Funding Agency:

U.S. Army Medical Research Acquisition Activity (Grant No. PR054755)

Total Project Period:

2/13/06 - 02/12/10

Total Project Award:

$2,000,000

Principal Investigator:

Patrick M. Kochanek, MD (Critical Care Medicine)

Co-Investigators:

Hulya Bayir, MD (Critical Care Medicine); Robert S.B. Clark, MD (Critical Care Medicine & Pediatrics); C. Edward Dixon, PhD, Larry W. Jenkins, PhD; Valerian E. Kagan, PhD (Environmental and Occupational Health); Chien Ho, PhD (Carnegie Mellon University, Biological Sciences); Carleton J.C. Hsia, PhD (SynZyme Technologies, LLC, Irvine, CA); Li Ma, PhD (SynZyme Technologies, LLC, Irvine, CA)

Project Summary:

Traumatic brain injury is among the most frequent causes of morbidity and mortality on the modern battle-field and is the leading cause of traumatic death in the USA. In the military setting, both blast injuries and vehicular accidents account for the greatest proportion of these casualties. Morbidity and mortality resulting from traumatic brain injury are greatly increased by secondary insults such as hemorrhagic shock. Marked vulnerability of casualties with traumatic brain injury to even modest hypotension distinguishes them from other casualties with hemorrhagic shock.

Traditional resuscitation with crystalloids exacerbates intracranial hypertension and brain edema and indicates the critical need to both carefully evaluate the efficacies of resuscitation strategies in this subpopulation of injured patients, and develop novel approaches.

Recent reports indicate that casualties resulting from improvised explosive devices (IEDs) often have combined blunt injury (such as traumatic brain injury) and penetrating injury—and can rapidly exsanguinate from multiple seemingly small hemorrhagic shock.

The nitroxide-base resuscitation approaches outlined in this proposal, used alone or in combination with standard resuscitation fluids have great promise to produce a “battlefield friendly” resuscitation solution. Nitroxide-based resuscitation solutions will optimize systemic hemodynamics with the smallest possible fluid volume, while minimizing vascular injury and brain edema—and thus maximizing survival and neurological outcome. Thus, novel nitroxide-based solutions target an important and emerging military need—particularly in the current combat environment, where blast injuries have become a prevalent mechanism.

Similarly, in the civilian setting, traumatic brain injury from road traffic accidents, falls, and assaults result in over 40% of all deaths from acute injuries in the USA. Over 200,000 victims require hospitalization each year and are often permanently disabled. Traumatic brain injury is a key contributor to life-long morbidity, since victims are typically young.

The cost of acute care, rehabilitation and loss of potential income in civilian traumatic brain injury are enormous—and the indirect costs associated with this condition are estimated to be as much as 40 billion dollars annually. Secondary hospitalization is the most powerful predictor of poor outcome after severe traumatic brain injury in civilians. This has been shown after severe traumatic brain injury in both adults and children.

Impaired oxygen delivery by hemorrhagic shock superimposed upon increased metabolic demands and disturbed microcirculation of the acutely injured brain synergistically magnify the damage—producing the poor outcomes. Similar to the military setting, standard crystalloid (normal saline or Lactated Ringers solutions) resuscitation is woefully inadequate. The nitroxide-based resuscitation approaches outlined in this proposal, thus, could also have an important impact on care of victims of combined traumatic brain injury and hemorrhagic shock in civilian trauma.