Hypertonic Resuscitation Following Traumatic Injury

Phase 3 Study of Hypertonic Resuscitation Following Traumatic Injury With Hypovolemic Shock

The purpose of this study is to determine if hypertonic saline with and without dextran can improve overall survival in victims of trauma with shock.

Injury and lost blood from trauma can cause your body to be in 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 resuscitation fluid most commonly used is "isotonic" or one that is the same 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 the investigators 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 your blood. Dextran is a sugar solution.

Study Overview

• Status: Terminated
• Conditions: Shock, Traumatic
• Intervention / Treatment: Drug: 7.5% hypertonic saline/6% Dextran-70 (HSD); Drug: 7.5% hypertonic saline (HS); Drug: 0.9% normal saline

Detailed Description

Specific Aim: To determine if prehospital administration of 7.5% hypertonic saline /6% Dextran-70 (HSD) OR 7.5% hypertonic saline alone (HS), compared to current standard therapy with normal saline (NS), as an initial resuscitation fluid, affects survival following traumatic injury with hypovolemic shock.

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 prehospital 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. The majority of previous clinical trials have focused on the use of HSD. The potential for 7.5% saline alone (HS) to have similar effects has not been well studied. Removal of the dextran component may enhance the anti-inflammatory effects of this solution, which could improve secondary outcomes such as acute respiratory distress syndrome (ARDS), multiple organ failure syndrome (MOFS) and rates of nosocomial infections.

This study is a randomized, double-blind, three-arm placebo controlled trial designed to evaluate the clinical outcome of trauma patients with hypovolemic shock, as manifested by prehospital hypotension. 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 prehospital resuscitation. No additional interventions will occur once the patient is admitted to the hospital. In hospital data collection will last up to 28 days.

• Study Type: Interventional
• Enrollment (Actual): 895
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Blunt or penetrating trauma
• Prehospital Systolic Blood Pressure (SBP) <= 70;OR
• Prehospital SBP 71-90 AND Hear Rate (HR) ≥108
• 15 years of age or older, or 50kg or more if age unknown

Exclusion Criteria:

• Known or suspected pregnancy
• Age younger than 15 or less than 50kg if age unknown
• Ongoing prehospital cardiopulmonary resuscitation (CPR)
• Administration of more than 2000cc crystalloid or any colloid or blood products
• Severe hypothermia (suspected Temperature less than 28 degrees celsius)
• Drowning or asphyxia due to hanging
• Burns Total Body Surface Area (TBSA) more than 20%
• Isolated penetrating injury to the head
• Inability to obtain prehospital intravenous access
• Time of call received at dispatch to study intervention greater than four hours
• Known prisoners

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; 7.5% hypertonic saline/6% Dextran-70 (HSD)	Drug: 7.5% hypertonic saline/6% Dextran-70 (HSD); 250 cc dose given as a one-time intravenous (IV) bolus in the pre-hospital setting.; Other Names: RescueFlo
Experimental: 2; 7.5% hypertonic saline (HS)	Drug: 7.5% hypertonic saline (HS); 250 cc dose given as a one-time IV bolus in the pre-hospital setting.
Placebo Comparator: 3; 0.9% normal saline	Drug: 0.9% normal saline; 250 cc dose given as a one-time IV bolus in the pre-hospital setting.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 Day Survival	The day of episode is counted as "Day 0". So for measures using a 28 day period, the maximum value is 29 (i.e. days 0 through 28).	28 days from time of Emergency Department (ED) arrival

