Etu J

Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits.

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.

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 (%&Dgr;) in CBF from the baseline due to changes in the minute ventilation, Total Dose (y) = 0.17 + 0.012 * %&Dgr; 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 * %&Dgr; 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.

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

OBJECTIVELocal 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. METHODSIn 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. RESULTSThe 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. CONCLUSIONThis 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% × 0.1 mL, 0.33% × 0.3 mL, 1% × 0.1 mL, and 1% × 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 × 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.

Comparison of intracarotid anesthetics for EEG silence.

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.

Videomicroscopy Reveals that EEG Silence after Intracarotid Propofol Injection is Function of Transit Time

delivery were significantly greater than the other two groups, intravenous, and intraarterial infusions, 68.4±24.5, vs. 14.2±8.3 and 3.0±1.6mg/g, n=5 P<0.0001, Group II: Injections of 0.3 ml of 4% BCNU (1.2mg), 1.8ml of 3% BCNU (5.4mg) generated significantly different tissue concentration compared to the injection of 3 ml of 4% BCNU (12mg) resulted in tissue concentrations of 2±0.9mg, 18.8±12.5 and 110±51mg/g, respectively, P<0.0001 and P=0.0003 respectively, Table 2. The tissue BCNU concentration was a linear function (y) of the bolus dose (x) injected during cerebral hypoperfusion, y=10.4* -21 (R=0.84, P<0.001). Group III: There no evidence of any adverse neurological injury with flow arrest delivery of drugs, the EEG activity remained comparable after 6 hour between the three groups of animals. Discussion: This study reveals how transient hypoperfusion can tremendously increase (5-7 fold) tissue concentration of anticancer drugs. There was no evidence of any injury to the brain with such a hypotension. These high tissue concentrations in the brain were achieved due two possible reasons. First, bolus injection of drugs transiently displaces the blood in the arterial dead space and avoids protein binding. This leads to disproportionately high tissue concentrations. Second, the decrease in blood flow increases the effective concentration of the drug, increases the transit time to enable greater uptake and decreases the washout. Transient manipulation of CBF therefore provides a valuable tool to enhance intraarterial drug delivery. Clinically, CBF can be manipulated by balloon occluding catheters, ventilation, or systemic hypotension. Conclusions: There results show that tissue concentrations generated after intraarterial injection of BCNU is significantly increased (5-7 folds) when the drug is injected during cerebral hypoperfusion. There was no evidence of any brain injury with transient cerebral hypoperfusion.