T HE value of the vasoconstrictor effect of epinephrine in angiography has now

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1 APRIL, 1969 CONTRAST-VASOCONSTRICTOR IN ANGIOGRAPHY* MIXTURES By PAUL C. KAHN, M.D. With the Technical Assistance of Joseph P. Zeppieri, A.B.,t and Gerald S. Lorch, B.S.t BOSTON, T HE value of the vasoconstrictor effect of epinephrine in angiography has now been well documented In most techniques the vasoconstrictor and the contrast medium are introduced sequentially with a variable time interval between the 2 injections. After intra-arterial administration the vascular response is almost instantaneous in onset, but also fades rather quickly. For this reason it was considered that the administration of a mixture of contrast media and catecholamines might prove an ideal method of standardizing and simplifying epinephrine angiographic techniques, as well as minimizing the dose of vasoconstrictor. A series of experiments in dogs partly substantiated this assumption, but also resulted in some interesting, but unexpected observations. The results of these experiments, as well as the preliminary clinical application of these mixtures are presented. MATERIAL AND METHODS MASSACHUSETTS Twenty-two experiments were performed on 9 mongrel dogs weighing 33 to 0 pounds. They were anesthetized with sodium pentobarbital, 0.2 mg. per pound. A cut-down was performed on a femoral artery and a PE 20 (Clay-Adams) polyethylene catheter was inserted into the abdominal aorta and positioned at the T 2-L i level. The electrocardiogram and the brachial arterial pressure were recorded on a Sanborn 96 recorder. Serial aortograms were obtained on a Sanchez-Perez film changer following the injection of i ml. per pound of each of the following: (i) Methylglucamine iothalamate 6o per cent (conray) ; (2) methylgiucamine iothalamate with i microgram of epinephrine per ml.; () methyiglucamine iothalamate with 5 micrograms of epinephrine per ml.; and (.) methylgiucamine iothalamate with microgram l-norepinephrine (levophed) per ml. The injections were randomized and not identified until after the data interpretation had been completed. There was at least a 5 minute delay between successive aortographies. Two injection speeds were used, one delivering the bolus in 1.5 seconds, the other in 7.5 seconds. The same speed was used throughout each experiment. Twelve roentgenograms spaced over a period of 21 seconds were taken with each injection. Each dog was studied up to times, with a rest interval of at least 3 days. Hemoglobin and serum creatinine were measured regularly. An autopsy was performed after the last experiment. RESULTS The hypotensive phase lasting i to 2 minutes after the injection of contrast media is well known and was clearly demonstrated in our animals, with a mean blood pressure drop of 25 mm. Hg (Fig. i). The addition of, g. per ml. of epinephrine reversed the curve, with a rise in blood pressure of about 25 mm. now measured. The addition of 5 tg. of epinephrine per ml. resuited in a much more marked blood pressure rise. The i tug. per ml. dose of 1-norepinephrine was intermediate between these two, corresponding roughly to 2 per ml. of epinephrine. Changes in heart rate were also apparent. Epinephrine prolonged the tachycardia which followed the * Presented at the Sixteenth Annual Meeting of the Association of University Radiologists, Columbus, Ohio, May 8-Il, i968. From the Department of Radiology, New England Medical Center Hospitals, Boston, Massachusetts. Supported by USPHS Research Grant No. HE o96a. t Summer Fellows, Department of Radiology, Tufts University School of Medicine. 772

2 VOL. io, No. Contrast-Vasoconstrictor Mixtures 773 injection of the contrast agent alone, but levophed diminished this effect, and, in fact, produced a slight bradycardia after 2 to 3 minutes. The effects of these mixtures on the aortogram were quite striking (Fig. 2, A and B). The aortic blood flow was markedly reduced, and the slow injections of contrastvasoconstrictor mixtures resulted in a complete aortogram, while in the control injections only faint aortic visualization was present. The renal arteries were filled out, although peripheral constriction could be seen. Adrenal visualization was usually improved in the injections with vasoconstrictors; however, the improvement was not really pronounced except when the large dose of epinephrine was employed (Fig. 3, A and B). Slightly increased opacification of the lumbar artery branches was also noted. One of the most surprising results was the prolonged, dense nephrogram seen after the injection with vasoconstrictors. Excellent parenchymal visualization was obtained 20 seconds after the injection, long J 120z log : / \ -- SALINE - CONWAY CONRAY WITH 5,ig EPIN(PHRINE CONWAY WITH I g (PIP$PHRINE CONWAY WITH I,. LEVOPHED 0 I Fic. 2. (M Aortogram at the conclusion of a 7.5 second injection of 38 ml. of conray 6o in a 38 pound dog. Note that very little contrast material remains in the aorta and major arteries. (B) Repeat aortogram with i pig. per ml. of epinephrine added to the contrast material. Roentgenogram at the end of injection shows dense filling of the aorta and most branches. The renal arteries (arrows) are well filled proximally, but are constricted peripherally. TIME -MINUTES Fic. i. Effect of contrast-vasoconstrictor mixtures on blood pressure. Abdominal aortogram with I ml. per pound of each mixture in dogs. Note that the contrast-vasoconstrictor combinations reverse the normal hypotensive phase seen with the control injection. after it had faded in the controls (Fig., A and B). Epinephrine and levophed appeared comparable in this effect, which was only slightly related to dose (Fig. 5). Along with persistent increase in density, a decrease of renal size of 2 to 3 mm. was found.

