Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

• Sponsor: University of Washington (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00316004
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), U.S. Army Medical Research and Development Command (U.S. Fed), Canadian Institutes of Health Research (CIHR) (Other), Canadian Department of National Defense (Other), Heart and Stroke Foundation of Canada (Other)
• Enrollment: 1,331
• Locations: 12
• Arms: 3
• Duration (Months): 44.1
• Patients Per Site: 110.9
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	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

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 Design

• Study Type: Interventional
• Actual Enrollment: 1331 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3 Study of Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis [6 months after injury]

   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.

2. Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis [6 months after injury]

   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

1. 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 [6 months after injury]

   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.

2. 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 [6 months after injury]

   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.

3. Disability Rating Score (DRS) Categories of Disability [6 months after injury]

   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.

4. 28 Day Survival [28 days after injury]

   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.

5. Survival at Hospital Discharge up to 6 Months From Date of Injury [Date of 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.

6. Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28 [From day of injury to 28 days after injury]

   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.

7. Worst Multiple Organ Dysfunction Score (MODS) Through Day 28 [From day of injury to 28 days after injury]

   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).

8. Ventilator-free Days Through Day 28 [From day of injury to 28 days after injury]

   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).

9. Days Alive Out of the Intensive Care Unit (ICU) Through Day 28 [From day of injury to 28 days after injury]

   The number of days the patient is alive and not being cared for in the intensive care unit

10. Days Alive Out of the Hospital Through Day 28 [From day of injury to 28 days after injury]

    The number of days the patient is alive and no longer an inpatient in the hospital through day 28

11. Presence of Nosocomial Infections [From day of injury to 28 days after injury]

    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

12. Total Fluids in First 24 Hours [First 24 hours from the time dispatch received 911 call]

    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

13. Packed Red Blood Cells (PRBC) First 24 Hours [First 24 hours from the time dispatch received 911 call]

    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.

14. Discharge Disposition [Duration of hospital stay]

    Disposition of patient at the time of discharge from the acute care hospital

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

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

Sponsors and Collaborators

• University of Washington
• National Heart, Lung, and Blood Institute (NHLBI)
• National Institute of Neurological Disorders and Stroke (NINDS)
• U.S. Army Medical Research and Development 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00316004
• Other Study ID Numbers: 28226-A - IND 12505; 5U01HL077863-05; IND #12505 TBI cohort
• First Posted: Apr 19, 2006
• Last Update Posted: May 19, 2011
• Last Verified: May 1, 2011

• Keywords provided by , ,: Traumatic; Brain injury
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Dextrans

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled by Emergency Medicine Services (EMS) personnel in the prehospital setting based on pre-defined inclusion/exclusion criteria. The first subject was enrolled in May 2006. The last subject was enrolled in May 2009.
Pre-assignment Detail	1331 subjects were randomized. 1282 were included in primary imputation analysis. 49 were randomized with study fluid package opened but no study fluid was given. Reasons given were: Did not meet inclusion criteria; Met an exclusion criterion; No intravenous access; Fluid bag sterility broken; EMS responder unsure of inclusion/exclusion criteria.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Period Title: Overall Study
STARTED	373	355	603
COMPLETED	359	341	582
NOT COMPLETED	14	14	21

Baseline Characteristics

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)	Total
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	Total of all reporting groups
Overall Participants	373	355	603	1331
Age (participants) [Number]
<=18 years	33 8.8%	19 5.4%	43 7.1%	95 7.1%
Between 18 and 65 years	296 79.4%	305 85.9%	484 80.3%	1085 81.5%
>=65 years	41 11%	29 8.2%	74 12.3%	144 10.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.5 (18.6)	38.6 (17.3)	39.5 (19.2)	39.0 (18.4)
Gender (participants) [Number]
Female	86 23.1%	68 19.2%	163 27%	317 23.8%
Male	284 76.1%	286 80.6%	438 72.6%	1008 75.7%
Region of Enrollment (participants) [Number]
United States	291 78%	259 73%	441 73.1%	991 74.5%
Canada	82 22%	96 27%	162 26.9%	340 25.5%

Outcome Measures

1. Primary Outcome

Title	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis
Description	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.
Time Frame	6 months after injury

