Transient cerebral hypoperfusion enhances intraarterial carmustine deposition into brain tissue.

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.

Augmentation of cerebral blood flow and reversal of endothelin-1-induced vasospasm: a comparison of intracarotid nicardipine and verapamil.

OBJECTIVE: Local intra-arterial infusions of verapamil and nicardipine have been used to treat human cerebral vasospasm. Only a few reports of early clinical experience with these medications are currently available, and limited data are available regarding their cerebral physiological activity. We assessed the efficacy of intracarotid administration of verapamil and nicardipine on augmenting cerebral blood flow of New Zealand White rabbits and compared the ability of these drugs with reverse topical endothelin (ET)-1-triggered vasospasm. METHODS: In the first group of New Zealand white rabbits, cerebral blood flow (laser Doppler) and systemic hemodynamic measurements were recorded at baseline and with increasing intracarotid doses of verapamil and nicardipine. In the second group, topical ET-1 (10(-4) mol/L) was applied in an acutely implanted cranial window. Dose responses to nonspecific reversal of ET-1-induced vasospasm were evaluated with intra-arterially administered nicardipine and verapamil. RESULTS: The dose-response studies revealed that intracarotid administration of nicardipine, compared with verapamil, was more effective in augmenting cerebral blood flow. Topical ET-1-induced vasospasm was completely reversed by nicardipine and partially reversed by verapamil. CONCLUSION: This study suggests that intra-arterially administered nicardipine is a more potent cerebral vasodilator and is superior to verapamil for treating ET-1-induced experimental cerebral vasospasm and supports further investigation of these agents in subarachnoid hemorrhage-induced vasospasm.

Bolus configuration affects dose requirements of intracarotid propofol for electroencephalographic silence.

We hypothesized that an intracarotid bolus injection of propofol to produce electroencephalographic (EEG) silence would require a smaller dose of the drug compared with the continuous infusion of the drug. Furthermore, the bolus propofol dose will be a function of the bolus characteristics in each bolus (mass/volume). We compared the dose requirements of intracarotid propofol needed to maintain EEG silence when delivered as bolus injections to continuous infusions in rabbits. Subsequently, we compared whether four different bolus characteristics (concentration and volume) of propofol (0.33% x 0.1 mL, 0.33% x 0.3 mL, 1% x 0.1 mL, and 1% x 0.3 mL) affected the dose required to produce EEG silence. We found that the infusion rate of propofol required to sustain EEG silence was three-fold larger than the dose required by bolus injections, 22.8 +/- 11.9 vs 6.2 +/- 2.9 mL/h for infusion versus bolus, respectively (n = 7, P < 0.004). Furthermore, during bolus injection, the doses of propofol required to produce EEG silence were a direct function of the bolus volume and the mass of drug in each bolus, total dose = 3.6 + 29 x mg/bolus, n = 32, r = 0.85. For maximum regional effects of the bolus intracarotid drug injection, the bolus characteristics (volume and drug concentration) have to be optimized.

Cerebral blood flow affects dose requirements of intracarotid propofol for electrocerebral silence.

BACKGROUND: The authors hypothesized that cerebral blood flow (CBF) changes will affect the dose of intracarotid propofol required to produce electrocerebral silence. METHODS: The authors tested their hypothesis on New Zealand White rabbits. The first group of 9 animals received intracarotid propofol during (1) normoventilation, (2) hyperventilation, and (3) hypoventilation. The second group of 14 animals received intracarotid propofol with or without concurrent intraarterial verapamil, a potent cerebral vasodilator. The third group of 8 animals received bolus injection of propofol during normotension, during severe cerebral hypoperfusion, and after hemodynamic recovery. RESULTS: In the first group, there was a linear correlation between the dose of intracarotid propofol and percent change (%Delta) in CBF from the baseline due to changes in the minute ventilation, Total Dose (y) = 0.17 + 0.012 * %Delta CBF (x), n = 27, r = 0.76. In the second group, the dose of propofol was also a function of CBF change after verapamil, Total Dose (y) = 0.98 + 0.1 * %Delta CBF (x), n = 14, r = 0.75. In the third group, the duration of electrocerebral silence after intracarotid propofol (3 mg) was significantly increased with concurrent cerebral hypoperfusion compared with prehypoperfusion and posthypoperfusion values (141 +/- 38 vs. 19 +/- 24 and 16 +/- 12 s, respectively, P < 0.0001). CONCLUSIONS: 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.

Reducing cerebral blood flow increases the duration of electroencephalographic silence by intracarotid thiopental.

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.