Jun 14, 1979 - trast material. It usually involves mild flushing, warmth, tingling sensations, a slight giddines, a metallic taste or perhaps nausea. This mild, tran-.
THE NESTERN Journal of Medicine Refer to: Bush WH Jr, Mullarkey MF, Webb DR: Adverse reactions to radiographic contrast material. West I Med 132: 95-98, Feb 1980
Adverse Reactions Contrast Material
to
Radiographic
WILLIAM H. BUSH, JR., MD; MICHAEL F. MULLARKEY, MD, and D. ROBERT WEBB, MD, Seattlo
Major adverse reactions to radiographic contrast media will occur more often contrast material is now also administered during computerized tomographic (CT) scanning. Differentiation of the two major contrast reactions, the vagus reaction and the anaphylactoid reaction, is essential. Bradycardia is the key finding for identifying the vagus reaction. The vagus reaction involving hypotension and bradycardia requires treatment with large doses of atropine given intravenously. The immediate generalized reaction or anaphylactoid reaction should be treated as anaphylaxis with administration of vasopressors, fluids, steroids and antihistamines. Steroids and antihistamines given before the examination may offer protection to those high-risk patients who have had previous anaphylactoid reactions to contrast material. as
THE USE of intravenously given radiographic contrast material is increasing. In addition to excretory urography, phlebography and aqgiography, radiographic contrast material is now frequently administered during computerized tomographic (CT) scanning of the head and body. Clinicians need to be aware of this practice bepause of its possible effects on patients who may have had previous reactions to the material. Treatment of these higher risk patients before repeat examinations has been advocated. The different types of adverse reactions need to be quickly recognized as well so that appropriate treatment can be initiated. Of those patients receiving radiographic contrast material, up to 50 percent will have some From the Department of Radiology and the Section of Allergy and Immunology The Mason Clinic, Seattle. Submitted, revised, June 14, 1979. Reprint requests to: William H. Bush, Jr., MD, Department of Radiology, The Mason Clinic, 1100 Ninth Avenue, Seattle, WA 98101.
type of untoward effect. Most of these will be mild, inconsequential vasomotor reactions. A mild or moderate immediate generalized reaction (IGR) or anaphylactoid reaction will develop in approximately 2 percent of patients. Severe reactions will occur in about one patient in a 1,000 and deaths in one in 40,000 of those receiving contrast material.1-4 Three types of adverse reactions have been recognized: (1) The vasomotor effect occurs in as many as 50 percent of patients receiving contrast material. It usually involves mild flushing, warmth, tingling sensations, a slight giddines, a metallic taste or perhaps nausea. This mild, transitory reaction is not life-threatening and is probably caused by the hypertonicity of the contrast material.5-7 (2) The immediate generalized reaction (IGR), also termed the anaphylactoid reaction, designates the condition previotisly called the hypersensitivity reaction. However, it is not a true THE WESTERN JOURNAL OF MEDICINE
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ABBREVIATIONS USED IN TEXT CT= computerized tomography IGR= immediate generalized reaction
anaphylactic reaction. The IGR may involve the development of urticaria, perhaps bronchospasm or laryngospasm, vasodilatation, hypotension and a compensatory tachycardia in patients.8-"1 The presence of tachycardia differentiates this type of reaction from the vagus reaction. (3) With the vagus reaction a patient becomes apprehensive, restless, gradually obtunded, sometimes loses sphincter control and may be apneic; hypotension and a profound bradycardia develop. Bradycardia is the key finding.12 The differentiation of these latter two major reactions is very important and should determine appropriate treatment. Discussion 'n Possible Mechanisms There are few universally accepted facts about the mechanism of adverse reactions to radiographic contrast media. It appears that the anaphylactoid reaction relates to release of vasoactive and inflammatory agents by basophils and mast cells, and probably involves histamine.5'9 The mechanism of release is uncertain but evidence suggests that a variety of mediators may be important. A direct effect by the contrast agent may occur in some cases;14 components of the complement system have been implicated, particularly the anaphylatoxins C3a and C5a,"13"1 and a role by components of the coagulation system and prostaglandin inactivation has been suggested as well.13"6 Although anaphylactoid reactions to contrast medium mimic IgE-mediated reactions, most evidence is against the contrast reaction being an immunologic reaction. Adverse reactions occur without previous exposure to contrast media and are nqt consistently reproducible, and attempts to show antibodies or circulating immune complexes have generally failed except in the study by Brasch.3,4'7,9,17-'9 Although the series is small, the study by Simon, Schatz and associates, comparing patients exposed to radiographic contrast media Without adverse reactions with those evidencing an anaphylactoid reaction showed no significant difference in the rise of plasma histamine, fall in complement level, presence of fibrin split products, personal history of allergy, previous ex96
