Systemic Anaphylactoid Reactions to Iodinated Contrast Media During Cardiac Catheterization Procedures:Guidelines for preventi

Jerome E. Goss, MD, Charles E. Chambers, MD, Frederick A. Heupler, MD, and Members of the Laboratory Performance Standards Committee of the Society for Cardiac Angiography and Interventions. From the New Mexico Heart Clinic, Albuquerque; Pennsylvania State University College of Medicine, Hershey; Cleveland Clinic Foundation, Cleveland, Ohio. Members of the Laboratory Standards Committee: Frederick A. Heupler, Jr., MD, Chairman; Jerome E. Goss, MD, Vice Chairman; Arfan J. Al-Hani, MD; William T. Armstrong, MD; Stephen Balter, PhD; Airlie A. C. Cameron, MD; Charles E. Chambers, MD; Larry S. Dean, MD; Wayne E. Dear, MD; Manuel de la Llata, MD; John P. Dervan, MD; James C. Dillion, MD; Lowell I. Gerber, MD; Kenneth R. Jutzy, MD; Neal S. Kleiman, MD; Francis Y. K. Lau, MD; Jeffrey W. Moses, MD; William J. Phillips, MD; Sheldon S. Sbar, MD; William C. Sheldon, MD.
Jerome E. Goss, MD, Charles E. Chambers, MD, Frederick A. Heupler, MD, and Members of the Laboratory Performance Standards Committee of the Society for Cardiac Angiography and Interventions. From the New Mexico Heart Clinic, Albuquerque; Pennsylvania State University College of Medicine, Hershey; Cleveland Clinic Foundation, Cleveland, Ohio. Members of the Laboratory Standards Committee: Frederick A. Heupler, Jr., MD, Chairman; Jerome E. Goss, MD, Vice Chairman; Arfan J. Al-Hani, MD; William T. Armstrong, MD; Stephen Balter, PhD; Airlie A. C. Cameron, MD; Charles E. Chambers, MD; Larry S. Dean, MD; Wayne E. Dear, MD; Manuel de la Llata, MD; John P. Dervan, MD; James C. Dillion, MD; Lowell I. Gerber, MD; Kenneth R. Jutzy, MD; Neal S. Kleiman, MD; Francis Y. K. Lau, MD; Jeffrey W. Moses, MD; William J. Phillips, MD; Sheldon S. Sbar, MD; William C. Sheldon, MD.
This report represents the first guidelines for prevention, diagnosis, and treatment of anaphylactoid reactions to contrast media occurring specifically during cardiac catheterization. The incidence of contrast media complications in the catheterization laboratory is 0.23% with 1 death per 55,000. Anaphylactoid reactions are non-immune mediated, but histamine release and other mediators produce a clinical presentation indistinguishable from anaphylaxis. In patients with known previous reactions, pretreatment with steroids and diphenhydramine and the use of nonionic contrast media have significantly reduced the potential of recurrent reaction. Minor reactions such as limited urticaria may be watched for progression or treatment with diphenhydramine, whereas more serious reactions such as angioedema or laryngeal edema require airway stability and ephinephrine administration. Shock should be vigorously treated simultaneously with intravenous epinephrine and large volumes of normal saline. If the patient can be stabilized, the study should be completed as histamine, leukotrienes, and other vasoactive products should be relatively depleted. Key words: shock, epinephrine, histamine Introduction General guidelines for diagnosis and treatment of anaphylactoid reactions to contrast media have been developed by several authors.1-4 Many treatment plans may be applicable to both the radiology department and the cardiac catheterization laboratory, but in the latter, the differential diagnosis may include a larger number of problems and treatment can be initiated more rapidly and directly since the patient already has an intravenous line and electrocardiographic and hemodynamic monitoring in progress. Using conventional ionic contrast agents, total adverse reactions can be expected with a frequency of 5-8%.1 Adverse reactions from intravascular contrast media may be classified as either anaphylactoid or chemotoxic. This review centers on only anaphylactoid reactions. The incidence of anaphylactoid reactions with arterial injections is less common, but more likely of major consequence than with intravenous. 1 The Registry of the Society for Cardiac Angiography and Intervention reported 519 major contrast media complications (0.23%) with four deaths (1 in 55,000) in 222,553 patients undergoing selective coronary cineangiography.5 With a systemic reaction to contrast media occurring in one of every 500,5 it is the goal of this report to provide the invasive cardiologist and staff with guidelines specifically developed for the cardiac catheterization laboratory for the prevention, diagnosis, and treatment of contrast media-induced anaphylactoid reactions. Definition of Terms Although not to be discussed in detail, the chemotoxic effects of contrast media are primarily related to the hyperosmolarity, viscosity, and calcium-binding properties of these agents. These effects are manifested as hypotension, bradyarrhythmias, and pulmonary congestion. Chemotoxic effects of contrast media may account for severe reactions in unstable patients. 1 However, these effects and their management generally differ from those of an anaphylactoid reaction. An anaphylactoid reaction differs from an anaphylactic reaction in its pathophysiology but not in its clinical manifestations or treatment. As described below, an anaphylactic reaction is an immune-mediated response requiring prior sensitization to the offending agent, but an anaphylactoid reaction is not immune-mediated. Anaphylactoid reactions encompass an entire spectrum from cutaneous lesions, the most common, through severe reactions potentially culminating in eventual respiratory or vascular collapse (Table I). Pathophysiology An anaphylactic reaction is an IgE-mediated hypersensitivity reaction requiring prior sensitization of the patient by a given antigen. Once the patient is sensitized, IgE antibodies are produced that combine with the offending agent as an antibody-antigen complex. This complex combines on the surface of mast cells and basophils stimulating histamine release. Unlike anaphylactic reactions, the exact mechanism of the nonimmune-mediated anaphylactoid reaction is not well worked out, but is most likely histamine-mediated. 1,6,7 Contrast media can stimulate histamine release not only as a result of an anaphylactoid reaction, but additionally can activate directly or indirectly the complement, coagulation, fibrinolytic, and kinin systems, which leads to the release of multiple mediators, including histamine, lysosomal enzymes, fibrin split products, bradykinin and leukotrienes, all capable of producing the anaphylactoid effects seen with a contrast media reaction. 1,2,6 Prevention This section reviews both the patients at increased risk for anaphylactoid reactions with contrast media administration and the current recommendations for prophylaxis. Although pretreatment has been shown to reduce the incidence of anaphyactoid reactions, prophylaxis is not completely protective. A heightened sense of preparedness must be present when these individuals are subjected to study with contrast media. In most instances, these patients will be concerned about contrast media administration; therefore, patient education is essential. In an attempt to reduce the patient’s anxiety, a detailed explanation should be provided of the indications for the study, proposed pretreatment regimen, and its expected efficacy. Anaphylactoid reactions are neither dose-related or always immediate. Therefore, a test dose of contrast media may induce a severe reaction or may fail to identify the patient at risk. 6 Prior night admission of patients with prior severe reactions to assure proper intravenous hydration and compliance with premedication should be considered. There are two main categories of patients at increased risk for contrast-induced anaphylactoid reactions who should be considered for pretreatment: the patient with prior anaphylactoid reaction with contrast administration and the allergic patient. Patients who have experienced an anaphylactoid reaction prior to contrast media administration have traditionally been considered at increased risk for recurrent reactions. Repeat anaphylactoid reactions to conventional ionic contrast media have been reported to occur in 16-44% of patients with prior contrast reactions.6,8 Therefore, this patient group should be considered for the appropriate pretreatment considerations prior to any further contrast agent injection. Controversy exists regarding the need for prophylaxis of paitents who have had prior minor anaphylactoid reactions. The risk/benefit for premedication often favors therapy, particularly if one considers anaphylactoid reactions a spectrum with the potential recurrence more severe than the initial event. The second category for potential prophylaxis is the patient with a history of atopy and asthma. 