Known that hyperthermia is associated with worse neurological outcomes

Adverse effects
• Requires sedation and neuromuscular blockade with the attendant adverse effects 
• Lower temperature predisposes to infective complications, in particular pneumonia
• Coagulopathy
• Cardiac dysrhythmias
• Overshoot can expose patients to adverse effects of more severe hypothermia
o Dysrhythmia
o Diuresis and electrolyte disturbance
o Immune suppression
• Adverse effects of cooling devices (loss of skin integrity) and monitoring devices 
(epistaxis) 
• Cost of prolonged ICU stay and increased requirement for intervention and monitoring
 

Evidence
• Initial studies and meta-analysis showed promising results with regards to improved 
neurological outcomes
• Subsequent studies are less positive
 

Cochrane Systematic Review 2009
No evidence of benefit. 
Significant benefit shown in low quality trials with tendency to over-estimate the treatment effect


Prophylactic Hypothermia: 
• Nine class I and II studies, and 3 Class III studies summarised in BTF.
• Since then two paediatric studies and a Japanese study have been published

Brain Trauma Foundation (2016): 
“Level II B: Early (within 2.5 hours), short-term (48 hours post-injury) prophylactic hypothermia is not  recommended to improve outcomes in patients with diffuse injury”.

Elevated ICP management:
• EUROTHERM-3235 study
o Induced hypothermia has an effect on reducing intracranial pressure, but the effect on 
outcome is variable
o Little clinical evidence on the effect on other important aspects of cerebral physiology 
e.g. cerebral blood flow or cellular metabolism
 

Summary
• It is important to avoid hyperthermia
• Routine use of induced hypothermia in all TBI patients is not warranted
• Careful reduction in core body temperature may help control ICP in selected severe TBI 
patients who may otherwise be at risk of a decompressive craniectomy.
• Await results of high-quality RCTs

Discussion

Introduction:

  • Induced hypothermia in traumatic brain injury is the therapeutic or prophylactic use of lower body temperature, to prevent secondary brain injury or to relieve refractory raised ICP.

Rationale:

  • 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 in TBI

  • 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):
    • Arrhythmias (AF, bradycardia)
    • Diuresis, hypokalemia
    • Need for paralysis and sedation
    • Poor neutrophil function: the rate of infectious complications is relatively high, eg. pneumonia (POLAR, 2018 had 70% vs 57% in the normothermic group)
    • Higher catecholamine reuqirements (POLAR, 2018): Catecholamine responsiveness is diminished at low temperature, making CPP more difficult to achieve with noradrenaline
  • The deeper the hypothermia, the greater the risk of complications
  • Haemodynamic instability in hypothermia may decrease CPP
  • Decreased platelet function may lead to expansion of conservatively managed haemorrhages or contusions

Evidence for and against hypothermia in TBI

  • Eurotherm 3235 trial (2015):
    • 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.
  • "Cochrane Systematic Review 2009" probably refers to Sydenham et al (2009). A new update was published by Lewis et al in 2017. Neither meta-analysis found any benefit (the 2009 version recommended that hypothermia should be relegated to the realm of experimental trial interventions rather than established practice).
  • POLAR (2018)
    • Enrolled 511 patients
    • Hypothermia was commenced early and sustained for at least 72 hours
    • There was no difference in neurological outcome between the groups
    • "These findings do not support the use of early prophylactic hypothermia in patients with severe traumatic brain injury", they concluded

"Own practice"

  • Prophylactic hypothermia for severe TBI is not indicated in routine practice
  • Therapeutic hypothermia for severe TBI with refractory raised ICP may reduce the ICP, and is an alternative or adjunct to decompressive craniectomy

If the college examiners had any investment in the process of writing these answers, they'd probably have offered their trainees some references beyond "two paediatric studies and a Japanese study". At least one of the "two paediatric studies" is Hutchison et al (2008),  who concluded that prophylactic hypothermia "does not improve the neurologic outcome and may increase mortality". The other paediatric trial may be Li et al (2009), which came to totally opposite conclusions ( "moderate hypothermia provided neuronal protection for children with severe TBI, and maintaining the intracranial temperature at 34.5°C for 72 h was safe"). Looking at the list of trials undergoing meta-analysis in Lewis et al (2017), the "Japanese study" is probably Hifumi et al (2016), whose B-HYPO trial did not find any significant difference in mortality or neurological outcome among 135 adult patients.

References

References

Sedzimir, C. B. "Therapeutic Hypothermia in Cases of Head Injury*." Journal of neurosurgery 16.4 (1959): 407-414.

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.

Drake, C. G., and T. A. Jory. "Hypothermia in the treatment of critical head injury." Canadian Medical Association journal 87.17 (1962): 887.

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

Fay, T. "Observations on generalized refrigeration in cases of severe cerebral trauma." Assoc Res Nerv Ment Dis Proc. Vol. 24. 1945.

Polderman, Kees H. "Mechanisms of action, physiological effects, and complications of hypothermia." Critical care medicine 37.7 (2009): S186-S202.

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.

Globus, Mordecai Y‐T., et al. "Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation." Journal of neurochemistry 65.3 (1995): 1250-1256.

Busto, Raul, et al. "Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain." Stroke 20.7 (1989): 904-910.

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.

Cooper, D. James, et al. "Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the POLAR randomized clinical trial." JAMA (2018) Published online October 24, 2018. doi:10.1001/jama.2018.17075

Hutchison, James S., et al. "Hypothermia therapy after traumatic brain injury in children." New England Journal of Medicine 358.23 (2008): 2447-2456.

Hifumi, Toru, et al. "Fever control management is preferable to mild therapeutic hypothermia in traumatic brain injury patients with abbreviated injury scale 3–4: a multi-center, randomized controlled trial." Journal of neurotrauma 33.11 (2016): 1047-1053.

Li, Hao, et al. "Protective effect of moderate hypothermia on severe traumatic brain injury in children." Journal of neurotrauma 26.11 (2009): 1905-1909.