Allergy grand rounds

Anaphylactoid reactions to radiocontrast material

John E. Etffmeyer, M.D., Robert L. Siegle, M.D., and Phil Lieberman, M.D.

Dullas and San Antonio, Texas, and Memphis, Tenn.

Dr. Erfkeyer: Diagnostic studies that require the administration of RCM are an important investigative modality. Adverse reactions to RCM, with anaphy- lactoid reactions being the most severe, constitute a significant health problem. A representative case will be presented.

CASE PRFSENTATION Dr. Erffmeyer: A 53-yr-old white man was having an

intravenous pyelogram performed to evaluate asymptomatic hematuria. Approximately 30 set after the RCM had been infused, the patient complained of generalized pruritus. This was followed in rapid succession by the appearance of scat- tered urticarial lesions and sensations of chest tightness, shortness of breath, and light-headedness. The patient was found on examination to have scattered expiratory wheezes on auscultation of the lungs, a blood pressure of SO/O mm Hg, and a regular .heart rate of 170 bpm. The patient was administered 0.3 ml of epinephrine subcutaneously. Within a few minutes the blood pressure had returned to normal, and the shortness of breath and pruritus had subsided. For- tunately, no further treatment was necessary, and the patienj, recovered completely.

This case is representative of a typical anaphylac- toid reaction to RCM. The prevention and manage- ment of such reactions will be discussed later. First, Dr. Robert Siegle will discuss the biochemistry of RCM. Then Dr. Phil LIeberman will deal with the epidemiology and pathogenesis of RCM reactions. 1 will follow with a final section on patient man- agement.

From the Presbyterian Hospital of Dallas, University of Texas Cen- ter for the Health Sciences and Veterans Administration Hospital, San Antonio, Texas, and University of Tennessee Center for the Health Sciences, Memphis, Tenn.

Received for publication Feb. 20, 1984. Accepted for publication July 4, 1984. Reprint requests: Phil Lieberman, M.D.. 920 Madison Ave., Suite

434 N, Memphis, TN 38103.

DISCUSSION

Biochemical and pharmacologic considerations

Dr. Siegle: All RCM are tri-iodinated benzene rings to which organic radicals have been attached. The benzene rings are iodinated at positions 2, 4, and 6, leaving positions 1, 3, and 5 open for various sub- stitutions (Fig. 1). Frequently used doses of RCM may contain as much as 15 gm to 30 gm of elemental iodine. The magnitude of this dose may be appreciated by noting that the total iodine content of the body is only 10 mg. It should be noted that the iodine is tightly bound to the benzene ring, and very little iodine is released in free form.

Radiocontrast agents that are approved for clinical use in the United States for intravascular and uro- graphic procedures are diatrizoate, iothalamate, and metrizoate. Agents that are in clinical testing but not yet approved for intravascular clinical usage include metrizamide, ioxaglate, iopamidol, and iohexol. Me- trizoate, diatriioate, and iothalamate are used in hy- pertonic concentrations and are administered at an osmolarity of three to five times that of plasma. All three are ionic agents, and this accounts for their hy- perosmolarity. For diatrizoate and iothalamate the cat- ion is either sodium or meglumine. The cations for metrizoate are meglumine, sodium, calcium, and magnesium. The cations are added to the carboxyl group at position 1 of the benzene ring. Meglumine is used to minimize the toxic effects of large amounts of sodium that can be irritating to the brain and myo- cardium and that significantly enhance the vasodila- tory properties of the contrast material.’ Normally

401

402 Etffmeyer et al. J. ALLERGY CLIN. IMMUNOL.

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Fig. 1. Structures of radiocontrast material.

only a limited amount of meglumine is used because it increases the viscosity of the contrast material and makes if difficult to inject: The hypertonicity of these agents is partly responsible for some of the untoward effects of rapid administration of large doses (150 to 250 ml) often required for angiograph or urography. Hypertonicity may .account for several undesirable ef- fects including red cell aggregation2 endothelial dis- ruption,3 vasodilatation, and hypervolemia.’

Metrizamide represents the first of a new generation of nonionic, isotonic RCM. It is produced by con- verting the carboxyl group at position 1 to a nonion- izing amide (Fig. 1). This maneuver reduces the os- molar&y by approximately one half. Furthermore, the molecules of this compound tend to aggregate, thus further reducing osmolarity. Metrizamide is therefore used in a nearly isotonic form that still contains enough elemental iodine to be sufficiently radiopaque.

Iohexol and iopamidol represent a second genera- tion of nonionic contrast agents still based on the same tri-iodinated benzene ring. These two agents are more stable in solution than is metrizamide and conse- quently would be available in the liquid form with a shelf life comparable to that of diatrizoate. Metriza- mide is provided in a lyophilized form and must be reconstituted just before use. Ioxaglate is a dimer also based on the tri-iodinated benzene ring. The carboxyl at position 1 on the first ring has an ionic linkage, and the carboxyl at position 1 on the second ring has a nonionic bond. There are twice as many iodines per

charged particle as with diatrizoate. Consequently, the same opacification can be achieved as with conven- tional ionic agents with the use of a much lower con- centration of ioxaglate. At this lower concentration the osmolality of ioxaglate is approximately that of the nonionic agents and confers the same degree of opacification.

Epidemiaic considerations and significance of the problem

Dr. Lieberman: The overall incidence of untoward reactions to RCM has been reported to range from 4.63% to 8.53%4-‘7 Approximately 20% to 30% of these are anaphylactoid in nature and characterized by urticaria, angioedema, airway obstruction and/or vas- cular collapse. ‘* Fatalities have been reported to range from 0.002%4 to 0.009%7 of patients examined. Based on the estimated number of radiocontrast procedures performed each year in the United States alone when the number of contrast medium vials and ampules sold in 1970 was in excess of 10 million,” it is apparent that reactions to RCM rival those to penicillin and insect stings as a world health problem.

The peak incidence of reactions occurs in patients 20 to 50 yr of age. Reactions are relatively infrequent in the pediatric age group. 13, 14. ” Although it has been reported that female patients experience a higher in- cidence of reactions, I3 the weight of evidence supports an equal incidence between the sexes.‘, ” Reactions occur during both intravenous and intra-arterial injec-

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tion, but there appears to be a higher incidence for intravenous procedures. I7 There appears to be an in- creased reaction rate during intravenous cholangio- graphic procedures. ” Whether or not fatalities occur more frequently to intravenous cholangiograms has not been established. The reason for the increased incidence may be related to the RCM (unsubstituted at position 5 of the benzene ring) used for intravenous cholangiograms (see below). There is no reported ra- cial difference in susceptibility to RCM reactions.

It is difficult to discern if atopy is a predisposing factor. In most prospective studies the presence of ‘ ‘ allergy ’ ’ appears to enhance the risk of a reaction in a given patient.4. 7. 13. 14. ” However, in these studies the term “allergy” has been used in an imprecise fashion. It has been used to refer to diverse reactions including idiosyncratic, nonatopic drug reactions, un- classified food intolerances, “general (not specified) allergy,” and nonallergic forms of asthma and rhinitis, as well as the atopic respiratory tract diseases. In the above studies no tests (cutaneous or RAST) were per- formed to confirm a history of allergic disease. A more recent investigation” involving small numbers of pa- tients failed to find an increased incidence of atopy among a group of reactor subjects. Nonetheless, sub- jects suffering from respiratory atopic disease may demonstrate an increased in vitro sensitivity to RCM as evidenced by histamine release from human ba- sophils . “’ Furthermore, although most subjects re- ceiving RCM develop asymptomatic obstruction to airflow,“‘, ‘2 the incidence of clinically apparent bron- chospasm and wheeze appears to be significantly higher in known asthmatic subjects.16

Thus anaphylactoid reactions to RCM occur with significant frequency and can be fatal. They have their peak incidence between 20 and 50 yr of age, show no sex or racial predilection, and can occur when RCM is administered by both intravenous and intra- arterial routes. It is not clear whether or not atopic subjects are more prone to anaphylactoid reactions to RCM.

