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Is there a role for corticosteroid prophylaxis in patients at increased risk of adverse reactions to intravascular contrast agents?
Clinical Radiology (1993) 48, 225-226
Review Is There a Role for Corticosteroid Prophylaxis in Patients at Increased Risk of Adverse Reactions to Intravascular Contrast Agents? P. D A W S O N and P. S. S I D H U
Department of Diagnostic Radiology, Hammersmith Hospital, London
The mechanisms of adverse reactions to intravascular iodinated radiological contrast agents are not completely clear. Even though they are known to be not truly anaphylactic in character, they appear frequently to involve elements of the immune system. This has led many radiologists to prescribe corticosteroids in some atrisk patients as empirical prophylaxis, a procedure rather hesitatingly supported by a recent circular from the Royal College o f Radiologists [1]. What seemed like solid support for this approach came in 1987 with the publication by Lasser e t al. [2] of the results of a multicentre trial in the United States which indicated that two doses of oral corticosteroids (Methylprednisolone 32 mg) administered approximately 12 h and 2 h before the injection of a contrast agent significantly reduced the incidence of reactions of all types except hives. The most significant claim of the paper was that the two dose steroid regime reduced 'Grade I I I ' (severe) reactions by some 62%. The paper has, however, been criticized [3-6]. Ackroyd [3] pointed out that the authors combined the values for the incidence of Grade III (serious) reaction in the two control groups (one or two dose placebo regime) with those for the incidence of Grade III reactions in patients given a single dose of steroid (which had not reduced the incidence of reactions), and compared the incidence of reactions in these three groups combined with the incidence of Grade III reactions in patients given two doses of steroid. Ackroyd claims that such manipulation of results by combining a treatment group with control groups in this way 'cannot be p e r m i t t e d . . , it can only be concluded that in this study, the administration of two doses of Methylprednisolone did not cause a significant reduction in the incidence of Grade III reactions'. Rose [4] made much the same point and allowed only that 'the data do show a trend in favour of steroid pretreatment'. Wolf [5] further claimed that though the study seemed large, 'it is inadequate to address such adverse effects as cardiovascular collapse, nephrotoxicity and death' on the grounds that there were such large variations in the number of patients entered from the 27 participating hospitals (a range of 10 to 1888 patients during the 4 year intake period). Baudouin and Wilkins [6] in a comment on the paper made the important suggestion that one patient in the study with diverticulitis may, in fact, have died because he was given
Correspondence to: Dr P. Dawson, Department of Diagnostic Radiology, Hammersmith Hospital, Du Cane Road, London WI 2 0HS.
corticosteroids and if this death were included in the analysis of the data, as they believed it should have been, 'interpretation of the study alters dramatically. The use of pretreatment corticosteroids becomes more dangerous than the use of ionic contrast media alone'. If Lasser's study, the most quoted on the subject, is flawed where can we turn for help? Wolfet al. [7] have also carried out a large scale study of ionic contrast agents alone, ionic contrast agents combined with corticosteroid prophylaxis (the same two dose regime recommended by Lasser et al. [2]) and non-ionic agents alone. They found that steroid premedication did indeed provide some protection but the use of a non-ionic agent alone was significantly better for prevention o f the occurrence of all categories of reactions. In particular, the differences in the incidence of 'severe' reactions in the three groups were dramatic - 0.32% with an ionic agent alone, 0.25~ with an ionic agent and corticosteroid prophylaxis and 0.01% with a non-ionic agent alone. In the detailed analysis, patients with no definable risk factors receiving the ionic agent and corticosteroid prophylaxis actually had more reactions than those receiving the ionic agent alone. The authors argue that the consent procedure, and premedication, may actually increase the likelihood of adverse drug reaction. They point out that Lasser's study exhibited evidence of a similar phenomenon. Patients with definable risk factors, however, did do somewhat better with corticosteroid pretreatment than when they received ionic agents alone but, with or without risks, the non-ionic agent alone was significantly safer. When individual categories of definable risk factor were examined singly, it was noted that in each one the non-ionic agent alone was considerably better than the ionic agent plus corticosteroids. In our view, the much cited paper of Lasser e t al. [2] is significantly flawed and should be interpreted as indicating no more than a trend toward corticosteroid prophylaxis efficacy. The work of Wolf e t al. [7], though itself not without flaws, provides more convincing evidence for a degree of efficacy for a regime of corticosteroid prophylaxis such as that suggested by Lasser. However, WoWs paper clearly demonstrates that the use of a non-ionic contrast alone in all patients, whether definably a risk or not, and in all individual categories of patients at risk, is associated with a much more dramatic reduction in incidence of severe reactions. Indeed, as discussed, patients with no definable risk factors who receive corticosteroid prophylaxis appear to be at somewhat greater risk than those who do not. The
226
CLINICAL RADIOLOGY
observation by Wolf of a significant reduction in the incidence of reactions in all grades of severity in patients receiving non-ionic contrast agents is in line with the earlier findings of Katayama e t al. [8] and Palmer [9]. There is no evidence at all to suggest that the possible small advantages of corticosteroid prophylaxis and the more certain gains from the use of a non-ionic agent may be combined by using both. Against the background of this imperfect database, what can be recommended? We suggest the following: (1) Non-ionic agents should always be used in patients with definable risk factors (see previous Guidelines
[1]), (2) The value ofcorticosteroid prophylaxis is not proven and may reasonably be abandoned. Whatever policy is adopted it must be remembered that the administration of intravenous contrast agents is associated with a risk. Even with non-ionic contrast agents there will unfortunately be occasional severe reactions and deaths.