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posure to contrast material or positive skin test to to contrast media.'7 Tissue responsiveness of each patient to mediators generated by several mechanisms may be the critical factor in adverse tions to radiographic contrast material.'3
reac-
Possible Risk Factors Patients with allergies to foods or iodine, those with hayfever and, particularly, those with atopy show a higher incidence (up to 4 percent) of anaphylactoid reactions to contrast material than the expected 2 percent in the general population."17'20 Of particular importance is the fact that patients who have had a previous IGR to contrast material show a much higher rate of reaction with a second administration of contrast medium-the rate increasing up to 35 per-
cent.'0,""'8 The frequency of major adverse reactions does not seem to increase with larger doses of contrast material' although the route of administration seems to affect the reaction rate. A larger number of reactions have been noted in patients after urograms (intravenous administration) were done than after arteriograms.3 However, equally severe reactions have been observed21 in the same patient when contrast material was given subcutaneously, intravenously and intraarterially. Small but definite intravascular levels of contrast medium can also be measured when retrograde pyelography or cystography is done. Therefore, even these examinations are not entirely innocuous in highrisk patients.'8 Pretesting for the IGR or anaphylactoid reaction is not reproducible and is not recommended."22'23 The value of graded intravenous pretesting has not been confirmed.
Vagus Reaction The vagus reaction is a special type of reaction and is the one most likely to occur in patients after proctoscopy, cholangiography (intravenous administration) and common duct manipulation. The vagus reaction also probably accounts, in part, for the "caine" reaction or so-called hypersensitivity to local anesthetics. A profound vagus discharge may be elicited by the needle puncture, and it is this reaction that may be related to the fear-anxiety type reaction discussed by Lalli.24 He strongly believes that the fear component plays a primary role in patients and their "allergic" reactions to contrast material. The vagus reaction differs from the anaphy-
RADIOGRAPHIC CONTRAST MATERIAL
lactoid reaction in that hypotension and a profound bradycardia occur. Recognizing the bradycardia is critical because treatment of the vagus reaction involves giving the patient atropine and, perhaps, fluids intravenously. Antihistamines have very little effect on the vagus reaction. The vagus excess found with the vagus reaction causes vasodilatation, primarily in the postarteriolar phase, with venous pooling, lack of venous return and hypotension. Simultaneously, there is a depression of sinoatrial node activity causing bradycardia and arrhythmias.2' Thus, instead of the expected tachycardia in response to the vasodilatation, a profound bradycardia occurs which, in turn, accentuates the hypotension. t Treatment of the vagus reaction requires aggressive intravenous administration of atropine.8' 1226 Some feel that treatment with low doses of atropine is more life-threatening than helpful, and that it initially depresses sinoatrial node activity and increases arrhythmias; it is only with higher doses that this initial adverse reaction is reversed.12 Treatment should begin with 0.6 to 0.8 mg of atropine given intravenously, followed by repeated doses every minute (while monitoring pulse rate) until a maximum total dosage of atropine (3 mg for adults) is administered. Fluids should then be given intravenously as well. The pulse rate is the most sensitive indicator of a patient's response to atropine because blood pressure may remain low for two to four hours despite adequate atropine treatment. However, by monitoring the pulse rate and administering large doses of atropine, the patient should respond clinically rather dramatically and show a reversal of apprehension, restlessness and depressed sensorium. Skin color may improve and pulse rate progressively increase. Routine pretreatment against the vagus reaction is not suggested for excretory urography because of the inability to predict in which patients a vagus reaction might develop. However, for angiography it may be worthwhile to treat highly anxious patients beforehand with intramuscular administration of 0.8 to 1 mg of atropine.