Theories of pathogenesis

Several theories have been proposed to explain the mechanism of production of reactions to RCM. With some overlap they can be classified into those involving complement activation, direct his- tamine release from mast cells and basophils, the recruitment of multiple inflammatory mediators, and antigen-antibody reactions. It is obvious that any classification of these theories is somewhat arti- ficial. For example, basophil histamine release can be the result of complement activation and can gen- erate kinin formation. Nonetheless, for the purpose

of this discussion, such classification is a useful tool for the organization of observations on the subject.

Complement activation. RCM has been demon- strated to activate complement both in vitro and in viva. ?3-27

Complement activation was first demonstrated in vivo in dogs*” and later in man.“” Subsequent studies confirmed these earlier observations, demonstrating that significant falls occur in most subjects receiving RCM.- Y*‘. Jo, ” Originally it was thought that in vivo complement activation was via the alternative path- way.24 However, later observations”‘- XL ” revealed that activation occurred nonsequentially, neither via the alternative nor the classical pathway, with simulta- neous reductions in CH50, C3, C4, Cly, and factor B. These in vivo reductions occur rapidly, being de- monstrable 90 set after the intravenous infusion of RCM.“’ They can be evanescent as well. returning to normal levels within 30 min.”

It should be noted, however, that falls in comple- ment do not correlate with reactions, and nonreactors cannot consistently be distinguished from reactors on the basis of such falls.“. “. ,I’ In contrast. “baseline” levels of serum complement (CH50) were found to be reduced in a group of reactors when levels were com- pared to control levels.“. ” Reactors were also found to have depressed Cl esterase inhibitor levels in both baseline and postinfusion serum samples.“” On the basis of these findings, it was postulated that reactions occur in patients with clinical conditions resulting in a “preceding sustained activity of either plasmin, kal- likrein, the intrinsic coagulation system. or the classic complement pathway” resulting in a ‘.gradual stoi- chiometric consumption of the inhibitor of the first component of complement and of total comple- ment.“‘” According to this hypothesis, patients with diseases characterized by ongoing complement use would be predisposed to anaphylactoid reactions to RCM. However, a prospective analysis of subjects experiencing reactions did not support this contention in that there appeared to be no predilection for reac- tions to occur in patients with diseases involving com- plement activation. ”

Several investigators have attempted to clarify the means by which RCM activates complement by in vitro incubation of RCM with serum.‘:’ ‘16. ” ” 14, Is. There is a great deal of evidence indicating that com- plement activation does not occur via the classic or alternative pathways. Activation occurs in serum de- pleted of C4’4 and C2”” and in agammaglobulinemic serum.‘J In addition It is not inhibited by ethylene- diaminetetraacetic acid or ethyleneglycol&s-(P-ami- noethyl ether)-N.N’-tetraacetic acid.‘” is. I’. I5 and RCM nonselectively and simuItaneou”ly depresses

404 Etffmever et al. J. ALLERGY CLIN. I~MUNOL.

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levels of components of both the alternative and classic pathways. 35 Finally, RCM complement activation pro- duces a cleavage product of C3 that is not identical to that produced by either the classic or alternative pathway.33

