Our research group uses many strategies to improve survival and reduce disability following trauma.
Activating Pro-Survival Mechanisms
Building on earlier work that identified damaging changes in cardiac and other cells from conventional crystalloid resuscitation fluids, we're currently focused on activating pro-survival genes and proteins using histone deacetylase inhibitors (HDACIs). These include but aren't limited to valproic acid (VPA), a commonly used anti-seizure medication that has been FDA-approved for decades. We have also investigated other novel agents such as mesenchymal exosomes to attenuate cellular injury and to promote recovery.
We've been investigating the effectiveness and optimal dosing of VPA in hemorrhage control, TBI, sepsis and in combined models. These findings have broader applications that extend beyond trauma care, for example we have discovered that VPA treatment can minimize cardiac damage following myocardial infarction, and kidney damage after ischemia-reperfusion. And we're further investigating targeted, isoform-specific HDACIs for patient-, organ-, and injury-specific uses. Eighteen HDACs have been identified in humans to date, each with distinct effects, which give us many potential new therapeutic targets.
Alternatives to Fresh Frozen Plasma
Problems with blood clotting, or coagulopathy, is ubiquitous in severely injured patients, and its presence correlates with high mortality. Administering fresh frozen plasma soon after injury can improve survival rates, but it needs refrigerated storage, which makes its use logistically impossible in the pre-hospital phases of care, especially in combat settings. Our lab continues to develop and test freeze- and spray-dried plasma and other blood products that don't require refrigeration -- alone and in combination with other strategies -- to treat trauma-induced coagulopathy.
Intra-aortic Balloon Pump to Stop Bleeding & Prevent Arrest
In this project that is funded by the DoD, we plan to combine two innovative strategies that have emerged in the recent years. The first is resuscitative endovascular balloon occlusion of the aorta (REBOA) that can control internal bleeding by stopping the blood flow below the level of the inflated balloon. The second, is Valproic acid (VPA), which is a drug that can sustain life despite massive blood loss. Both of these interventions have limitations, which we believe can be overcome by using them together to achieve synergistic effects. Limitation for standard REBOA is that it stops the blood flow below the level of balloon occlusion (complete or cREBOA), which can have serious consequences due to ischemia-reperfusion. This limits its use to less than 30 minutes. VPA, on the other hand, can make the cells/organs tolerant to ischemia but lacks the ability to actually stop the bleeding. We are testing a dual pronged approach which can significantly extend (6 fold or more) the safe ischemia time for REBOA, while minimizing its adverse consequences. As both the REBOA and VPA are in clinical use, these refinements, if successful, can easily be translated into clinical domain. By significantly increasing the safe duration of REBOA, we can make the technology suitable for military field-hospitals (and for the smaller civilian hospitals), where aortic balloons may have to be kept inflated for hours while the patients are transferred to other facilities for definitive care.
Hypothermia and Hibernation Strategies
Induced hypothermia, or emergency preservation and resuscitation (EPR), can help brain, heart and other cells survive while patients are treated for hemorrhage, hemorrhagic shock and TBI. We investigate approaches to inducing hypothermia and to controlled resuscitation to preserve neurologic and organ function after traumatic injury.
Since the clinical signs of infection and inflammatory responses to hemorrhagic shock overlap, we're working to identify biomarkers to more effectively discern patients developing sepsis — who need rapid antibiotic administration — from those with a systemic inflammatory response to injury. We're also working toward a point-of-care device to measure protein and metabolite biomarkers in the brain to help monitor and treat TBI.
A number of clinical trials and other studies in these areas are currently underway or forthcoming, including:
- Phase 2 and 3 trials of the HDAC inhibitor VPA
- Phase 1 trial of VPA (recently completed)
- Dose optimization study of VPA in large animal models of combat injuries
- Prolonged field care (72 hours) in hemorrhage and TBI with VPA and other strategies, including freeze-dried plasma in large animal models of combat injuries
- Studies of isoform-specific HDACIs in clinically relevant large animal models
- Administration of high dose intra-nasal insulin and light therapy as novel treatments for TBI in larege animal models
- Preclinical studies of mesenchymal stem cell-derived exosomes in in clinically relevant large animal models of TBI