Anaphylactoid Reaction Treatment for the immediate generalized reaction (anaphylactoid reaction) includes adminis-
tration of vasopressors, fluids (intravenously), oxygen and, perhaps, antihistamines or steroids. Antihistamines are much less helpful once the reaction has fully developed although they probably
neutralize circulating unbound histamine. Aminophylline is helpful for bronchospasm even though the aminophylline can accentuate any existing hypotension. Steroids are often empirically used, and most authors suggest giving high doses of corticosteroids intravenously when treating a severe immediate generalized reaction.9""' 8'27 Pretreatment or premedication for the anaphylactoid type reaction is now being advocated.10""128 Both the Schatz group and the Zweiman group found it impossible to justify developing a control series of patients who previously had reacted to contrast material. In evaluating the contrastreactive patients who were treated before the repeat examination (one group with antihistamines only, the other group with steroids only) and those who were not, the authors found that instead of an expected rate of 35 percent repeat contrast reaction there was a lower rate of 9 perpercent to 12 percent.'0"' Without controls the significance of this finding can be argued. However, Kelly and associates report a recent prospective study that suggests that pretreatment offers protection against serious systemic reactions for high-risk patients who previously had experienced IGR.28 For those patients at high risk of having an anaphylactoid reaction, treatment with a combination of steroids and antihistamines is advocated using the following schedule.28'29 Beginning 18 to 24 hours before the examination give 50 mg of prednisone orally every six to eight hours for three doses. Then give an antihistamine (such as Benadryl, 50 mg) orally or intramuscularly an hour before the examination. This recommended pretreatment with prednisone can be terminated without problem. When a patient says, "I am allergic to x-ray -dye" it is important to determine the type of adverse reaction that had actually occurred previously. If a patient had nausea, felt a tingling sensation or felt "flushed" after injection of the contrast medium, then a benign vasomotor effect had occurred. This reaction can be disregarded and does not need pretreatment or premedication. Conversely, if a patient had prominent hives, angioedema, bronchoconstriction or a hypotensive reaction, an IGR or anaphylactoid type reaction had occurred. It is suggested that these patients be treated with a combination of steroids and antihistamines before any further similar radiographic contrast material is administered. If a patient experienced hypotension and bradycarTHE WESTERN JOURNAL OF MEDICINE
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dia indicating a vagus reaction then administration of atropine before the test may be helpful. It is extremely important in patients with a serious history of previous contrast reactions that physicians review the indications for repeating the procedure and consider alternative diagnostic modalities such as ultrasonography, radionuclide imaging or CT scanning without use of contrast material.
Summary Three types of adverse reactions to contrast media occur, the exact mechanisms of which are unknown. The vasomotor effect is usually not clinically significant. The immediate generalized reaction or anaphylactoid reaction varies in severity and is potentially life-threatening as is the vagus reaction. The anaphylactoid reaction should be managed like anaphylaxis with administration of fluids and vasopressors. Conversely, profound bradycardia in combination with hypotension identifies the vagus reaction and differentiates it from the IGR. Large doses of atropine given intravenously are specifically indicated for the vagus reaction. It is important to characterize the type of previous reactions, identify high-risk patients, and review the indications for any repeat examination. For those patients who have had a significant previous anaphylactoid reaction, treatment with a combination of steroids and antihistamines before the test is