Although the exact nature of the activation process is unknown, there is evidence to support the conten- tion that activation occurs indirectly via the induction of a lytic enzyme system that in turn cleaves several complement components simultaneously (nonsequen- tially).26. 33s 34, 35 A c eavage 1 product of C3 is antigen- ically distinct as noted from that produced by the classic or the alternative pathway, thus incriminating another lytic system.33 F’urified C3 also does not ap- pear to be cleaved directly by RCM. Cleavage of C3 occurs only in the presence of serum, thus implying the recruitment of a secondary lytic system.34 The most likely candidate for the lytic enzyme system responsible for the production of cleavage products is the plasmin~en activator-plasmin system,35 since ac- tivation of complement is not inhibited by a trypsin inhibitor.’ or trasyloP’ but is significantly reduced by e-aminocaproic acid, a plasminogen activator inhibi- tor.35 This in vitro phenomenon is in keeping with observations in vivo demonstmting a simultaneous consumptive coagulopathy and complement activa- tion in a patient undergoing a severe anaphylac- toid reaction,36 the simultaneous presence of both depressions in complement, and the presence of fi- brin-split products in subjects administered RCM in- travenously. 32

Although cleavage products may not be identical to those produced by classic or alternative pathway activation, such products still possess biologic activ- ity. RCM activation of complement produces products with both anaphylatoxic and chemotactic properties.26 It should be noted that not every investigation has confirmed the ability of RCM to activate complement in vitro. In two investigations? 37 only iodipamide, and no other agent, was capable of activating com- plement. In one of these investigations,37 no actual cleavage of complement proteins occurred. The ap- pearance of activation was created by the direct bind- ing of RCM to complement components. This binding simulated a reduction in these components when they were measured antigenically. This artificial reduction was presumably the result of an alteration or masking of antigenic sites on these com~nents produced by their nonspecific binding to RCM.37

Characteristics of RCM-induced complement activation

Histamine release. RCM has been demonstrated to induce histamine release as well as complement ac- tivation both in vitro and in vivo.38-54 In vitro histamine

release occurs in a dose-dependent fashion.47, 48 It is effected more easily by methylgluc~ine salts than by sodium salts.42 Histamine is liberated from both mast cells38 and basophils.47. 48 In vitro histamine re- lease from human basophils may be specific for the RCM producing the anaphylactoid episode in a given patient,46. 49 thus the prosthetic group as well as the iodinated benzene ring may play a role in the de- ~anulation process. In vitro basophil histamine re- lease appears to be independent of osmo1arity4*~ 49 and resembles ionophore-induced release rather than an- tigen release in that it is delayed in onset (10 min after incubation) and slow to peak (45 min after incuba- tion). It is enhanced by the presence of serum.49 This implies that ~aphylatoxins generated by complement activation play a role in the release process. Histamine release does not appear to be dependent on the pres- ence of iodine since specially produced noniodinated RCM (diatizoate) is as effective as iodinated RCM in binding to leukocyte? and since noni~inated RCM analogs can cause re1ease.48 Since both iodinated and noniodinated RCM binds to human leukocytes but not to human red blood cells, it has been postulated that release is due to a direct interaction between RCM and a cell surface receptor,” but evidence to support this hypothesis was lacking when attempts were made to study structure-function relationships between RCM and the postulated receptor. No definite and consistent structure-function relationship could be es- tablished to delineate the area of the molecule re- sponsible for binding to the postulated receptor and inducing release when RCM analogs (benzoic acid, diamino benzoic acid, and 3-aceto benzoic acid) were compared to RCM (diatrizoate and metrizamide) for their ability to induce release.9

Finally, basophils from atopic subjects are more sensitive to RCM than those from nonatopic sub- jects,s4 and the basophils of previous reactor patients are more sensitive than those who have received RCM without reactions.48, 49

In vivo histamine release has been demonstrated in animal model@‘, ” and man during both intrave- nous3’, 39, 48 and intraarterial0 administration of RCM. However, except in animal models,40* 52 the release of histamine could not be correlated with the induction of pathophysiologic events. Release occurs in both reactor and nonreactor subjects receiving RCM32* 39. 43

The mech~ism by which histamine release is pro- duced has not been clarified. There are three postu- lated means: (1) a direct effect on mast cells and basophils via interaction with a cell membrane recep- tor, (2) release through the generation of anaphyla- toxins via complement activation, and (3) release due to the hy~~srnol~~ of RCM.

