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Timothy C. Wirt, Zell A. McGee, Edward H. Oldfield and William F. Meacham

✓ Four pediatric neurosurgical patients with Gram-negative meningitis and ventriculitis were treated with parenteral and intraventricular amikacin, a new aminoglycoside. The organisms infecting these patients were resistant to multiple antimicrobial drugs but were sensitive to amikacin. Treatment was continued for 14 days after cerebrospinal fluid cultures became negative. All four patients were cured and have demonstrated no nephrotoxicity, ototoxicity, or evidence of persistent infection on follow-up examination.

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Byron Young, Edward H. Oldfield, William R. Markesbery, Dennis Haack, Phillip A. Tibbs, Paul McCombs, Hong W. Chin, Yosh Maruyama and William F. Meacham

✓ The results of a second operation for tumor removal in 24 adult patients with supratentorial glioblastoma multiforme or anaplastic astrocytoma were analyzed. The median survival time after reoperation was 14 weeks. Five of the 24 patients lived 6 months or longer after reoperation. Only three of these patients maintained a Karnofsky rating (KR) of at least 60 for 6 months or longer after reoperation.

Preoperative neurological status (KR) is the most significant determinant of survival after reoperation (p = 0.02). When the KR is at least 60, median survival after reoperation is 22 weeks. When the KR prior to reoperation is less than 60, median survival is 9 weeks. Only one of 13 patients with a KR of less than 60 prior to reoperation survived longer than 6 months after the second operation. The interval between first and second operation is significantly related to survival (p = 0.03), but when adjustment is made for the KR the interoperative interval is no longer significantly related to survival after the second operation (p = 0.39). Age, sex, and location of tumor were not significantly related to duration of survival.

This study suggests that reoperation is most likely to produce the best result when the KR is at least 60 and the interval between operations is longer than 6 months. Using these criteria, one-third of the patients could be expected to survive with a KR of at least 60 for 6 months. The study indicates that reoperation should not be carried out when the KR is less than 60.

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Edward H. Oldfield, Robert J. Plunkett, William A. Nylander Jr. and William F. Meacham

✓ Ischemia is the pathophysiological mechanism in many types of spinal cord injury. In the present study, the infrarenal segment of the aorta was occluded for 25 minutes to produce spinal cord infarction in rabbits. Paraplegia occurred in 100% of control animals. Thiopental administered before aortic occlusion resulted in paraplegia in only 40% of animals so treated (p < 0.01). Histological study of the spinal cord demonstrated infarction of the gray matter in all paraplegic animals, whereas the microscopic appearance was normal in animals without neurological deficit. The protective influence of thiopental therapy in spinal cord ischemia was demonstrated.

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Edward H. Oldfield, Giovanni Di Chiro, Eugene A. Quindlen, Kenneth G. Rieth and John L. Doppman

✓ As demonstrated by selective spinal cord arteriography, over 80% of spinal cord arteriovenous malformations (AVM's) occupy a predominantly extramedullary position. Current therapy frequently requires surgical stripping of the long dorsal intradural vessel(s) from the underlying spinal cord over many cord segments. The authors report six patients with a dural arteriovenous fistula fed by a cluster of abnormal epidural arteries. These vessels, which surrounded and were embedded into the dural covering of a thoracic nerve root, drained into a long sinuous intrathecal paramedullary vein(s). The angiographic and surgical appearance of the intradural component of these lesions was identical to that of lesions previously classified as Type I AVM's of the spinal cord. All patients had symptoms and signs of myelopathy. In five patients, surgery was limited to coagulation and excision of the extradural vessels and division of the intradural arterialized vein. Progressive improvement began within days following surgery. No residual abnormality was demonstrated by postoperative selective spinal cord arteriography, which was performed in all five patients.

The findings support those of Kendall and Logue, that surgery restricted to elimination of the arteriovenous fistula at the intervertebral foramen is curative, and that more extensive surgery is unnecessary for this subgroup of AVM's of the spinal cord. These lesions comprise a sizable percent of all spinal AVM's. Resolution of myelopathy in these patients supports the hypothesis that venous hypertension causes chronic progressive myelopathy.

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W. Craig Clark, Cheryl E. Daniels, Robert L. Dedrick, Mary E. Girton, John L. Doppman and Edward H. Oldfield

✓ Circulation of blood in the ipsilateral jugular vein through an extracorporeal circuit for drug removal during intracarotid chemotherapy has recently been reported to decrease the systemic drug exposure. The reduced systemic exposure achieved by the use of this technique should permit a several-fold increase of the intracarotid dose of chemotherapy without increasing systemic toxicity. To determine the influence of the rate of blood removal from the jugular vein on the fraction of the blood flowing through the ipsilateral internal carotid artery (ICA) collected for extracorporeal drug removal, the authors aspirated blood from the jugular bulb into an extracorporeal circuit at varying rates during a constant infusion of the indicator dye, indocyanine green (ICG), into the ICA of rhesus monkeys. The fraction of the ipsilateral carotid blood channeled into the extracorporeal circuit increased linearly with the rate of aspiration of jugular blood. This suggests that the absence of valves in the intracranial venous system should permit increasing fractions of drug removal during intracarotid infusion by increasing the rate of collection of venous blood from the ipsilateral jugular bulb. The measurement of ICG concentrations in a similar manner in patients undergoing isolated perfusion may prove to be a clinically useful method for estimating the maximum safe dose in high-dose intra-arterial chemotherapy.