suggested. REFERENCES 1. Davies P, Roberts MB, Roylance J: Acute reactions to urographic contrast media. Br Med J 2:434-437, 1975 2. Ochsner SF, Calonje MA: Reactions to intravenous iodide in urography. South Med J 64:907-911, 1971 3. Shehadi WH: Adverse reactions to intravascularly administered contrast media. Am J Roentgenol 124:145, 1975 4. Witten DM, Hirsch FD, Hartman GW: Acute reactions to urographic medium. Am J Roentgenol 119:832, 1973 5. Bhat KN, Arroyave CM, Crown R: Reactions to radiographic contrast agents-New developments in etiology. Ann Allergy
37:169-173, 1976
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6. Dahl SG, Linader 0, Mellbye A, et al: Influence of the cation on the side effects of urographic contrast media. Acta Radiol (Diagn) 17:461-471, 1976 7. Lasser EC: Basic mechanism of contrast media reaction. Radiology 91:63-65, 1968 8. Andrews EJ: The vagus reaction as a possible cause of severe complication of radiological procedures. Radiology 121: 14, 1976 9. Miller WL, Doppman JL, Kaplan AP: Renal arteriography following systemic reaction to contrast material. J Allergy Clin Immunol 56:291, 1975 10. Schatz M, Patterson R, O'Rourke J, et al: The administration of radiographic contrast media to patients with a history of previous reaction. J Allergy Clin Immunol 55:358-366, 1975 11. Zweiman B, Mishkin MM, Hildreth EA: An approach to the performance of contrast studies in contrast material reactive patients. Ann Intern Med 83:159-162, 1975 12. Stanley RJ, Pfister RC: Bradycardia and hypotension following use of intravenous contrast media. Radiology 121:5-7, 1976 13. Gorevic P, Kaplan AP: Contrast agents and anaphylacticlike reactions (editorial). J Allergy Clin Immunol 63:225-227, 1979 14. Ring J, Arroyave CM, Fritzler MJ, et al: "In vitro" histamine release and serotonin release by radiographic contrast media-Complement dependent and independent release reaction and changes in ultrastructure of human blood cells. Clin Exp Immunol 32:105, 1978 15. Arroyave CM, Schatz M, Simon RA: Activation of the complement system by radiographic contrast media-Studies in vivo and in vitro. J Allergy Clin Immunol 63:276-280, 1979 16. Lasser EC, Slivka J, Lang JH, et al: Complement and coagulation-Causative considerations in contrast catastrophes. Am J Roentgenol 132:171-176, 1979 17. Simon RA, Schatz M, Stevenson DD, et al: Radiographic contrast media infusions-Measurement of histamine, complement, and fibrin split products and correlation with clinical parameters. J Allergy Clin Immunol 63:281-288, 1979 18. Siegle RL, Lieberman P: A review of untoward reactions to iodinated contrast material. J Urol 119:581-587, 1978 19. Brasch RC, Caldwell JL, The allergic theory of radiographic contrast toxicity, demonstration of antibody activity in sera of patients suffering major radiocontrast agent reactions. Invest Radiol 11:347, 1976 20. Littner MR, Rosefeld AT, Ulrich S, et al: Evaluation of bronchospasm during excretory urography. Radiology 124:17-21, 1977 21. Cho KJ, Thornbury JR: Severe reactions to contrast material by three consecutive routes: Intravenous, subcutaneous and intra-arterial. Am J Roentgenol 131:509-510, 1978 22. Fischer HW, Doust VL: An evaluation of pretesting in the problem of serious and fatal reactions to excretory urography. Radiology 103:497, 1972 23. Gooding CA, Berdon WE, Brodeur AE, et al: Adverse reactions to intravenous pyelography in children. Am J Roentgenol 123:802-804, 1975 24. Lalli AF: Urographic contrast media reactions and anxiety. Radiology 112:267-271, 1974 25. Higgins CB: Effects of contrast media on the conducting system of the heart. Radiology 124:599-606, 1977 26. Lasser EC, Lang J, Sovak M, et al: Steroids: Theoretical and experimental basis for utilization in prevention of contrast media reactions. Radiology 125:1-9, 1977 27. Fisher HW, Colgan FJ: Causes of contrast media reactions. Radiology 121:223, 1976 28. Kelly JF, Patterson R, Lieberman P, et al: Radiographic contrast media studies in high-risk patients. J Allergy Clin Immunol 62:181-184, 1978 29. Patterson R, Schatz M: Administration of radiographic contrast medium (letter to the editor). J Allergy Clin Immunol 56:328, 1975
