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.

The authors conclude that CBF affects the dose requirements of intracarotid propofol required to produce electrocerebral silence. Furthermore, the manipulation of CBF might be a useful tool to enhance the efficacy of intracarotid drugs.

The effects of IV anesthetics are enhanced by increased cerebral blood flow (CBF) because of a greater delivery of drugs to the brain. In contrast, mathematical simulations suggest that a decrease in CBF, by increasing regional drug uptake and decreasing drug washout, enhances the efficacy of intraarterial drugs. We hypothesized that administrating intracarotid anesthetics during cerebral hypoperfusion will significantly prolong the duration of electroencephalographic (EEG) silence. We tested our hypothesis on New Zealand White rabbits. In the first group of 7 animals, we observed that decreasing CBF by approximately 70% attenuated, but did not abolish, EEG activity. Subsequently, 9 animals received 3 intracarotid injections of 3 mg of thiopental (thiopental-1, thiopental + hypoperfusion, and thiopental-2). The first and third injections were made under physiological conditions. The second drug injection was made during cerebral hypoperfusion. Compared with injection of thiopental-1 and -2, thiopental + hypoperfusion resulted in a profound increase in EEG silence (from 45 +/- 5 and 67 +/- 27 s, to 206 +/- 46 s, respectively, n = 9, P < 0.0001). The EEG recovery profile was similar during all three thiopental challenges. The study suggests that modulation of CBF is an important tool for enhancing intraarterial drug delivery to the brain.

We hypothesized that bolus injections of lipid soluble chemotherapeutic drugs during transient cerebral hypoperfusion could significantly boost regional drug delivery. In the first two groups of New Zealand White rabbits we measured brain tissue carmustine concentrations after intravenous infusion, intraarterial infusion with normal perfusion, and after intraarterial injections during transient cerebral hypoperfusion. In the third group of animals we assessed the safety of the technique by assessing electroencephalographic changes for 6 h after flow arrest carmustine administration and subsequent histological examination. The brain tissue carmustine concentrations were fivefold to sevenfold higher when the drug was injected during cerebral hypoperfusion compared to a conventional intracarotid infusion (68.4 +/- 24.5 vs. 14.2 +/- 8.3 microg/g, n = 5 each, respectively, P < 0.0001). The brain tissue carmustine concentrations (y) were a linear function of the bolus dose (x) injected during cerebral hypoperfusion, y = 10.4 x x - 21 (R = 0.84, P < 0.001). Stable EEGs were recorded several hours after flow arrest carmustine exposure and histological examinations did not reveal any gross evidence of cerebral injury. Transient cerebral hypoperfusion during intraarterial bolus injection of carmustine significantly increases drug delivery. Clinical techniques that decrease CBF, such as, transient arterial occlusion by balloon tipped catheters, hyperventilation, hypothermia, induced hypotension, or transient circulatory arrest, could enhance intraarterial drug delivery to the brain. We believe that the mechanisms for improved drug delivery is the decrease in drug dilution by reduced or absent blood flow, decreased protein binding and a longer time for high concentrations of free drugs to transit through the blood brain barrier.

The goal of this study was to compare systemic and cerebrovascular effects of three anesthetic drugs (etomidate, thiopental, and propofol) when delivered by intracarotid and intravenous routes in doses that produce electrocerebral silence (electroencephalography [EEG]). EEG activity, mean arterial pressure (MAP), and laser Doppler flow as a proxy of cerebral blood flow (CBF) of 24 anesthetized New Zealand white rabbits were continuously recorded. Data were compared at three timepoints: baseline, during EEG silence, and after recovery of EEG activity. Drugs were randomly injected via the carotid artery to produce 10 minutes of EEG silence. After 30 minutes of rest, intravenous boluses of the same drug were injected to achieve 10 minutes of EEG silence. During EEG silence, transient hypotension was seen with intracarotid propofol, but there was no decrease in CBF. MAP and CBF did not decrease with either intracarotid etomidate or thiopental during EEG silence. Intracarotid/intravenous dose ratio of propofol (26%+/-22%; n=8, P<0.02) was much higher than that of etomidate and thiopental (14%+/-2% and 19%+/-11%, respectively; NS). Collectively, these results suggest intracarotid etomidate and thiopental are more useful than propofol in producing EEG silence because they offer better dose advantage and are less likely to impair cerebral or systemic hemodynamics.