Intraventricular hemorrhage (IVH) occurs in a significant number of low birth weight infants, causing acute intracranial hypertension, neurological deterioration, and possibly permanent post-hemorrhagic hydrocephalus (PHH). In the adult, IVH often complicates aneurysm, vascular malformation, hypertension and vasculitidis with the same dire consequences. Ventricular drainage during the acute phase of IVH is often frustrated by clogging of catheters by solid blood clots that may persist for weeks in ventricular cerebrospinal fluid (CSF) due to the latter's weak fibrinolytic activity. It is hypothesized (1) that urokinase (UK), a plasminogen activator, instilled intraventricularly can effect rapid clot lysis, lower intracranial pressure, and facilitate CSF drainage; (2) that by promptly removing blood products from the ventricles and subarachnoid space, UK may minimize subependymal damage and subarachnoid fibrosis, and reduce the likelihood of PHH. 10 control dogs will receive intraventricular injections of autologous blood clots. The kinetics of """"""""natural"""""""" intraventricular thrombolysis and subsequent ventricular volume changes will be studied using computed tomographic volumetric data, neurological examinations, blood tests reflecting systemic fibrinolytic profile, and necropsy examination of the brain and meninges. The rate of clot lysis and the degree of ventricular enlargement of the control dogs will be compared to those of 10 UK dogs with similar ventricular clots treated by repeated intraventricular injection of UK and followed with the same parameters, so as to document the thrombolytic capability of UK for intraventricular clots as well as its ability to prevent PHH. Safety of intraventricular UK, previously established in adult dogs, will also be tested on 5 newborn puppies. Control and urokinase trial experiments identical to those used in adult dogs will be performed on newborn puppies to examine any age-related differences. Finally, intraventricular UK will be given to adult dogs bearing recent experimentally induced periventricular (caudate) infarction to examine the susceptibility of freshly infarcted tissue to local plasminogen activation. Since the long-term objectives of this study include using intraventricular UK on patients with recent IVII, the last group of experiments will provide crucial data pertinent to premature infants with germinal matrix hemorrhage, and older patients with fresh brain lesions.
