Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

This study has been terminated.
(Futility)
Sponsor:
Collaborators:
U.S. Army Medical Research and Materiel Command
Canadian Institutes of Health Research (CIHR)
Canadian Department of National Defense
Heart and Stroke Foundation of Canada
Information provided by:
University of Washington
ClinicalTrials.gov Identifier:
NCT00316004
First received: April 17, 2006
Last updated: May 16, 2011
Last verified: May 2011
  Purpose

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.


Condition Intervention Phase
Brain Injuries, Traumatic
Drug: 7.5% Hypertonic Saline in 6% Dextran-70 (HSD)
Drug: 7.5% Hypertonic Saline (HS)
Drug: 0.9% Normal Saline (NS)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 3 Study of Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis [ Time Frame: 6 months after injury ] [ Designated as safety issue: No ]
    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.

  • Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis [ Time Frame: 6 months after injury ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 [ Time Frame: 6 months after injury ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: 6 months after injury ] [ Designated as safety issue: No ]
    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.

  • Disability Rating Score (DRS) Categories of Disability [ Time Frame: 6 months after injury ] [ Designated as safety issue: No ]
    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.

  • 28 Day Survival [ Time Frame: 28 days after injury ] [ Designated as safety issue: No ]
    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.

  • Survival at Hospital Discharge up to 6 Months From Date of Injury [ Time Frame: Date of hospital discharge up to 6 months from date of injury ] [ Designated as safety issue: No ]
    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.

  • Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28 [ Time Frame: From day of injury to 28 days after injury ] [ Designated as safety issue: No ]
    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.

  • Worst Multiple Organ Dysfunction Score (MODS) Through Day 28 [ Time Frame: From day of injury to 28 days after injury ] [ Designated as safety issue: No ]
    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).

  • Ventilator-free Days Through Day 28 [ Time Frame: From day of injury to 28 days after injury ] [ Designated as safety issue: No ]
    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).

  • Days Alive Out of the Intensive Care Unit (ICU) Through Day 28 [ Time Frame: From day of injury to 28 days after injury ] [ Designated as safety issue: No ]
    The number of days the patient is alive and not being cared for in the intensive care unit

  • Days Alive Out of the Hospital Through Day 28 [ Time Frame: From day of injury to 28 days after injury ] [ Designated as safety issue: No ]
    The number of days the patient is alive and no longer an inpatient in the hospital through day 28

  • Presence of Nosocomial Infections [ Time Frame: From day of injury to 28 days after injury ] [ Designated as safety issue: No ]
    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

  • Total Fluids in First 24 Hours [ Time Frame: First 24 hours from the time dispatch received 911 call ] [ Designated as safety issue: No ]
    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

  • Packed Red Blood Cells (PRBC) First 24 Hours [ Time Frame: First 24 hours from the time dispatch received 911 call ] [ Designated as safety issue: No ]
    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.

  • Discharge Disposition [ Time Frame: Duration of hospital stay ] [ Designated as safety issue: No ]
    Disposition of patient at the time of discharge from the acute care hospital


Enrollment: 1331
Study Start Date: May 2006
Study Completion Date: January 2010
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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.

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.

  Eligibility

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00316004

Locations
United States, Alabama
Alabama Resuscitation Center, University of Alabama
Birmingham, Alabama, United States, 35249
United States, California
Orange County/UC Irvine
Orange, California, United States, 92868
UCSD-San Diego Resuscitation Research Center
San Diego, California, United States, 92103
United States, Iowa
Iowa Resuscitation Network, University of Iowa Carver College of Medicine
Iowa City, Iowa, United States, 52242
United States, Oregon
Portland Resuscitation Outcomes Consortium, Oregon Health & Sciences University
Portland, Oregon, United States, 97239
United States, Pennsylvania
The Pittsburgh Resuscitation Network, University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
The Regional Medical Center at Memphis
Memphis, Tennessee, United States, 38103
United States, Texas
Dallas Center for Resuscitation Research, University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
United States, Washington
Seattle-King County Center for Resuscitation Research, University of Washington
Seattle, Washington, United States, 98195
United States, Wisconsin
Milwaukee Resuscitation Network, Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Canada, Ontario
University of Ottawa/University of British Columbia Collaborative RCC, Ottawa Health Research Institute
Ottawa, Ontario, Canada, K1Y4E9
Toronto Regional Resuscitation Research Out-of-Hospital Network, University of Toronto
Toronto, Ontario, Canada, M5B1W8
Sponsors and Collaborators
University of Washington
U.S. Army Medical Research and Materiel Command
Canadian Institutes of Health Research (CIHR)
Canadian Department of National Defense
Heart and Stroke Foundation of Canada
Investigators
Study Chair: Myron L Weisfeldt, MD Resuscitation Outcomes Consortium
  More Information

Additional Information:
Publications:
Responsible Party: Gerald Van Belle, PhD/Principal Investigator, Resuscitation Outcomes Consortium Data Coordinating Center
ClinicalTrials.gov Identifier: NCT00316004     History of Changes
Other Study ID Numbers: 28226-A - IND 12505, 5U01HL077863-05, IND #12505 TBI cohort
Study First Received: April 17, 2006
Results First Received: February 11, 2011
Last Updated: May 16, 2011
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
Canada: Ethics Review Committees
Canada: Health Canada

Keywords provided by University of Washington:
Traumatic
Brain injury

Additional relevant MeSH terms:
Brain Injuries
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Dextrans
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Plasma Substitutes
Blood Substitutes

ClinicalTrials.gov processed this record on July 26, 2014