Discover Portal

Xray scanning for brain injury

NIHR Signal Early cooling provides no benefit following traumatic brain injury

Published on 29 January 2019

doi: 10.3310/signal-000722

Deliberate cooling (prophylactic hypothermia) in the early management of traumatic brain injury does not improve neurological outcomes at six months. Inducing hypothermia may also increase the risk of pneumonia.  

Hypothermia (33-35oC) is sometimes induced to try and limit brain damage in people with severe head injuries. However, evidence for its safety and effectiveness has been mixed. A 2015 trial (Eurotherm 3235) found that therapeutic hypothermia, for adults with raised intracranial pressure despite treatment, was associated with poorer neurological outcomes and increased mortality.

This POLAR trial was larger, and hypothermia was induced as soon as possible following brain injury, regardless of signs of brain swelling. Taken together the trials do not support the practice of prophylactic or therapeutic hypothermia following brain injury.

Share your views on the research.

Why was this study needed?

In 2016/17 almost 156,000 people were admitted to UK hospitals following head injury. Roughly one fifth will have features suggesting skull fracture or have evidence of brain damage (traumatic brain injury). The long-term effects of traumatic brain injury can vary widely in severity but include cognitive (thinking), functional (activity), behavioural and emotional difficulties.

Swelling or bleeding in or around the brain as a result of head injury can increase pressure within the skull, causing damage to the brain or restricting blood supply. Hypothermia can be effective in reducing intracranial pressure, but it isn't clear whether this improves survival or brain function. Trials to date have had methodological limitations, such as a delay in starting the cooling or a limited period of hypothermia.

This large randomised controlled trial aimed to address these limitations and assess the effects of early and prolonged prophylactic hypothermia, induced regardless of intracranial pressure.

What did this study do?

The POLAR trial randomised 511 adults with severe traumatic brain injury to early prophylactic hypothermia or normal temperature care. The average age was 35, and 80% were male. Six countries participated, not including the UK. Eligible patients had a Glasgow Coma Scale <9/15 and required endotracheal intubation. Those with significant bleeding were excluded.

Hypothermia was induced on average 1.8 hours after the injury either out-of-hospital or in the emergency department. It involved intravenous ice-cold saline and surface cooling wraps to reach a target of 33oC. After 72 hours, if intracranial pressure was not elevated, the patient was rewarmed gradually. If pressure was increased, they were re-cooled. The maximum period of hypothermia was seven days.

One-third of patients did not reach the target 33oC due to unsuitability (e.g. non-survivable injury or bleeding risk).

What did it find?

  • Prophylactic hypothermia made no difference to favourable neurological outcome at six months (Glasgow Outcome Scale-Extended score of 5-8). This was achieved by 48.8% (117/240) of the hypothermia group and 49.1% (111/226) of the usual care group (relative risk [RR] 0.99, 95% confidence interval [CI] 0.82 to 1.19).
  • At six months, there was no difference in mortality between the groups: 21.1% (54/256) of the hypothermia group died compared to 18.4% (44/239) of the usual care group (RR 1.15, 95% CI 0.80 to 1.64). Neither was there a difference in time to death.
  • At 10 days, there were slightly more adverse events in the hypothermia group, but again this did not reach statistical significance: pneumonia 55.0% hypothermia vs 51.3% usual care (RR 1.07, 95% CI 0.91 to 1.27); new or increased intracranial bleeding 18.1% vs 15.4% usual care (RR 1.23, 95% CI 0.43 to 3.5).
  • When analysing only those who received treatment according to protocol (defined as ≤35oC initiated within 96 hours and maintained for >48 hours), or according to treatment received (i.e. those not achieving hypothermia transferred to the opposite group), there remained no difference for any outcome with the exception of pneumonia. Rates of pneumonia were higher in the hypothermia group in both per-protocol (70.5% vs 57.1%; RR 1.23, 95% CI 1.04 to 1.47) and as-treated analyses (70.7% vs 54.6%; RR 1.29, 95% CI 1.09 to 1.53). 

What does current guidance say on this issue?

NICE guidelines on the management of head injuries (updated 2017) do not mention the use of therapeutic hypothermia. Guidelines from the Brain Trauma Foundation (2007) gave only a low-level recommendation for use of therapeutic hypothermia as there were concerns about the evidence.  

The pooled results from six moderate quality randomised controlled trials indicated that hypothermia may improve neurological outcomes, but there was no consistent or statistically significant reduction in mortality. The trials also had limitations, such as small samples and potential for confounding.

What are the implications?

This study does not support the practice of deliberate cooling following severe brain injury. There is no neurological benefit, and it may increase risk of harms like pneumonia.

It provides supporting evidence for previous studies. The smaller Eurotherm 3235 trial found poorer outcomes from inducing hypothermia in people with raised intracranial pressure. An earlier Cochrane review noted a benefit was seen only in low-quality trials that may overestimate treatment effect. The POLAR trial overcomes several methodological limitations in earlier studies. Drop-out due to unsuitability was high but is likely to reflect real-world practice.

Prophylactic or therapeutic hypothermia seems to have no place in the management of severe brain injury.

Citation and Funding

Cooper DJ, Nichol AD, Bailey M 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;320(21):2211-20.

This study was funded by grants from the National Health and Medical Research Council of Australia (545901 and 1121037), the Victorian Neurotrauma Initiative (VNI for the Transport Accident Commission, Victoria, Australia) (VNI D162), the Teaching Hospital of Besançon, France, and the Health Research Board of Ireland Clinical Trial Network Program.

Bibliography

Andrews PJD, Sinclair HL, Rodriguez A, et al; Eurotherm3235 Trial Collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J of Med. 2015;373(25):2403-12.

Brain Trauma Foundation. Guidelines for the management of severe traumatic brain injury: 3rd edition. J Neurotrauma. 2007;24 Suppl 1:S1-106.

Headway – the brain injury association. Statistics. Nottingham: Headway – the brain injury association; 2016-17.

NICE. Head injury: assessment and early management. CG176. London: National Institute for Health and Care Excellence; 2014.

NICE. Therapeutic hypothermia following cardiac arrest. IPG386. London: National Institute for Health and Care Excellence; 2011.

NICE. Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury. IPG347. London: National Institute for Health and Care Excellence; 2010.

Sydenham E, Roberts I, Alderson P. Hypothermia for traumatic head injury. Cochrane Database of Syst Rev. 2009;(2):CD001048.

Why was this study needed?

In 2016/17 almost 156,000 people were admitted to UK hospitals following head injury. Roughly one fifth will have features suggesting skull fracture or have evidence of brain damage (traumatic brain injury). The long-term effects of traumatic brain injury can vary widely in severity but include cognitive (thinking), functional (activity), behavioural and emotional difficulties.

Swelling or bleeding in or around the brain as a result of head injury can increase pressure within the skull, causing damage to the brain or restricting blood supply. Hypothermia can be effective in reducing intracranial pressure, but it isn't clear whether this improves survival or brain function. Trials to date have had methodological limitations, such as a delay in starting the cooling or a limited period of hypothermia.

This large randomised controlled trial aimed to address these limitations and assess the effects of early and prolonged prophylactic hypothermia, induced regardless of intracranial pressure.

What did this study do?

The POLAR trial randomised 511 adults with severe traumatic brain injury to early prophylactic hypothermia or normal temperature care. The average age was 35, and 80% were male. Six countries participated, not including the UK. Eligible patients had a Glasgow Coma Scale <9/15 and required endotracheal intubation. Those with significant bleeding were excluded.

Hypothermia was induced on average 1.8 hours after the injury either out-of-hospital or in the emergency department. It involved intravenous ice-cold saline and surface cooling wraps to reach a target of 33oC. After 72 hours, if intracranial pressure was not elevated, the patient was rewarmed gradually. If pressure was increased, they were re-cooled. The maximum period of hypothermia was seven days.

One-third of patients did not reach the target 33oC due to unsuitability (e.g. non-survivable injury or bleeding risk).

What did it find?

  • Prophylactic hypothermia made no difference to favourable neurological outcome at six months (Glasgow Outcome Scale-Extended score of 5-8). This was achieved by 48.8% (117/240) of the hypothermia group and 49.1% (111/226) of the usual care group (relative risk [RR] 0.99, 95% confidence interval [CI] 0.82 to 1.19).
  • At six months, there was no difference in mortality between the groups: 21.1% (54/256) of the hypothermia group died compared to 18.4% (44/239) of the usual care group (RR 1.15, 95% CI 0.80 to 1.64). Neither was there a difference in time to death.
  • At 10 days, there were slightly more adverse events in the hypothermia group, but again this did not reach statistical significance: pneumonia 55.0% hypothermia vs 51.3% usual care (RR 1.07, 95% CI 0.91 to 1.27); new or increased intracranial bleeding 18.1% vs 15.4% usual care (RR 1.23, 95% CI 0.43 to 3.5).
  • When analysing only those who received treatment according to protocol (defined as ≤35oC initiated within 96 hours and maintained for >48 hours), or according to treatment received (i.e. those not achieving hypothermia transferred to the opposite group), there remained no difference for any outcome with the exception of pneumonia. Rates of pneumonia were higher in the hypothermia group in both per-protocol (70.5% vs 57.1%; RR 1.23, 95% CI 1.04 to 1.47) and as-treated analyses (70.7% vs 54.6%; RR 1.29, 95% CI 1.09 to 1.53). 

