Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

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

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00316004

Enrollment

1331

Registered

2006-04-19

Start date

2006-05-31

Completion date

2010-01-31

Last updated

2011-05-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Brain Injuries, Traumatic

Keywords

Traumatic, Brain injury

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.

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.

Interventions

DRUG7.5% 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.

DRUG7.5% 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.

DRUG0.9% 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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

15 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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.
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

Measure	Time frame	Description
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.
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.
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.
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.
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.
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).
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
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
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
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
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.
Discharge Disposition	Duration of hospital stay	Disposition of patient at the time of discharge from the acute care hospital
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).
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.

Countries

Canada, United States

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 details

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.

Participants by arm

Arm	Count
7.5% Hypertonic Saline/6% Dextran (HSD) 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.	373
7.5% Hypertonic Saline (HS) 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.	355
0.9% Normal Saline (NS) 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.	603
Total	1,331

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Subject was not given study fluid.	14	14	21

Baseline characteristics

Characteristic	7.5% Hypertonic Saline/6% Dextran (HSD)	7.5% Hypertonic Saline (HS)	0.9% Normal Saline (NS)	Total
Age Categorical <=18 years	33 participants	19 participants	43 participants	95 participants
Age Categorical >=65 years	41 participants	29 participants	74 participants	144 participants
Age Categorical Between 18 and 65 years	296 participants	305 participants	484 participants	1085 participants
Age Continuous	38.5 years STANDARD_DEVIATION 18.6	38.6 years STANDARD_DEVIATION 17.3	39.5 years STANDARD_DEVIATION 19.2	39.0 years STANDARD_DEVIATION 18.4
Gender Female	86 participants	68 participants	163 participants	317 participants
Gender Male	284 participants	286 participants	438 participants	1008 participants
Region of Enrollment Canada	82 participants	96 participants	162 participants	340 participants
Region of Enrollment United States	291 participants	259 participants	441 participants	991 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	0 / 359	0 / 341	0 / 582
serious Total, serious adverse events	69 / 359	72 / 341	141 / 582

Outcome results

Primary

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.

Time frame: 6 months after injury

Population: 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	Measure	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis	181 Participants
7.5% Hypertonic Saline (HS)	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis	171 Participants
0.9% Normal Saline (NS)	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis	276 Participants

Comparison: The null hypothesis is that there are no differences in the percent prevalence of poor outcome between the three groups.p-value: 0.55test for differences in proportions

Primary

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.

Time frame: 6 months after injury

Population: 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	Measure	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis	192.9 Participants (with imputed values)
7.5% Hypertonic Saline (HS)	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis	185.4 Participants (with imputed values)
0.9% Normal Saline (NS)	Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis	299.8 Participants (with imputed values)

Comparison: The null hypothesis is that there are no differences in the percent prevalence of poor outcome between the three groups.p-value: 0.67test for differences in proportions

Secondary

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.

Time frame: 28 days after injury

Population: 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	Measure	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	28 Day Survival	268 Participants
7.5% Hypertonic Saline (HS)	28 Day Survival	260 Participants
0.9% Normal Saline (NS)	28 Day Survival	432 Participants

Comparison: 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.p-value: 0.88test for differences in proportions

Secondary

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.

Time frame: From day of injury to 28 days after injury

Population: 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	Measure	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28	247 Participants
7.5% Hypertonic Saline (HS)	Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28	239 Participants
0.9% Normal Saline (NS)	Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28	401 Participants

Comparison: 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.p-value: 0.91test for differences in proportions

Secondary

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

Time frame: From day of injury to 28 days after injury

Arm	Measure	Value (MEAN)	Dispersion
7.5% Hypertonic Saline/6% Dextran (HSD)	Days Alive Out of the Hospital Through Day 28	9.8 Days	Standard Deviation 10.9
7.5% Hypertonic Saline (HS)	Days Alive Out of the Hospital Through Day 28	10 Days	Standard Deviation 11
0.9% Normal Saline (NS)	Days Alive Out of the Hospital Through Day 28	10.7 Days	Standard Deviation 11.2

Comparison: 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.p-value: 0.43ANOVA

Secondary

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

Time frame: From day of injury to 28 days after injury

Arm	Measure	Value (MEAN)	Dispersion
7.5% Hypertonic Saline/6% Dextran (HSD)	Days Alive Out of the Intensive Care Unit (ICU) Through Day 28	15.2 Days	Standard Deviation 11.5
7.5% Hypertonic Saline (HS)	Days Alive Out of the Intensive Care Unit (ICU) Through Day 28	15.8 Days	Standard Deviation 11.4
0.9% Normal Saline (NS)	Days Alive Out of the Intensive Care Unit (ICU) Through Day 28	15.6 Days	Standard Deviation 11.7

Comparison: 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.p-value: 0.76ANOVA

Secondary

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.

