The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury

NCT ID: NCT00987688

Last Updated: 2018-08-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 511 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30
• Study Completion Date: 2018-06-15

Brief Summary

Traumatic brain injury (TBI) is a leading cause of death and long term disability, particularly in young adults. Studies from Australia have shown that approximately half of those with severe traumatic brain injury will be severely disabled or dead 6 months post injury. Given the young age of many patients with severe TBI and the long term prevalence of major disability, the economic and more importantly the social cost to the community is very high.

Pre-hospital and hospital management of patients with severe brain injury focuses on prevention of additional injury due primarily to lack of oxygen and insufficient blood pressure. This includes optimising sedation and ventilation, maintaining the fluid balance and draining Cerebrospinal Fluid (CSF) and performing surgery where appropriate. In recent years there has been a research focus on specific pharmacologic interventions, however, to date, there has been no treatment that has been associated with improvement of neurological outcomes.

One treatment that shows promise is the application of hypothermia (cooling). This treatment is commonly used in Australia to decrease brain injury in patients with brain injury following out-of-hospital cardiac arrest. Cooling is thought to protect the brain using a number of mechanisms. There have been a number of animal studies that have looked at how cooling is protective and also some clinical research that suggests some benefit. However at the current time there is insufficient evidence to provide enough proof that cooling should be used routinely for patients with brain injury and like all treatments there can be some risks and side effects.

The POLAR trial has been developed to investigate whether early cooling of patients with severe traumatic brain injury is associated with better outcomes. It is a randomised controlled trial, which is a type of trial that provides the highest quality of evidence.

The null hypothesis is that there is no difference in the proportion of favourable neurological outcomes six months after severe traumatic brain injury in patients treated with early and sustained hypothermia, compared to standard normothermic management.

Detailed Description

Eligible patients will be randomised in the pre-hospital setting or on admission to the Emergency Department. POLAR study trained paramedics and physicians will screen patients in the pre-hospital setting. Eligible patients will be randomised if they fulfil the inclusion criteria with no pre-hospital exclusion criteria. Those randomised to the normothermia group will follow standard care. For those randomised to the "cooling arm", pre-hospital prophylactic hypothermia will be induced by exposure and by infusing up to 2 litres intravenous cold (4°C) 0.9% sodium chloride aiming for a core temperature of 35°C during transport. In the emergency department the "cooling arm" patients will be assessed to exclude significant bleeding and, once significant bleeding has been excluded, surface cooling vests/wraps will be applied to reach the target core temperature of 33°C. The patient will be then maintained at this temperature for a further 72 hours. Patients with significant bleeding will have cooling withheld until it is safe to decrease the temperature to the target core temperature of 33°C. Patients who have not been randomised pre-hospital will be re-screened in the ED. Eligible patients will be randomised if they fulfil the inclusion criteria with no ED exclusion criteria. Hypothermia will be induced by administration of up to 2L intravenous ice-cold (4°C) 0.9% sodium chloride followed by application of the surface cooling vests/wraps to achieve the target core temperature of 33°C. Patients allocated to standard 'normothermic' care will be maintained at a core temperature of 37°C ± 0.5°C.

Conditions

Brain Injuries, Traumatic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Hypothermia

Early and sustained hypothermia.

Group Type: EXPERIMENTAL

Hypothermia

Intervention Type: OTHER

exposure: Early and sustained hypothermia. Hypothermia will initially be induced by infusion of up to 2L ice cold saline. Following a safety assessment the patient will be rapidly cooled to 33C using surface temperature control equipment. They will be maintained at 33C for 72 hours. Rewarming will occur at a rate of 1C/4hrs and will be titrated to intracranial pressure (ICP) control and BP.

Normothermia

Standard management

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Hypothermia

exposure: Early and sustained hypothermia. Hypothermia will initially be induced by infusion of up to 2L ice cold saline. Following a safety assessment the patient will be rapidly cooled to 33C using surface temperature control equipment. They will be maintained at 33C for 72 hours. Rewarming will occur at a rate of 1C/4hrs and will be titrated to intracranial pressure (ICP) control and BP.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Blunt trauma with clinical diagnosis of severe TBI and GCS <9
• Estimated age ≥ 18 and < 60 years of age
• The patient is intubated or intubation is imminent

Exclusion Criteria

• Pre-hospital:

• Clinical diagnosis of drug or alcohol intoxication as predominant cause of coma
• Randomisation unable to be performed within 3 hrs of estimated time of injury
• Estimated transport time to study hospital >2.5hrs
• Able to be intubated without drugs
• Systolic BP <90mmHg
• Heart rate > 120bpm
• GCS=3 + un-reactive pupils
• Penetrating neck/torso injury
• Known or obvious pregnancy
• Receiving hospital is not a study site
• Evidence of current anti-coagulant treatment
• Emergency Dept:

• Clinical diagnosis of drug or alcohol intoxication as predominant cause of coma
• Randomisation unable to be performed within 3 hrs of estimated time of injury
• Able to be intubated without drugs
• GCS=3 + un-reactive pupils
• Persistent Systolic BP <90mmHg
• Clinically significant bleeding likely to require haemostatic intervention, for example:

