Remsen L G, Pagel M A, McCormick C I, Fiamengo S A, Sexton G, Neuwelt E A
Department of Neurology, Oregon Health Sciences University, Portland 97201, USA.
Anesth Analg. 1999 Mar;88(3):559-67. doi: 10.1097/00000539-199903000-00018.
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.
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.
增加治疗药物向脑内的递送可改善脑肿瘤患者的预后。血脑屏障（BBB）的渗透性开放可显著增加药物递送，但实现持续、高质量的血脑屏障破坏（BBBD）至关重要。我们评估了四项实验，与我们的标准异氟烷/O₂方案进行比较，以提高BBBD的质量和一致性，以及在大鼠模型中向脑肿瘤和正常脑递送药物的能力。使用大分子标记物伊文思蓝白蛋白对BBBD的成功进行定性评估，并通过测量小分子标记物[³H] - 甲氨蝶呤的递送进行定量评估。在异氟烷/O₂麻醉下，评估了两种不同渗透压的BBBD药物在两种不同输注速率和输注持续时间下的效果。在24只动物中的16只中，阿拉伯糖在获得一致的伊文思蓝染色方面优于生理盐水（P = 0.006），并且与生理盐水相比，它显著增加了肿瘤（0.388±0.03对0.135±0.04；P = 0.0001）、肿瘤周围脑区（0.269±0.03对0.035±0.03；P = 0.0001）、远离肿瘤的脑区（0.445±0.05对0.034±0.07；P = 0.001）以及对侧半球（0.024±0.00对0.016±0.00；P = 0.0452）中[³H] - 甲氨蝶呤的递送。对于向肿瘤递送药物，40秒优于30秒（P = 0.0372）。在异氟烷/O₂麻醉下（n = 30），维持低碳酸血症比高碳酸血症更有利于实现良好的BBBD（P = 0.025）。将丙泊酚/N₂O方案与异氟烷/O₂方案进行比较，将血压、心率和动脉血二氧化碳分压（PaCO₂）作为协变量（n = 48）。丙泊酚/N₂O在定性和定量测量方面均优于异氟烷/O₂（P < 0.0001）。评估了丙泊酚/N₂O方案的神经毒性和神经病理学，未发现异常。这些数据支持在患有肿瘤的动物中使用丙泊酚/N₂O并维持低碳酸血症以优化BBBD。
丙泊酚/N₂O麻醉在优化渗透性血脑屏障破坏以将化疗药物递送至脑肿瘤和正常脑方面可能优于异氟烷/O₂麻醉。
