Prolonged Convection-enhanced Delivery into the Rat Brainstem

Abstract

Prolonged convection-enhanced delivery was used in an attempt to achieve large volumes of distribution (V(d)) in the rat brainstem. Clinical assessment and histological analysis were performed to establish the safety of this approach. For evaluation of V(d,), 10 rats underwent stereotactic cannula placement into the brainstem. Five rats underwent a 24-hour infusion (volume of infusion [V(i)], 200 microl), and 5 rats underwent a 7-day infusion (V(i), 2 ml) of fluorescein isothiocyanate-dextran. Serial brainstem sections were imaged with ultraviolet illumination, and V(d) was assessed. For assessment of clinical tolerance, 30 additional rats underwent chronic infusions of an isotonic saline solution into the brainstem. Serial neurological examinations were performed, followed by histological analysis after the animals' death. No animal demonstrated clinically recognized neurological deficits. Foci of organizing necrosis were limited to the site of infusion and cannula tract. V(d) increased linearly with increasing V(i) (range, 24.8-130.6 mm(3)). Maximal cross sectional area of fluorescence and craniocaudal extent of fluorescence increased with increasing V(i). Fluorescence was detected throughout the entire brainstem beyond the compact area of highly concentrated tracer. Prolonged convection-enhanced delivery can be applied safely in the rat brainstem with no recognized limitations of V(d) and minimal histological changes beyond the site of infusion. Chronic brainstem infusions may enhance the potential application of convection-enhanced delivery for therapeutic purposes in treating diffuse pontine gliomas.