This Mentored Patient-Oriented Research Career Development Award application requests support (or a proposal which includes mentorship by an experienced investigator, multidisciplinary support from the Chairs and faculty of several Departments. formal training in an NIH-funded Clinical Research Training Program. and a research project dissecting the regional and systemic effects of traditional and novel vasoactive drugs in critically ill patients with septic shock. Sepsis. the systemic inflammatory response to infection. may lead to refractorv hypotension (septic shock) and multiple organ system failure (MOSF). Despite increased cardiac output and oxygen delivery, death often ensues from refractory hypotension or subsequent MOSF. Standard indicators of adequate tissue perfusion which are used to titrate therapy in hypovolemic or cardiogenic shock are unreliable in hyperdynamic septic shock. Rational septic shock therapy would preferably be guided by targeted interventions tc? optimize end-organ perfusion and function, and reverse detectable tissue hypoperfusion. The primary end-organ index of adequate perfusion used in current clinical practice is renal perfusion and function. The effects of vasoactive drug therapy on renal perfusion and function are reliably quantifiable with sophisticated existing technology. This application seeks to determine the regional circulatory effects of restoring vascular contractility with standard exogenous catecholamines and the novel use of exogenous vasopressin, alone or in combination, in septic humans, focusing on renal perfusion and function. We will also examine the systemic and regional effects of targeted vasodilator therapy with fenoldopam (a novel dopaminergic agonist) in septic humans, alone or in combination with the aforementioned vasoconstrictors. Specifically, we will address the hypotheses that: 1) Addition of inotropic support (b-adrenoceptor stimulation) to intravenous fluids alone, or in combination with pure vasopressor therapy (a-adrenoceptor stimulation), improves renal perfusion and function in patients with sepsis or septic shock. 2) Titration of vasopressor therapy to a mean arterial pressure above the lower renal autoregulation threshold improves renal perfusion in patients with vasopressor-dependent septic shock. 3) Vasopressin therapy restores septic vascular contractility, augments vasopressor-responsiveness, reverses hypotension. and improves systemic and renal perfusion in human subjects receiving standard therapy for sepsis or septic shock. 4) Septic renal vasoconstriction is reversed, and renal perfusion and function improved, by selective renal vasodilator therapy. The overall aim of these experiments is to develop rational pharmacologic regimens and strategies for hemodynamic support in septic shock. focusing on prevention and management of septic acute renal failure, as a surrogate endpoint to optimize systemic perfusion in hyperdynamic states.
