The influence of anesthetic choice, Paco2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts
The influence of anesthetic choice, Paco2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts
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DOI：
10.1097/00000539-199903000-00018
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发表时间：
1999-03-01
影响因子：
5.7
通讯作者：
Neuwelt, EA
中科院分区：
文献类型：
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作者：
Remsen, LG;Pagel, MA;Neuwelt, EA
增加治疗药物对大脑的输送可以改善脑瘤患者的预后。渗透开放血脑屏障(BBB)可以显著增加药物的输送，但实现持续的、高质量的血脑屏障破坏(BBBD)是必不可少的。我们评估了四个实验，与我们的标准异氟醚/氧-2方案相比较，以提高BBBD的质量和一致性，并在大鼠模型中向脑瘤和正常脑递送药物。用大分子标志物伊文思蓝白蛋白定性评价BBBD的成功，通过测量低分子标志物[H-3]-甲氨蝶呤的释放来定量评价BBBD的成功。在异氟醚/氧气麻醉下，观察两种不同渗透压的BBBD药物在两种不同的输注速率和输注时间下的效果。在24只动物中，有16只在获得一致的伊文思蓝染色方面阿拉伯糖优于生理盐水(P=0.006)，而且它显著增加了[H-3]-甲氨蝶呤在肿瘤(0.388+/-0.03vs0.135+/-0.04；P=0.0001)、肿瘤周围(0.269+/-0.03vs0.035+0.03；P=0.0001)、远离肿瘤(0.445+/-0.05vs0.034+/-0.07；对侧大脑半球(0.024+/-0.00vs 0.016+/-0.00；P=0.0452)。40s给药优于S 30s(P=0.0372)。异氟醚/氧气复合麻醉(n=30)维持低碳酸血症效果优于高碳酸血症(P=0.025)，可获得良好的BBBD。比较异丙酚/N2O方案和异氟醚/O2方案，以改变血压、心率和PaCO2为协变量(n=48)。异丙酚/N2O在定性和定量指标上均优于异氟醚/O-2(P<；0.0001)。对异丙酚/N2O方案的神经毒性和神经病理学进行了评估，没有发现任何结果。这些数据支持在维持低碳酸血症的同时使用异丙酚/N2O来优化患有肿瘤的动物的BBBD。异丙酚/N2O麻醉在优化渗透性血脑屏障阻断方面可能优于异氟醚/O2麻醉，用于脑肿瘤和正常脑的化疗药物输送。
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/O-2 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 [H-3]-methotrexate. With isoflurane/O-2 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 [H-3]-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/O-2 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/O-2 regimen, altering blood pressure, heart rate, and PaCO2 as covariates (n = 48). Propofol/N2O was superior to isoflurane/O-2 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/O-2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain.