Adverse Reactions to Contrast Media

1. Adverse Reactions to Contrast Media Ri 陳達慶

2. Articles Acute serious and fatal reactions to contrast media: our current understanding • S K Morcos, FRCS, FRCR • British Journal of Radiology (2005) 78, 686-693 Adverse Reactions to Intravenous Iodinated Contrast Media: An Update • Saravanan Namasivayam MD, DNB, DHA, Mannudeep K. Kalra MD, DNB, William E. Torres MD and William C. Small MD, PhD • Current Problems in Diagnostic Radiology Volume 35, Issue 4 , July-August 2006, Pages 164-169

3. Introduction • unpredictable and not dose related • CM particles absorbed into the circulation • all the features of anaphylaxis • but IgE negative in most cases • developed within 5–30 min after exposure to CM • may present as generalized skin reactions, airway obstruction, angioedema or cardiovascular collapse • intermediate risk for anaphylaxis with CM

4. Prevalence of life threatening and fatal reactions to contrast media • severe and very severe reactions (IV push of CM) 0.22% and 0.04% after high-osmolar contrast media (HOCM) 0.04% and 0.004% after low-osmolar contrast media (LOCM) However  no difference in fatal reactions (1:170 000) • UK & USA(FDA)  (per million examinations) high with low osmolar CM 194 vs 44 for all reactions 37 vs 11 for severe reactions 3.9 vs 2.1 for fatal reactions. • high osmolar agents V.S.ioxaglate (a low osmolar ionic dimer) total reactions 194 vs 143 severe reactions 37 vs 34 fatal reactions 3.9 vs 6.4 • low osmolar non ionic CM is the best, besides no definite reduction in fatal reactions,

5. Risk factors • 1. A history of previous severe adverse reaction to a contrast agent 6 (both ionic and non-ionic CM) • 2. Asthma6~10 • 3. A strong history of allergic reactions to different substances (hay fever….) • 4. Treated with ß-adrenergic blockers and interleukin-2 (IL-2)  acute adverse reactions to CM. (including the ophthalmic preparations) • 5. Iodinated CM 3 • 6. Female<-> the fatality rate :men with old age?! • 7. Race • 8. Malignant tumours an increase in histamine release • Pre-testing with an intravenous injection of a small amount of CM is not useful • High awareness !!

6. Table 1. European Society of Urogenital Radiology (ESUR) guidelines on prevention of generalized contrast medium reactions in adults

7. Pathophysiology of life threatening/fatal reactions to contrast media • adverse reactions to drugs type B reactions, not dose dependent and unpredictable • Aronson and Ferner: a new classification (DoTS) based on dose relatedness (Do), timing (T) and patient susceptibility (S) • drug (pharmacology and the dose dependence of its effects) • the properties of the reaction (time course of its appearance and its severity) • properties of the individual (the genetic, pathological and other biological differences that confer susceptibility) • Do-hyper susceptibility; T – first dose; S – not understood.

8. Pathophysiology • Type 1 hypersensitivity reaction (anaphylaxis) --- lack of consistency in demonstrating antibodies to CM • Within minutes • Chemotactic, vasoactive and spasmogenic compounds. leukotrienes, prostaglandins, enzymes • basophils and mast cells  degranulation Histamine primary mediator ; intense immediate manifestations. (be reproduced by histamine infusion)  vasodilatation, increasing vascular permeability  edema  contraction of smooth muscle cells  bronchospasm ; increasing mucus secretion of airways  recruit WBC additional waves of cytokines • direct effect of CM particles on these cells • non ionic monomers  low levels of histamine release • Hyperosmolarity  yes • Increasing the size and complexity of the molecule  enhance the release of histamine