Time frame: 6 months after injury

Population: 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	Measure	Group	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	Disability Rating Score (DRS) Categories of Disability	0-1 (none/mild disability)	124.8 Participants (with imputed values)
7.5% Hypertonic Saline/6% Dextran (HSD)	Disability Rating Score (DRS) Categories of Disability	2-6 (Partial/Moderate Disability)	98.3 Participants (with imputed values)
7.5% Hypertonic Saline/6% Dextran (HSD)	Disability Rating Score (DRS) Categories of Disability	7-21 (moderately severe/severe/extremely severe)	33.0 Participants (with imputed values)
7.5% Hypertonic Saline/6% Dextran (HSD)	Disability Rating Score (DRS) Categories of Disability	22-30 (vegetative/extreme vegetative/dead)	102.9 Participants (with imputed values)
7.5% Hypertonic Saline (HS)	Disability Rating Score (DRS) Categories of Disability	22-30 (vegetative/extreme vegetative/dead)	97.0 Participants (with imputed values)
7.5% Hypertonic Saline (HS)	Disability Rating Score (DRS) Categories of Disability	0-1 (none/mild disability)	128.0 Participants (with imputed values)
7.5% Hypertonic Saline (HS)	Disability Rating Score (DRS) Categories of Disability	7-21 (moderately severe/severe/extremely severe)	26.6 Participants (with imputed values)
7.5% Hypertonic Saline (HS)	Disability Rating Score (DRS) Categories of Disability	2-6 (Partial/Moderate Disability)	89.4 Participants (with imputed values)
0.9% Normal Saline (NS)	Disability Rating Score (DRS) Categories of Disability	22-30 (vegetative/extreme vegetative/dead)	163.4 Participants (with imputed values)
0.9% Normal Saline (NS)	Disability Rating Score (DRS) Categories of Disability	2-6 (Partial/Moderate Disability)	143.2 Participants (with imputed values)
0.9% Normal Saline (NS)	Disability Rating Score (DRS) Categories of Disability	7-21 (moderately severe/severe/extremely severe)	43.3 Participants (with imputed values)
0.9% Normal Saline (NS)	Disability Rating Score (DRS) Categories of Disability	0-1 (none/mild disability)	232.0 Participants (with imputed values)

Comparison: The null hypothesis is that there are no differences in the percent of patients at any level of disability between the three groups.p-value: 0.84test for proportions

Secondary

Discharge Disposition

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

Time frame: Duration of hospital stay

Arm	Measure	Group	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	Discharge Disposition	Home	138 Participants
7.5% Hypertonic Saline/6% Dextran (HSD)	Discharge Disposition	Inpatient Rehabilitation	84 Participants
7.5% Hypertonic Saline/6% Dextran (HSD)	Discharge Disposition	Death	89 Participants
7.5% Hypertonic Saline/6% Dextran (HSD)	Discharge Disposition	Nursing Home or Inpatient Psychiatric Facility	4 Participants
7.5% Hypertonic Saline/6% Dextran (HSD)	Discharge Disposition	Skilled Nursing Facility	37 Participants
7.5% Hypertonic Saline (HS)	Discharge Disposition	Home	134 Participants
7.5% Hypertonic Saline (HS)	Discharge Disposition	Death	81 Participants
7.5% Hypertonic Saline (HS)	Discharge Disposition	Inpatient Rehabilitation	90 Participants
7.5% Hypertonic Saline (HS)	Discharge Disposition	Skilled Nursing Facility	28 Participants
7.5% Hypertonic Saline (HS)	Discharge Disposition	Nursing Home or Inpatient Psychiatric Facility	3 Participants
0.9% Normal Saline (NS)	Discharge Disposition	Nursing Home or Inpatient Psychiatric Facility	12 Participants
0.9% Normal Saline (NS)	Discharge Disposition	Skilled Nursing Facility	40 Participants
0.9% Normal Saline (NS)	Discharge Disposition	Home	253 Participants
0.9% Normal Saline (NS)	Discharge Disposition	Inpatient Rehabilitation	122 Participants
0.9% Normal Saline (NS)	Discharge Disposition	Death	147 Participants