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adult Respiratory Distress Syndrome(ARDS)-Free Survival Through Day 28	Absence of diagnosis of Adult Respiratory Distress Syndrome and alive through day 28	28 days from time of ED arrival
Worst Multiple Organ Dysfunction Score (MODS) Mean Through Day 28	Multiple Organ Dysfunction Score is described as: Six organ systems were chosen, and a score of 0-4 allotted for each organ according to function (0 being normal function through to 4 for most severe dysfunction) with a maximum score of 24. The worst score based on available data (missing values were assumed normal) in each 24-hour period is taken for calculation of the aggregate score.	28 days from time of ED arrival
Presence of Nosocomial Infection Through Day 28	Includes one or more nosocomial infections from the following list: pneumonia, blood stream infection, urinary tract infection and wound infection	Within 28 days of injury, while hospitalized
Packed Red Blood Cells (PRBC) First 24 Hours	The numbers of units of packed red blood cells transfused in the first 24 hours	First 24 hours from the time of 911 call
Total Fluids First 24 Hours	The total amount of IV fluids given in the pre-hospital setting and the hospital setting in the first 24 hours following the time of 911 call	First 24 hours from the time of of 911 call
Ventilator-free Days Through Day 28	The number of days beginning with the day of 911 call counted as "Day O" through day 28 that the patient did not require mechanical ventilation	Duration of hospital stay through day 28
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	First 28 days from the time of 911 call
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	First 28 days from the time of 911 call
Survival at Hospital Discharge	Alive at the time of discharge from the Level One or Two trauma hospital. This did not include disposition from rehabilitation facilities.	Duration of hospital stay through to discharge
Zero Units PRBC in First 24 Hours	This is the total number of subjects who received no blood products in the first 24 hours from the time of the 911 call.	From the time dispatch received the 911 call to the end of the first 24 hours
Zero Units PRBC and Died in Field or Emergency Department (ED)	This is the total number of subjects who died in the field or the ED from the set of subjects who received no blood products.	From the time dispatch received 911 call to the time of death in the field or ED
Zero Units PRBC and Died Within 6 Hours of Admission to the Hospital	This is the total number of subjects who died within the first 6 hours from the time of admission to the hospital among the patients who received no blood products.	The first 6 hours from the time of admission to the hospital
Zero Units PRBC and Died Within 28 Days From the Time of the 911 Call	This is the total number of subjects who died within 28 days from the time of the 911 call among the patients who received no units of PRBC.	From the time dispatch received the 911 call to 28 days
1-9 Units PRBC in First 24 Hours	This is the total number of subjects who received 1 to 9 units of packed red blood cells (PRBC) in the first 24 hours from the time of the 911 call.	From the time dispatch received the 911 call to the end of the first 24 hours
1-9 Units PRBC and Died in Field or ED	This is the total number of subjects who received 1 to 9 units of packed red blood cells (PRBC) among the patients who died in the field or the ED.	From the time dispatch received 911 call to the time of death in the field or ED
1-9 Units PRBC and Died Within 6 Hours of Admission to the Hospital	This is the total number of subjects who died within the first 6 hours from the time of admission to the hospital among the patients who received 1 to 9 units of packed red blood cells (PRBC).	The first 6 hours from the time of admission to the hospital
1-9 Units PRBC and Died Within 28 Days From the Time of the 911 Call	This is the total number of subjects who died within 28 days from the time of the 911 call among the patients who received 1 to 9 units of packed red blood cells (PRBC).	From the time dispatch received the 911 call to 28 days
Greater Than 10 Units PRBC in First 24 Hours	This is the total number of subjects who received greater than 10 units of packed red blood cells (PRBC) in the first 24 hours from the time of the 911 call.	From the time dispatch received the 911 call to the end of the first 24 hours
Greater Than 10 Units PRBC and Died in Field or ED	This is the total number of subjects who died in the field or the ED among the patients who received greater than 10 units of packed red blood cells (PRBC).	From the time dispatch received 911 call to the time of death in the field or ED
Greater Than 10 Units PRBC and Died Within 6 Hours of Admission to the Hospital	This is the total number of subjects who died within the first 6 hours from the time of admission to the hospital among the patients who received greater than 10 units of packed red blood cells (PRBC).	The first 6 hours from the time of admission to the hospital
Greater Than 10 Units PRBC and Died Within 28 Days From the Time of the 911 Call	This is the total number of subjects who died within 28 days from the time of the 911 call among the patients who received greater than 10 units of packed red blood cells (PRBC).	From the time dispatch received the 911 call to 28 days

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institute of Neurological Disorders and Stroke (NINDS); The Institute of Circulatory and Respiratory Health (ICRH); Defence Research and Development Canada
• Investigators: Study Chair: Myron L Weisfeldt, MD, Resuscitation Outcomes Consortium

Publications and helpful links

General Publications

• Tisherman SA, Schmicker RH, Brasel KJ, Bulger EM, Kerby JD, Minei JP, Powell JL, Reiff DA, Rizoli SB, Schreiber MA. Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium. Ann Surg. 2015 Mar;261(3):586-90. doi: 10.1097/SLA.0000000000000837.
• Bulger EM, May S, Kerby JD, Emerson S, Stiell IG, Schreiber MA, Brasel KJ, Tisherman SA, Coimbra R, Rizoli S, Minei JP, Hata JS, Sopko G, Evans DC, Hoyt DB; ROC investigators. Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg. 2011 Mar;253(3):431-41. doi: 10.1097/SLA.0b013e3181fcdb22.

Study record dates

Study Major Dates

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

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Estimate): March 1, 2011
• Last Update Submitted That Met QC Criteria: February 25, 2011
• Last Verified: February 1, 2011

More Information

Terms related to this study

• Keywords: Shock; Trauma
• Additional Relevant MeSH Terms: Pathologic Processes; Wounds and Injuries; Shock; Shock, Traumatic; Anticoagulants; Plasma Substitutes; Blood Substitutes; Dextrans
• Other Study ID Numbers: 28226-A - IND 12506; 5U01HL077863-05 (U.S. NIH Grant/Contract); IND #12506 (shock cohort) (Other Identifier: FDA)