9. Pathophysiology--2 • Activation of factor XII (Hageman factor)kinin system production of bradykinin  induce vasodilatation, bronchospasm and increase vascular permeability. • Bradykinin  arachidonic acid  cyclooxygenase and lipooxygenase pathways synthesis of PGs & LTs • Patients who are asthmatic or allergic increased concentration of factor XII products • CM DOESN’T act as haptens (non-reactive chemically) • p-I concept  drugs may directly activate T cells via receptors that can interact with the drug.  unlikely  T cell VS. acute life threatening CM  not clear • IgE antibodies? • Complement system (C3a, C4a and C5a) ?  no significant difference

10. Diagnosis of serious or fatal reaction to contrast media • Histamine --- basophils and mast cells, tryptase---mast cells • Tryptase : 1–2 h after the reaction (not greater than 6 h) • Only very high concentrations of serum tryptase should be regarded specific • Histamine: 10 min to 1 h after the reaction • Methylhistamine, the main metabolite of histamine  measured in urine • Specific IgE antibodies reliable drug RAST tests are not widely available • Positive intradermal tests some severe reaction to CM • it is advisable to measure serum tryptase routinely in severe or fatal patients (AMI or severe vasovagal attack may develop during examinations) • Post-mortem findings --- High level of seum tryptase, macroscopic findings including pulmonary oedema, signs of asthma (mucous plugging and/or hyperinflated lungs), petechial haemorrhages and pharyngeal/laryngeal oedema

11. Prevention of acute reactions to contrast media • Explained to the patient & the resuscitation team • Non-iodinated CM: 1. carbon dioxide (CO2) --- nausea, abdominal and leg pain may be observed with its administration 2. gadolinium based CM--- intravascular, no above 0.3 mmol kg–1 body weight  induce nephrotoxicity (not sure) • Non-ionic contrast media (sure) • The prophylactic use of corticosteroids --- mechanism unclear • Antihistamines (H1 and H2) and ephedrine --- (not sure) • Corticosteroids complex with the cytoplasmic receptormigrate into the cell nucleus  activate DNA dependent RNA synthesis  accelerated formation of specific enzymes inhibitors  take time 1. significant elevation in functional C1-esterase inhibitorlevels, 12 h after ; inhibits the activated form of factor XII 2. Decreased arachidonic acid from cell membranes  production of PGs &LTs (not sure)

12. Prevention of acute reactions to contrast media-2 • fatality may still occur in patients who received pre-medication and low osmolar CM • Prompt recognition and treatment of adverse side effects to CM  invaluable • never be left alone for at least 20 min after CM injection • the venous access • Emergency administration of contrast media in high-risk patients 1. pre-treatment with hydrocortisone, 200 mg intravenously, immediately, and every 4 h until the procedure is completed 2. diphenhydramine, 50 mg intravenously before the procedure 3. low osmolar non-ionic CM

13. Treatment of acute severe reactions to contrast media • Important first-line management 1. Adequate airway, oxygen supplementation, (adrenaline use) 2. IV physiological fluids, measuring BP &HR (most effective treatment for hypotension) 3. Adrenaline effective drug  increases BP, reverses peripheral vasodilatation, decreases angioedema and urticaria, reverses bronchoconstriction, and produces positive inotropic and chronotropic cardiac effects (avoided in the pregnant patient) Only one concentration (1:1000)  IM of 0.5 ml of 1:1000 adrenaline preparation IV IS NOT GOOD requires careful ECG monitoring (arrhythmia) • Antihistamine H1 receptor blockers  reduce symptoms from skin reactions  slow onset of action, and they cannot block “ ALREADY” events • H2-antagonists  not essential • IV injection of high-dose corticosteroids an immediate stabilizing effect on the cell membrane  second-line treatment.  reducing delayed recurrent symptoms • Inhaled ß-2-adrenergic agonists (albuterol, metaproterenol and terbutaline)  bronchodilating • Atropine blocks vagal stimulation of the cardiac conduction system. Large doses of aptropine (0.6–1.0 mg) are indicated 

14. Table 2. First-line emergency drugs and instruments that should be in the room where contrast medium is injected

15. Table 3. Simple guidelines for first-line treatment of acute severe reactions to contrast media

16. Thanks for your attention! 