Inconsistent blood brain barrier disruption by intraarterial mannitol in rabbits: implications for chemotherapy

The novel ability to quantify drug and tracer concentrations in vivo by optical means leads to the possibility of detecting and quantifying blood brain barrier (BBB) disruption in real-time by monitoring concentrations of chromophores such as Evan's Blue. In this study, experiments were conducted to assess the disruption of the BBB, by intraarterial injection of mannitol, in New Zealand white rabbits. Surgical preparation included: tracheotomy for mechanical ventilation, femoral and selective internal carotid artery (ICA) catheterizations, skull screws for monitoring electrocerebral activity, bilateral placement of laser Doppler probes and a small craniotomy for the placement of a fiber optic probe to determine tissue Evan's Blue dye concentrations. Evans Blue (6.5 mg/kg) was injected intravenously (IV) just before BBB disruption with intracarotid mannitol (25%, 8 ml/40 s). Brain tissue concentrations of the dye in mannitol-treated and control animals were monitored using the method of optical pharmacokinetics (OP) during the subsequent 60 min. Hemodynamic parameters, heart rate, blood pressure, and EKG remained stable throughout the experiments in both the control and the mannitol-treated group. Brain tissue concentrations of Evan's Blue and the brain:plasma Evan's Blue partition coefficient progressively increased during the period of observation. A wide variation in brain tissue Evan's Blue concentrations was observed in the mannitol group. The experiments demonstrate the feasibility of measuring tissue concentrations of Evan's Blue without invading the brain parenchyma, and in real-time. The data suggest that there are significant variations in the degree and duration of BBB disruption induced with intraarterial mannitol. The ability to optically monitor the BBB disruption in real-time could provide a feedback control for hypertonic disruption and/or facilitate dosage control for chemotherapeutic drugs that require such disruption.