ToxicologyLetters, 64f65 (1992) 717-723 0 1992 Elsevier Science Publishers B.V., All rights reserved 03784274/92/$5.00

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Epidemiology of adverse reactions to intravascular iodinated contrast media G. Ansell Liverpool (UK) Key words: Adverse reactions; Contrast media; Ionic; Non-ionic. SUMMARY Non-ionic contrast media cause fewer acute reactions than ionic media but there is insufficient data on mortality rates. An international reference centre is suggested for histological assessment of fatal reactions. Risk factors, delayed reactions, renal, neural, haemic and other miscellaneous reactions are briefly discussed.

INTRODUCTION

There are no reliable data on the numbers of contrast media examinations performed worldwide but this is likely to be many millions annually. Complications of contrast media are reviewed in detail elsewhere [1,21. The conventional high osmolar media are ionic monomers such as diatrizoate, iothalamate, etc. In the lower osmolar media, the ionic dimer, sodium methylglucamine ioxaglate should be differentiated from the non-ionic media such as iopamidol or iohexol. Ioxaglate is generally recognised to cause a higher incidence of vomiting and anaphylactoid effects 131. IDIOSYNCRATIC REACTIONS

Idiosyncratic reactions can broadly be categorised into four grades of severity [41: 1. Minor reactions usually require no treatment. 2. Intermediate reactions normally respond to simple treatment. 3. Severe reactions may endanger the patient’s life and usually require intensive treatment. 4. Fatal reactions. Correspondence to: G. Ansell, 101 Childwall Park Avenue, Liverpool, L16 OJF, UK.

718 TABLE I REACTION MEDIA

RATES FOR INTRAVENOUS

Shehadi (1980) 151North America Toni010 (1980) I51Italy Ansell et al. (1980) [4l UK

IONIC* AND NON-IONIC**

Examns.

Minor

Intermed.

Severe

Fatal

146 904+

1:29

1:60

1:2800

1:15 000

67 129’

1:31

1:130

1:1200

1:34 000

164 475’

1:15

1:76

1:4200

79 000’

1:30

30 OOO*+ 1:96 Katayama et al. (1990) [Sl Japan

1:45 000 1:75 000

Hartman et al. (1982) [61 Mayo 300 OOo+ Clinic Palmer (1988) [71Australasia

CONTRAST

1:284

1:1117

1:lOlO

1:6056

1:40 000

169 284+

1:394

1:169 000

168 363**

1:2215

1:168 000

Different studies have used variations of this classification; for example, in some studies the term ‘severe’ is restricted to patients requiring hospitalisation but this begs the question as to how one classifies existing inpatients. Minor and intermediate reactions are relatively common but severe and fatal reactions are fortunately rare. Large surveys are required to evaluate these rare reactions (Table I). There can be problems in comparing different surveys due to variations in survey techniques and other factors. Even in the combined study by Shehadi and Toniolo k51,using the same criteria, Shehadi’s mortality rate of 1 in 15 000 for North America and other countries is double that found by Toni010 in Italy. The earlier surveys refer to conventional ionic contrast media. In the two large non-randomised comparisons of ionic and non-ionic media performed in Australasia [71 and Japan Bl, the incidence rates for severe reactions varied, but in each study, there was an approximate 5-6 fold reduction using non-ionic media. The small numbers of deaths reported, make it difficult to evaluate mortality rates. Hitherto. the generally accepted figure for ionic media has been in the region of I:40 000 and the recent Australasian [71 study gives a similar rate. Neither of the deaths in the Japanese survey [I31 was attributed to the contrast medium but a mortality rate of even 1:169,000 for ionic medium appears unusually low. There have been a number of published [91 and unpublished deaths due to non-ionic media. Although one would expect the reduced incidence of severe reactions with non-ionic media to lower the mortality rate, this must still be speculative. Whichever contrast medium is used, it is important to

