Hypertonic Modulation of Inflammation Following Injury

This project seeks to determine the effect of prehospital resuscitation with hypertonic saline vs. conventional crystalloids on the inflammatory response after injury. The leading cause of late mortality following injury is multiple organ dysfunction syndrome (MODS), which results from a dysfunctional inflammatory response after injury. Previous studies suggest that hypertonic saline may be beneficial by modulating this initial response and decreasing subsequent organ injury. This project takes advantage of a unique opportunity, afforded by an NIH-funded multi-center clinical trial of hypertonic resuscitation (conducted by the Resuscitation Outcomes Consortium), to obtain blood samples from patients enrolled in this trial to analyze inflammatory responses early after hypertonic vs. conventional resuscitation. This study was an ancillary study to the main randomized clinical trial and thus prospective observational in nature

The proposed study will be carried out in experiments grouped in three Specific Aims: Aim 1 provides a thorough investigation of the immunomodulatory response following hypertonic resuscitation with regard to neutrophil, monocyte, and T cell responses at serial time points after injury and resuscitation. Aim 2 comprises experiments to investigate the mechanisms by which hypertonicity may alter inflammatory cell signaling. Aim 3 seeks to correlate the laboratory findings with clinical endpoints reflective of immune dysfunction including inflammation, organ failure, nosocomial infection, and sepsis.

The investigators hypothesize that hypertonic resuscitation will be associated with modulation of the excessive inflammatory response seen after injury and thus will result in reduced rates of inflammatory organ injury.

Study Overview

• Status: Terminated
• Conditions: Traumatic Brain Injury; Hemorrhagic Shock
• Intervention / Treatment: Drug: hypertonic saline

Detailed Description

This was an ancillary study to the larger clinical trials of prehospital hypertonic resuscitation conducted by the resuscitation outcomes consortium. This study investigated markers of immune function and coagulation in a subset of patients enrolled in the larger trials at two of the clinical sites. Four publications detail the results please see references

• Study Type: Observational
• Enrollment (Actual): 119

Contacts and Locations

Study Locations

• Canada
  • Toronto, Canada
    • University of Toronto
• United States
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington

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

• Sampling Method: Non-Probability Sample

Study Population

Patients enrolled in clinical trial of Hypertonic Resuscitation based on prehospital evidence of hypovolemic shock or severe brain injury

Description

Inclusion Criteria:

• Blunt or Penetrating trauma with prehospital systolic blood pressure < 70 or 70-90 mmHg with Heart rate > 108 OR Blunt trauma with prehospital Glasgow coma score <= 8

Exclusion Criteria:

• Age < 15 yrs
• Known prisoners
• Pregnancy
• Ongoing Cardiopulmonary resuscitation (CPR)
• Burns < 20%
• Hypothermia < 28 C
• > 2 liters intravenous fluid prior to study fluid administration
• > 4 hour from time of dispatch

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Hypertonic saline; Hypertonic resuscitation	Drug: hypertonic saline; patients in parent trial were randomized to 250cc 7.5% saline, 7.5%saline with 6%dextran or normal saline as control as the initial resuscitation fluid after injury with signs of either hemorrhagic shock or severe traumatic brain injury; Other Names: hypertonic saline with dextran
Control: normal saline; Normal saline resuscitation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
neutrophil activation	several parameters of neutrophil activation were assessed	Emergency department admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial cell activation	several parameters of endothelial cell activation were assessed	Emergency department admission
coagulation parameters	several parameters of coagulation were assessed	Emergency department admission
monocyte activation	several parameters of monocyte activation were assessed	Emergency department admission

Collaborators and Investigators

• Sponsor: University of Washington
• Investigators: Principal Investigator: Eileen M Bulger, MD, University of Washington

Publications and helpful links

General Publications

• Delano MJ, Rizoli SB, Rhind SG, Cuschieri J, Junger W, Baker AJ, Dubick MA, Hoyt DB, Bulger EM. Prehospital Resuscitation of Traumatic Hemorrhagic Shock with Hypertonic Solutions Worsens Hypocoagulation and Hyperfibrinolysis. Shock. 2015 Jul;44(1):25-31. doi: 10.1097/SHK.0000000000000368.
• Junger WG, Rhind SG, Rizoli SB, Cuschieri J, Baker AJ, Shek PN, Hoyt DB, Bulger EM. Prehospital hypertonic saline resuscitation attenuates the activation and promotes apoptosis of neutrophils in patients with severe traumatic brain injury. Shock. 2013 Nov;40(5):366-74. doi: 10.1097/SHK.0000000000000038.
• Junger WG, Rhind SG, Rizoli SB, Cuschieri J, Shiu MY, Baker AJ, Li L, Shek PN, Hoyt DB, Bulger EM. Resuscitation of traumatic hemorrhagic shock patients with hypertonic saline-without dextran-inhibits neutrophil and endothelial cell activation. Shock. 2012 Oct;38(4):341-50. doi: 10.1097/SHK.0b013e3182635aca.
• Bulger EM, Tower CM, Warner KJ, Garland T, Cuschieri J, Rizoli S, Rhind S, Junger WG. Increased neutrophil adenosine a3 receptor expression is associated with hemorrhagic shock and injury severity in trauma patients. Shock. 2011 Nov;36(5):435-9. doi: 10.1097/SHK.0b013e318231ee2e.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: September 10, 2008
• First Submitted That Met QC Criteria: September 10, 2008
• First Posted (Estimate): September 11, 2008

Study Record Updates

• Last Update Posted (Actual): May 1, 2017
• Last Update Submitted That Met QC Criteria: April 27, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hemorrhage; Shock; Craniocerebral Trauma; Trauma, Nervous System; Inflammation; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Shock, Hemorrhagic; Anticoagulants; Plasma Substitutes; Blood Substitutes; Dextrans
• Other Study ID Numbers: 28233

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data from the primary RCT will be made available through the Resuscitation Outcomes consortium. This was an ancillary study