Randomized Controlled Trial of Long-term Mild Hypothermia for Severe Traumatic Brain Injury

Study Overview
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Brief Summary
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This study is a prospective multi-centre randomized trial to compare the effect of long-term mild hypothermia versus routine normothermic intensive management in patients with severe traumatic brain injury. The primary hypothesis is that the induction of mild hypothermia (maintained at 34-35℃) for 5 days will improve the outcome of patients at six months post injury compared with normothermia.

Detailed Description
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Traumatic brain injury (TBI) remains a leading cause of death and disability in people with injuries and constitutes a major public health concern both in developed and developing countries. There are multiple clinical trials of hypothermia therapy for TBI conducted, however, with conflicting results. Subgroup analysis of most meta-analysis showed that therapeutic effect was significant when hypothermia was maintained more than 48 hours. We have previously reported a multicenter trial of mild hypothermia (33-35℃) for severe traumatic brain injury, in which 215 patients was randomized to long-term mild hypothermia group (n = 108) for 5 ±1.3 days mild hypothermia therapy and short-term mild hypothermia group ( n = 107) for 2±0.6 days mild hypothermia therapy. The results shown improved outcomes in patients with long-term mild hypothermia and similar frequency of complications. Therefore we concluded that long-term hypothermia, which maintains at 33-35℃ for 5 days, could be considered in the management of severe traumatic brain injury. Hypothermia therapy was recommend as the level III evidence by the 2007 Brain Trauma Foundation's guideline and this treatment is currently used in our department and other large neurosurgical centers across China, with the aim to decrease the high intracranial pressure (ICP) and improve the functional outcome of TBI patients. When the decision was made, the injured patients would be placed on cooling blankets, tracheotomized and ventilated. The patients would receive continuous infusions of a paralytic drug (Tracrium 10-40 mg/hour) and chlorpromazine (5-10 mg/hour) administered using an infusion pump to prevent shivering. The dosage was given according to each patient's temperature, blood pressure, heart rate, and muscular tone. Once the patient's rectal temperature reached 33˚C, it was kept at approximately that temperature (33-35˚C) 5 to 7 days. Then the patients were passively rewarmed to a temperature of 37 to 38˚C at a rate no greater than 1˚C/hour, by gradual adjustment of the blanket thermostat. The present multi-center, randomized controlled trials is designed to investigate the efficacy and safety of long-term (5 days) mild hypothermia versus normothermia on the outcome of patients following severe traumatic brain injury. The primary outcome is the neurological function assessed at 1, 6 months post injury with the Glasgow Outcome Score (GOS). Additionally, the following data will also be recorded and compared: the baseline data, Glasgow Coma Score,imaging examination (e.g. CT scan), need of surgery, intracranial pressure, laboratory tests (e.g. blood routine test, liver and kidney function, blood gas analysis, etc), the complications (e.g. pneumonia, significant bleeding) and so on.

Official Title
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A Multi-center, Randomized, Controlled Trial to Evaluate the Efficacy and Safety of Long-term Mild Hypothermia in Adult Patients With Severe Traumatic Brain Injury

Conditions
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Brain Injuries, Craniocerebral Trauma

Intervention / Treatment
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* Other: Long-term mild hypothermia
* Other: Normothermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 65 years within 6 hours post injury; Closed head injury; Glasgow Coma Scale(GCS) score 4 to 8 after resuscitation; The intracranial pressure is more than 25 mmHg; Cerebral contusion on computed tomographic scan. Exclusion Criteria: GCS of 3 with bilateral fixed and dilated pupils; A life-threatening injury to an organ other than the brain; No spontaneous breathing or cardiac arrest at the scene of the injury; No consent; Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Long-term mild hypothermia<br>Focused intervention | Other: Long-term mild hypothermia<br>* Hypothermia will be induced within 6 hours of injury and maintained at 34-35℃ for 5 days.Then the patients will be passively rewarmed to a temperature of 36 to 37˚C at a rate no greater than 0.5˚C/4 hours.<br>* Other names: Mild hypothermia therapy;|
| Other: Normothermia<br>Standard management | Other: Normothermia<br>* Patients assigned to the normothermia group will be kept at 36-37℃.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurological function | The neurological function will be evaluated at 6 months post injury by a specialized investigator who is unaware of the patients' allocation according to five-category Glasgow Outcome Scale as follows: 1, death; 2, vegetative state - unable to interact with the environment; 3, severe disability - unable to live independently but able to follow commands; 4, moderate disability - capable of living independently but unable to return to work or school; and 5, good recovery - able to return to work or school. | 6 months post injury | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial pressure (ICP) control | The effect of long-term hypothermia on ICP control will be determined. | Admission, day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 14, or until the monitor is removed | 
| Glasgow Coma Score (GCS) | The neurological function improvement during study intervention will be evaluated. | Admission, day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 14, day 21, day 28 post injury | 
| Length of ICU stay | The numbers of days in the ICU. | 6 months post injury | 
| Length of hospital stay | The numbers of days in the hospital. | 6 months post injury | 
| Frequency of complications | Frequency of complications during the the study such as pneumonia, significant bleeding, liver and kidney function abnormality will be recorded and compared between groups. | 6 months post injury | 
| Mortality rate | The proportion of death will be determined at 6 months post injury. | 6 months post injury | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Traumatic brain injury