PATHOGENESIS OF MULTIPLE ORGAN FAILURE

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As regional trauma systems mature and early interventions improve, severely injured patients who would have previously died, now survive but are at high risk for multiple organ failure (MOF). With advances in intensive care unit (ICU) therapy, the mortality of MOF is decreasing, but.it still remains the leading cause of late ICU deaths and prolonged hospital stays. MOF occurs as a result of a dysfunctional inflammatory response. The gastrointestinal tract is both an instigator and a victim of this response, and the resulting gut dysfunctions contribute to ongoing MOF. A multidisciplinary team of basic and clinical scientists will continue to characterize gut injury and dysfunction in laboratory models of hemorrhagic shock, ischemia/reperfusion (I/R), and sepsis. In this funding cycle, they will test the HYPOTHESIS that therapeutic interventions can modulate gut inflammation and resulting gut dysfunction in critically injured patients to improve outcome. To make meaningful advances a better understanding of the molecular events that regulate gut inflammation is needed. We will therefore characterize cell specific molecular programs that activate pro- and anti-inflammation after mesenteric I/R and investigate how these are modulated by different protective interventions (ischemic preconditioning, hypothermia, alpha-melanocyte stimulating hormone) to identify common pathways to limit gut injury and/or hasten its repair. Resuscitation is an obligatory intervention that saves lives. The current standard of care is early volume loading with isotonic crystalloids (principally lactated Ringer's) and blood transfusions to limit the severity of the ischemic insult. For severe shock, this approach could be improved by modifying it to minimize iatrogenic gut edema and by altering it to specifically control gut I/R induced inflammation. We will therefore study the factors that cause problematic bowel edema with standard of care isotonic crystalloid resuscitation and how increasing edema affects vital gut functions. We will focus on how alternative resuscitation strategies (hypertonic saline with or without colloids) can favorably modulate gut I/R induced inflammation. Enteral nutrition (EN) is another important aspect of care that improves patient outcome. Unfortunately, gastric injury and dysfunction impair the ability to enterally feed high risk patients as well as mandate the use of expensive and potentially harmful prophylaxis against stress gastritis. We will study how resuscitation, sedatives, and analgesics can modify the inflammatory response in the stomach to limit mucosal injury and improve gastric emptying. We will study how the novel intraluminal interventions can modify inflammation in the stomach and ileum to preserve barrier function. Knowledge from these projects will allow modification of routine care to facilitate gastric feeding and to expand the definition of EN to include intraluminal agents whose role is to limit gut inflammation and dysfunction to enhance EN tolerance. Simultaneously, in our HUMAN SUBJECTS CORE laboratory observations will be tested in focused observational studies to determine their relevance in human pathophysiology. These clinical observations will in turn redirect ongoing laboratory investigations and serve as pilot and feasibility data to leverage funding for larger clinical trials.