Evidence favoring the hypothesis that release is due

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Reactions to radiocontrast material 405

to the interaction between RCM and a cell membrane receptor is as follows: (1) In vitro release may be specific for the RCM producing a reaction in a given individual,~ 49 thus implying a role for the prosthetic group in the induction of release and suggesting the existence of a subtle stoichiometric relationship be- tween RCM and a cell surface receptor. (2) Release occurs when washed basophils are used in vitro, thus serum complement is not necessary for degran- ulation.46. 49 (3) In vitro release resembles iono- phore-induced release.49 (4) RCM binds to the surface of human leukocytes but not to human red blood cells.54

However, as noted, an attempt to define a definite st~ctu~-function relationship between RCM and a proposed basophil receptor was unsuccessful.“’

Evidence for the role of complement in the de- granulation process is limited to the observation that in vitro release is enhanced by serum and that this enhancement is eliminated when serum is first de- pleted of complement.50 Nonetheless, in vitro release occurs in the absence of complement.46”“

It has been postulated that hy~~onicity is respon- sible for the histamine release produced by RCM, since most presently used RCM are markedly hyper- tonic and have osmolalities of three to five times that of plasma.’ Hypertonic agents have been demon- strated to induce histamine release in vitro,55 and hyperosmolarity enhances the in vitro release of his- tamine induced by ragweed and antigen E.5h Also. isotonic RCM agents probably produce reactions less frequently than the older hypertonic agents and have been administered to a small number of previous re- actors without the production of recurrent anaphylac- toid episodes.57 However, the time course of histamine release produced by other hypertonic agents” differs from that described for RCM-induced release.49 Other hypertonic agents infused intravenously into rabbits also failed to produce the same effects (histamine re- lease, complement, consumption, and microvascular changes) as RCM of equal hypertonicity.” Metriza- mide, an isotonic RCM, is capable of producing his- tamine release from washed human basophiis in amounts equal to that released by diatrizoate, a hy- pertonic agent.‘” Finally, hypertonic agents infused in~venous~y do not appear to significantly elevate general serum osmolarity.“’ It should be noted, how- ever, that osmolarity may be elevated at the injection site. Thus the hypertonicity of these agents is an in- sufficient explanation alone to explain the in vitro degranulation process. However, the role of hyper- tonicity in the production of the anaphylactoid reaction in vivo may be related to its effects on tissues other than basophits. Hedonic RCM agents are capable of altering red cell structure. disrupting endothe-

ha1 integrity, and producing peripheral vasodilata- tionl The assessment of the importance of these ef- fects in the causation of the anaphylactoid reaction awaits more widespread clinical use of nonionic, isotonic agents and the use of these agents in in vitro models.

From the above, it is abundantly clear that RCM is capable of inducing significant histamine release via degranulation of basophils and mast cells both in vitro and in vivo. However, it is not yet clear whether this histamine release is the “final common pathway” of the anaphyIactoid response, nor has the mechanism of production of degranulation been elucidated. The characteristics of RCM-induced histamine release are: (1) occurs in vitro and in vivo, (2) noncytotoxic in vitro, (3) demonstrates a clearcut dose-response curve, (4) existence of a possible relationship between the structure of the agent and its capacity to induce histamine release in a given subject, (5) enhanced by serum, (6) time response resembles ionophore- rather than antigen-induced release in vitro, (7) iodine con- tent irrelevant, and (8) enhanced in basophils of pre- vious reactors.

Other biologic effects of RCM and the importance of these effects in the produ~ion of the anaphyle~oid reaction

Multimediator activation. RCM is capable of a number of biologic effects other than the activation of complement and the induction of the release of histamine from mast cells and basophiis: (1) serotonin release from platelets with platelet aggregation, (2) activation of clotting and clot lysis systems, (3) kinin formation, (4) enzyme system inactivation, (5) in- crease in airway resistance, (6) local endothelial dis- ruption and vasodilatation, (7) clumping of red blood cells, and (8) hypocalcemia. These effects might con- tribute to the production of anaphyiactoid episodes.