Comparison: The null hypothesis is that there are no differences in the percent of patients who died during hospitalization between the three groups.p-value: 0.88test for proportions

Comparison: 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.p-value: 0.26test for differences in proportions

Comparison: 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.p-value: 0.16test for differences in proportions

Comparison: 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.p-value: 0.17test for differences in proportions

Secondary

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.

Time frame: First 24 hours from the time dispatch received 911 call

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

Arm	Measure	Value (MEAN)	Dispersion
7.5% Hypertonic Saline/6% Dextran (HSD)	Packed Red Blood Cells (PRBC) First 24 Hours	1.4 Unit of PRBC	Standard Deviation 3.6
7.5% Hypertonic Saline (HS)	Packed Red Blood Cells (PRBC) First 24 Hours	1.2 Unit of PRBC	Standard Deviation 3.4
0.9% Normal Saline (NS)	Packed Red Blood Cells (PRBC) First 24 Hours	1.5 Unit of PRBC	Standard Deviation 4.3

Comparison: 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.p-value: 0.43ANOVA

Secondary

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

Time frame: From day of injury to 28 days after injury

Population: 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	Measure	Group	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	Presence of Nosocomial Infections	Urinary Tract Infection	30 Diagnoses
7.5% Hypertonic Saline/6% Dextran (HSD)	Presence of Nosocomial Infections	Bloodstream Infection	23 Diagnoses
7.5% Hypertonic Saline/6% Dextran (HSD)	Presence of Nosocomial Infections	Nosocomial Infections ≥ 1	102 Diagnoses
7.5% Hypertonic Saline/6% Dextran (HSD)	Presence of Nosocomial Infections	Pneumonia	72 Diagnoses
7.5% Hypertonic Saline/6% Dextran (HSD)	Presence of Nosocomial Infections	Wound Infection	8 Diagnoses
7.5% Hypertonic Saline (HS)	Presence of Nosocomial Infections	Bloodstream Infection	21 Diagnoses
7.5% Hypertonic Saline (HS)	Presence of Nosocomial Infections	Nosocomial Infections ≥ 1	101 Diagnoses
7.5% Hypertonic Saline (HS)	Presence of Nosocomial Infections	Pneumonia	71 Diagnoses
7.5% Hypertonic Saline (HS)	Presence of Nosocomial Infections	Urinary Tract Infection	32 Diagnoses
7.5% Hypertonic Saline (HS)	Presence of Nosocomial Infections	Wound Infection	8 Diagnoses
0.9% Normal Saline (NS)	Presence of Nosocomial Infections	Wound Infection	16 Diagnoses
0.9% Normal Saline (NS)	Presence of Nosocomial Infections	Urinary Tract Infection	32 Diagnoses
0.9% Normal Saline (NS)	Presence of Nosocomial Infections	Nosocomial Infections ≥ 1	136 Diagnoses
0.9% Normal Saline (NS)	Presence of Nosocomial Infections	Bloodstream Infection	19 Diagnoses
0.9% Normal Saline (NS)	Presence of Nosocomial Infections	Pneumonia	100 Diagnoses

Comparison: 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.p-value: 0.06test for differences in proportions

Comparison: The null hypothesis is that there are no differences in the percent of patients with pneumonia through hospital stay between the three groups.p-value: 0.3test for differences in proportions

Comparison: The null hypothesis is that there are no differences in the percent of patients with bloodstream infections through hospital stay between the three groups.p-value: 0.04test for differences in proportions

Comparison: 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.p-value: 0.06test for differences in proportions

Comparison: The null hypothesis is that there are no differences in the percent of patients with wound infections through hospital stay between the three groups.p-value: 0.88test for differences in proportions

Secondary

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.

