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NEUROSURGICAL ANESTHESIA

The Influence of Anesthetic Choice, PaCO₂, and Other Factors on Osmotic Blood-Brain Barrier Disruption in Rats with Brain Tumor Xenografts

Laura G. Remsen, DVM, PhD^*, Michael A. Pagel, BS^*,§, Christopher I. McCormick, AHT, LATG^*,§, Steven A. Fiamengo, MD, Gary Sexton, PhD^,,, and Edward A. Neuwelt, MD^*,§

Departments of *Neurology, Surgery, Medicine, Preventive Medicine and Public Health, and Anesthesiology, Oregon Health Sciences University and §Veterans Administration Medical Center, Portland, Oregon

Address correspondence and reprint requests to Edward A. Neuwelt, MD, Oregon Health Sciences University, Department of Neurology, L603, 3181 SW Sam Jackson Park Rd., Portland, OR 97201. Address e-mail to neuwelte{at}ohsu.edu

Increasing the delivery of therapeutic drugs to the brain improves outcome for patients with brain tumors. Osmotic opening of the blood-brain barrier (BBB) can markedly increase drug delivery, but achieving consistent, good quality BBB disruption (BBBD) is essential. We evaluated four experiments compared with our standard isoflurane/O₂ protocol to improve the quality and consistency of BBBD and drug delivery to brain tumor and normal brain in a rat model. Success of BBBD was assessed qualitatively with the large molecular weight marker Evans blue albumin and quantitatively by measuring delivery of the low molecular weight marker [³H]-methotrexate. With isoflurane/O₂ anesthesia, the effects of two BBBD drugs of different osmolalities were evaluated at two different infusion rates and infusion durations. Arabinose was superior to saline (P = 0.006) in obtaining consistent Evans blue staining in 16 of 24 animals, and it significantly increased [³H]-methotrexate delivery compared with saline in the tumor (0.388 ± 0.03 vs 0.135 ± 0.04; P = 0.0001), brain around the tumor (0.269 ± 0.03 vs 0.035 ± 0.03; P = 0.0001), brain distant to the tumor (0.445 ± 0.05 vs 0.034 ± 0.07; P = 0.001), and opposite hemisphere (0.024 ± 0.00 vs 0.016 ± 0.00; P = 0.0452). Forty seconds was better than 30 s (P = 0.0372) for drug delivery to the tumor. Under isoflurane/O₂ anesthesia (n = 30), maintaining hypocarbia was better than hypercarbia (P = 0.025) for attaining good BBBD. A propofol/N₂O regimen was compared with the isoflurane/O₂ regimen, altering blood pressure, heart rate, and PaCO₂ as covariates (n = 48). Propofol/N₂O was superior to isoflurane/O₂ by both qualitative and quantitative measures (P < 0.0001). Neurotoxicity and neuropathology with the propofol/N₂O regimen was evaluated, and none was found. These data support the use of propofol/N₂O along with maintaining hypocarbia to optimize BBBD in animals with tumors.

Implications: Propofol/N₂O anesthesia may be better than isoflurane/O₂ for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain.

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