RCM can induce serotonin release from platelets and cause the aggregation of platelets around baso- phils in vitro, presumably as a result of the release of platelet aggregating factor.” Contrast agents can in- hibit platelet aggregation in viva.‘” They exert pro- found effects on the clotting system both in vitro” and in vivo.32. J6. 59, ho Disseminated intravascular co- agulation has occurred in patients undergoing reac- tions to RCM,36. ‘O and fibrin-split products can be found in the sera of both reactors and nonreactors receiving RCM. 32 Mortality in rabbits receiving lethal doses of RCM can be related to the activation of the clotting cascade. 59 In vitro RCM can exert a dose- dependent prolongation of the coagulation time, in- hibit fibrin polymerization, and generate fibrin-split products.‘7 RCM may also nonspeci~cally bind to clotting factors37 and other serum proteins.h’-h’ This

406 Etffmeyer et al. J. ALLERGY CLIN. I~MUNOL.

MARCH 1985

binding occurs with greater affinity in agents with an unsubstituted position 5 of the benzene ring (iodipa- mide) . I2 It is interesting to note that the ability to activate complement is also enhanced when position 5 is unsubstitutedz3. 33 and that the incidence of re- actions is higher during intravenous cholangiography when an unsubstituted RCM is used than when an RCM substituted at position 5 is used.” RCM inac- tivates a number of enzyme systems including acetyl- cholinesterase, @-glucuronidase, lysozyme, alcohol dehydrogenase, glucose-6-phosphate dehydrogenase, adenosine triphosphatase, and carbonic acid anhy- drase.63v @ RCM infusion produces subtle but consis- tent increases in airway resistance,2’~22 can alter myo- cardial conduction,65 and causes hypocalcemia during infusions.31 Red blood cell structure and flow can be significantly effected.“. 66 RCM produces red blood cell agglutination and sludging in vivo5*, 66 and in vi- tr~.~~ Vascular endothelium is disrupted and damaged by RCM a~inist~tion in~avascul~ly.67 It has been suggested that this disruption might activate factor XII, which in turn would activate clotting, clot lysis, and the kinin cascade,2g, 68 and that this multimedi- ator activity is responsible for the anaphylactoid event. It was additionally postulated that, if this were the case, subjects defective in their ability to inhibit the activation of these cascades would be prone to reac- tions . In support of this contention, reactors have been found to have depressed Cl esterase inhibitor func- tion.2g This enzyme inhibits complement activation, kinin fo~ation, and plasmin activity6’ and would thus be germane in preventing reactions to RCM via sev- eral of the mechanisms noted above. In keeping with this hypothesis is the observation that reactors con- vert prekallikrein to kallikrein more efficiently and rapidly than do nonreactors, thus implying that re- actors may be deficient in an inhibitor of this con- version.6a

Antigen-antibody interaction. Finally, RCM can be immunogenic. 54, 70-76 A recent investigation, presented only in abstract form to date,76 has presented evidence that reactors, but not nonreactors, have specific IgE anti-RCM. However, many investigators have tried without success to demonstrate that RCM is immu- nogenic, and clearly the weight of evidence fails to support the thesis that RCM reactions are immuno- logically mediated. 12* 45-77

Approach to the petient with a history of a previous reaction to RCM

Dr. ErOlneyer: The physician is often faced with the dilemma of managing the patient who has had a previous anaphylactoid reaction to RCM and who needs a diagnostic procedure with the use of RCM.

