AN E X P E R I M E N T A L METHOD FOR THE EVALUATION OF CONTRAST M E D I A USED IN CEREBRAL ANGIOGRAPHY

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1 AN E X P E R I M E N T A L METHOD FOR THE EVALUATION OF CONTRAST M E D I A USED IN CEREBRAL ANGIOGRAPHY BYRON M. BLOOR, M.D.,* FRANK R. WRENN, JR., M.D., t AND MAJOR GEORGE J. HAYES, M.C., U.S.A.:~ Division of Neurological Surgery, Department of Surgery, Duke University School of Medicine and Duke Hospital, Durham, North Carolina (Received for publication December 16, 1950) ONTRAST media used for cerebral angiography must not only visualize the cerebral vascular tree in an adequate manner but must also be relatively non-toxic in volumes and concentrations necessary for their primary purpose. Several clinical studies have noted immediate untoward effects following the injection of Diodrast, emphasizing chiefly subjective head pain and rare sensitivity reactions. 6,7,9,1~ Pathological changes secondary to the injection of Thorotrast have been reported. 5,12 One experimental study has concerned itself with histopathologic changes following the use of Perabrodil (Diodrast).11 Neither the clinical nor the histopathological studies have furnished sufficient information to deter the use of these substances. Broman, on the other hand, using the physiological approach of injecting the dye trypan blue with Diodrast-like substances, has demonstrated unequivocal changes in the permeability of the vessels, m,4 He attributes these changes to a chemo-toxic influence upon the endothelium of the vessel wall. While this report was in preparation, Broman reported further studies along this same line. ~ It is desirable to objectively evaluate the effect of any contrast medium upon the function as well as structure of the brain. The present method of study combines the dye indicator technique with concomitant electroencephalography in an effort to obtain evidence of more subtle changes in cerebral physiology as well as correlative data. C EXPERIMENTAL METHOD Adult rabbits were used in this study, since, of all common laboratory animals, they alone receive a significant volume of blood to the cerebral hemisphere through the internal carotid artery. Friedemann s has shown that anionic dyes permeate damaged vascular endothelium while sparing unaltered blood vessels. The tetra-sulfonic acid of copper phthalo-cyanine (tetra-sulfon-tetra-benzo-tetra-azo-porphin) is such an anionic dye, and other work in this laboratory has revealed that it fulfills these requirements. * DamonRunyanClinicalResearchFellow. t PostdoctoralFellowof the AtomicEnergyCommission. :~Presentaddress:NeurosurgicalSection,WalterReedGeneralHospital,Washington,D. C. 435

2 436 B. M. BLOOR, F. R. WRENN, JR., AND G. J. HAYES This dye is readily soluble in Ringer's solution, yielding a brilliant blue solution when prepared for injection. Under light nembutal and local procaine anesthesia, the right or left internal carotid artery of alternate animals was isolated in the neck. A small polyethylene catheter was inserted into the common carotid artery proximal to the ostium of the internal carotid. Tracheotomy was then done; the animal was curarized and placed upon mechanical respiration. FIG. I. (A) Normal control record. (B) An immediate effect of injections through the right internal carotid; amplitude decrease most marked on right. (C) Well developed delta activity over the right hemisphere 1 min. after injections. (D) Seizure discharges occurring e0 rain. after injections. Last two channels of the record have been deleted.

3 EVALUATION OF CONTRAST MEDIA IN ANGIOGRAPHY 437 FIG. 2. (A) Normal control record. (B) An immediate amplitude decrease, and appearance of generalized slow activity. (C) Example of generalized disappearance of cortical activity following the ~nd injection of the test substance. The test substance was injected, as a rule, in four increments 10 sec, apart in order to allow circulation of blood between injections. The usual injection time was ~ to 3 sec. for a volume of 0.4 cc. and larger amounts required correspondingly longer times. All test injections were controlled with similar amounts of Ringer's solution. The dye indicator was subsequently administered in the course of the acute experiment in 80 to 100 mg. amounts either intravenously or through the

4 438 B. M. BLOOR, F. R. WRENN, JR., AND G. J. HAYES internal carotid artery. In positive experiments, more intense staining was noted when the dye was injected by the carotid route. The dye was allowed to circulate at least 45 min. before completion of the experiment. Each preparation was checked for filling of the internal carotid by the removal of the brain and the injection of fluid through the catheter. Fia. 3. (A) Normal control record. (B) Example of seizure discharges immediately after the ~nd injection of the test substance. Note the EKG changes. All EEGs (Figs. 1, ~ and 3) were obtained on a standard 6 channel Grass electroencephalograph, using 6 needle electrodes inserted symmetrically in the scalp. Records were obtained continually with bipolar leads during the study period. So that EEG changes could be tabulated, the following classification was established: 0 =No change. 1-{-=An amplitude decrease with diminished secondary activity or transient delta activity lasting less than 5 min. ~-[-=A well developed delta focus and/or generalized slow activity lasting 5 to 10 min. 3~-=A delta focus and/or generalized slow activity lasting more than 10 min. 4~-= Severe depression of all cortical activity persisting up to 1 hr.

