The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Brain Injuries, Traumatic

Intervention / Treatment
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* Other: Hypothermia


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypothermia<br>Early and sustained hypothermia. | Other: Hypothermia<br>* 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.<br>|
| No Intervention: Normothermia<br>Standard management | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of favourable neurological outcomes (Glasgow Outcome Score Extended: GOSE 5 to 8) | The Glasgow Outcome Scale Extended (GOSE) is an ordinal rating scale. The 8 scores in the scale are: Dead (1), Vegetative State (2), Lower Severe Disability (3), Upper Severe Disability (4), Lower Moderate Disability (5), Upper Moderate Disability (6), Lower Good Recovery (7), and Upper Good Recovery (8). | 6 months post injury | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | The Glasgow Outcome Scale Extended (GOSE) is an ordinal rating scale. The 8 scores in the scale are: Dead (1), Vegetative State (2), Lower Severe Disability (3), Upper Severe Disability (4), Lower Moderate Disability (5), Upper Moderate Disability (6), Lower Good Recovery (7), and Upper Good Recovery (8). | 6 months post injury | 
| Quality of life assessments (QOL) o EQ5D o SF12 | Quality of life assessments using the EQ-5D-3L and SF12. The EQ-5D-3L descriptive system that comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The SF-12® Health Survey (SF-12) is a 12-item questionnaire used to assess health outcomes from the patient's perspective. | 6 months post injury | 
| Average causal effect of hypothermia on GOSE at 6 months comparing hypothermia and control patients who would survive regardless of treatment assignment. | This complier average causal effect (CACE) analysis will be conducted to estimate the average effect of cooling treatment on the primary outcome for patients who would comply with whichever cooling group they were assigned to, considering both the binary and continuous definitions of compliance with cooling. | 6 months post injury | 
| Mortality | All Cause Mortality | Hospital Discharge and 6 Months post injury | 
| Incidence of adverse events, specifically: o Bleeding o Infection. | The incidence of adverse events will be measured up to day 10 in both groups. The principle adverse events of interest will be bleeding (intracranial or extracranial) and infection (by site). | Up to study day 10 | 
| Health economic evaluation | Cost-effectiveness from the health-care payer perspective will be calculated as a cost per additional patient with a favourable neurological outcome at 6 months following randomisation (defined as GOSE 5-8) and the cost per additional quality-adjusted life year, with quality-adjusted life years calculated using utility scores derived from the EQ-5D-3L conducted at 6 months post randomisation. Costs will be determined based on resource use during the intensive care, acute and post-acute periods up to six months post-randomisation. Where available, total costs of care provided by the state government through the relevant compensation scheme will be obtained for the subgroup of road trauma patients, and this data will be used to determine the cost per additional QALY and cost per additional favourable neurological outcome in this subgroup. | 6 Months post injury | 
| Pre-Specified sub group | The primary and secondary outcomes will be evaluated according to (i) the presence of surgically evacuated intracranial mass lesions (Marshall score V); and (ii) the presence of any intracranial mass lesion whether or not surgically evacuated (Marshall V or VI). | 6 Months post injury | 
| Dose effect / Intensity of cooling | Intensity of cooling in intervention arm patients will be categorised according to the time after randomization to first reach one of two core temperature thresholds, being 35°C and also 34°C. Cooling intensity categories are defined as never achieving hypothermia and tertiles of time in those reaching hypothermia. Primary and secondary outcomes of patients in these intensity categories will be compared across categories and to standard care patients. | 6 months post injury | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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trauma, Brain injury, Pre-hospital, cooling