Outcome Measure Data

Analysis Population Description

The primary analysis was designed as modified intent-to-treat, with all patients who had fluid connected to intravenous (IV) tubing included regardless of how much fluid was administered. Per the a priori trial design, patients for whom the fluid bag was opened but not connected to the IV were not considered enrolled in the trial.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	302	293	492
Number [Participants]	181 48.5%	171 48.2%	276 45.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent prevalence of poor outcome between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

2. Secondary Outcome

Title	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
Description	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.
Time Frame	6 months after injury

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	208	193	331
Number [Participants (with imputed values)]	146.1 39.2%	128.0 36.1%	219.0 36.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent prevalence of poor outcome between the three treatment groups among patients with head AIS≥4.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments	Adjusted for multiple imputations

3. Primary Outcome

Title	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis
Description	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.
Time Frame	6 months after injury

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	359	341	582
Number [Participants (with imputed values)]	192.9 51.7%	185.4 52.2%	299.8 49.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent prevalence of poor outcome between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments	Adjusted for multiple imputations.

4. Secondary Outcome

Title	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
Description	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.
Time Frame	6 months after injury

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	281	268	458
Number [Participants (with imputed values)]	166.7 44.7%	150.6 42.4%	253.2 42%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent prevalence of poor outcome between the three treatment groups among patients with head AIS≥2.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments	Adjusted for multiple imputations

5. Secondary Outcome

Title	Disability Rating Score (DRS) Categories of Disability
Description	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.
Time Frame	6 months after injury

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	359	341	582
0-1 (none/mild disability)	124.8 33.5%	128.0 36.1%	232.0 38.5%
2-6 (Partial/Moderate Disability)	98.3 26.4%	89.4 25.2%	143.2 23.7%
7-21 (moderately severe/severe/extremely severe)	33.0 8.8%	26.6 7.5%	43.3 7.2%
22-30 (vegetative/extreme vegetative/dead)	102.9 27.6%	97.0 27.3%	163.4 27.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients at any level of disability between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.84
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for proportions
	Comments	Adjusted for multiple imputations

6. Secondary Outcome

Title	28 Day Survival
Description	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.
Time Frame	28 days after injury

Outcome Measure Data

Analysis Population Description

An analysis of this secondary outcome was done for all participants assigned to each of the three groups who did not refuse or were lost to follow-up prior to discharge.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	357	340	575
Number [Participants]	268 71.8%	260 73.2%	432 71.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients who were alive on the 28th day after injury between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments	The numbers differ from the JAMA manuscript because of typos and version control issues that were discovered after publication.

7. Secondary Outcome

Title	Survival at Hospital Discharge up to 6 Months From Date of Injury
Description	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.
Time Frame	Date of hospital discharge up to 6 months from date of injury

Outcome Measure Data

Analysis Population Description

An analysis of this secondary outcome was done for all participants assigned to each of the three groups who had relevant data.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	354	337	575
Number [Participants]	263 70.5%	255 71.8%	427 70.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients who were alive on the day discharged from the hospital after injury between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments	The numbers differ from the JAMA manuscript because of typos and version control issues that were discovered after publication.

8. Secondary Outcome

Title	Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28
Description	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.
Time Frame	From day of injury to 28 days after injury

Outcome Measure Data

Analysis Population Description

Number of participants analyzed in each group is the actual number analyzed, which does not include participants with one of the following: 1. prehospital death; 2. transfer to another hospital without IRB approval; or 3. patient, family member, or legally authorized representative refused consent and was withdrawn from the study.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	356	337	572
Number [Participants]	247 66.2%	239 67.3%	401 66.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients who were alive and free of ARDS from the day of injury to the 28th day after injury between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.91
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments	The numbers differ from the JAMA manuscript because of typos and version control issues that were discovered after publication.

9. Secondary Outcome

Title	Worst Multiple Organ Dysfunction Score (MODS) Through Day 28
Description	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).
Time Frame	From day of injury to 28 days after injury

Outcome Measure Data

Analysis Population Description

Number of participants analyzed in each group is the actual number analyzed, which does not include participants with one of the following: 1. prehospital death; 2. transfer to another hospital without IRB approval; or 3. patient, family member, or legally authorized representative refused consent and was withdrawn from the study.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	348	329	558
Mean (Standard Deviation) [Scores on a scale]	9 (9.3)	8.6 (9.3)	8.6 (9.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in average Worst Multiple Organ Dysfunction Scores (MODS) through day 28 between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.81
	Comments	The p-value was not adjusted for multiple comparisons. Test compares averages across all three treatment groups.
	Method	ANOVA
	Comments	The numbers differ from the JAMA manuscript because of typos and version control issues that were discovered after publication.