9,10 Enright and his colleagues 11 reported that individuals with previously documented allergy/hypersensitivity were twice as likely to demonstrate contrast media anaphylactoid reactions compared to controls without allergies. In 28,978 patients receiving intravenous contrast media, Lang12 demonstrated a significant increase in risk for contrast-media induced anaphylactoid reactions in the asthmatic patient and in those receiving beta blockers (p = 0.005). But a history of allergy to food containing iodine, such as seafood, is of no predictive value, 12,13 and the same holds true for skin reactions to betadine. The two areas for pretreatment consideration are prophylaxis medications and choice of contrast media agent. Steroids and H1 blockers are the basic components of most premedication regimens for patients at high risk for an anaphylactoid reaction. Rednisone 50 mg p.o. should be administered 13, 7 and 1 hour before procedure together with diphenhydramine 50 mg p.o. 1 hr before procedure. This is effective in the reduction of recurrent anaphylactoid reactions to standard contrast agents. 1,6 The addition of an H2 blocker to the above standard regimen would be logical if an IgE-mediated antigen/ antibody reaction were involved. This is not as clear with the nonimmune-mediated anaphylactoid reaction and may explain the limited data supporting routine H2 blocker administration. 7,14 Despite limited documented benefit, H2 blocker prophylaxis is likely of low risk. This has resulted in its routine administration as anaphylactoid prophylaxis in many catheterization laboratories. Low osmolarity nonionic contrast media has been evaluated in patients with prior contrast reactions. Siegle8 reported 291 prior contrast reactors studied with the nonionic contrast media, iohexol. At the discretion of the physician, 30.6% of these patients received concomitant steroid and H1 blockers. Only 16 patients (5.5%) had a repeat anaphylactoid contrast reaction with 12 of these being minimal or mild, and none severe. Of 22 patients with a prior history of severe reaction, only five had mild to moderate recurrent reactions, and no severe recurrence occurred. Greenberger15 investigated the use of nonionic contrast media in patients with known anaphylactoid reactions to contrast agents. In combination with the standard steroid and H1 blocker regimen, nonionic contrast media was used in 181 intravascular studies of which 100 were intra-arterial. Only one patient who received intravenous contrast media developed an anaphylactoid reaction, which was mild, and no patient who received intra-arterial contrast media had a repeat reaction. The overall recurrence rate was only 0.5% compared to a 10% recurrence rate for patients treated only with medical pretreatment regimens. 15 Therefore, to further reduce recurrent contrast media reactions in those patients with known previous severe anaphylactoid reactions, nonionic contrast media is recommended in combination with medical pretreatment regimens. 8,16 Finally, special discussion is required for patients with known prior anaphylactoid reactions to contrast media who present for emergency cardiac angiography. Steroids given just 1 hr prior to contrast administration are likely ineffective in the prevention of anaphylactoid reactions. 6,17 Greenberger studied nine patients with prior anaphylactoid contrast reactions requiring emergent repeat contrast media administration. Patients received both hydrocortisone, 200 mg IV, immediately and repeated every 4 hr until study completion as well as diphenhydramine, 50 mg IV, 1 hr before the study. No reactions occurred. 18 A significant anaphylactoid reaction in an already critically ill patient would obviously be poorly tolerated. However, the risk of the procedure must be compared with the potential benefit, particularly in the patient with cardiogenic shock. Clinical Presentation and Differential Diagnosis The differential diagnosis for a patient experiencing a contrast media-related anaphylactoid reaction includes both cardiac and noncardiac causes (Table II). An anaphylactoid reaction must be considered in any patient with hypotension during catheterization. Although physiologically distinguished from a vagal reaction by the absence of bradycardia, an anaphylactoid reaction without classic tachycardia may occur in the patient receiving beta blockers12 and in patients with VVI pacemakers. Central venous pressure monitoring during anaphylactoid reaction demonstrates low pressures. Although further hemodynamic data is limited for patients experiencing an anaphylactoid reaction, a low pulmonary capillary wedge pressure and a low systemic vascular resistance due to massive vasodilatation would likely be expected. The majority of anaphylactoid reactions occur within 20 min of exposure to contrast media. 6,19 In one epidemiologic study, 64% of patients who developed severe or fatal reactions did so within 5 min after injection. 19 Severe anaphylactoid reactions may begin with very mild symptoms but progress rapidly in a matter of minutes. 2 Rapid diagnosis, cessation of contrast administration, and appropriate therapy are essential. Necessary intravenous access, drugs, and equipment for prompt treatment must be readily available at all times. Treatment The specific treatment of an anaphylactoid reaction is based upon the pathophysiology and directed toward the specific clinical manifestations. This section addresses two specific areas. Initially, the pharmacologic agents utilized for the treatment of anaphylactoid reactions are reviewed. With this background, specific treatment regimens are provided for minor, moderate, and severe anaphylactoid reactions to contrast media. Five pharmacologic (therapeutic) agents are discussed for the treatment of anaphylactoid reactions: epinephrine, steroids, H1 blockers, H2 blockers, and volume administration. Epinephrine is the adrenergic drug of choice for treating severe anaphylactoid reactions. 3,20 Epinephrine stimulates both alpha and beta receptors. The alpha adrenergic effect produces arteriolar and venous vasoconstriction. The beta1 adrenergic effect produces increased myocardial contractility and heart rate, whereas beta2 adrenergic stimulation produces bronchodilatation. 1 At the cellular level, beta1 adrenergic effects raise the level of cyclic AMP, which restricts the release of histamine and the leukotrienes, the primary mediators of an anaphylactoid reaction. 3 Epinephrine should be cautiously administered to patients treated with beta blocker therapy. If the beta adrenergic effect of epinephrine is blocked, the alpha adrenergic effect will predominate, resulting in a hypertensive reaction. 1,2 Epinephrine may be administered subcutaneously or intravenously. It can be administered subcutaneously as 0.3cc of 1:1,000 dilution every 15 min up to a total dose of 1 cc. Epinephrine administered intravenously provides rapid effect and avoids erratic, incomplete absorption from subcutaneous sites. 1 Although controversy exists regarding its intravenous use for anaphylactoid reactions except when shock is present, intravenous administration of epinephrine is appropriate in the catheterization laboratory where hemodynamic and electrocardiographic monitoring are in progress. 1,3,20 An initial bolus of 10 µg/min may be given safely and repeated until the desired initial result is obtained. This is followed by an infusion of 1-4 µg/min as clinically indicated.20 The bolus dose is prepared by diluting 0.1 cc of 1:1,000 or 1 cc of 1:10,000 solution in 10 cc 0.9% normal saline (10 µg/cc) and the infusion by diluting 1 mg (1 cc of 1:1,000 or 10 cc of 1:10,000) of epinephrine in 250 cc 0.9% normal saline (4 µg/cc). Patients who have had previously documented severe systemic anaphylactoid reactions should have pre-mixed epinephrine solution available for immediate intravenous administration. High-dose intravenous steroids are frequently used in the treatment of anaphylactoid reactions despite the exact mechanism of action remaining unclear. 21 Steroids most likely produce a stabilizing effect on cell membranes and inhibit the generation of arachiodonic acid, leukotrines, prostaglandins, and platelet-activating factor. 1,22 However, this effect occurs over hours, resulting in steroids being of little value in the acute treatment of a a contrast media-induced anaphylactoid reaction. 1 Although acute administration of steroids may be of little benefit, they can potentially reduce the chance of delayed recurrent symptoms, which can be observed as long as 48 hrs after the initial reaction. 2,23 Diphenhydramine (Benadryl), an H1 histamine receptor blocker, is commonly administered in the treatment of anaphylactoid reactions in 25-50 mg intravenous doses. It most likely inactivates unbound circulating histamine. Even at maximal dosages, this effect alone is minimal for two reasons. Severe anaphylactoid reactions are associated with massive histamine release, 4 and diphenhydramine neither inactivates nor blocks the action of leukotrienes whose effects are several times greater than histamine. 1 As with the H1 blockers, H2 histamine receptor blockers are not independent first-line therapy for severe reactions. However, the H2 histamine receptor blocker cimetidine has effectively reversed acute allergic reactions. 2,24 Therefore, H2 blocking agents should be considered in patients not responding to other measures. 1,2 It is essential to remember that unopposed H1 histamine receptor stimulation may result in vasoconstriction of the coronary arteries. 