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Edward H. Oldfield, Robert L. Dedrick, Russell L. Yeager, W. Craig Clark, Hetty L. DeVroom, Dulal C. Chatterji and John L. Doppman

✓ Four patients with malignant cerebral gliomas received 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) into the internal carotid artery (ICA) while the ipsilateral jugular drainage was pumped extracorporeally through a hemoperfusion cartridge containing a nonionic adsorbant resin. Each patient received 220 mg/sq m BCNU, infused over 45 minutes through a toposcopic catheter positioned with the tip in the ICA beyond the origin of the ophthalmic artery. Jugular blood was pumped extracorporeally at 300 ml/min through a large-bore catheter in the jugular bulb. Plasma samples were obtained for BCNU measurement at frequent intervals from the right atrium. During a separate treatment, 6 weeks before or after the hemoperfusion treatment, the same dose of BCNU was infused into the ICA and atrial samples were obtained on a similar schedule.

Hemoperfusion of the jugular blood during intracarotid infusion reduced the systemic exposure by 56% to 87% and increased total body clearance of BCNU by two- to eightfold. The calculated pharmacokinetic advantage (brain:body exposure ratio) was between 21 and 55:1 when the combined treatment was used.

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J. Bob Blacklock, Donald C. Wright, Robert L. Dedrick, Ronald G. Blasberg, Robert J. Lutz, John L. Doppman and Edward H. Oldfield

✓ Treatment of brain tumors by intra-arterial (IA) chemotherapy is occasionally complicated by sites of focal toxicity in the brain and retina. A possible cause of focal toxicity is non-uniform drug delivery due to intravascular drug streaming. To investigate this phenomenon in vivo, the authors examined the distribution of drug delivery after internal carotid artery (ICA) infusion in rhesus monkeys. Carbon-14 (14C)-labeled iodoantipyrine was delivered into the ICA of eight monkeys at slow infusion rates (1% to 2% of ICA flow) or at fast infusion rates (20% of ICA flow) combined with additional techniques to promote mixing with ICA blood. Two monkeys received intravenous (IV) 14C-antipyrine. Uniformity of delivery was assessed by comparing high-to-low ratios of isotope concentration in four brain regions evaluated by quantitative autoradiography.

There was striking non-uniformity of drug delivery in the slow IA infusion group, with as much as 13-fold differences in drug concentration in anatomically contiguous areas. The values of high-to-low concentration ratios (mean ± standard deviation) in individual autoradiographic planes were: 1) frontoparietal cortex: slow IA infusion 4.54 ± 2.07, fast IA infusion 1.71 ± 0.31, IV infusion 1.30 ± 0.174; 2) frontoparietal white matter: slow IA infusion 2.94 ± 1.45, fast IA infusion 1.59 ± 0.41, IV infusion 1.34 ± 0.21; 3) temporal cortex: slow IA infusion 5.43 ± 3.57, fast IA infusion 1.69 ± 0.24, IV infusion 1.67 ± 0.25; 4) basal ganglia: slow IA infusion 3.6 ± 2.9, fast IA infusion 1.18 ± 0.10, IV infusion 1.09 ± 0.04. Differences between concentration ratios after slow IA and fast IA infusion are significant (p < 0.01); those between fast IA and IV infusion are not significant.

Intra-arterial drug administration at infusion rates analogous to those currently used clinically results in drug streaming with markedly heterogeneous drug deposition in the perfused hemisphere. This may cause suboptimal drug levels in the tumor, and toxic levels at sites within the perfused hemisphere. This effect can be abrogated by techniques that eliminate drug streaming.

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Robert J. Lutz, Robert L. Dedrick, John W. Boretos, Edward H. Oldfield, J. Bob Blacklock and John L. Doppman

✓ Sporadic instances of retinal damage and of focal brain toxicity have been observed following intracarotid artery infusions of chemotherapeutic agents (such as BCNU and cis-platinum) for the treatment of glioblastomas. The episodic nature of these toxicities is consistent with the possibility that the drug solutions were streaming from the catheter tip and, therefore, were not well mixed or not uniformly distributed in all branches distal to the catheter tip location. To test this hypothesis, an in vitro system was fabricated which included a transparent model of the human carotid artery and its major branches. These were furnished with pulsatile flow of a blood simulant. Dye solutions infused at several infusion rates through various types of catheters in both supraophthalmic and infraophthalmic positions were monitored and recorded on videotape and photographic film. The effluent streams from distal branches of the model were collected, and the relative concentrations of dye in each branch were determined spectrophotometrically. The results indicate that infusate streaming occurs at low infusion rates. In some cases, the concentration in a given branch can be at least five times the expected concentration. Similar occurrences of streaming in vivo could cause focal toxicity. Methods to improve mixing should be used during intra-arterial administration of drugs; these include increasing the infusion rates and improving catheter tip design.

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Bruce R. Rosenblum, Robert F. Bonner and Edward H. Oldfield

✓ Standard methods for measurement of cerebral blood flow (CBF) are not optimal for continuous intraoperative recording. Laser Doppler velocimetry has been used for evaluation of microcirculatory flow in a variety of human tissues, including skin, muscle, and retina. The authors report the use of this technique for measuring flow in human cerebral cortex. The physiological changes associated with excision of a cerebral arteriovenous malformation are interpreted using CBF recorded intraoperatively with the laser Doppler probe.