Systemic Anaphylactoid Reactions to Contrast Media During Cardiac Catheterization Procedures

1. Systemic Anaphylactoid Reactions to Contrast Media During Cardiac Catheterization Procedures Diagnosis, Prevention, and Treatment Brandon E. Brown, M.D. Department of Internal Medicine

2. Clinical Scenario • HPI: 65 yo WM with known ASCAD, HTN, DM, and dyslipidemia presents with a compelling history of USA. He indicates that during his last catheterization, ten years ago, he experienced “anaphylaxis” and was given epinephrine. • Pmedhx.: as above. No history of asthma, allergies • Meds: Atenolol, Atorvastatin, Benazepril, ASA • Allergies: NKDA • PE: non-contributory • ECG: new anterolateral T wave inversions • Labs: normal initial CK, CK-MB, and troponin I

3. Definition of Terms Anaphylactoid events vs. Anaphylaxis • Anaphylaxis: an immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral blood basophils • Anaphylactoid events: immediate systemic reactions that mimic anaphylaxis but are not caused by IgE-mediated immune responses

4. Incidence* Radiocontrast material (RCM) • Estimated that 8 million people receive RCM annually in U.S. • Overall frequency of adverse reactions is 5% to 8% • Life-threatening reactions occur less than 0.1% with older (hyperosmolar) agents • Mortality estimated at one in every 75,000 patients • With advent of second generation agents (low-osmolar or iso-osmolar agents) incidence of adverse reactions 1/5 that of first generation agents *Neuget AI. Ghatak AT. Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Archives of Internal Medicine. 161(1):15-21, 2001 Jan 8.

5. What RCM do we use in our cardiac catheterization lab? • Optiray (Ioversol) • A lower osmolar nonionic monomer • Available in various osmolalities (ranging from 355 to 792) and various levels of iodine content (160 to 350)

6. Clinical Presentation and Differential Diagnosis • Anaphylactoid reactions clinically indistinguishable from anaphylaxis • Suspected in any patient with hypotension during catheterization • Diff. Dx. Includes cardiac and non-cardiac causes • Vasovagal reaction: bradycardia as opposed to typical tachycardia in anaphylactoid rxn (however, B-blockers and VVI PM’s may blunt this response) • CVP, SVR, and/or PCWP will be low reflecting hypoTN • Usually occur within 20 min. of exposure

7. Pathophysiology The substantial reduction in toxicity with introduction of low-osmolar agents suggests hypertonicity of older agents played a role In vitro data indicates RCM can activate basophils and mast cells by an IgE-independent mechanism (ie anaphylactoid) RCM’s have been shown to activate (directly and indirectly) complement, fibrinolytic, and kinin systems Several factors argue against an immunologic pathogenesis: • RCM reactions usually occur on first administration • Relatively dose-independent (test dose not helpful) • They do not always occur on subsequent exposure (estimated only 16%) • Efforts to raise anti-sera to RCM have confirmed its very weak immungenicity (related to chemical structure)

8. Pathophysiology (continued) However, • Reports of detection of IgE antibodies specific for ioxaglate (Hexabrix) in patients repeatedly exposed to this RCM • Mast cell activation demonstrated in vivo by detection of tryptase in serum of patients with RCM reactions • Report of a patient who experienced a delayed hypersensitivity rxn. after second exposure to RCM who had previous positive patch testing *Mita H, Tadokoro K, Akiyama K. Detection of IgE antibody to a radiocontrast medium. Allergy 1998; 53:1133-40.

9. Prevention Who’s at risk? • Those with previous RCM anaphylactoid reactions • Atopic patients (2X risk) • Patients on B-blockers • Less common with intra-arterial vs. intravenous injection (but reaction more severe) • No evidence to support that patients with known allergic sensitivity to iodine are at higher risk* *Coakley FV, Pannicck DM. Iodine allergy:an oyster without a pearl? Am J Roengenol 1997:169:951-2 *Leder R. How well does a history of seafood allergy predict the likelihood of an adverse reaction to IV contrast material? Am J Roentgenol 1997:906-7.

10. Prevention (continued) What can you do to minimize risk? • Determine if study is essential • Make certain patient understands risks • Ensure proper hydration (consider early admission) • Use non-ionic, lower osmolar RCM • Use a pre-treatment medical regimen proven effective (next slide)

11. Prevention (continued) A Pre-treatment Medical regimen*: • Steroids: Prednisone 50mg p.o. 13, 7, and 1 hours before the procedure • H1 Antihistamines: Diphenhydramine 50 mg 1 hour before procedure • Bronchodilators: Ephedrine 25 mg or albuterol 4 mg p.o. 1 hour prior to procedure • H2 Antihistamines? *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. *Marshall GD Jr., Lieberman PL. Comparison of three pretreatment protocols to prevent anaphylactoid reactions to radiocontrast media. Annals of Allergy. 67(1):70-4, 1991 Jul.

12. Treatment Depends on severity of reaction and specific clinical manifestation Minor (erythema, pruritis),Moderate (urticaria, angioedema, bronchospasm), and Severe (shock, respiratory arrest) reactions Pharmacologic Agents: • Epinephrine: for severe rxn.; alpha effect causes vasoconstriction; beta-1 effect causes chronotropy and inotropy; beta-2 cause bronchodilation; at cellular level, increases cAMP; caution in B-blockers; dose: 0.3 cc of 1:1000 dilution Q15 min. to max of 1 cc; IV dose 10ug/min bolus followed by gtt 1-4 ug/min. • IV Steroids: mechanism unclear-stabilizes cell membranes? Prevents biphasic rxn.?; Hydrocortisone 400 mg IV • Antihistamines: inactivate unbound histamine; Diphenhydramine 25-50 mg IV; Cimetidine 300 mg IV or Ranitidine 50 mg IV • IVF: necessary for severe reactions; NS vs. LR • Glucagon: 1-4 mg IV (or atropine)

13. Conclusions • Relatively uncommon but potentially life-threatening • Anaphylactoid reaction • Pathogenesis in debate • Importance of prevention • Rapid diagnosis and treatment is essential

14. Additional References • “Practice parameters for the diagnosis and treatment of anaphylaxis,” The Journal of Allergy and Immunology, volume 96, no. 5, part 2, Nov. 1995. • Allergy. Principles and Practice, fifth edition, Middlelton, jr., et al, vol. 2, pp.1079-1092. • Optiray 350 package insert, September 2000 • Goss, et al., “Systemic anapohylactoid reactions to iodinated contrast media during cardiac catheterization procedures: guidelines for prevention, diagnosis, and treatment. Laboratory Performance Standards Committee of the Society for Cardiac Angiography and Interventions. Catheterization and Cardiovascular Diagnosis. 34(2):99-104, 1995 Feb. • Adkisson, Jr., “Pathophysiology of contrast media anaphylactoid reactions: new perspectives on an old problem.” (letter, comment) Allergy. 53(12):1111-1113, 1998 Dec. • Bashmore et al., ACC/SCA&I Clinical Expert Consensus Document On Catheterization Laboratory Standards. JACC Vol. 37, No. 8, June 2001:2170-2714.