The effect of large volume intrathecal bolus on the cerebral blood vessels

1629 Objectives: The blood-brain barrier prevents the entrance of biopharmaceuticals and other macromolecular therapeutics from reaching their respective targets in the CNS. However, there appears to be a barrier-free route to the CNS parenchyma through the perivascular spaces (PVS) communicating with the cerebrospinal fluid (CSF). It is important, therefore, to understand the mechanisms governing solute transport in the CSF and PVS. Our earlier studies have shown that the volume of intrathecal administration defines the initial disposition of the administered solute in the CSF. A large volume bolus (15-25% of the CSF volume) transports the solute from the lumbar administration site directly to the cerebro-cervical CSF pool. The boundaries of the leptomeningeal space containing the CSF are rigid (bones and cartilage) and cannot expand to accept the administered volume. It is conceivable that CNS vasculature (in particular, veins) contributes to the hydrostatic compliance of the compartment through compression under the elevated pressure resulting from the large volume bolus. Such compression, if significant, could present a considerable safety risk. The goal of our studies was to investigate the dynamics of the CNS vasculature compression after a large volume intrathecal bolus. Methods: The studies were carried out in Macaca mulatta and Macaca fascicularis. The animals were anesthetized with isoflurane. The blood pool of the animals was labeled with [89Zr] labeled deferoxamine modified albumin. Manual administrations of boluses of different volumes (1, 3, and 5 ml) and CSF pressure variations were carried out through the pre-implanted lumbar intrathecal port opening into the CSF at approximately L1-L2. Pressure in the catheter was monitored with high resolution semiconductor microsensor (Millar, Inc.). The cerebro-cervical region was imaged dynamically by PET (before, during and 0-30 min after the injection) using Siemens MicroPET focus 220 imager. The images were processed to determine whether the intrathecal bolus reduces blood content in various CNS regions, including the entire brain and major venous sinuses. Results. Transient vasculature compression (10%-15% of the venous blood volume for 1-3 minutes) was detected in the regions drawn closely around the superior and inferior sagittal and transverse venous sinuses. However, in the regions drawn around the entire brain or other subcompartments of the CNS no blood volume changes exceeding normal baseline fluctuations were detected. The pressure in the intrathecal catheter was elevated during the bolus delivery up to 81-141 mm Hg (largely due to the hydrostatic resistance of the catheter) and returned to 30.3-50.3-50 mm Hg immediately after the bolus delivery. Subsequently, the pressure rapidly (t1/2=41.9-71.4 s) returned to normal values (2-3 mm Hg). In a separate experiment with constant-pressure infusion, no changes in the respiration and heart rates were observed below 45 mm Hg. Conclusions: . (1) Vasculature contraction is not a significant factor of the hydrostatic compliance of the leptomeningeal space. The data suggest that the major compliant element is likely the atlanto-occipital membrane. (2) Elevation of the CSF pressure is transient and does not result in significant compression of the CSF vasculature until pressure levels comparable with the diastolic pressure are reached. Support. The studies were supported by NIH grant R01NS092838.