REFERENCES
1 Dawson P, Grainger RG. Guidelines for use of low osmolar contrast agents. Faculty of Clinical Radiology of Royal College of Radiologists 1992. 2 Lasser EC, Berry CC, Talner LB, Santini LC, Lang EK, Gerber FH et al. Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material. New England Journal of Medicine 1987;317:845-849. 3 Ackroyd JF. Letter to the Editor. New England Journal o f Medicine 1988;31:856. 4 Rose TG. Letter to the Editor. New England Journal of Medicine 1988;31:856. 5 Wolf GF. Letter to the Editor. New England Journal of Medicine 1988;31:856. 6 Baudouin CJ, Wilkins RA. Letter to the Editor. New England Journal of Medicine 1988;31:856. 7 Wolf GL, Mishkin MM, Roux SG, Halpern EF, Gottlieb J, Zimmerman J, Gillen J, Thellman C. Comparison of the rates of adverse drug reactions. Ionic agents, ionic agents combined with steroids, and non-ionic agents. Investigative Radiology 1991;26:404 410. 8 Katayama M, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and non-ionic contrast media. Final report for the Japanese Committee on Safety of Contrast Media. Radiology 1990;175:621-628. 9 Palmer FJ. The RACR Surrey of intravenous contrast media reactions. Final report. Australasian Radiology 1988;32:426 428.
Review Is There a Role for Corticosteroid Prophylaxis in Patients at Increased Risk of Adverse Reactions to Intravascular Contrast Agents? P. D A W S O N and P. S. S I D H U
Department of Diagnostic Radiology, Hammersmith Hospital, London
The mechanisms of adverse reactions to intravascular iodinated radiological contrast agents are not completely clear. Even though they are known to be not truly anaphylactic in character, they appear frequently to involve elements of the immune system. This has led many radiologists to prescribe corticosteroids in some atrisk patients as empirical prophylaxis, a procedure rather hesitatingly supported by a recent circular from the Royal College o f Radiologists [1]. What seemed like solid support for this approach came in 1987 with the publication by Lasser e t al. [2] of the results of a multicentre trial in the United States which indicated that two doses of oral corticosteroids (Methylprednisolone 32 mg) administered approximately 12 h and 2 h before the injection of a contrast agent significantly reduced the incidence of reactions of all types except hives. The most significant claim of the paper was that the two dose steroid regime reduced 'Grade I I I ' (severe) reactions by some 62%. The paper has, however, been criticized [3-6]. Ackroyd [3] pointed out that the authors combined the values for the incidence of Grade III (serious) reaction in the two control groups (one or two dose placebo regime) with those for the incidence of Grade III reactions in patients given a single dose of steroid (which had not reduced the incidence of reactions), and compared the incidence of reactions in these three groups combined with the incidence of Grade III reactions in patients given two doses of steroid. Ackroyd claims that such manipulation of results by combining a treatment group with control groups in this way 'cannot be p e r m i t t e d . . , it can only be concluded that in this study, the administration of two doses of Methylprednisolone did not cause a significant reduction in the incidence of Grade III reactions'. Rose [4] made much the same point and allowed only that 'the data do show a trend in favour of steroid pretreatment'. Wolf [5] further claimed that though the study seemed large, 'it is inadequate to address such adverse effects as cardiovascular collapse, nephrotoxicity and death' on the grounds that there were such large variations in the number of patients entered from the 27 participating hospitals (a range of 10 to 1888 patients during the 4 year intake period). Baudouin and Wilkins [6] in a comment on the paper made the important suggestion that one patient in the study with diverticulitis may, in fact, have died because he was given
Correspondence to: Dr P. Dawson, Department of Diagnostic Radiology, Hammersmith Hospital, Du Cane Road, London WI 2 0HS.
