By Philip N. Panto, M.A., M.B.B.S. and Peter Davies, D.M., F.R.C.R.. Department of Radiology, City Hospital, Nottingham. JANUARY 1986. (Received September ...
1986, The British Journal of Radiology, 59, 41-44
JANUARY
1986
Delayed reactions to urographic contrast media By Philip N. Panto, M.A., M.B.B.S. and Peter Davies, D.M., F.R.C.R. Department of Radiology, City Hospital, Nottingham (Received September 1984 and in revised form June 1985)
Each patient was given a letter with a questionnaire and asked to return the questionnaire, using a postagepaid envelope, at least one week after the examination. The following questions were asked: — Did you have pain in the arm after the examination? — If so, was it where the injection was made? was it above this site? — How many days after the examination did it come on? — How many days did it last? — Did you have a rash after the examination? — If so, could you give brief details — Do you have any other comments? The returned forms were analysed manually.
ABSTRACT
Reactions to urographic contrast media occurring after the patient had left the department were studied by giving patients a questionnaire to complete. 841 questionnaires were returned (about 80% of those issued). 70% of patients had no delayed reactions and 7% expressed a positive response to urography i.e., found the procedure interesting and not unpleasant; 13% had arm pain, 5% a rash and 14% had a variety of reactions, many of which were the same as those described in iodism. Women had significantly more rashes (7%) than men (4%) and those media containing the meglumine or iodamide ions caused more rashes than other media. Conray 420 caused more arm pain than Conray 280 or the non-ionic media, which would be expected from the known effects on vascular endothelium. Symptoms of iodism were equally common from the various contrast media.
During the course of a large survey of reactions to urographic contrast media carried out in the United Bristol Hospitals from 1968 to 1970 (Davies et al, 1975) one of the present authors observed that some patients had had delayed rashes after previous urography. In two cases these recurred after the current urogram with exactly the same clinical features. Other patients had a 'flu-like illness on the evening of urography. The occurrence of delayed phlebitis is common knowledge. The introduction of non-ionic agents suitable (if expensive) for urography prompted the setting up of a trial to compare various contrast media and as part of the trial it was decided to investigate delayed reactions by means of a questionnaire.
RESULTS
841 questionnaires were returned (78% of those issued) of which 485 were from men and 356 from women (79% and 76% respectively). Nine per cent of the men and 5% of women expressed positive comments about the examination, either thanking the staff, stating that they had found the warm feeling not unpleasant, or commending the carrying out of the trial. Altogether 70% had no adverse delayed reactions. The returned forms provided two types of data—(i) replies to specific questions, and (ii) free text comments. Tables I (Type (i) data) and II (Type (ii) data) summarise the incidence of the most frequently reported reactions.
PATIENTS, MATERIALS AND METHODS
All patients aged between 18 and 70 years, with no known renal disease or impairment, and who were referred for non-emergency urography over a ninemonth period were included in the study. Seven different agents were used, viz. sodium iothalamate (Conray 420), meglumine iothalamate (Conray 280), sodium/meglumine diatrizoate (Urografin 370), sodium iodamide (Uromiro 300), iopamidol (Niopam 370) and two strengths of iohexol (Omnipaque 240 and Omnipaque 350). In no case was it considered necessary to select a particular agent on the basis of previous reaction to contrast examinations. Urography was performed using 50 ml of the selected medium. Patients who received a second injection were excluded from the present study. Immediate reactions have been reported elsewhere (Davies et al, 1985).
TABLE I REACTIONS REPORTED BY PATIENTS AS OCCURRING AFTER THEY HAD LEFT THE DEPARTMENT (TYPE (I) DATA)
Total cases No reaction Delayed arm pain — At injection site — Above injection site — Unspecified site — Total* Delayed rash
Male
Female
Total
485 363(75)
356 227(64)
841 590(70)
20(4) 28(6) 2(0.4) 46(9)
36(10) 45(13) 66(19)
56(7) 73(9) 5(0.5) 112(13)
17(4)
26(7)
43(5)
3(D
*Some patients experienced pain at more than one site.
