Pulsatile Perfusion Therapy Phase II

Hemorrhage due to trauma is one of the leading causes of morbidity and mortality worldwide in both the civilian and military settings. A major factor contributing to death and disability from severe blood loss is poor tissue perfusion and oxygenation of the vital organs. Traditionally, protection of absolute cerebral blood flow (CBF) has been deemed the most important factor in maintaining perfusion and oxygenation. In recent years, it has been shown that low frequency (LF, \~0.1 Hz) pulsatile CBF is associated with increased tolerance to simulated hemorrhage in healthy human subjects, despite ≥30% reductions in absolute CBF. The underlying mechanism for this improvement in tolerance is unclear; the proposed study aims to address this knowledge gap. The central hypothesis is that LF oscillations (\~0.1 Hz) will improve CBF and tissue oxygenation under hypoxic and/or hypovolemic conditions, due to increased shear stress and the release of vasoactive mediators that facilitate vasodilation and enhanced tissue perfusion. This hypothesis will be addressed in two Specific Aims under hypoxic and hypovolemic conditions: 1) determine if inducing oscillations in arterial blood pressure and CBF at 0.1 Hz elicits shear stress-induced vasodilation, subsequently increasing CBF and oxygenation; and, 2) assess the effect of 0.1 Hz oscillations on the release of shear stress-induced vasoactive mediators. Twenty human subjects (males and females) will be recruited to address these aims using oscillatory lower body negative pressure (OLBNP) to induce 0.1 Hz oscillations. Measurements will include CBF (intracranial \& extracranial arteries), shear stress, cerebral oxygenation, arterial pressure, and venous blood samples for assessment of nitric oxide, prostaglandin E2, 6-keto-PGF1α (a metabolite of prostacyclin, PGI2), histamine, and endothelin-1. The rationale for the proposed research is to identify a mechanism for the previously observed increase in tolerance to simulated hemorrhage with increases in LF oscillations in arterial pressure and CBF. The approach is innovative as it challenges the traditional association of hemodynamic variability with negative clinical outcomes using a novel methodological approach in human subjects. This contribution is significant as the findings may provide an alternative approach to maintaining cerebral perfusion and oxygenation under conditions of hypovolemia and/or hypoxia.