Effect of Eythropoietin on Vascular Dysfunction in Human TBI

Baylor College Of Medicine, Houston TX

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Abstract

Traumatic brain injury (TBI) induces a spectrum of cerebrovascular dysfunction, ranging from impaired[unreadable] pressure autoregulation which causes TBI patients to be more vulnerable to secondary ischemic insults to[unreadable] severe global ischemia. Cerebral blood flow (CBF), especially within the first 12 hr after injury, is strongly[unreadable] predictive of neurological outcome, with each 10ml/100g/min increase in cortical CBF resulting in a 3-fold[unreadable] increase in the chances of surviving to hospital discharge. In past studies, a TBI management strategy that[unreadable] maintained an increased cerebral perfusion pressure to prevent ischemia in patients with severe TBI was[unreadable] very successful at reducing the incidence of jugular desaturation. However, when this management strategy[unreadable] was applied to all patients with severe TBI, adverse effects (especially increased incidence of adult[unreadable] respiratory distress syndrome) appeared to offset any beneficial effect on long-term outcome. Currently, we[unreadable] are studying the role that testing of dynamic pressure autoregulation might play in identifying those patients[unreadable] at greatest risk for developing ischemia and who might therefore benefit most from a hypertensive[unreadable] management strategy. However, we have found that after severe TBI, almost all (87%) patients have[unreadable] impaired dynamic pressure autoregulation. We now believe that any effective therapy directed at vascular[unreadable] dysfunction will have to be applied to all patients with severe TBI.[unreadable] Trauma is the most common cause of death in the 1-44 yr age group, and the third most common cause[unreadable] for the entire US population. Trauma accounts for more loss of work life-years than cancer and[unreadable] cardiovascular diseases combined. Effective treatments for this important public health disorder are needed.[unreadable] Treatment of the cerebrovascular dysfunction caused by TBI could significantly improve neurological[unreadable] recovery following trauma.[unreadable] We propose to study the physiological effects of administration of recombinant human erythropoietin[unreadable] (rhEpo), an agent that has been found to have potent neuroprotective effects after experimental TBI and[unreadable] spinal cord injury and that has the added benefit of stimulating erythropoiesis in critically ill patients.[unreadable] Preliminary data suggests that part of the mechanism of neuroprotection by rhEpo is likely to be amelioration[unreadable] of cerebrovascular dysfunction, possibly through upregulation of endothelial nitric oxide synthase. The goals[unreadable] of this project include the following: 1. To study the natural history of Epo and Epo receptor expression by[unreadable] the injured brain; 2. To study the acute effects of rhEpo administration on cerebral hemodynamics; 3. To[unreadable] study the chronic effects of rhEpo administration on the brain's response to injury.[unreadable]