Trial of Long-term Therapeutic Hypothermia for Poor-grade Aneurysmal Subarachnoid Hemorrhage

Study Overview
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Brief Summary
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This study is a prospective, multi-centre, randomized,controlled trial to compare the efficacy of long-term mild hypothermia with normothermic intensive management in patients with poor-grade aneurysmal subarachnoid hemorrhage. The primary hypothesis is that the induction of mild hypothermia (maintained at 32-35℃) for at least 5 days would improve the outcome of patients at six months post hemorrhage compared with normothermia.

Detailed Description
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Aneurysmal subarachnoid hemorrhage (aSAH), especially poor-grade aSAH, is a medical emergency with very high morbidity and mortality rates. SAH constitutes a major public health concern in developed and developing countries. There were several clinical trials of hypothermia for aSAH conducted, however, with conflicting results. Hypothermia therapy treatment is currently used in our department and other large neurosurgical centers across China to decrease the intracranial pressure (ICP), mitigate some of the destructive processes, and improve the functional outcome of patients with poor-grade aSAH. When the decision was made, the patients would be placed in wrapped cooling blankets or intravascular cooling device after they were sedated, intubated and mechanically ventilated. The patients would receive continuous infusions of some drugs using an infusion pump to prevent shivering. Once the patient's rectal, nasopharyngeal or blood temperature reached 32˚C, it was kept at approximately that temperature (32-35˚C) 3 to 7 days. Then the patients were passively rewarmed to a temperature of 36 to 37˚C at a rate no greater than 0.25˚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 (3 days) mild hypothermia versus normothermia on the outcome of patients with poor-grade aSAH. The primary outcome is the neurological function assessed at 1,3, 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), 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 Investigate the Efficacy and Safety of Long-term Therapeutic Hypothermia in Adult Patients With Poor-grade Aneurysmal Subarachnoid Hemorrhage

Conditions
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Hypothermia, Aneurysmal Subarachnoid Hemorrhage

Intervention / Treatment
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* Procedure: Zoll 2000 and/or CureWrap 3500 cooling system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 65 years within 72 hours after subarachnoid hemorrhage; Neurosurgical clipping or coiling for aneurysm; Hunt-Hess IV-V scale; The intracranial pressure is more than 20 mmHg. Exclusion Criteria: GCS of 3 with bilateral fixed and dilated pupils; No spontaneous breathing or cardiac arrest at the scene of hemorrhage; 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: mild hypothermia<br>Device: Zoll 2000 and/or CureWrap 3500 cooling system,lasting 5 to 7 days, the core temperature will be controlled in 33-35 degree. | Procedure: Zoll 2000 and/or CureWrap 3500 cooling system<br>* Device(Zoll 2000 and/or CureWrap 3500 cooling system),lasting 5 to 7 days, the core temperature will be controlled in 33-35 degree.<br>|
| Placebo Comparator: northermia<br>normal physical cooling methods,like ice bag, conditionally required. | Procedure: Zoll 2000 and/or CureWrap 3500 cooling system<br>* Device(Zoll 2000 and/or CureWrap 3500 cooling system),lasting 5 to 7 days, the core temperature will be controlled in 33-35 degree.<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 after hemorrhage by 2 specialized investigators who are 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 after hemorrhage | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial pressure | 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, until the monitor is removed | 
| Length of ICU stay | The numbers of days in the ICU | 6 months post hemorrhage | 
| Length of hospital stay | The numbers of days in the hospital. | 6 months post hemorrhage | 
| Frequency of complications | Frequency of complications during the the study such as pneumonia, coagulation disturbance,electrolyte disturbances, liver and kidney function abnormality will be recorded and compared between groups. | 6 months post hemorrhage | 
| Mortality rate | The proportion of death will be determined | 6 months after hemorrhage |