3 77 Paul C. Kahn APRIL, G. 3. (ii) Conray aortogram shows a density medial to the right kidney faintly suggesting an adrenal gland. (B) Repeat aortogram with 5 jig. per ml. epinephrine added to the contrast agent shows a dense adrenal arteriogram (arrows). Roentgenograms with i jig. per ml. of epinephrine or l-norepinephrine were only slightly better than the control. DISCUSSION Slowing of aortic blood flow with contrast-vasoconstrictor mixtures is expected. While the renal and gastrointestinal circulations are most reduced, flow through the muscular branches also decreases slightly. The ability to produce a satisfactory aortogram with a prolonged injection is potentially clinically useful. For example, good roentgenograms could be obtained through a small translum bar needle. With a catheter aortogram, a manual rather than a pump injection could be used. Another potential application might be for adrenal visualization.9 However, the large dose of epinephrine required to obtain good adrenal filling is not practical for clinical use at present. A combined pharmacologic approach with vasoconstrictors plus other stimulants of adrenal blood flow (e.g., angiotensin or ACTH) may prove more rewarding. The prolonged nephrogram after injection of the contrast-vasoconstrictor mixtures requires some explanation. When epinephrine and a contrast agent are administered sequentially, practically no nephrogram is obtained.5 This is due to the marked vasoconstriction of the renal arteries. One must assume that when the mixture is used some of the contrast material enters the small renal vessels before vasoconstriction occurs, and then is trapped by the cessation of blood flow. Although there is potential clinical application for this prolonged nephrogram, for example in nephrotomography, this technique must be approached with caution. It is generally believed that one of the parameters of renal toxicity of contrast medium is the length of time which the contrast material remains within the renal parenchyma. However, none of the animals in this study developed serum creatinine elevations, despite repeated injections with

4 \OL. 105, No. Con trast-vasoconstrictor \Ii xtures FIG.. (A) Conray aortogram i seconds after injection shows only a faint residual nephrogram. (B) Aortogram ig seconds after an injection with a mixture of i g. per ml. of epinephrine in the contrast material shows a dense nephrogram. The kidney is reduced 3 mm. in length. doses 2 to times as great on a weight basis as would be used in patients. The elimination of the hypotensive phase of the contrast medium injection by the use of vasoconstrictors offers another possibility for clinical application. It has been assumed that some of the serious sequelae of contrast injections may be due to this hypotension. Only a very small amount of epinephrine is required to eliminate this effect. Because this dose is well within the range used for tumor evaluation (e.g., 10-is ag.) a limited clinical trial was made. In a few patients, mixtures of 0.2 j.ig. of epinephrine per ml. of methylglucamine iothalamate 6o per cent (conray) were used for distal aortic injection well below the renal arteries during fern oral arteriography. i wenty to thirty milliliters of the mixture was used for one of 3 to injections usually done as part of the procedure, and blood pressure was monitored through the catheter after all of the injections. The addition of epinephrine largely eliminated the 1O-15 mm. blood pressure drop present in other injections. No difference was seen in the filling of the muscular branches of the lower extremity arteries. Interestingly enough, the patients noted markedly less discomfort with the injection of the contrast-epinephrine mixture. CONCLUSION AND SUMMARY An experiment was designed to test in dogs the effectiveness of mixtures of epinephrine and l-norepinephrine with methylglucamine iothalamate (conray) as a meth- 0(1 of utilizing the epinephrine effect in arteriograph v. It was shown that the use of such combinations can reverse the hypotensive phase which ordinarily occurs after contrast medium injections. A reduction of aortic blood flow, which is

5 776 Paul C. Kahn AI RIL, CONWAY WITH 5.MQ EPiN#{128}PRIN#{128} Paul C. Kahn, M.D. CONWAY WITH I )IQ EPINEPtRINE Department of Radiology > 12 I- Inz 10 w z 0 IlJ I- -J IJJ 6 WITH IsO LEVOP$ED CONRAY - CONWAY New England Medical Center Hospitals 171 Harrison Avenue 5 10 IS 20 SECONDS AFTER INJECTION Boston, Massachusetts 021 I I RE FERENCES I. ABRAMS, H. L. Response of neoplastic renal yessels to epinephrine in man. Radiology, 196, 82, 2! BoDFoRss, B., MUTH, T., and OLIN, T. Renal function judged with radioactive diodrast after selective renal angiography in dogs. Acta radio!. (Diag.), 196, 2, Boijs, E., and REDMAN, H. Effect of epineph- rine on celiac and superior mesenteric angiog- FIG. 5. Effect of addition of vasoconstrictors on the raphy. Invest. Radio!., 1967, 2, persistence of the nephrogram after arteriography.. EFSEN, F., and MUNKNER, T. Influence of ab- Note that the nephrogram fades rapidly after the dominal aortography on arterial blood pressure, control injection. With the contrast-vasoconstric- cardiac output and heart rate. Invest. Radiol., tor mixtures the nephrogram remains intense for 1968, to 20 seconds. 5. KAHN, P. C. Epinephrine effect in selective renal angiography. Radiology, 1965, 85, KAHN, P. C., FRATES, W. J., and PAUL, R. E., JR. Epinephrine effect in angiography of gastro.. potentially useful in angiography, was intestinal tract tumors. Radiology, 1967, 88, noted o. A dense persistent nephrogram seen after 7. KAHN, P. C., and WISE, H. M., JR. Use of epinephrine in selective angiography of renal the injection of the contrast-vasoconstric- masses. 7. Urol., 1968, 99, tor mixtures was attributed to trapping of 8. ROCKOFF, S. D., DOPPMAN, J., BLOCK, J. B., and contrast medium in the kidneys. KETCHAM, A. Variable response of tumor yes- Improved adrenal visualization could al- sels to intra-arterial epinephrine: angiographic so be obtained, but only when larger doses study in man. Invest. Radiol., 1966, I, WINKLER, S. S., and KAHN, P. C. Pharmacologic of epinephrine were used than are clinically aids in adrenal angiography. Invest. Radiol., practical. 1967, 2, 8-52.