Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

Study Overview
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Brief Summary
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The purpose of this study is to determine if hypertonic saline with and without dextran can improve neurologic outcomes in victims of severe traumatic brain injury (TBI). Injury and lost blood from trauma can cause your body to go into shock (low blood pressure related to blood loss). This decreased blood flow can lead to organ damage. In order to restore the blood pressure and blood flow, the medics give fluids into the patients' veins as soon as possible. This is called resuscitation. The fluid most commonly used is isotonic or one that is the same salt concentration as the blood. The investigators are trying to determine if infusing a hypertonic fluid or one more concentrated than the blood can increase the blood pressure and restore blood flow more efficiently. The hypertonic fluids they are using are called hypertonic saline with dextran (HSD) and hypertonic saline (no dextran). Hypertonic saline is a salt solution that is slightly more concentrated than blood. Dextran is a sugar solution.

Detailed Description
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To determine if prehospital administration of 7.5% Hypertonic Saline in 6% Dextran-70 (HSD) OR 7.5% Hypertonic Saline (HS) compared to current standard therapy with NS as an initial resuscitation fluid affects neurological outcome following severe traumatic brain injury. Trauma is the leading cause of death among North Americans between the ages of 1 and 44 years. The majority of these deaths result from hypovolemic shock or severe brain injury. Patients in hypovolemic shock develop a state of systemic tissue ischemia then a subsequent reperfusion injury at the time of fluid resuscitation. Conventional resuscitation involves the IV administration of a large volume of isotonic or slightly hypotonic (lactated ringers, LR) solutions beginning in the pre-hospital setting. Although not conclusive, prior studies have suggested that alternative resuscitation with hypertonic saline (7.5%) solutions may reduce morbidity or mortality in these patients. Furthermore, hypertonic fluids may have specific advantages in the brain-injured patient, as they may aid in the rapid restoration of cerebral perfusion and prevent extravascular fluid sequestration, thereby limiting secondary brain injury. In addition, recent studies have demonstrated that hypertonicity significantly alters the activation of inflammatory cells, an effect that may reduce subsequent organ injury from ischemia-reperfusion and decrease nosocomial infection. This study is a randomized, double-blind, three-arm placebo controlled trial designed to evaluate the clinical outcome of trauma patients with severe TBI as manifested by a pre-hospital GCS of 8 or less. Patients will be randomized to a single 250cc IV dose of 7.5% saline in 6% Dextran-70 (HSD), 7.5% saline (HS) or normal saline as the initial fluid for pre-hospital resuscitation. No additional interventions will occur once the patient is admitted to the hospital. In hospital data collection will last up to 28 days. Patients will have neurologic outcome measurements at discharge, 1 month post discharge, and 6 months post injury. Enrollment will be restricted to age ≥ 15 years or ≥ 50 kg if age is unknown.

Official Title
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Phase 3 Study of Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

Conditions
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Brain Injuries, Traumatic

Intervention / Treatment
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* Drug: 7.5% Hypertonic Saline in 6% Dextran-70 (HSD)
* Drug: 7.5% Hypertonic Saline (HS)
* Drug: 0.9% Normal Saline (NS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Blunt trauma Pre-hospital Glasgow Coma Scale equal to or less than 8(GCS≤8)* Age 15 years or older or 50 kg or more Patients who met the inclusion criteria above and did not meet the exclusion criteria below but who had systolic blood pressure (SBP) ≤70 or SBP>70 and SBP≤90 and heart rate (HR)≥108 were included in the Hypertonic Resuscitation following Traumatic Injury study that focused on shock patients who may or may not have a traumatic brain injury (TBI). In other words, patients with both TBI and shock would not be included in this study of TBI patients without shock at the time of enrollment. Exclusion Criteria: Known or suspected pregnancy Age younger than 15 years or less than 50 kg if age unknown Ongoing pre-hospital cardiopulmonary resuscitation (CPR) Administration of more than 2L crystalloid or any colloid or blood products Severe hypothermia (T less than 28C) Drowning or asphyxia due to hanging Burns TBSA more than 20% Isolated penetrating injury to the head Inability to obtain pre-hospital intravenous access Time of call received at dispatch to study intervention more than four hours Known prisoners

Ages Eligible for Study
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Minimum Age: 15 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 |
| --- | --- |
| Experimental: 7.5% hypertonic saline/6% dextran (HSD)<br>250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 | Drug: 7.5% Hypertonic Saline in 6% Dextran-70 (HSD)<br>* 250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 administered as a one-time bolus fluid for initial resuscitation to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.<br>* Other names: RescueFlo;|
| Experimental: 7.5% hypertonic saline (HS)<br>250 ml intravenous bolus administration of 7.5% hypertonic saline | Drug: 7.5% Hypertonic Saline (HS)<br>* 250 ml intravenous bolus administration of 7.5% hypertonic saline administered as a one-time bolus fluid for initial resuscitation to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.<br>|
| Placebo Comparator: 0.9% normal saline (NS)<br>250 ml intravenous bolus administration of 0.9% saline | Drug: 0.9% Normal Saline (NS)<br>* 250 ml intravenous bolus administration of 0.9% saline administered as a one-time bolus fluid for initial resuscitation to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis | Glasgow outcome score extended (GOSE) contains eight categories: 1. Dead, 2. Vegetative State (VS), 3. Lower Severe Disability (Lower SD), 4. Upper Severe Disability (Upper SD), 5. Lower Moderate Disability (Lower MD), 6. Upper Moderate Disability (Upper MD), 7. Lower Good Recovery (Lower GR) and 8. Upper Good Recovery (Upper GR). A measured neurological outcome of GOSE≤4 is a poor outcome of severe disability, vegetative state, or death. Completer analysis includes only those patients with GOSE completed at 6 months after injury. | 6 months after injury | 
| Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis | Glasgow outcome score extended (GOSE) contains 8 categories: 1. Dead, 2. Vegetative State, 3. Lower Severe Disability, 4. Upper Severe Disability, 5. Lower Moderate Disability, 6. Upper Moderate Disability, 7. Lower Good Recovery and 8. Upper Good Recovery. To adjust for 15% of subjects with absent 6-month GOSE data, an analysis using 20 hot deck imputations for the 6-month GOSE was done using data from patients who were discharged alive based on 1-month post discharge GOSE data or discharge GOSE (if 1-month post discharge data were not available), length of hospital stay, and treatment group. | 6 months after injury | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subgroup of Participants With Head Abbreviated Injury Scores (AIS) Greater Than or Equal to 4 (Head AIS≥4) Assessed to Have Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis | The Abbreviated Injury Scale (AIS) ranks injuries on a scale of 1 to 6, with 1 being minor, 2 moderate, 3 serious, 4 severe, 5 critical and 6 an unsurvivable injury. A priori secondary analyses included the subgroup of participants in each intervention group with a head AIS≥4, which is a diagnostic indicator of severe to lethal head injury. Of this subset of participants with AIS≥4, a second subset of participants with a GOSE≤4 at the 6 month follow up was analyzed. GOSE≤4 represents Upper Severe Disability or worse outcomes. 15% of subjects required imputation analysis for 6-month GOSE. | 6 months after injury | 
| Subgroup of Participants With Head Abbreviated Injury Scores (AIS) Greater Than or Equal to 2 (Head AIS≥2) Assessed to Have Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis | The Abbreviated Injury Scale (AIS) ranks injuries on a scale of 1 to 6, with 1 being minor, 2 moderate, 3 serious, 4 severe, 5 critical and 6 an unsurvivable injury. A priori secondary analyses included the subgroup of participants in each intervention group with a head AIS≥2, which is a diagnostic indicator of moderate to lethal head injury. Of this subset of participants with AIS≥2, a second subset of participants with a GOSE≤4 at the 6 month follow up was analyzed. GOSE≤4 represents Upper Severe Disability or worse outcomes. 15% of subjects required imputation analysis for 6-month GOSE. | 6 months after injury | 
| Disability Rating Score (DRS) Categories of Disability | The DRS is an additional measure of neurological outcome that categorizes the patient's level of disability on a scale of 0 to 29, with 0 indicating no disability to 29 indicating extreme vegetative state. To adjust for 15% of subjects with absent 6-month DRS data, an analysis using 20 hot deck imputations for the 6-month DRS was done using data from patients who were discharged alive based on 1-month post discharge DRS data or discharge DRS (if 1-month post discharge data were not available), length of hospital stay, and treatment group. | 6 months after injury | 
| 28 Day Survival | The patient who is admitted to the hospital after injury and is alive on the 28th day after injury. For 28-day survival, patients with missing 28-day vital status who were known to be discharged alive prior to 28 days were assumed to be alive at day 28. | 28 days after injury | 
| Survival at Hospital Discharge up to 6 Months From Date of Injury | The patient who is admitted to the hospital alive after injury and is alive when discharged from the hospital up to 6 months from the date of injury. | Date of hospital discharge up to 6 months from date of injury | 
| Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28 | The patient is alive and free of ARDS from the date of injury through to the 28th day following injury. The diagnosis of ARDS is based on standard criteria: a) hypoxia with a ratio of arterial oxygen pressure to percent oxygen delivered of less than 200; b) bilateral infiltrates on chest X-ray; and c) clinical evidence of increased left atrial pressure or pulmonary artery wedge pressure of greater than 18 mmHg. | From day of injury to 28 days after injury | 
| Worst Multiple Organ Dysfunction Score (MODS) Through Day 28 | Multiple Organ Dysfunction Score is described as: Six organ systems were chosen: 1) respiratory; 2) renal; 3) hepatic; 4) cardiovascular; 5) hematologic; and 6) neurologica. A score of 0-4 was allotted for each organ according to function (0 being normal function through 4 for most severe dysfunction) with a maximum score of 24. The worst score based on available data (missing values were assumed normal) was taken for calculation of the aggregate score. Deaths are assigned the worst score (24). | From day of injury to 28 days after injury | 
| Ventilator-free Days Through Day 28 | The number of days beginning with the day of 911 call counted as Day 0 through day 28 that the patient did not require mechanical ventilation. Deaths are assigned the worst score (0). | From day of injury to 28 days after injury | 
| Days Alive Out of the Intensive Care Unit (ICU) Through Day 28 | The number of days the patient is alive and not being cared for in the intensive care unit | From day of injury to 28 days after injury | 
| Days Alive Out of the Hospital Through Day 28 | The number of days the patient is alive and no longer an inpatient in the hospital through day 28 | From day of injury to 28 days after injury | 
| Presence of Nosocomial Infections | Includes one or more nosocomial infections diagnosed during the hospital stay but not present on admission to the hospital from the following list: pneumonia, bloodstream infection, urinary tract infection, and/or wound infection | From day of injury to 28 days after injury | 
| Total Fluids in First 24 Hours | The average (mean) total amount of intravenous (IV) fluids given in the pre-hospital setting and the hospital setting in the first 24 hours following the time of the 911 call | First 24 hours from the time dispatch received 911 call | 
| Packed Red Blood Cells (PRBC) First 24 Hours | The average (mean) number of units of packed red blood cells (PRBC) transfused in the first 24 hours following the time of the 911 call in each group. | First 24 hours from the time dispatch received 911 call | 
| Discharge Disposition | Disposition of patient at the time of discharge from the acute care hospital | Duration of hospital stay | 

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