41
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59, No. 697 Philip N. Panto and Peter Davies TABLE III
TABLE II
INCIDENCE OF RASHES
REACTIONS REPORTED BY PATIENTS AS OCCURRING AFTER THEY HAD LEFT THE DEPARTMENT (TYPE (II) DATA)
Reaction Headache Tired, weak, etc. Felt ill, unwell (symptoms not specified) Dizzy Vomiting Nausea Taste disturbance Diarrhoea Stomach ache/pain Aching joints Upper respiratory symptoms
Agent
Total no.
No. of cases
Conray 420 Conray 280 Urografin 370 Uromiro 300 Niopam 370 Omnipaque 240 Omnipaque 350 Total
24 40 23 9 8 6 5 4 10 6 10
230 188 119 90 69 69 76 841
No. of rashes (%) 6(3) 14(7) 9(8) 7(8) 3(4)
1(0 3(4) 43(5)
Other delayed reactions (Type (ii) data) Many other reactions were reported. The most common are listed in Table II: others were itching (3), sweating or fever (3), loss of appetite (3), constipation (2), depression (1), swelling of testicle (2), vaginal irritation (1), loss of libido (1), ankle swelling (1). Eight patients reported feeling sick and generally unwell for between three and seven days, three with vomiting. Three further patients reported severe vomiting which was delayed for three, five and ten hours respectively. Two patients suffered asthma attacks, one of which lasted for three days in a patient who had not suffered with asthma for 38 years, the other coming on three days after the injection, although the asthmatic status of the patient was not known. An interesting effect was reported by two patients who said that their previously cold feet had not been cold since the examination (Omnipaque 240 and Conray 420 respectively).
Delayed rashes (Type (i) data) Delayed rashes were reported by 43 patients (5%) The onset was within 3 days and the duration up to 8 days. The most commonly described lesions were "red blotches", "red raised lumps", and "heat lumps", and itching was a prominent feature. One patient described a scaly rash on his forehead, and another dry skin with blisters around the nose which lasted several days. The incidence of rashes with each agent was compared (Table III). Women had more rashes than men (0.05 > p > 0.02). Altogether 7% of the women and 4% of the men reported delayed rashes. There was no significant difference between Conray 420 (6 rashes in 230 cases) and the non-ionics (7 rashes in 214 cases). There was a significant difference between Urografin 370, Conray 280 and Uromiro 300 as one group and Conray 420, Niopam and Omnipaque as the other (0.01 >p> 0.001).
Iodism Patients reporting loss of appetite, sickness, headache, abdominal pain, constipation, diarrhoea, 'flu-like symptoms, extreme tiredness, depression or taste disturbance were grouped together as these are all
Arm pain (Type (i) data) Delayed arm pain was reported by 112 patients altogether (13%) of whom 73 (9%) stated the pain was above the site of injection. The onset of pain ranged from 0 to 8 days (mean 1.6 days). The duration of pain ranged from 1 to 30 days (mean 3.4 days). In 82 cases, the pain lasted two days or more. Ten patients commented that the pain was severe, and three reported that a diagnosis of phlebitis had been made by their GP, and treatment given. Women had a significantly higher incidence of delayed arm pain than men. The incidence of delayed arm pain with each agent was compared (Table IV). The incidence following the use of Conray 420 was significantly greater than that following Conray 280 (0.02 >p> 0.01) or non-ionic agents (0.01 > p > 0.001). There was no significant difference between Conray 420 and Urografin (0.5 > p > 0.1) nor between Conray 420 and Uromiro.