10. Secondary Outcome

Title	Ventilator-free Days Through Day 28
Description	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).
Time Frame	From day of injury to 28 days after injury

Outcome Measure Data

Analysis Population Description

Number of participants analyzed in each group is the actual number analyzed, which does not include participants with one of the following: 1. prehospital death; 2. transfer to another hospital without IRB approval; or 3. patient, family member, or legally authorized representative refused consent and was withdrawn from the study.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	355	337	572
Mean (Standard Deviation) [Days]	17.0 (11.6)	17.6 (11.5)	17.4 (11.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the average number of Ventilator-free days through day 28 between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments	The p-value was not adjusted for multiple comparisons. Test compares averages across all three treatment groups.
	Method	ANOVA
	Comments	The numbers differ from the JAMA manuscript because of typos and version control issues that were discovered after publication.

11. Secondary Outcome

Title	Days Alive Out of the Intensive Care Unit (ICU) Through Day 28
Description	The number of days the patient is alive and not being cared for in the intensive care unit
Time Frame	From day of injury to 28 days after injury

Outcome Measure Data

Analysis Population Description

Number of participants analyzed in each group is the actual number analyzed, which does not include participants with one of the following: 1. prehospital death; 2. transfer to another hospital without IRB approval; or 3. patient, family member, or legally authorized representative refused consent and was withdrawn from the study.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	355	337	572
Mean (Standard Deviation) [Days]	15.2 (11.5)	15.8 (11.4)	15.6 (11.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the average number of days alive out of the ICU through day 28 between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments	The p-value was not adjusted for multiple comparisons. Test compares averages across all three treatment groups.
	Method	ANOVA
	Comments	The numbers differ from the JAMA manuscript because of typos and version control issues that were discovered after publication.

12. Secondary Outcome

Title	Days Alive Out of the Hospital Through Day 28
Description	The number of days the patient is alive and no longer an inpatient in the hospital through day 28
Time Frame	From day of injury to 28 days after injury

Outcome Measure Data

Analysis Population Description

Number of participants analyzed in each group is the actual number analyzed, which does not include participants with one of the following: 1. prehospital death; 2. transfer to another hospital without IRB approval; or 3. patient, family member, or legally authorized representative refused consent and was withdrawn from the study.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	354	337	575
Mean (Standard Deviation) [Days]	9.8 (10.9)	10 (11.0)	10.7 (11.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the average number of days alive out of the hospital through day 28 between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments	The p-value was not adjusted for multiple comparisons. Test compares averages across all three treatment groups.
	Method	ANOVA
	Comments	The numbers differ from the JAMA manuscript because of typos and version control issues that were discovered after publication.

13. Secondary Outcome

Title	Presence of Nosocomial Infections
Description	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
Time Frame	From day of injury to 28 days after injury

Outcome Measure Data

Analysis Population Description

An analysis of this secondary outcome was done for all participants assigned to each of the three groups who had relevant data. Percentages were based on population at risk. Row 1 nosocomial infections; Row 2 pneumonia; Row 3 bloodstream infections; Row 4 urinary tract infections; and Row 5 wound infections

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	320	313	530
Nosocomial Infections ≥ 1	102	101	136
Pneumonia	72	71	100
Bloodstream Infection	23	21	19
Urinary Tract Infection	30	32	32
Wound Infection	8	8	16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients with any nosocomial infections through hospital stay between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients with pneumonia through hospital stay between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients with bloodstream infections through hospital stay between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients with urinary tract infections through hospital stay between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients with wound infections through hospital stay between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

14. Secondary Outcome

Title	Total Fluids in First 24 Hours
Description	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
Time Frame	First 24 hours from the time dispatch received 911 call

Outcome Measure Data

Analysis Population Description

An analysis of this secondary outcome was done for all participants assigned to each of the three groups who had relevant data.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	357	341	581
Mean (Standard Deviation) [Liters]	6.7 (5.5)	6.7 (5.5)	6.9 (5.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the average amount of total fluids given within the first 24 hours between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.68
	Comments	The p-value was not adjusted for multiple comparisons. Test compares averages across all three treatment groups.
	Method	ANOVA
	Comments

