Introduction
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 brings to bear the resources of the Resuscitation Outcomes Consortium (ROC) to evaluate the effect of early administration of HSD and HS on outcome for patients in hypovolemic shock and those with severe traumatic brain injury. This is a consortium of 10 clinical centers in the United States and Canada along with a Data Coordinating Center, which is tasked with conducting prehospital clinical trials for cardiac arrest and life threatening trauma.

Specific Aims
Aim 1: To determine if prehospital administration of 7.5% hypertonic saline /dextran (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.
Aim 2: To determine if prehospital administration of 7.5% HSD OR 7.5% HS alone compared to current standard therapy with NS as an initial resuscitation fluid affects neurological outcome following severe traumatic brain injury.

Study Design
This study is a randomized, double-blind, three-arm placebo controlled trial designed to evaluate the clinical outcome of trauma patients with either hypovolemic shock, as manifested by prehospital hypotension, or severe TBI as manifested by a prehospital 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 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. TBI patients will have neurologic outcomes measurements at discharge and at 1 and 6 months post injury. Enrollment will be restricted to age ≥ 15 yrs or ≥ 50kg if age is unknown.

Inclusion criteria

Hypovolemic Shock Cohort

• Blunt or Penetrating Trauma
• Prehospital SBP ≤ 70mmHg OR
  Prehospital SBP 71-90 And HR ≥ 108
• Age ≥ 15yrs or ≥ 50 kg

TBI Cohort

• Blunt Trauma
• Prehospital GCS ≤ 8
• Age ≥ 15yrs or ≥ 50 kg

Exclusion criteria (both cohorts)

• Known or suspected pregnancy
• Age < 15 or < 50kg if age unknown
• Ongoing prehospital Cardiopulmonary Resuscitation (CPR)
• Administration of > 2000cc crystalloid or any colloid or blood products
• Severe hypothermia (T < 28C)
• Drowning or asphyxia due to hanging
• Burns TBSA > 20%
• Isolated penetrating injury to the head
• Inability to obtain prehospital intravenous access
• Time of call received at dispatch to study intervention > four hours
• Known prisoners

Sample Size
Shock cohort: N = 3726. The anticipated length of this trial with this sample size will be approximately 3.5 years.
TBI Cohort: N = 2122. The anticipated length of this trial with this sample size will be approximately 1.5 years

Consent
It is expected that the majority of patients who meet the enrollment criteria will either be unconscious or have an altered mental status. These studies qualify for the "Exception from informed consent required for emergency research" outlined in FDA regulation 21CFR50.24. The protocols will be conducted under strict FDA guidelines that allow for patients in life threatening situations to participate in research without standard informed consent. Patients and/or family will be notified of their participation as soon as feasible and consent will be sought for continued participation. Each site's IRB will decide how best to consult the community and perform public notification, recommending local-specific approaches.

• ROC Hypertonic Saline Protocol

OHRI members:

Cathy Clement
Jane Banek
Jennifer Brinkhurst
Julia Foxall
Ghislaine LePage
Mary Jo Lewis
Angela Marcantonio
Tracy McArdle
Stan Morrow
Connor Sheehan
Christine Tym
Irene Watpool