5 EVALUATION OF CONTRAST MEDIA IN ANGIOGRAPHY 4S9 TABLE 1 Media Total EEG Ipsilateral Dose Change Staining R O 70% S.~ cc. 4+ yes R O 70% 3.2 cc. 4+ yes R O 70% 1.6 cc. 4+ F yes R 0 70% 0.4 cc. 4+ yes Urokon 80% 1.6 ee. 4+ no Diodrast 70% 0.8 cc. 4+ F yes Neoiopax 75% 4.8 cc. 4+ G yes Neoiopax 75% 4.8 cc. 4 + G yes Neoiopax 75% ~.4 cc G yes Neoiopax 75% 0.8 cc. 4+ G yes Diodrast 35% 4.8 cc. 3+ G yes Diodrast S5% 3.2 cc. 3+ F no Diodrast S5% 1.6 ec. 8+ F no Diodrast 35% 0.8 cc. S+ F no Diodrast 70% 1.6 cc. 8+ F no Neoiopax 75% 1.6 cc. S+ F no F = Focal electrical seizure. G = Generalized electrical seizure. RESULTS At this time, 39 observations have been made on 34 animals, using as test substances Thorotrast, 35 per cent Diodrast, 70 per cent Diodrast, 75 per cent Neoiopax, and 30 per cent Urokon, all commercially available contrast substances. In addition, 3, 4 dioxo-3 iodo, 6 methyl-tetra-hydropyridine-n-acetic acid in 70 per cent solution (RO), an experimental medium, has been used (Hoffmann-La Roche, Inc.). The results secured in the preliminary application of this method of contrast media study are tabulated (Tables 1 and 3). The correlation between dye staining and EEG changes shows that 9 of 10 animals with 4+ EEG changes showed brain staining, an indication of altered vascular permeability. Only 1 of 6 animals with 3-{- changes showed brain staining. Vital staining was never observed in animals with 1 + and 3 + EEG alterations. No statistical correlation is possible between the incidence of seizures and tissue staining. TABLE Media Total EEG lpsilateral Dose Change Staining Thorotrast 4.8 cc. g-4- no Urokon S0% 8.~ ee. 2-i- F no Urokon 80% 1.6 ce. g-l- no Urokon 80% 1.6 cc no Diodrast S5% 1.6 cc Neoiopax 75% 1.6 ce Thorotrast 1.6 cc. 1 + no Thorotrast 8.0 ce no Thorotrast 8.0 cc. 1 + no

6 440 B. M. BLOOR, F. R. WRENN, JR., AND G. J. HAYES DISCUSSION From these results it appears that the combined method of indicator dye injection and electroencephalography will serve as a useful technique for the objective evaluation of contrast media used or proposed for cerebral angiography. The contrast media tested appear capable of altering both cerebral vascular permeability and cerebral electroactivity when injected within the cerebral circulation in the dosages indicated. Studies now in progress will enlarge the statistical import of these findings in terms of separate media and will include histopathological preparations of the stained brain parenchyma. The authors wish to thank Dr. Barnes Woodhall for his assistance in the conduct of this investigation and the preparation of the manuscript. REFERENCES 1. BROMAN, T., FORSSMAN, B., and 0LSSON, 0. Further experimental investigations of injuries from contrast media in cerebral angiography. Summation of various injurious factors. Acta radiol., Stockh., 1950, 34: ~. BROMAN, T., and LINDBERG-BROMAN, A.M. An experimental study of disorders in the permeability of the cerebral vessels ("the blood-brain barrier") produced by chemical and physico-chemical agents. Acta physiol, scand., 1945, 10: 10~o-1~5. 3. BROMAN, W., and OrSSON, O. The tolerance of cerebral blood-vessels to a contrast medium of the diodrast group. An experimental study of the effect on the blood-brain-barrier. Acta radiol., Stockh., 1948, 30: 3~6-34~. 4. BROMAN, T., and OrSSON, 0. Experimental study of contrast media for cerebral angiography with reference to possible injurious effects on the cerebral blood vessels. Acta radiol., Stockh., 1949, 31: 3~ EKSTR6M, G., and LINDGREN, A. G.H. Gehirnschi~digungen nach cerebraler Arteriographie mit Thorotrast. Zbl. Neurochir., 1938, 3: ~ ENGESET, A. Cerebral angiography with perabrodil (carotis angiography), Acta radiol., Stoekh., 1944, suppl. 56, ~07 pp. 7. FRENCH, L..A., and BLAKE, P.S. Complications following the use of neo-iopax in cerebral angiography. Amer. J. Roentgenol., 1950, 64: FRIEDEMANN, U. Blood-brain barrier. Physiol. Rev., 1942, 22: 1~ GREEN, J. R., and ARANA, R. Cerebral angiography. A clinical evaluation based on 107 cases. Amer. J. Roentgenol., 1948, 59: HODES, P. J., PERRYMAN, C. R., and CIIAMBERLAIN, R.H. Cerebral angiography. Amer. J. Roentgenol., 1947, 58: ~. 11. KmSTIANSEN, K., and CAMMERMEYER, J. An experimental investigation on the effect of arteriography with perabrodil on the brain. Acta radiol., Stockh., 194~, 23: NORTHFIELD, D. W. C., and RUSSELL, D.S. The fate of thorium dioxide (thorotrast) in cerebral arteriography. Lancet, 1987, 1: OLSSON, O. Cerebral angiography: tolerance for contrast media of diodrast type. J. Neurol. Neurosurg. Psychiat., 1949, n.s. 12: 31~ WILKINSON, M., STANTON, J. B., JONES, D. P., and SPALDING, J. M.K. Fercutaneous carotid angiography. A team technique. With a report of the results in seventy cases. J. Neurol. Neurosurg. Psychiat., 1949, n.s. 12: