Hemorrhagic encephalitis produced by selective non-occlusive intracarotid BCNU injection in dogs

Abstract

A selective non-occlusive technique was developed for administration of BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) into the internal carotid artery of the dog, and the neuropathological effects in the brain were studied. One out of three dogs showed ipsilateral hemorrhagic necrotizing encephalitis at doses of 102 mg/sq m, and all of three dogs showed similar but more severe pathology at doses of 215 to 232 mg/sq m. This study and previous studies in the dog and monkey suggest definite thresholds above which cerebral toxicity occurs when BCNU is administered via the intracarotid route. Greater dilution of drug in the larger territory of supply of the human internal carotid artery allows somewhat higher doses in man. The pathology of the lesion induced by BCNU suggests a primary vascular injury as a pathogenic mechanism, consonant with similar findings following high-dose systemic BCNU administration in man. Investigators conducting ongoing and future trials of intracarotid BCNU in the human for the treatment of intracranial neoplasms should be especially vigilant for a similar toxic effect.

Cerebral Injury from Intracarotid Injection in an Alpaca (Vicugna Pacos)

“…4 Hemorrhagic necrosis, most prominent in white matter, and neutrophils and mononuclear cells within damaged vessel walls and in the perivascular space were present in the ipsilateral cerebrum of dogs examined 3 to 7 days after experimental intracarotid injection of a lipidsoluble nitrosourea chemotherapeutic agent. 7 Clinical signs in this case were indicative of right cerebral injury, and pathologic findings were confined to the right meninges, cerebrum, hippocampus, and thalamus. Ketamine, the primary component of the injected mixture, is hyperosmolar with an acidic pH, but a study of myotoxicity of ketamine after intramuscular injection concluded that ketamine also had a direct cytotoxic effect.…”

“…Time of death following intraarterial injection in prior reports was 5 min, 1,9 6 hr, 2 up to 24 hr, 4 and 3-7 days. 7 No convincing evidence of neuronal necrosis or perivascular edema was detected in the brain of cattle that died 5 min after inadvertent injection of a lipidbased antibiotic into the right auricular artery. 1 Neuronal necrosis was reported in a cow that died within 5 min of intracarotid injection of chloramphenicol, 9 although the very short time from injection to death suggests that neuronal changes might have been artifactual.…”

“…2,4 Experimental studies indicate that the cerebrum and thalamus are the most commonly affected areas, and that neural lesions occur primarily on the same side as the injection. 6,7,13 The nature and degree of pathologic findings are also dependent on time from injection until death. Time of death following intraarterial injection in prior reports was 5 min, 1,9 6 hr, 2 up to 24 hr, 4 and 3-7 days.…”

“…6,10 Factors associated with parenchymal injury include the nature of the injected compounds, in particular high osmolality, 6,8,13 direct cytotoxicity, 13 and lipid solubility. 7 Arteriolar spasm 6,10 and thrombosis as a consequence of endothelial injury 2,4,6 contribute to the potential for parenchymal injury.…”

“…Numerous experimental studies document disruption of the blood-brain barrier by intracarotid injection of various compounds. 4,[6][7][8]10,13 Breakdown of the blood-brain barrier by material injected into the carotid artery can be due to reversible endothelial changes 8 or to vascular endothelial or mural necrosis. 6,10 Factors associated with parenchymal injury include the nature of the injected compounds, in particular high osmolality, 6,8,13 direct cytotoxicity, 13 and lipid solubility.…”