What does current guidance say on this issue?

NICE guidelines on the management of head injuries (updated 2017) do not mention the use of therapeutic hypothermia. Guidelines from the Brain Trauma Foundation (2007) gave only a low-level recommendation for use of therapeutic hypothermia as there were concerns about the evidence.  

The pooled results from six moderate quality randomised controlled trials indicated that hypothermia may improve neurological outcomes, but there was no consistent or statistically significant reduction in mortality. The trials also had limitations, such as small samples and potential for confounding.

What are the implications?

This study does not support the practice of deliberate cooling following severe brain injury. There is no neurological benefit, and it may increase risk of harms like pneumonia.

It provides supporting evidence for previous studies. The smaller Eurotherm 3235 trial found poorer outcomes from inducing hypothermia in people with raised intracranial pressure. An earlier Cochrane review noted a benefit was seen only in low-quality trials that may overestimate treatment effect. The POLAR trial overcomes several methodological limitations in earlier studies. Drop-out due to unsuitability was high but is likely to reflect real-world practice.

Prophylactic or therapeutic hypothermia seems to have no place in the management of severe brain injury.

Citation and Funding

Cooper DJ, Nichol AD, Bailey M 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;320(21):2211-20.

This study was funded by grants from the National Health and Medical Research Council of Australia (545901 and 1121037), the Victorian Neurotrauma Initiative (VNI for the Transport Accident Commission, Victoria, Australia) (VNI D162), the Teaching Hospital of Besançon, France, and the Health Research Board of Ireland Clinical Trial Network Program.

Bibliography

Andrews PJD, Sinclair HL, Rodriguez A, et al; Eurotherm3235 Trial Collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J of Med. 2015;373(25):2403-12.

Brain Trauma Foundation. Guidelines for the management of severe traumatic brain injury: 3rd edition. J Neurotrauma. 2007;24 Suppl 1:S1-106.

Headway – the brain injury association. Statistics. Nottingham: Headway – the brain injury association; 2016-17.

NICE. Head injury: assessment and early management. CG176. London: National Institute for Health and Care Excellence; 2014.

NICE. Therapeutic hypothermia following cardiac arrest. IPG386. London: National Institute for Health and Care Excellence; 2011.

NICE. Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury. IPG347. London: National Institute for Health and Care Excellence; 2010.

Sydenham E, Roberts I, Alderson P. Hypothermia for traumatic head injury. Cochrane Database of Syst Rev. 2009;(2):CD001048.

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial

Published on 26 October 2018

Cooper, D. J.,Nichol, A. D.,Bailey, M.,Bernard, S.,Cameron, P. A.,Pili-Floury, S.,Forbes, A.,Gantner, D.,Higgins, A. M.,Huet, O.,Kasza, J.,Murray, L.,Newby, L.,Presneill, J. J.,Rashford, S.,Rosenfeld, J. V.,Stephenson, M.,Vallance, S.,Varma, D.,Webb, S. A. R.,Trapani, T.,McArthur, C.

Jama , 2018

Importance: After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. Objective: To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. Design, Setting, and Participants: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. Interventions: There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33 degrees C-35 degrees C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37 degrees C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury. Results: Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, -9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. Conclusions and Relevance: Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury. Trial Registration: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235.

A Glasgow Outcome Scale–Extended score of 1 indicates death, 2 a vegetative state, 3 to 4 severe disability, 5 to 6 moderate disability, and score 7 to 8 indicates good recovery. Therefore, a favourable neurological outcome on the POLAR trial was defined as moderate disability at worst.

Expert commentary

Hypothermia has been commonly used in neurointensive care settings to help control raised intracranial pressure in an attempt to improve outcomes. Previous studies have demonstrated harm and increased adverse effects from prolonged extreme hypothermia.

The Eurotherm3235 study showed no benefit of hypothermia for managing acutely raised intracranial pressure. However, a large-scale study of prophylactic hypothermia was still required - which this study provides. This study is helpful as it demonstrates that (1) there is no significant increase in adverse events between normothermic and hypothermic patients and (2) there is no benefit for prophylactic hypothermia.

Therefore, this paper is helpful in confirming that commencing this intervention early and prophylactically does not improve outcomes so should not be used.

Mr John Goodden, Consultant Neurosurgeon (Adult & Paediatric), Leeds General Infirmary

The commentator declares no conflicting interests