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have full facilities for emergency treatment. Lalli [lo] has analysed the causes of death from the available data in 140 intravenous urograms using ionic contrast media. The major factors in these deaths were cardiac or respiratory. The mean age of the patients was 58 years. Deaths may occur at any age but the great majority of deaths occur in patients over the age of 50. In the UK survey 141,the mortality rate in patients over 50 increased to 1:20 000. Infants are another susceptible group. There is a scarcity of reliable information on the histology of fatal reactions. Findings have usually been non-specific. In perhaps most cases, pathologists performing the autopsies have had no particular experience in drug toxicology. In my opinion, it would be invaluable if IUTOX could designate an independent central pathological institute to which material could be sent for study and to build up a data base. This could also be of value for all major drug reactions. In severe reactions, the main clinical features were mainly of a cardiovascular nature but bronchospasm was also a major problem 141. RISK FACTORS

Many reactions are unpredictable but the clinical history can provide a pointer to some of the higher risk groups. A history of asthma, increased the risk of a severe reaction by a factor of about 5 and a history of a previous reaction to contrast medium increased the risk by a factor of 10.9. A history of heart disease increased the risk of a severe reaction by a factor of 4.5 and was even more relevant in the fatal reactions with a risk ratio of 8.5 and a mortality of about I:9000 [43. Cardiac disease is, of course, a major risk factor in cardioangiography where contrast medium is delivered directly to the heart and coronary arteries. It can then produce haemodynamic changes, angina, bradycardia, arrhythmias ventricular fibrillation, etc. Some preparations of ionic contrast media cause calcium binding and these preparations tend to be more liable to cause ventricular fibrillation. Low osmolar media generally cause fewer cardiac changes [121. Other risk factors include allergy and previous reactions to drugs such as penicillin.The effect of age is disputed, but certainly, most of the deaths occur in the older age group. Dose and rate of injection are probably relevant factors [4,8,111. In the UK survey, beta-blockers appeared to be associated with an increased incidence of bronchospasm [131. A recent study has also shown that they appear to be a predisposing factor for severe reactions. They may also make the treatment of a reaction more difficult [141. Lalli 1101has stressed the factor of anxiety, indeed, patients may collapse after a simple venipuncture. In the

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UK survey, Indians appeared to have an increased risk of severe reactions. The reason for this is uncertain but ethnic factors cannot be dismissed 141. Patients who are receiving therapeutic steroids will have some adrenal suppression and should probably be given an increased dose before contrast use. Poor general condition of the patient, dehydration etc. are likely to increase the risk. PROPHYLAXIS

In a careful randomised study, Lasser has shown that a Z-dose pretreatment regime with methylprednisolone decreases the incidence of reactions to ionic media by some 30-60% Elll. In patients who have previously had contrast medium reactions, Greenberger 1151 recommends a prophylactic regime of steroids, diphenhydramine, and also ephedrine if there is no cardiac contraindication. With this regime, and using a non-ionic medium, the incidence of recurrent reactions was reduced from an expected 40% to less than 1%. In the UK survey, there was a suggestion that cromoglycate might possibly have a protective effect in asthmatics [13l. DELAYED REACTIONS

Delayed skin rashes occurred in some 5% of patients up to several days after contrast administration but they may be missed if they are not specifically looked for. Other delayed effects included arm pain and vague symptoms thought to be suggestive of iodism. Transient salivary gland swelling may also occur 1161. There may rarely be severe delayed skin reactions.These severe cutaneous reactions are usually diagnosed by dermatologists. The radiologist and manufacturers may not always be aware of their occurrence. These cutaneous manifestations are probably mainly related to iodism. They may occur after both ionic and non-ionic media [Il. There have perhaps been rather more reports after non-ionic media 1171, but this may be partly due to the more recent recognition of these syndromes and to the increasing use of non-ionic medium. NEPHROTOXICITY

The overall reported incidence rates for contrast media nephrotoxicity have varied from 0 to 22% depending on the case mix, the diagnostic criteria and the adequacy of follow up [18,191. The greatest risk factor is in diabetes with renal insufficiency. Renal insufficiency itself is the next commonest risk factor. Other factors include dehydration, dose, multiple contrast stu-