Time frame: 6 months after injury

Arm	Measure	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	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	166.7 Participants (with imputed values)
7.5% Hypertonic Saline (HS)	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	150.6 Participants (with imputed values)
0.9% Normal Saline (NS)	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	253.2 Participants (with imputed values)

Comparison: 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.p-value: 0.57test for differences in proportions

Secondary

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.

Time frame: 6 months after injury

Arm	Measure	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	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	146.1 Participants (with imputed values)
7.5% Hypertonic Saline (HS)	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	128.0 Participants (with imputed values)
0.9% Normal Saline (NS)	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	219.0 Participants (with imputed values)

Comparison: 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.p-value: 0.59test for differences in proportions

Secondary

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.

Time frame: Date of hospital discharge up to 6 months from date of injury

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

Arm	Measure	Value (NUMBER)
7.5% Hypertonic Saline/6% Dextran (HSD)	Survival at Hospital Discharge up to 6 Months From Date of Injury	263 Participants
7.5% Hypertonic Saline (HS)	Survival at Hospital Discharge up to 6 Months From Date of Injury	255 Participants
0.9% Normal Saline (NS)	Survival at Hospital Discharge up to 6 Months From Date of Injury	427 Participants

Comparison: 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.p-value: 0.88test for differences in proportions

Secondary

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

Time frame: First 24 hours from the time dispatch received 911 call

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

Arm	Measure	Value (MEAN)	Dispersion
7.5% Hypertonic Saline/6% Dextran (HSD)	Total Fluids in First 24 Hours	6.7 Liters	Standard Deviation 5.5
7.5% Hypertonic Saline (HS)	Total Fluids in First 24 Hours	6.7 Liters	Standard Deviation 5.5
0.9% Normal Saline (NS)	Total Fluids in First 24 Hours	6.9 Liters	Standard Deviation 5.7

Comparison: 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.p-value: 0.68ANOVA

Secondary

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).

Time frame: From day of injury to 28 days after injury

Arm	Measure	Value (MEAN)	Dispersion
7.5% Hypertonic Saline/6% Dextran (HSD)	Ventilator-free Days Through Day 28	17.0 Days	Standard Deviation 11.6
7.5% Hypertonic Saline (HS)	Ventilator-free Days Through Day 28	17.6 Days	Standard Deviation 11.5
0.9% Normal Saline (NS)	Ventilator-free Days Through Day 28	17.4 Days	Standard Deviation 11.7

Comparison: The null hypothesis is that there are no differences in the average number of Ventilator-free days through day 28 between the three groups.p-value: 0.77ANOVA

Secondary

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).

Time frame: From day of injury to 28 days after injury

Arm	Measure	Value (MEAN)	Dispersion
7.5% Hypertonic Saline/6% Dextran (HSD)	Worst Multiple Organ Dysfunction Score (MODS) Through Day 28	9 Scores on a scale	Standard Deviation 9.3
7.5% Hypertonic Saline (HS)	Worst Multiple Organ Dysfunction Score (MODS) Through Day 28	8.6 Scores on a scale	Standard Deviation 9.3
0.9% Normal Saline (NS)	Worst Multiple Organ Dysfunction Score (MODS) Through Day 28	8.6 Scores on a scale	Standard Deviation 9.5

Comparison: The null hypothesis is that there are no differences in average Worst Multiple Organ Dysfunction Scores (MODS) through day 28 between the three groups.p-value: 0.81ANOVA

Source: ClinicalTrials.gov · Data processed: Mar 30, 2026

Hypertonic Resuscitation Following Severe Traumatic Brain Injury (TBI)

Conditions

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Related papers

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Study design

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Exclusion criteria

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Primary

Secondary

Countries

Participant flow

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Participants by arm

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Outcome results

Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Completer Analysis

Glasgow Outcome Scale-Extended (GOSE)≤4 at 6 Months: Imputed Analysis

28 Day Survival

Acute Respiratory Distress Syndrome (ARDS)-Free Survival to Day 28

Days Alive Out of the Hospital Through Day 28

Days Alive Out of the Intensive Care Unit (ICU) Through Day 28

Disability Rating Score (DRS) Categories of Disability

Discharge Disposition

Packed Red Blood Cells (PRBC) First 24 Hours

Presence of Nosocomial Infections

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

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

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

Total Fluids in First 24 Hours

Ventilator-free Days Through Day 28

Worst Multiple Organ Dysfunction Score (MODS) Through Day 28