TABLE IV INCIDENCE OF ARM PAIN
Delayed arm pain above injection site No. (%) Conray 420 Conray 280 Urografin 370 Uromiro 300 Niopam 370 Omnipaque 240 Omnipaque 350 Total
42
35(15) 13(7) 11(9) 10(11) 3(4) 0(0)
HI) 73(9)
Delayed arm pain—all sites No. (%) 45(20) 21(11) 16(13) 14(16) 7(10) 3(4) 6(8) 112(13)
JANUARY
1986
Delayed reactions to urographic contrast media TABLE V PATIENTS SUFFERING FROM SYMPTOMS OF IODISM
Conray 280 Conray 420 Uromiro 300 Urografin 370 Niopam 370 Omnipaque 240 Omnipaque 350 Total
Cases (men)
Reaction no. (%)
Cases (women)
Reaction no. (%)
Cases (total)
Reaction no. (%)
1034 137 52 69 40 41 43 485
6(6) 10(7) 2(4) 6(9) 4(10) 2(5) 3(7) 33(7)
85 93 38 50 29 28 33 356
12(14) 11(12) 4(11) 2(4) 4(14) 4(14) 5(15) 42(12)
188 230 90 119 69 69 76 841
18(10) 21(9) 6(7) 8(7) 8(12) 6(9) 8(11) 75(9)
concentration of the contrast medium (Mersereau & Robertson, 1961; Penry & Livingston, 1972). Thrombophlebitis has long been recognised as a complication of lower limb phlebography, with incidences of up to 32% being reported, and it has been suggested that this might occur in the arm following urography (Bettmann & Paulin, 1977). The present study shows that delayed arm pain is in fact very common, with an incidence of up to 14%. Presumably, the majority of cases resolve without treatment and probably constitute little more than a nuisance to the patient. However, it is clearly an undesirable side effect of urography, resulting in some patients in severe pain and disability. Our present results indicate an increase in the incidence of arm pain following the use of agents containing sodium salts (Conray 420, Urografin 370 and Uromiro), there being no significant difference between these agents, thus supporting Penry's experimental findings. There was a greater incidence of arm pain from ionic than non-ionic agents which supports the findings of Lea Thomas that non-ionic contrast media cause less endothelial damage (Lea Thomas et al, 1984).
recognised symptoms of iodism. The results for the seven contrast agents are laid out in Table V. None of the differences is statistically significant and in particular there is no evidence of any relation to dose. DISCUSSION
Reports in the literature of delayed reactions are infrequent and usually anecdotal. This paper reports the first attempt to study delayed reactions in a formal manner. We think the response rate of about 80% with a level of reactions of 3 1 % indicates that any bias in reporting reactions is small. Rashes Ansell et al (1980) have suggested that delayed rashes may be more common than is realised, and a number of cases have been reported (Ansell, 1968, 1970; Heydenreich & Larsen, 1977; Good et al, 1980). Delayed rashes were reported by 5% of patients in the present study. About 1% of patients have been shown to develop immediate rashes (Davies et al, 1975). Urografin 370, Conray 280 (both containing the meglumine ion) and Uromiro Sodium 300 formed one statistical group, with more rashes than Conray 420 and the two non-ionics. Thus the iothalamate ion is responsible for the same number of delayed rashes as the non-ionics, and presumably the sodium ion has no effect on this. The increased number for Conray 280 and Urografin 370 can be attributed to the meglumine ion. Presumably the iodamide ion produces more delayed rashes than the iothalamate ion.
Iodine toxicity (iodism) Iodism is a syndrome caused by iodine or any iodine compound, which includes the following amongst recognised symptoms: unpleasant brassy taste; soreness of teeth and gums; coryza, sneezing and irritation of the eyes; "head cold"; severe headache; productive cough; inflammation of the salivary glands, pharynx, larynx and tonsils; skin lesions of varying types (see above); gastric irritation and diarrhoea. Fever is occasionally observed and patients may develop anorexia and depression (Goodman & Gilman, 1980). Harris et al (1970) stated that high doses of inorganic iodides taken for extended periods will provoke chronic iodide poisoning, but that symptoms of iodism were not conspicuous following urography. However, one of its more dramatic, if infrequent manifestations—that of acute parotitis or "iodide mumps"—has been reported
Delayed arm pain Arm pain during the injection of contrast agents has been shown to result from clinically inapparent perivenous injections and venous spasm (Davies et al, 1975). Delayed pain, particularly some distance from the site of injection, is likely to be due to a direct toxic effect on the endothelium with thrombophlebitis. This effect has been demonstrated experimentally, and shown to increase with the osmolality and sodium 43
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on a number of occasions following urography (Koch et al, 1969; Kohri et al, 1977; Navani et al, 1972; Sussman & Miller, 1956; Talner et al, 1971). Seventy-five patients in our present study (9%) reported symptoms which could be attributed to iodism, and which lasted more than one day, and several patients reported quite severe constitutional upsets lasting for several days. That there was no significant difference in the incidence of iodism between the media is not surprising, since iodism is known not to be dose-dependent and to represent, at least in part, an idiosyncratic reaction. Iodism is significantly more common than delayed rashes and is a more important side effect of urographic agents.