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dies, hyperuricaemia, nephrotoxic drugs and myeloma. Experimental studies suggested that non-ionic media were less nephrotoxic than conventional contrast media but earlier clinical studies failed to show a significant difference in nephrotoxicity. However, there were few higher risk cases in these early studies. More recent studies involving higher risk cases have in fact shown a significant reduction in nephrotoxicity with non-ionic media. In a multi-centre randomised trial of nearly 2000 cases, iohexol caused a significant decrease in nephrotoxicity, in both diabetics and non-diabetics with pre-existing renal insufficiency, when compared with diatrizoate [203. NEURAL

TOXICITY

Convulsions may occur during computed tomography with ionic contrast media in patients with cerebral tumours. Premeditation with diazepam significantly reduces the incidence of these convulsions 111.In one report, there were two deaths from uncontrollable status epilepticus 1211. In another series of 169 patients having CT with high dose iopamidol, there were no seizures even though no premeditation was given. This suggests that non-ionic media are probably safer in such cases 1221. HAEMIC

EFFECTS

Ionic media have a slight anticoagulant action whereas with non-ionic media this effect is less marked. It has been suggested that there may be an increased risk of thromboembolism with non-ionic media [231 but this is subject to dispute. Ionic media have rarely caused a sickle cell crisis. Non-ionic media cause significantly less sickling. Other effects of ionic media include haemolysis and rarely, thrombocytopaenic purpura [ll. MISCELLANEOUS

Contrast media may precipitate an acute myasthenic crisis in patients with myasthenia gravis. This has been reported with both ionic and nonionic media 1241. Isolated cases of acute myopathy [251 and malignant hyperthermia 1261 have also been reported. Interleukin-2 may induce a curious form of contrast medium hypersensitivity in a significant proportion of patients. Steroids are effective in prophylaxis and treatment 1271. The majority of contrast media reactions do not appear to be immunologically induced, but there appear to be a few cases who develop increasing hypersensitivity with repeated administration of contrast media. There have been anecdotal reports of radiologists and radiographers becoming allergic to contrast media. In a recent study of 17 nurses occupationally

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exposed to contrast media, 11 had a positive lymphocyte transformation test to diatrizoate and 6 had allergic symptoms on handling contrast media [281.