corticosteroids and if this death were included in the analysis of the data, as they believed it should have been, 'interpretation of the study alters dramatically. The use of pretreatment corticosteroids becomes more dangerous than the use of ionic contrast media alone'. If Lasser's study, the most quoted on the subject, is flawed where can we turn for help? Wolfet al. [7] have also carried out a large scale study of ionic contrast agents alone, ionic contrast agents combined with corticosteroid prophylaxis (the same two dose regime recommended by Lasser et al. [2]) and non-ionic agents alone. They found that steroid premedication did indeed provide some protection but the use of a non-ionic agent alone was significantly better for prevention o f the occurrence of all categories of reactions. In particular, the differences in the incidence of 'severe' reactions in the three groups were dramatic - 0.32% with an ionic agent alone, 0.25~ with an ionic agent and corticosteroid prophylaxis and 0.01% with a non-ionic agent alone. In the detailed analysis, patients with no definable risk factors receiving the ionic agent and corticosteroid prophylaxis actually had more reactions than those receiving the ionic agent alone. The authors argue that the consent procedure, and premedication, may actually increase the likelihood of adverse drug reaction. They point out that Lasser's study exhibited evidence of a similar phenomenon. Patients with definable risk factors, however, did do somewhat better with corticosteroid pretreatment than when they received ionic agents alone but, with or without risks, the non-ionic agent alone was significantly safer. When individual categories of definable risk factor were examined singly, it was noted that in each one the non-ionic agent alone was considerably better than the ionic agent plus corticosteroids. In our view, the much cited paper of Lasser e t al. [2] is significantly flawed and should be interpreted as indicating no more than a trend toward corticosteroid prophylaxis efficacy. The work of Wolf e t al. [7], though itself not without flaws, provides more convincing evidence for a degree of efficacy for a regime of corticosteroid prophylaxis such as that suggested by Lasser. However, WoWs paper clearly demonstrates that the use of a non-ionic contrast alone in all patients, whether definably a risk or not, and in all individual categories of patients at risk, is associated with a much more dramatic reduction in incidence of severe reactions. Indeed, as discussed, patients with no definable risk factors who receive corticosteroid prophylaxis appear to be at somewhat greater risk than those who do not. The
226
CLINICAL RADIOLOGY
observation by Wolf of a significant reduction in the incidence of reactions in all grades of severity in patients receiving non-ionic contrast agents is in line with the earlier findings of Katayama e t al. [8] and Palmer [9]. There is no evidence at all to suggest that the possible small advantages of corticosteroid prophylaxis and the more certain gains from the use of a non-ionic agent may be combined by using both. Against the background of this imperfect database, what can be recommended? We suggest the following: (1) Non-ionic agents should always be used in patients with definable risk factors (see previous Guidelines
[1]), (2) The value ofcorticosteroid prophylaxis is not proven and may reasonably be abandoned. Whatever policy is adopted it must be remembered that the administration of intravenous contrast agents is associated with a risk. Even with non-ionic contrast agents there will unfortunately be occasional severe reactions and deaths.
REFERENCES
1 Dawson P, Grainger RG. Guidelines for use of low osmolar contrast agents. Faculty of Clinical Radiology of Royal College of Radiologists 1992. 2 Lasser EC, Berry CC, Talner LB, Santini LC, Lang EK, Gerber FH et al. Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material. New England Journal of Medicine 1987;317:845-849. 3 Ackroyd JF. Letter to the Editor. New England Journal o f Medicine 1988;31:856. 4 Rose TG. Letter to the Editor. New England Journal of Medicine 1988;31:856. 5 Wolf GF. Letter to the Editor. New England Journal of Medicine 1988;31:856. 6 Baudouin CJ, Wilkins RA. Letter to the Editor. New England Journal of Medicine 1988;31:856. 7 Wolf GL, Mishkin MM, Roux SG, Halpern EF, Gottlieb J, Zimmerman J, Gillen J, Thellman C. Comparison of the rates of adverse drug reactions. Ionic agents, ionic agents combined with steroids, and non-ionic agents. Investigative Radiology 1991;26:404 410. 8 Katayama M, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and non-ionic contrast media. Final report for the Japanese Committee on Safety of Contrast Media. Radiology 1990;175:621-628. 9 Palmer FJ. The RACR Surrey of intravenous contrast media reactions. Final report. Australasian Radiology 1988;32:426 428.