• Bleeding into the chest, abdomen or retro-peritoneum likely to require surgery +/- embolisation
• Pelvic fracture likely to require surgery +/- embolisation
• More than two long bone fractures requiring operative fixation
• Penetrating neck/torso injury
• Positive urine or blood pregnancy test
• Evidence of current anti-coagulant treatment
• In the treating clinician's opinion, "cooling" is not in the patient's best interest

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Australian and New Zealand Intensive Care Society Clinical Trials Group

NETWORK

Sponsor Role: collaborator

National Health and Medical Research Council, Australia

OTHER

Sponsor Role: collaborator

Transport Accident Commision, Victoria

UNKNOWN

Sponsor Role: collaborator

Monash University

OTHER

Sponsor Role: collaborator

Délégation à la Recherche Clinique et à l'Innovation (DRCI) CHU Besançon

UNKNOWN

Sponsor Role: collaborator

Australian and New Zealand Intensive Care Research Centre

OTHER

Sponsor Role: lead

Responsible Party

David James Cooper

Director, ANZIC rc

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jamie Cooper, BMBS, MD

Role: STUDY_CHAIR

ANZIC RC

Locations

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Gold Coast University Hospital

Gold Coast, Queensland, Australia

The Royal Melbourne Hospital

Melbourne, Victoria, Australia

Alfred Hospital

Prahran, Victoria, Australia

Royal Perth Hospital

Perth, Western Australia, Australia

Hôpital St Jacques + CHRU Besançon

Besançon, Franche Comte, France

Hôpital La Cavale Blanche + CHRU Brest

Brest, , France

Hôpital Gabriel Montpied + CHU Clermont-Ferrand

Clermont-Ferrand, , France

Hôpital Carémeau + CHU de Nimes

Nîmes, , France

Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre

Strasbourg, , France

Auckland DCCM

Auckland, North Island, New Zealand

Waikato District Health Board

Hamilton, North Island, New Zealand

Hamad General Hospital

Doha, , Qatar

King Abdulaziz Medical City

Riyadh, , Saudi Arabia

Inselspital, Bern University Hospital

Bern, , Switzerland

Countries

Australia; France; New Zealand; Qatar; Saudi Arabia; Switzerland

References

Nichol A, Gantner D, Presneill J, Murray L, Trapani T, Bernard S, Cameron P, Capellier G, Forbes A, McArthur C, Newby L, Rashford S, Rosenfeld JV, Smith T, Stephenson M, Varma D, Walker T, Webb S, Cooper DJ. Protocol for a multicentre randomised controlled trial of early and sustained prophylactic hypothermia in the management of traumatic brain injury. Crit Care Resusc. 2015 Jun;17(2):92-100.

Reference Type: BACKGROUND

PMID: 26017126 (View on PubMed)

Presneill J, Gantner D, Nichol A, McArthur C, Forbes A, Kasza J, Trapani T, Murray L, Bernard S, Cameron P, Capellier G, Huet O, Newby L, Rashford S, Rosenfeld JV, Smith T, Stephenson M, Varma D, Vallance S, Walker T, Webb S, James Cooper D; POLAR investigators and the ANZICS Clinical Trials Group. Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial. Trials. 2018 Apr 27;19(1):259. doi: 10.1186/s13063-018-2610-y.

Reference Type: BACKGROUND

PMID: 29703266 (View on PubMed)

Ridley EJ, Davies AR, Bernard S, McArthur C, Murray L, Paul E, Trapani A, Cooper DJ; ANZICS Clinical Trials Group. Measured energy expenditure in mildly hypothermic critically ill patients with traumatic brain injury: A sub-study of a randomized controlled trial. Clin Nutr. 2021 Jun;40(6):3875-3882. doi: 10.1016/j.clnu.2021.05.012. Epub 2021 May 24.

Reference Type: DERIVED

PMID: 34130035 (View on PubMed)

Cooper DJ, Nichol AD, Bailey M, Bernard S, Cameron PA, Pili-Floury S, Forbes A, Gantner D, Higgins AM, Huet O, Kasza J, Murray L, Newby L, Presneill JJ, Rashford S, Rosenfeld JV, Stephenson M, Vallance S, Varma D, Webb SAR, Trapani T, McArthur C; POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial. JAMA. 2018 Dec 4;320(21):2211-2220. doi: 10.1001/jama.2018.17075.

Reference Type: DERIVED

PMID: 30357266 (View on PubMed)

Moore EM, Nichol AD, Bernard SA, Bellomo R. Therapeutic hypothermia: benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury. Injury. 2011 Sep;42(9):843-54. doi: 10.1016/j.injury.2011.03.027. Epub 2011 Apr 9.

Reference Type: DERIVED

PMID: 21481385 (View on PubMed)

Other Identifiers

ANZIC-RC/DJC003

Identifier Type: -

Identifier Source: org_study_id