REFERENCES

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Ansell, G. (1987) Contrast media and urography. In: G. Ansell and R.A. Wilkins (Eds.), Complications in Diagnostic Imaging (2nd ed.) Blackwell, Oxford, pp. l-36. Ansell, G. (1992) Radiological contrast media and radiopharmaceuticals. In: M.N.G. Dukes (Ed.), Meyler’s Side Effects of Drugs (12th ed.) Elsevier, Amsterdam. (In press.) Vacek, J.L., Gersema, L., Woods, M., Bower, C. and Beauchamp, G.D. (1990) Frequencies of reactions to iohexol and ioxaglate. Am. J. Cardiol. 66,1277-1278. Ansell, G., Tweedie, M.C.K., West, C.R., Evans, D.A.P. and Couch, L. (1980) The current status of reactions to intravenous contrast media. Invest. Radial. Suppl. 15, S32-S39. Shehadi, W.H. and Toniolo, G. (1980) Adverse reactions to contrast media. A report from the Committee on Safety of Contrast Media of the International Society of Radiology. Radiology, 137,299-302. Hartman, G.W., Hattery, R.R., Witten, D.M. and Williamson, B. (1982) Mortality during excretory urography: Mayo Clinic experience. A.J.R. 139,919-922. Palmer, F.G. (1988) The RACR survey of intravenous contrast media reactions: final report. Australas. Radiol. 32,426-428. Katayama, H., Yamaguchi, K., Kozuka, T., Takashima, T., Seez, P. and Matsuura, K. (1990) Adverse reactions to ionic and nonionic media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology, 1756X-628. Curry, N.S., Schabel, S.I., Reiheld, C.T., Henry, W.D. and Savoca, W.J. (1991) Fatal reactions to intravenous nonionic contrast material. Radiology, 178,361~362. Lalli, A.F. (1980) Contrast media reactions: data analysis and hypothesis. Radiology, 131, 1-12. Lasser, E.C., Berry, C.C., Talner, L.B., Santini, L.C., Lang, E.K., Gerber, F.H. and Stolberg, H. (1987) Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material. New Engl. J. Med. 317,845849. Hirshfield, J.W. (1992) Low-osmolality contrast agents - who needs them. New Engl. J. Med. 326,482-484 Ansell, G., Tweedie, M.C.K., West, C.R. and Evans, D.A.P. (1982) Risk factors for adverse reactions in intravenous urography. In: M. Amiel (Ed.), Contrast Media in Radiology. Springer-Verlag, Berlin, pp. 7-10. Lang, D.M., Alpern, M.B., Visintainer, P.F. and Smith, S.T. (1991) Increased risk for anaphylactoid reaction from contrast media in patients on beta-adrenergic blockers or with asthma. Annals Int. Med. 115,270-276. Greenberger, P.A., Patterson, R. (1991) The prevention of immediate generalised reactions to radiocontrast media in high-risk patients. J. Allergy Clin. Immunol. 87,868872. Panto, P.N. and Davies, P. (1986) Delayed reactions to urographic contrast media. Br. J. Radiol. 58,41-44. Mineyama, H., Katayama, Y., Go, H. (1989) Delayed reactions to non-ionic contrast medium. Western Japan Urology, 51,2023-2026. Porter, G.A. (1989) Contrast associated nephropathy. Am. J. Cardiol. 64,22E-26E. Brezis, M. and Epstein, F.H. (1989) A closer look at radiocontrast-induced nephropathy. New Engl. J. Med. 320,179-181. Wexler, L., Cohen, B., Rudnick, M.R., Murphy, M.J. and Halpern, E.F. (1991) Multicentre trial of ionic and anonionic contrast media: nephrotoxicity following cardiac angiography. Abstract 1159, RSNA Annual Meeting Chicago. Radiology, 292-293 Avrahami, E., Weiss-Peretz, J. and Cohn, D.F. (1989) Epilepsy in brain metastases triggered by intravenous contrast medium. Clin. Radiol. 40,422-423.

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Leonardi, M., Lavaroni, A., Biassizo, E. et al. (1989) High dose computed tomography (CECT) with iopamidol in the detection of cerebral secondaries. Neroradiology, 31, 148150. Fareed, J., Walenga, J.M., Saravia, G.E. and Moncada, R.M. (1990) Thrombogenicpotential of nonionic contrast media. Radiology, 174,321. Eliashiv, S., Wirguin, I., Brenner, T. and Argov, 2. (1990) Aggravation of human and experimental myasthenia gravis by contrast media. Neurology, 40,1628-1625. Stinchcombe, S.J. and Davies, P. (1989) Acute toxic myopathy: a delayed adverse effect of intravenous urography with iopamidol370. Br. J. Radiol. 62,949-950. Mozley, P.D., (1981) Malignant hyperthermia following intravenous iodinated contrast media. Report of a fatal case. Diagn. Gynecol. Obstet. 3,81-85. Fishman, J.E., Aberle, D.R., Moldower, N.P., Belldegrun, A. and Figlin, R.A. (1991) Atypical contrast reactions associated with systemic interleukin-2 therapy. A.J.R. 156, 833-834. Stejskal, V., Nillson, R. and Grepe, A. (1990) Immunologic basis for adverse reactions to radiographic contrast media. Acta Radiol. 31,605-610.

Epidemiology of adverse reactions to intravascular iodinated contrast media.

Non-ionic contrast media cause fewer acute reactions than ionic media but there is insufficient data on mortality rates. An international reference ce...
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