Treatment of Intracranial Hypertension of Severe Tramatic Brain Injured Patients. Physiopathologic Effects of Neuromuscular Blocking Agents

Study Overview
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Brief Summary
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Severely brain injured patients are at high risk of intracranial hypertension. Among medical treatments (sedatives), neuromuscular blocking agents (NMBA) are recommended by french but not english speaking societies. Effects of NMBA are unknown. The present study is designed to compare the effects of NMBA versus placebo in the treatment of intracranial hypertension, and the underlying physiopathologic effects.

Detailed Description
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In case of intracranial hypertension, french neurocritical care society argue for the use of neuromuscular blocking agents before osmotherapy, barbituric coma, hypothermia and craniectomy. English speaking societies don't sustain this approach. Since then, the use of NMBA remains controversial in case of intracranial hypertension and no study is available. We propose to study severely brain injured patients presenting with intracranial hypertension and treat them with cisatracurium besilate or placebo. Our hypothesis is that neuromuscular blockade might act on several parameters: Hemodynamics respiratory parameters, mechanical ventilation and blood gaz analysis cerebral velocities diminished O2 peripheral consumption cerebrospinal diffusion and concentration of cisatracurium and a metabolite laudanosine We wish to assess changes in ICP according to the above parameters in a controlled randomized non blinded fashion against placebo (NaCl 0,9%).

Official Title
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Treatment of Intracranial Hypertension of Severe Tramatic Brain Injured Patients. Physiopathologic Effects of Neuromuscular Blocking Agents. A Controlled Randomized Study Versus Placebo

Conditions
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Traumatic Brain Injury, Intracranial Hypertension

Intervention / Treatment
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* Drug: cisatracurium besilate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Age over 18 Mechanical ventilation and deep sedation Severe traumatic brain injury Intracranial hypertension (ICP > 20 mmHg during > 15 minutes) Intracranial pressure monitoring Hemodynamically stable Exclusion Criteria: - History of anaphylaxia with neuromuscular agents Hemodynamic instability Pregnant and/or breast feeding women

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CISATRACURIUM<br>To compare the evolution of intracranial pressure (ICP) of severely brain injured patients with intracranial hypertension after administration of cisatracurium versus placebo. | Drug: cisatracurium besilate<br> <br> |
| Placebo Comparator: PLACEBO<br>To compare the evolution of intracranial pressure (ICP) of severely brain injured patients with intracranial hypertension after administration of cisatracurium versus placebo. | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| area under the curve of the temporal evolution of intracranial pressure | The primary outcome is the area under the curve of the temporal evolution of intracranial pressure, over a period of 30 minutes after the administration of neuromuscular blocking agent or placebo. | at day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Course of intracranial and cerebral perfusion pressures and various cerebral monitoring data if available (SvjO2, PtiO2) |  | at day 1 | 
| Monitoring of the time spent by intracranial pressure above 20 mmHg using continuous recording |  | at day 1 | 
| Course of intracranial pressure based on the type of brain injury | diffuse axonal injury, subarachnoid hemorrhage, intracerebral hematoma) | at day 1 | 
| Monitoring of the curare effect | train of four and PTC | at day 1 | 
| Course of ventilation parameters | tidal volume, FiO2, PEEP | at day 1 | 
| Course of transcranial Doppler data | velocities | at day 1 | 
| Course of arterial blood gas data | pH, paO2, paCO2, Excess Base, HCO3- | at day 1 | 
| Course of plasma and cerebrospinal fluid concentrations of cistracurium and laudanosine |  | at day 1 | 
| Cerebrospinal fluid concentrations of cisatracurium and laudanosin in case of cerebrospinal fluid derivation |  | at day 1 | 
| Occurrence of cardiovascular complications | hypotension, myocardial ischemia | at day 1 | 
| Occurrence of pulmonary complications | acute respiratory distress syndrome, pneumonia acquired under mechanical ventilation | at day 1 | 
| Occurrence of renal complications | use of renal replacement therapy | at day 1 | 
| Occurrence of infectious complications |  | at day 1 | 
| Doses of vasopressors or catecholamines |  | at day 1 | 
| Need to increase therapeutics | barbiturate coma, hypothermia, osmotherapy, decompressive craniectomy | at day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICU, Deep sedation, Mechanical ventilation, Traumatic brain injury, Intracranial hypertension, Cisatracurium, Neuromuscular Blocking Agent, Randomization versus placebo