Enhanced Disruption of the Blood Brain Barrier by Intracarotid Mannitol Injection During Transient Cerebral Hypoperfusion in Rabbits

Abstract

Fairly large volumes of intracarotid mannitol (20% to 25%) are required to disrupt the blood brain barrier (BBB), that is, 200 to 300 mL/30 s in humans or 10 mL/40 s in rabbits. During transient cerebral hypoperfusion blood flow to the rabbit brain is decreased to 0.2 to 0.3 mL/30 s. We therefore hypothesized that if the disruption of the BBB by intracarotid mannitol was primarily due to its osmotic effects, injection of 0.2 to 0.3 mL of mannitol during transient cerebral hypoperfusion will be sufficient to disrupt the BBB, thereby dramatically (by 20-folds) decrease the dose requirements compared with injections during normal blood flow. After preliminary studies, 4 doses of intracarotid mannitol were first tested: (1) 2 mL with cerebral hypoperfusion, (2) 4 mL with cerebral hypoperfusion, (3) 4 mL without cerebral hypoperfusion, and (4) 8 mL without cerebral hypoperfusion. Next, we compared the extent to which methods of drug delivery (infusion vs. bolus injection) affected BBB disruption in 12 rabbits. Finally, we assessed the duration of BBB disruption with intracarotid mannitol in another 12 rabbits. We observed that BBB disruption during injection of 4 mL of mannitol with cerebral hypoperfusion was comparable to 8 mL mannitol without cerebral hypoperfusion. Bolus injections of 4 mL mannitol were more effective than steady-state infusions. The BBB disruption with intracarotid mannitol lasted for 60 minutes postinjection. We conclude that cerebral hypoperfusion decreases the dose of intracarotid mannitol by a modest 2-fold. Our results suggest that mechanical factors may play a significant role in the osmotic disruption of the BBB by intracarotid mannitol.

Noninvasive in vivo optical assessment of blood brain barrier permeability and brain tissue drug deposition in rabbits

“…7 In parallel studies, we had observed that BBBD in rabbits with IA mannitol was highly variable. 11,12 Similar variability in the degree of BBBD has also been reported in human subjects. 13 Such variability could have a very significant impact on the delivery of chemotherapeutic drugs that require BBBD.…”

“…One millilitres of ICG was injected by solenoid controlled pneumatic pump over 2 s. MTX, a water soluble chemotherapy agent, was selected as the drug, and 3 ml of 0.1% (1 mg∕ml) of MTX in normal saline (Sigma Aldridge Co., St. Louis, MO) was injected with an IVAC syringe pump in bolus mode over 30 s. Mannitol, warmed to 37°C and filtered through a 0.2 micrometer filter, was hand injected (25%, 0.25 ml∕kg∕s for 30 s) after it was determined that mechanical pumps were unable to reliably administer the IA dose of mannitol required for this experiment. 11 In the control group, equivalent intravenous volume of saline was injected instead of mannitol over the same time period.…”

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