NIHR DC Discover

NIHR Signal Unexpected results from a trial of therapeutic hypothermia for severe head injury

Published on 1 December 2015

doi: 10.3310/signal-000154

This NIHR-funded trial of cooling the body temperature (therapeutic hypothermia) to treat traumatic head injury was stopped early by the researchers because it appeared that the treatment might be harmful.

People who have severe head injuries from trauma can suffer from injury to the brain, which can be very harmful, even fatal. Survivors of traumatic brain injury can be left with highly variable long-term effects, such as difficulty in communicating, understanding and emotional problems.

This trial was testing therapeutic hypothermia compared to standard care alone to see if it produced benefits six months later. The trial was stopped early because of ethical concerns that outcomes were worse when therapeutic hypothermia was used. Treated patients appeared to have a less favourable functional outcome at six months. They also had higher risk of death. This study indicates that therapeutic hypothermia is probably not effective in people with traumatic brain injury, and may be harmful. But the fact that it was stopped early affects how confident we can be about its conclusions, and a full trial might have had different findings. Further analysis of this and other trials may be required.

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Why was this study needed?

Annually, about 200,000 people are admitted to hospital with head injury. Of these, one-fifth 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 can include problems with communication, cognition (problem-solving) and emotional changes. An estimated one million people live with the long-term effects of a serious brain injury.

Intracranial pressure is the pressure inside the skull. Swelling or bleeding in or around the brain as a result of head injury can increase pressure, causing damage to the brain or restricting blood supply. Controlled cooling of the body (induced or therapeutic hypothermia) is used to reduce intracranial pressure. However, the evidence for its effectiveness is unclear. The NIHR funded this trial to help doctors decide whether whole body cooling should continue to be used in the NHS for people with raised intracranial pressure after a severe head injury.

What did this study do?

The Eurotherm3235 was conducted across 55 hospitals in 18 countries. The trial randomly allocated 387 people with a traumatic brain injury to receive either standard care alone or with the addition of therapeutic hypothermia. Participants had an intracranial pressure of above 20mm Hg for at least five minutes within the first 10 days of injury and after initial (Stage 1) treatment such as sedation or mechanical ventilation.

Participants’ body temperature was lowered using an intravenous infusion of cooled salt water, then maintained according to the usual protocol at each hospital (for example ice packs or further fluid). Body temperature was maintained between 32 and 35⁰C – the minimum required to keep pressure below 20mm Hg – for at least 48 hours, or for as long as was needed to control intracranial pressure. Both the hypothermia and control groups could receive standard Stage 2 treatments as needed, such as mannitol, a diuretic to increase urine production. If Stage 2 treatment was not successful, then participants received Stage 3 treatment such as sedation or surgery.

What did it find?

  • At six months, those who received hypothermia had higher risk of having an unfavourable outcome on the Extended Glasgow Outcome Scale compared with the standard care alone group (odds ratio 1.53, 95% confidence interval [CI] 1.02 to 2.30).
  • Fewer people in the hypothermia group had a “favourable outcome” – moderate disability to good recovery – 27.5% compared with 36.5% in the standard care group.
  • The risk of death by six months was higher in the hypothermia group than in the standard care group (hazard ratio 1.45, 95% CI 1.01 to 2.10).
  • Outcomes were not affected by other factors such as age, Glasgow Coma Score, time since the traumatic brain injury or whether the participant was in the UK or elsewhere.

What does current guidance say on this issue?

2014 NICE guidance on the management of head injuries does not provide information about the use of therapeutic hypothermia. Brain Trauma Foundation guidelines on the management of traumatic brain injury concluded that there was no clear evidence that hypothermia reduced mortality. This was based on the pooled results of six moderate quality randomised controlled trials. These trials had various limitations, such as small sample and lack of adjustment for the influence of other factors – which restrict the level of recommendation that could be made for therapeutic hypothermia.

What are the implications?

The study suggests that therapeutic hypothermia in the treatment of raised intracranial pressure from traumatic brain injury doesn’t have benefits and may be  associated with poorer functional outcomes and increased mortality risk compared to standard care alone.

The study was pragmatic in allowing local protocols to be followed where possible, increasing its relevance to the NHS. But as with all trials that are stopped early because of an apparent benefit or harm, we should recognise that if the trial had continued, the finding could have disappeared. It seems unlikely that it would have shown benefit however.

Citation

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. [Epub ahead of print].

This project was funded by the National Institute for Health Research Health Technology Appraisal programme (project number 11/01/30).

Bibliography

Brain Injury Group. Brain injury – the facts. Redhill: Brain Injury Group; 2015.

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

Headway. Traumatic brain injury. Nottingham: Headway – the brain injury association; 2015

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

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

Why was this study needed?

Annually, about 200,000 people are admitted to hospital with head injury. Of these, one-fifth 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 can include problems with communication, cognition (problem-solving) and emotional changes. An estimated one million people live with the long-term effects of a serious brain injury.