15. Secondary Outcome

Title	Packed Red Blood Cells (PRBC) First 24 Hours
Description	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.
Time Frame	First 24 hours from the time dispatch received 911 call

Outcome Measure Data

Analysis Population Description

An analysis of this secondary outcome was done for all participants assigned to each of the three groups who had relevant data.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	356	341	580
Mean (Standard Deviation) [Unit of PRBC]	1.4 (3.6)	1.2 (3.4)	1.5 (4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the average number of PRBC units given within the first 24 hours between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments	The p-value was not adjusted for multiple comparisons. Test compares averages across all three treatment groups.
	Method	ANOVA
	Comments

16. Secondary Outcome

Title	Discharge Disposition
Description	Disposition of patient at the time of discharge from the acute care hospital
Time Frame	Duration of hospital stay

Outcome Measure Data

Analysis Population Description

Number of participants analyzed in each group is the actual number analyzed, which does not include participants with one of the following: 1. prehospital death; 2. transfer to another hospital without IRB approval; or 3. patient, family member, or legally authorized representative refused consent and was withdrawn from the study.

Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.	250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
Measure Participants	352	336	574
Death	89 23.9%	81 22.8%	147 24.4%
Home	138 37%	134 37.7%	253 42%
Inpatient Rehabilitation	84 22.5%	90 25.4%	122 20.2%
Skilled Nursing Facility	37 9.9%	28 7.9%	40 6.6%
Nursing Home or Inpatient Psychiatric Facility	4 1.1%	3 0.8%	12 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients who died during hospitalization between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for proportions
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients who were discharged alive from the hospital to home between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients who were discharged alive from the hospital to inpatient rehabilitation facilities between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	7.5% Hypertonic Saline/6% Dextran (HSD), 7.5% Hypertonic Saline (HS), 0.9% Normal Saline (NS)
	Comments	The null hypothesis is that there are no differences in the percent of patients who were discharged alive from the hospital to skilled nursing facilities between the three groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments	The p-value was not adjusted for multiple comparisons. Test compares proportions across all three treatment groups.
	Method	test for differences in proportions
	Comments

Adverse Events

Time Frame	The time frame was from May 2006 through May 2009, which was 3 years
Adverse Event Reporting Description	Serial blood sodium levels were drawn to monitor the effects of the hypertonic saline solutions; Serial head CT's (computed tomography) were done to monitor for increased intracranial hemorrhage; and incidents of seizures in the first 24 hours.
Arm/Group Title	7.5% Hypertonic Saline/6% Dextran (HSD)		7.5% Hypertonic Saline (HS)		0.9% Normal Saline (NS)
Arm/Group Description	250 ml intravenous bolus administration of 7.5% saline/6% dextran 70 as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.		250 ml intravenous bolus administration of 7.5% hypertonic saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.		250 ml intravenous bolus administration of 0.9% saline as the initial resuscitation fluid given to injured patients with suspected severe traumatic brain injury in the out-of-hospital setting.
All Cause Mortality
	7.5% Hypertonic Saline/6% Dextran (HSD)		7.5% Hypertonic Saline (HS)		0.9% Normal Saline (NS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	7.5% Hypertonic Saline/6% Dextran (HSD)		7.5% Hypertonic Saline (HS)		0.9% Normal Saline (NS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/359 (19.2%)		72/341 (21.1%)		141/582 (24.2%)
Blood and lymphatic system disorders
Hypernatremia (sodium>160 mEq/L) requiring intervention	10/349 (2.9%)	10	14/334 (4.2%)	14	13/573 (2.3%)	13
Nervous system disorders
Increased intracranial hemorrhage on serial head CT	57/349 (16.3%)	57	60/325 (18.5%)	60	122/560 (21.8%)	122
Seizures in the first 24 hours	4/359 (1.1%)	4	3/341 (0.9%)	3	12/582 (2.1%)	12
Other (Not Including Serious) Adverse Events
	7.5% Hypertonic Saline/6% Dextran (HSD)		7.5% Hypertonic Saline (HS)		0.9% Normal Saline (NS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/359 (0%)		0/341 (0%)		0/582 (0%)

Limitations/Caveats

The trial was stopped early for futility at a planned data and safety monitoring board review. The futility boundary was crossed for each of the 2 group comparisons (hypertonic saline/dextran vs normal saline and hypertonic saline vs normal saline).

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.