A B S T R A C T The present study describes a canine model of transient reversible blood-brain barrier disruption with hyperosmolar mannitol infusion into the internal carotid artery. Studies in this model show that osmotic blood-brain barrier disruption before intracarotid infusion of methotrexate results in markedly elevated (therapeutic) levels of drug in the ipsilateral cerebral hemisphere. Levels in the cerebrospinal fluid correlate poorly and inconsistently with brain levels. Computerized tomograms in this canine model provide a noninvasive monitor of the degree, timecourse, and localization of osmotic blood-brain barrier disruption.

Effects of adrenal cortical steroids and osmotic blood-brain barrier opening on methotrexate delivery to.gliomas in the rodent: The factor of the blood-brain barrier ( 15, 1982 ABSTRACT The effect of adrenal cortical steroids and osmotic blood-brain barrier modification on methotrexate delivery to normal and glioma-bearing rats was studied. In animals with the avian sarcoma virus-induced glioma, osmotic blood-brain barrier modification resulted in significantly increased delivery of methotrexate to the tumor-bearing'hemisphere (including the tumor, the brain around the tumor, and the brain distant to the tumor), compared to the nonmodified hemisphere or to control animals. The administration of adrenal steroids, followed by intracarotid methotrexate, resulted in slightly decreased chemotherapeutic agent (methotrexate) delivery to the tumor, the brain around the tumor, and the brain distant to the tumor. When adrenal steroids were given prior to barrier modification and methotrexate therapy, the level of methotrexate was significantly less in the tumor. These studies provide evidence that the blood-brain barrier exists in tumors and is a factor in drug delivery to tumors. Steroid administration greatly interferes with the enhancement of drug delivery, to tumors that can be achieved with osmotic blood-brain barrier modification.

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We examined in 47 dogs the effects of 5-fluorouracil, Adriamycin (doxorubicin hydrochloride), cis-platinum (cis-diamminedichloroplatinum) cyclophosphamide, and bleomycin given in association with osmotic blood-brain barrier modification. The dose of drug ranged from 100% to as little as 5 to 10% of the conventional systemic dosage. Serial neurological observation and subsequent postmortem neuropathological evaluation at times varying from 2.5 hours to 52 days after drug administration showed that cis-platinum and Adriamycin were highly neurotoxic, as evidenced by neurological deficits and pathological changes in the central nervous system parenchyma; 5-fluorouracil and bleomycin had much less, but consequential neurotoxicity; and cyclophosphamide was not associated with substantial toxicity. Intracarotid cis-platinum, unlike the other drugs, damaged the blood-brain barrier and resulted in marked neurotoxicity in the absence of osmotic blood-brain barrier opening. The neural lesions produced by these agents were not specific but were manifested as foci of hemorrhagic necrosis and edema. In addition, secondary brainstem hemorrhage was observed in animals that developed transtentorial herniation. On the basis of these studies, of five drugs studied at a wide range of doses, only cyclophosphamide appears to be safe enough to evaluate in clinical trials that utilize blood-brain barrier modification to enhance drug delivery. These studies also suggest that the lack of neurotoxicity associated with the usual administration of most chemotherapeutic agents probably stems from limited entry of drug into the brain through an intact blood-brain barrier.

Decompressive craniectomy has been advocated as a treatment for the cerebral edema associated with massive head injury. Although craniectomy has been successful in lowering intracranial pressure after head injury, a comparison of computerized tomographic scans of comparable patients with traumatic brain edema treated by medical means or decompressive craniectomy showed that bony decompression resulted in apparent exacerbation of edema. To investigate the possibility of enhancement of brain edema by craniectomy, we produced standardized cold lesions in the brains of 10 dogs. Five animals served as controls. In the other 5 animals we performed large decompressive craniectomies after lesioning. Physiological parameters were comparable in both groups. The dogs were killed 8 hours after lesioning. After fixation, their brains were cut into 1-mm-thick slices. We used an image analysis facility built around a PDP 11/105 computer to measure the volume of edema as outlined by Evans blue staining. The mean volume of the brain edema in the control animals was 0.27 +/- 0.19 ml. Mean edema volume was over 7 times greater in craniectomized animals (1.96 +/- 1.89 ml). This difference is statistically significant (p less than 0.05). The driving force for the formation of edema fluid is the difference between intravascular and interstitial presssure. Decompression of the brain by bone removal probably results in a reduction of interstitial fluid pressure and edema enhancement. The clinical literature contains no evidence that craniectomy decreases the morbidity or mortality of human head injury. In view of our experimental findings, this is not surprising. Indeed, pathological evidence indicates that severe edema (such as that accentuated by craniectomy) may produce permanent changes in the neuropil.