Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

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

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.

Study Overview

• Status: Terminated
• Conditions: Brain Injuries, Traumatic
• Intervention / Treatment: Drug: 7.5% Hypertonic Saline in 6% Dextran-70 (HSD); Drug: 7.5% Hypertonic Saline (HS); Drug: 0.9% Normal Saline (NS)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1331
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y4E9
      • University of Ottawa/University of British Columbia Collaborative RCC, Ottawa Health Research Institute
    • Toronto, Ontario, Canada, M5B1W8
      • Toronto Regional Resuscitation Research Out-of-Hospital Network, University of Toronto
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • Alabama Resuscitation Center, University of Alabama
  • California
    • Orange, California, United States, 92868
      • Orange County/UC Irvine
    • San Diego, California, United States, 92103
      • UCSD-San Diego Resuscitation Research Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Iowa Resuscitation Network, University of Iowa Carver College of Medicine
  • Oregon
    • Portland, Oregon, United States, 97239
      • Portland Resuscitation Outcomes Consortium, Oregon Health & Sciences University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • The Pittsburgh Resuscitation Network, University of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • The Regional Medical Center at Memphis
  • Texas
    • Dallas, Texas, United States, 75390
      • Dallas Center for Resuscitation Research, University of Texas Southwestern Medical Center
  • Washington
    • Seattle, Washington, United States, 98195
      • Seattle-King County Center for Resuscitation Research, University of Washington
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Milwaukee Resuscitation Network, Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 7.5% hypertonic saline/6% dextran (HSD); 250 ml intravenous bolus administration of 7.5% saline/6% dextran 70	Drug: 7.5% Hypertonic Saline in 6% Dextran-70 (HSD); 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.; Other Names: RescueFlo
Experimental: 7.5% hypertonic saline (HS); 250 ml intravenous bolus administration of 7.5% hypertonic saline	Drug: 7.5% Hypertonic Saline (HS); 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.
Placebo Comparator: 0.9% normal saline (NS); 250 ml intravenous bolus administration of 0.9% saline	Drug: 0.9% Normal Saline (NS); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Canadian Institutes of Health Research (CIHR); National Institute of Neurological Disorders and Stroke (NINDS); U.S. Army Medical Research and Development Command; Heart and Stroke Foundation of Canada; Canadian Department of National Defense
• Investigators: Study Chair: Myron L Weisfeldt, MD, Resuscitation Outcomes Consortium

Publications and helpful links

General Publications

• Bulger EM, May S, Brasel KJ, Schreiber M, Kerby JD, Tisherman SA, Newgard C, Slutsky A, Coimbra R, Emerson S, Minei JP, Bardarson B, Kudenchuk P, Baker A, Christenson J, Idris A, Davis D, Fabian TC, Aufderheide TP, Callaway C, Williams C, Banek J, Vaillancourt C, van Heest R, Sopko G, Hata JS, Hoyt DB; ROC Investigators. Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. JAMA. 2010 Oct 6;304(13):1455-64. doi: 10.1001/jama.2010.1405.
• Tisherman SA, Schmicker RH, Brasel KJ, Bulger EM, Kerby JD, Minei JP, Powell JL, Reiff DA, Rizoli SB, Schreiber MA. Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium. Ann Surg. 2015 Mar;261(3):586-90. doi: 10.1097/SLA.0000000000000837.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: April 17, 2006
• First Submitted That Met QC Criteria: April 17, 2006
• First Posted (Estimate): April 19, 2006

Study Record Updates

• Last Update Posted (Estimate): May 19, 2011
• Last Update Submitted That Met QC Criteria: May 16, 2011
• Last Verified: May 1, 2011

More Information

Terms related to this study

• Keywords: Traumatic; Brain injury
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Anticoagulants; Plasma Substitutes; Blood Substitutes; Dextrans
• Other Study ID Numbers: 28226-A - IND 12505; 5U01HL077863-05 (U.S. NIH Grant/Contract); IND #12505 TBI cohort (Other Identifier: FDA)