Clinical trial NCT00987688: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury
Official title: Multi-centre Randomised Trial to Evaluate the Effect of Early Hypothermia on Neurological Function in Patients With Severe Traumatic Brain Injury. Including Renal Sub Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Brain Injuries, Traumatic
Keywords: trauma
Brain injury
Pre-hospital
cooling
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
Collaborators: name: Australian and New Zealand Intensive Care Society Clinical Trials Group
name: National Health and Medical Research Council, Australia
name: Transport Accident Commision, Victoria
name: Monash University
name: Délégation à la Recherche Clinique et à l'Innovation (DRCI) CHU Besançon
First posted: 2009-10-01
Enrollment: 511
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: The proportion of favourable neurological outcomes (Glasgow Outcome Score Extended: GOSE 5 to 8)
timeFrame: 6 months post injury
Secondary outcomes:
measure: Probability of an equal or greater GOSE level at 6 months compared to the probability of a lesser GOSE level, using a proportional odds model or partial proportional odds model
timeFrame: 6 months post injury
measure: Quality of life assessments (QOL) o EQ5D o SF12
timeFrame: 6 months post injury
measure: Average causal effect of hypothermia on GOSE at 6 months comparing hypothermia and control patients who would survive regardless of treatment assignment.
timeFrame: 6 months post injury
measure: Mortality
timeFrame: Hospital Discharge and 6 Months post injury
measure: Incidence of adverse events, specifically: o Bleeding o Infection.
timeFrame: Up to study day 10
measure: Health economic evaluation
timeFrame: 6 Months post injury
measure: Pre-Specified sub group
timeFrame: 6 Months post injury
measure: Dose effect / Intensity of cooling
timeFrame: 6 months post injury
Other outcomes:
Locations:
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Gold Coast
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Melbourne
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Prahran
country: Australia
facility: Alfred Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Besancon
country: France
facility: Hôpital St Jacques + CHRU Besançon
state: Franche Comte
city: Brest
country: France
facility: Hôpital La Cavale Blanche + CHRU Brest
city: Clermont-Ferrand
country: France
facility: Hôpital Gabriel Montpied + CHU Clermont-Ferrand
city: Nimes
country: France
facility: Hôpital Carémeau + CHU de Nimes
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre
city: Auckland
country: New Zealand
facility: Auckland DCCM
state: North Island
city: Hamilton
country: New Zealand
facility: Waikato District Health Board
state: North Island
city: Doha
country: Qatar
facility: Hamad General Hospital
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Bern
country: Switzerland
facility: Inselspital, Bern University Hospital
Study officials:
affiliation: ANZIC RC
name: Jamie Cooper, BMBS, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.