Intracranial pressure is the pressure inside the skull. Swelling or bleeding in or around the brain as a result of head injury can increase pressure, causing damage to the brain or restricting blood supply. Controlled cooling of the body (induced or therapeutic hypothermia) is used to reduce intracranial pressure. However, the evidence for its effectiveness is unclear. The NIHR funded this trial to help doctors decide whether whole body cooling should continue to be used in the NHS for people with raised intracranial pressure after a severe head injury.

What did this study do?

The Eurotherm3235 was conducted across 55 hospitals in 18 countries. The trial randomly allocated 387 people with a traumatic brain injury to receive either standard care alone or with the addition of therapeutic hypothermia. Participants had an intracranial pressure of above 20mm Hg for at least five minutes within the first 10 days of injury and after initial (Stage 1) treatment such as sedation or mechanical ventilation.

Participants’ body temperature was lowered using an intravenous infusion of cooled salt water, then maintained according to the usual protocol at each hospital (for example ice packs or further fluid). Body temperature was maintained between 32 and 35⁰C – the minimum required to keep pressure below 20mm Hg – for at least 48 hours, or for as long as was needed to control intracranial pressure. Both the hypothermia and control groups could receive standard Stage 2 treatments as needed, such as mannitol, a diuretic to increase urine production. If Stage 2 treatment was not successful, then participants received Stage 3 treatment such as sedation or surgery.

What did it find?

  • At six months, those who received hypothermia had higher risk of having an unfavourable outcome on the Extended Glasgow Outcome Scale compared with the standard care alone group (odds ratio 1.53, 95% confidence interval [CI] 1.02 to 2.30).
  • Fewer people in the hypothermia group had a “favourable outcome” – moderate disability to good recovery – 27.5% compared with 36.5% in the standard care group.
  • The risk of death by six months was higher in the hypothermia group than in the standard care group (hazard ratio 1.45, 95% CI 1.01 to 2.10).
  • Outcomes were not affected by other factors such as age, Glasgow Coma Score, time since the traumatic brain injury or whether the participant was in the UK or elsewhere.

What does current guidance say on this issue?

2014 NICE guidance on the management of head injuries does not provide information about the use of therapeutic hypothermia. Brain Trauma Foundation guidelines on the management of traumatic brain injury concluded that there was no clear evidence that hypothermia reduced mortality. This was based on the pooled results of six moderate quality randomised controlled trials. These trials had various limitations, such as small sample and lack of adjustment for the influence of other factors – which restrict the level of recommendation that could be made for therapeutic hypothermia.

What are the implications?

The study suggests that therapeutic hypothermia in the treatment of raised intracranial pressure from traumatic brain injury doesn’t have benefits and may be  associated with poorer functional outcomes and increased mortality risk compared to standard care alone.

The study was pragmatic in allowing local protocols to be followed where possible, increasing its relevance to the NHS. But as with all trials that are stopped early because of an apparent benefit or harm, we should recognise that if the trial had continued, the finding could have disappeared. It seems unlikely that it would have shown benefit however.

Citation

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. [Epub ahead of print].

This project was funded by the National Institute for Health Research Health Technology Appraisal programme (project number 11/01/30).

Bibliography

Brain Injury Group. Brain injury – the facts. Redhill: Brain Injury Group; 2015.

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

Headway. Traumatic brain injury. Nottingham: Headway – the brain injury association; 2015

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

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

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury

Published on 7 October 2015

Andrews,PJD, Sinclair HL, Rodriguez A, Harris, BA, Battison CG, Rhodes JKJ, Murray GD, for the Eurotherm3235 Trial Collaborators

New England Journal of Medicine , 2015

BACKGROUND In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. METHODS We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia). RESULTS We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03). CONCLUSIONS In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number.

Outcomes in this trial were assessed using the Extended Glasgow Outcome Scale, an eight-point scale evaluating the impact of a traumatic brain injury on various functional areas of life such as independence, impact on family and friendships, and the return to a normal life. A score of 1 indicates death, 2 is a vegetative state, 3 or 4 is severe disability, 5 or 6 is moderate disability, 7 or 8 is good recovery.

Expert commentary

This small randomised trial of hypothermia for the treatment of traumatic brain injury makes a disappointingly meagre contribution to knowledge. The trial sample size was reduced from 1800 to 600 patients on the basis of implausibly large treatment benefits (reductions in mortality and increases in favourable outcomes) from a meta-analysis of small trials. The resulting small sample size was then justified by the inappropriate use of covariate adjustment. The resulting seriously underpowered trial was then stopped after 387 participants had been enrolled due “safety concerns” and futility. Because trials are often stopped early on random highs and random lows, the evidence for “safety concerns” is not as strong as might be suggested by the p values (p=0.04). Consequently, the extent to which this trial has contributed to resolving uncertainty about hypothermia in the treatment of head injury is open to question. It will be interesting to see what effect this trial has on the overall evidence when the results are included in an update systematic review.

Ian Roberts, Professor of Population Health and Epidemiology, The London School of Hygiene and Tropical Medicine