1,3 If an H2 histamine receptor blocker is administered to a patient with coronary artery disease, an H1 histamine receptor blocker must also be administered. Finally, large volumes of fluid may be required for treatment of severe anaphylactoid reactions associated with hypotension. 25 Due to peripheral vasodilation and increased vascular permeability, up to 37% of the blood volume may be lost within 10 min of the onset of reaction. 26 Despite the theoretical benefit of colloid solutions with this vascular permeability, crystalloid replacement with normal saline is effective and is preferable to Ringer’s lactate or hypo-osmolar solutions. 2 Central venous pressure monitoring or placement of Swan-Ganz catheter may be necessary if large volumes of fluid replacement are needed. In discussing the various therapeutic regimens, the benign end of the anaphylactoid spectrum includes the minor reactions such as scattered urticaria, erythema, and pruritus without respiratory symptoms. With these minor reactions, only recognition may be required. There is no definitive evidence that medications reduce the severity of the skin reactions once developed. 2 However, the H1 blocker diphenhydramine is frequently administered intravenously for symptomatic relief. The H2 blocker cimetidine administered as 300 mg diluted and given over 15 min may provide further symptomatic relief. 4,24 Moderate and severe anaphylactoid reactions comprise the cardiovascular and respiratory system. Angioedema with facial, pharyngeal, or laryngeal edema should have prompt airway evaluation and intubation may be necessary. 3 When pharyngeal or laryngeal edema is progressive, the patient may require tracheostomy. 2 Mild bronchospasm without evidence of hypotension can be treated with an inhaled beta adrenergic agonist bronchodilator such as albuterol or terbutaline. 1 But patients with angioedema or severe bronchospasm should receive intravenous epinephrine. In severe cases of anaphlyactoid reactions, the basic principles of patient management for emergency situations in the catheterization laboratory apply. Supporting the airway in patients with respiratory compromise may require oxygen therapy or even early intubation. 2 Establishing central venous access with appropriate hemodynamic and blood gas monitoring is standard care for the critically ill cardiac patient. For severe anaphylactoid reactions with hypotension or shock, simultaneous administration of intravenous epinephrine and rapid infusion of isotonic fluid should be undertaken. 2,3,4,20,25,26 Pharmacologic therapy without volume replacement may not only be ineffective but may result in major iatrogenic complications. H1 and H2 histamine receptor blockers should be considered for hypotension refractory to fluid and epinephrine. 2,24 If hypotension persists is spite of all of the above maneuvers, dopamine is the vasopressor of choice to be infused at the usual recommended dosage. 2 Cardiovascular collapse and cardiac arrest are treated with standard advanced cardiac life support methods. If a severe anaphylactoid reaction develops during a cardiac angiographic procedure, should the procedure be aborted? The literature provides no direction in this situation, but if the reaction can be controlled and stabilized, it would seem reasonable to complete the study as histamine, leukotrienes, and other vasoactive products should be relatively depleted. If cardiorespiratory stabilization cannot be obtained, then the study should be aborted and the patient transferred to an intensive care unit. The question, then, arises as to whether the study should be completed and when. With pretreatment and nonionic contrast media, the risk of recurrent anaphylactoid reaction is very low, so if clinically indicated, the study could be completed when the patient stabilizes. Conclusions The prevention, diagnosis, and treatment of contrast media-induced anaphylactoid reactions are essential knowledge for all invasive cardiologists. This article was designed to provide a current review of this potentially life-threatening condition. With this information and the algorithm provided, the invasive cardiologist and cardiac catheterization staff should have a useful overview of this important subject. Acknowledgements This work was approved by the Board of Trustees of the Society for Cardiac Angiography and Intervention, July 25, 1994.
1. Bush WH, Swanson DP. Acute reactions to intravascular contrast media: types, risk factors, recognition, and specific treatment. Am J Roentgenology 1991;157:1153-61.

2. Cohen RH, Dunnick NR, Bashore TM. Treatment of reactions tp radiographic contrast media. AJR 1988;151:263-270.

3. Bush WH. Treatment of systemic reactions to contrast media. Urology 1990;35: 145-150.

4. Sage DJ. Management of acute anaphylactoid reactions. Anesthesiol Clin 1985;23:175-186.

5. Johnson L, Lozner E, Johnson S, et al. Coronary angiography 1984-1987: A report of the registry of the society for cardiac angiography and interventions I. Results and complications. Cathet Cardiovasc Diagn 1989;17:5-10.

6. Greenberger PA, Patterson R. Adverse reactions to radiocontrast media. Prog Card Dis 1988;31:239-248.

7. Greenberger PA. Contrast media reactions. J Allergy Clin Immunol 1984;74:600-605.

8. Siegle RL, Halvorsen RA, Dillion J, et al. The use of iohexol in patients with previous reactions to ionic contrast media. Invest Radiol 1991;26:411-416.

9. Ansell G, Tweedie MCK, West CR, et al. The current status of reactions to intravenous contrast media. Invest Radiol (suppl. 6) 1980;15:532.

10. Shehadi WH. Contrast media adverse reactions: Occurrence, recurrence, and distribution patterns. Radiology 1982;143:11-17.

11. Enright T, Chua-Lim A, Duda E, et al. The role of a documented allergic profile as a risk factor for radiographic contrast media reaction. Ann Allergy 1989;62(4):302-305.

12. Lang DM, Alpern MB. Visintainer PF, et al. Increased risk for anaphylactoid reaction from contrast media in patients on beta-adrenergic blockers or with asthma. Ann Int Med 1991;115(4):270-276.

13. Hildreth EA. Anaphylactoid reactions to iodinated contrast media. Hosp Practice 1987;22(5A):77-95.

14. Marshall GD, Jr., Lieberman PL. Comparison of three pretreatment protocols to prevent anaphylactoid reactions to radiocontrast media. Ann Allergy 1991;67(1): 70-74.

15. Greenberger PA, Patterson R. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. J Allergy Clin Immunol 1991;87:867-872.

16. Swanson DP, Thrall JH, Sketty PC. Evaluation of intravascular low-osmolality contrast agents. Clin Pharm 1986;5: 877-891.

17. Slack JD, Slack LA, Orr C. Recurrent severe reaction to iodinated contrast media during cardiac catheterization. Heart Lung 1982;11:348-352.

18. Greenberger PA, Halwig JM, Patterson R, et al. Emergency administration of radiocontrast media in high-risk patients. J Allergy Clin Immunol 1986;77:630-634.

19. Ansell G. An epidemiological report on adverse reactions or urography: ionic and non-ionic media. Diagn Imag May 1987 (suppl.):5-10.

20. Barach EM, Norvak RM, Tennyson GL, et al. Epinephrine for treatment of anaphylactic shock. JAMA 1984;251:2118-2122.

21. Lasser EC, Lang J, Sovak M, et al. Steroids: Theoretical and experimental basis for utilization in prevention of contrast media reactions. Radiology 1977;125:1-9.

22. Zipser RD, Laffi G. Prostaglandins, thromboxanes, and leukotrienes in clinical medicine. West J Med 1985;143:485-497.

23. Stein R, Kwee YN, Greenbaum J. The need for extended treatment of anaphylaxis. Can Med Assoc 1980;122:1229-1230.

24. Mayumi H, Kimura S, Asano M, et al. Intravenous cimetidine as an effective treatment for systemic anaphylaxis and acute allergic skin reactions. Ann Allergy 1987;58:447-450.

25. VanSonnenberg E, Neff CC, Pfister RC. Life-threatening hypotensive reactions to contrast media administration: Comparison of pharmacologic and fluid therapy. Radiology 1987:162:15-19.

26. Fisher M. Blood volume replacement in acute anaphylactic cardiovascular collapse related to anesthesia. Br J Anaesth 1977;49:1023-1026.