Intraventricular hemorrhage (PIVH) causes death and neurologic handicap in the preterm human. We have shown the newborn puppy to be a model for PIVH and to be useful for determining the pathophysiology of PIVH. Factors associated with hemorrhage in this animal model include (1) rapid increases in arterial pressure, with or without hypercapnia; and (2) re- expansion of blood volume after acute hypovolemic hypotension. Our studies have shown that a marked increase in brain blood flow is common to these insults, and that such hyperemia is associated with the production of microvascular lesions in the pup brain. These lesions, which are thought to be initiated by the release of prostaglandin metabolites and free radical species, may impair endothelial integrity, blood-brain barrier, and autoregulatory functions and result in hemorrhages. We have found that phenobarbital (PBS) in anti-convulsant concentrations reduces cerebral hyperemia and decreases the incidence of hemorrhage in the pup model. It is not clear that PBS will reduce hyperemia or hemorrhages in pups that have been made hypoxic or hypercarbic; it is also not clear that PBS and other suggested preventative measures can be used safely in the newborn to prevent hyperemia without inducing ischemia. Thus, the goal of these studies is to use the microsphere method of blood flow measurement plus ultrastructural techniques to evaluate the suggested prophylactic agents phenobarbital, indomethacin, (prostaglandin synthesis inhibitor) atropine, hypocarbia, and two oxygen radical scavengers (vitamin E and superoxide dismutase) for their efficacy in (1) reducing cerebral hyperemia; (2) reducing the incidence and severity of cerebral microvascular lesions and blood-brain barrier disruption, and (3) reducing cerebral hemorrhages in the newborn pup. In addition, the effects of the vasoactive agents on autoregulation and on blood flow to hypercarbia. These studies have relevance for prevention of hemorrhages in newborns and in others at risk for hyperemic cerebral injury.
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