Double Blind Study of Hypertonic Saline vs Mannitol in the Management of Increased Intracranial Pressure (ICP).

Study Overview
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Brief Summary
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The study goal is to compare the management of increased intra-cranial pressure (ICP) using 3% hypertonic saline vs. mannitol (given in same osmolar loads). Primary hypothesis: 1. Hypertonic saline will be non-inferior to mannitol in decreasing elevated ICP. Secondary hypotheses: Hypertonic saline therapy will result with fewer complications than mannitol ICP reduction duration will be longer using hypertonic saline when compared with mannitol

Detailed Description
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There is growing evidence in the literature indicating that ICP and Cerebral Perfusion Pressure measurements may not be sufficient in the management of elevated ICP. Based on this evidence, monitoring of partial brain tissue oxygenation has gain acceptance among neurosurgeons and neurointensivists, and has become a standard of care monitor in some centers across the country. There is, however, insufficient information in the literature describing the effects of hyperosmolar medications on regional brain tissue oxygenation. We intend to undertake this non-inferiority, prospective, randomized double-blind study to answer very important clinical questions not yet answered in the literature: Will hypertonic saline therapy, given at equiosmolar load, be non-inferior to mannitol in reducing elevated ICP?

Official Title
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Double Blind Study of Hypertonic Saline vs Mannitol in the Management of Increased Intracranial Pressure (ICP).

Conditions
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Elevated Intracranial Pressure

Intervention / Treatment
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* Drug: hypertonic saline
* Drug: Mannitol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years elevated ICP requiring ICP monitoring ICP ≥ 25 mmHg 5 min after ICP bolt or EVD placement Exclusion Criteria: Requiring decompressive craniotomy or post decompressive craniotomy Hyponatremia (sodium level < 125 mEq/L) Hypernatremia (sodium > 155 mmol/L) Serum osmolality ≤ 250 mOsm/kg Serum osmolality ≥ 320 mOsm/kg Physical exam compatible with brain death Patients on hemodialysis with end-stage renal disease

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: hypertonic saline<br>3% hypertonic saline, dosed by ideal patient weight | Drug: hypertonic saline<br>* 3% hypertonic saline, dosed by ideal patient weight<br>|
| Active Comparator: Mannitol<br>20% mannitol, dosed by patient's ideal body weight | Drug: Mannitol<br>* Mannitol 20% intravenous solution, dosed by patient's ideal body weight<br>* Other names: Osmitrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent reduction of ICP from baseline |  | 30 minutes from completion of medication administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from study drug administration completion to ICP < 25 mmHg |  | First 72 hours | 
| Cumulative duration of ICP below 25 mmHg |  | First 24 hours | 
| Cumulative duration of ICP below 25 mmHg |  | First 72 hours | 
| Cumulative duration of cerebral perfusion pressure (CPP) above 60 mmHg |  | First 24 hours | 
| Cumulative duration of cerebral perfusion pressure (CPP) above 60 mmHg |  | First 72 hours | 
| Cumulative duration of regional oxygen partial pressure (pbtO2) > 20% |  | two hours following each dose administration during the first 24 hours | 
| Total dose of medications given |  | First 24 hours; also over 3 days | 
| Frequency of treatment failure | Treatment failure defined as ICP > 30 mmHg for > 30 minutes | First 72 hours | 
| Frequency of rebound intracranial hypertension | Rebound intracranial hypertension defined as ICP > 25 mmHg for more than 10 minutes following ICP stabilization | First 72 hours | 
| Frequency of composite Major Adverse Events | acute kidney injury as defined by an increase in creatinine x 2 or GFR decrease > 50% or urine output < 0.5 ml/kg/h for 12 hours, compared to baseline, as per RIFLE criteria hypotensive episodes (SBP < 90 mmHg for more than 10 minutes) hemodynamic instability as measured by decrease of cardiac output by more than 15% within two hours following medication administration pulmonary edema as defined by ELWI I> 10 | 3 days | 
| Difference in inflammatory response | Determined by analysis of cytokine and inflammatory biomarkers. | Regular intervals over first 3 days | 
| Difference in average pre-discharge stroke scale score |  | hospital discharge (or 30 days if not discharged) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clinical trial, mannitol, intracranial pressure (ICP), hypertonic saline, cerebral edema, traumatic brain injury (TBI)