The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR-RCT)

• Quality of life assessments *SF-12 (version 1) *EQ5D [ Time Frame: 6 months post injury ] [ Designated as safety issue: No ]
• Mortality [ Time Frame: 6 months post injury ] [ Designated as safety issue: Yes ]
• Proportion of favourable (GOSE 5-8) neurological outcomes in survivors [ Time Frame: 6 months post injury ] [ Designated as safety issue: No ]
• Incidence of adverse events *Significant bleeding - assessed clinically *Infection - assessed clinically [ Time Frame: During the study intervention ] [ Designated as safety issue: Yes ]
• Cumulative proportion of patients with Acute Kidney Injury (Injury/Failure Risk Injury Failure Loss End stage (RIFLE) categories) in those receiving cooling v. normothermia [ Time Frame: Day 7 of hospital admission ] [ Designated as safety issue: No ]
• Levels of biomarkers neutrophil gelatinase-associated lipocalin (NGAL), cystatin C and liver-type fatty acid binding protein (L-FABP) will be measured in plasma and urine from blood and urine specimens obtained from 50 patients. [ Time Frame: 24hrs, 48 hrs, 72 hrs post Intensive Care admission ] [ Designated as safety issue: No ]

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.

• Other: 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 3 days. Rewarming will occur at a rate of 0.17C/hr and will be titrated to intracranial pressure (ICP) control.
• Other: Normothermia
  Standard management. Patients will be kept at normothermia (37C). If they develop a fever >38C they will be treated with paracetamol and surface temperature control equipment will be applied to maintain normothermia. Cooling to 35C is an option for refractory ICP.

• Experimental: Hypothermia
  Early and sustained hypothermia.
  Interventions:

  • Other: Hypothermia
  • Other: Normothermia
• No Intervention: Normothermia
  Standard management

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
  • 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

• Australian and New Zealand Intensive Care Society Clinical Trials Group
• National Health and Medical Research Council, Australia
• Victorian Neurotrauma Initiative