Effect of Eythropoietin on Vascular Dysfunction in Human TBI

外伤性脑损伤（TBI）引起一系列脑血管功能障碍，从受损

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