BETTMANN, M. A. & PAULIN, S., 1977. Leg phlebography: The
incidence, nature and modification of undesirable side effects. Radiology, 122, 101-104. DAVIES, P., PANTO, P. N., BUCKLEY, J. & RICHARDSON, R. E.,
1985. The old and the new: a study offivecontrast media for urography. British Journal of Radiology, 58, 593-597. DAVIES, P., ROBERTS, M. B. & ROYLANCE, J., 1975. Acute
reactions to urographic contrast media. British Medical Journal, 2, 434-437. GOOD, A. E., NOVAK, E. & SONDA, L. P., 1980. Fixed eruption
and fever after urography. Southern Medical Journal, 73, 948-949. GOODMAN, L. S. & GILMAN, A. Z., 1980. The Pharmacological
Basis of Therapeutics. 6th Edit. (Macmillan, New York). HARRIS, P. F., SANCHEZ, J. F. & MODE, D. G., 1970. Iodide
mumps (Letter). Journal of the American Medical Association, 213, 2271-2272. HEYDENREICH, G. & OLHOM LARSEN, P., 1977. Iododerma after
CONCLUSIONS
(1) Delayed reactions after urography are relatively common; about 30% of patients suffer from them. (2) Delayed rashes (5%) are more common than immediate rashes (1%). (3) Arm pain is less common after the administration of non-ionic media than of sodiumcontaining ionic media. (4) The incidence of "iodism" is the same for nonionic and ionic media (9%) and is nearly twice the incidence of delayed rashes.
high-dose urography in an oliguric patient. British Journal of Dermatology, 97, 567-569. KOCH, R. L., BYL, F. M. & FIRPO, J. J., 1969. Parotid swelling
with facial paralysis: a complication urography. Radiology, 92, 1043-1044.
of intravenous
KOHRI, K., MIYOSHI, S., NAGAHARA. A. & OHTANI, M., 1977.
Bilateral parotid enlargement ("iodide mumps") following excretion urography. Radiology, 122, 654. LEA THOMAS, M., KEELING, F. P., PIAGGIO, R. B. & TREWEEKE,
T. P., 1984. Contrast agent induced thrombophlebitis following leg phlebography: iopamidol versus meglumine iothalamate. British Journal of Radiology, 57, 205-208. MERSEREAU, W. A. & ROBERTSON, H. R., 1961. Observations
on venous endothelial injury following the injection of various radiographic contrast media in the rat. Journal of Neurosurgery, 18, 289-294.
ACKNOWLEDGMENTS
We are grateful to E. Merck Ltd and Nyegaard (UK) Ltd for generous supplies of contrast medium; also to Sue Beadsworth and Karen Kelly for typing the manuscript.
NAVANI, S., TAYLOR, C. E., KAUFMAN, S. A. & PARLEE, R. H.,
1972. Evanescent enlargement of salivary glands following tri-iodinated contrast media. British Journal of Radiology, 45, 19-20. PENRY, J. B. & LIVINGSTON, A.,
1972. A comparison
of
REFERENCES ANSELL, G., 1968. A national survey of radiological complications: interim report. Clinical Radiology, 19, 175-191. 1970. Adverse reactions to contrast agents: scope of problem. Investigative Radiology, 5, 374-384.
diagnostic effectiveness and vascular side-effects of various diatrizoate salts used for intravenous pyelography. Clinical Radiology, 23, 362-369. SUSSMAN, R. M. & MILLER, J., 1956. Iodide "mumps" after intravenous urography. New England Journal of Medicine, 255, 433-434.
ANSELL, G., TWEEDIE, M. C. K , WEST, C. R., PRICE EVANS,
TALNER, L. B., LANG, J. H., BRASCH, R. C. & LASSER, E. C ,
D. A. & COUCH, L., 1980. The current status of reactions to intravenous contrast media. Investigative Radiology, Supplement 15, 32-39.
1971. Elevated salivary iodine and salivary gland enlargement due to iodinated contrast media. American Journal of Radiology, 122, 380-382.
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