Such patients are clearly at an increased risk of ex- periencing another reaction on the adminis~tion of RCM. The incidence of recurrence ranges from a low of 15% to 16%13 to a high of about 30%.78-80

It is not likely that anaphylactoid reactions to RCM will cease being a problem in the future. As new diagnostic and therapeutic techniques are used that require knowledge gained from RCM procedures, it can be anticipated that patients will require repeat RCM studies despite previous anaphylactoid reac- tions ,

During the previous years, various methods have been used to reduce the frequency and severity of reactions. It was observed that mixing an antihista- mine with the RCM before administration resulted in a decreased number of reactions.*’ Others found that pretreating patients with an Hl antihistamine before the RCM procedure reduced the number of reactions.78. “, 82 Subsequently, investigators no- ticed that pretreating high-risk patients with Hl an- tihistamines,” corticosteroids,83 or a combination of the two greatly reduced the number of repeat re- actions.84-87

Some authors have advocated pretesting patients by administe~ng the RCM to be used via subcu~eous, intravenous, or intra-arterial routes.s8*8g It is clear that pretesting with 1 to 2 ml of RCM is not an effective means of reducing the severity of recurrent reactions, since fatal reactions to the tests have been reported on several occasions. *‘* ” A method of intravenous pretesting with RCM, which is actually a p~vocative challenge performed in a controlled environment, has been proposed.gO This method entails the gradual ad- ministration of the dilute concentrations of RCM to be used. By administering the RCM in such a fashion, it was theorized that, if a reaction occurred, it would be less severe, more easily treated, and would also allow the physician to reconsider the necessity of per- forming the procedure. Progressively stronger con- centrations are administered at 15-minute intervals until full strength RCM is administered. At the con- clusion of an uneven~ul adminis~ation procedure, the RCM study is performed. This procedure has been effective in preventing serious reactions by producing minor reactions during the provocation testing. Thus RCM reactions are probably dose-dependent, but the 1 to 2 ml pretest dose appears to be at the “top end” of a sigmoid-shad, dose-response curve and, con- sequently, pretesting with undiluted RCM offers no advantage over administering the full diagnostic dose.88, 89 By contrast, graded administration of great- ly diluted but progressively more concentrated amounts apparently engages the “steep” portion of the dose-response curve and thereby can reduce the

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incidence of life-threatening reactions by producing a “warning” and less serious response. Obvious dis- advantages of the provocative pretesting include the time required (about 1% hr) to complete the procedure and the necessity of a physician being present through- out the entire procedure. However, if a patient has experienced an anaphylactoid reaction that was indeed life-threatening, the physician may elect to use the provocative intravenous pretesting method in addition to the prednisone-diphenhydramine pretreatment reg- imen (see below). Most patients will not require this additional measure because the pretreatment regimen is effective in the vast majority of cases.”

Pretreating the patient, mentioned earlier, who pre- viously experienced an anaphylactoid reaction with H 1 antihistamines, corticosteroids, or both have been helpful in reducing the number of repeat reactions. The most effective protocol evaluated to date appears to be the pretreatment regimen by use of a combination of diphenhydramine and prednisone.84-“7 Of 318 pro- cedures with the use of RCM, when such high risk patients were pretreated, no adverse effects were ob- served in 294 (92.5%).87 Mild reactions occurred in 23 (7.1%) procedures.R7 A serious reaction (transient hypotension, wheezing, and urticaria) occurred in one patient.x7

The mechanism whereby this pretreatment protocol is able to confer protection has not been elucidated. Work in animals has demonstrated that successful pre- treatment with corticosteroids has been associated with elevated serum levels of some components (Cl esterase inhibitor and factor XII) involved with the pathway of inflammation.” This modulation of these acute phase reactants was thought to be responsible for the observed protective effect.” The significance of this observation as it applies to humans remains to be determined. Teleologically, it is not unreasonable to hypothesize that diphenhydramine exerts some beneficial action by minimizing the effect of histamine that may be released secondary to RCM adminis- tration .

When an essential indication for a repeat RCM study in a high-risk patient exists, the potential risks should be explained to the patient. It has been sug- gested that patients should give informed consent for the pretreatment program.37 The pretreatment protocol consists of administering 50 mg of prednisone orally every 6 hr for three doses, ending 1 hr before the procedure, and administering 50 mg of diphenhydra- mine intramuscularly 1 hr before the procedure.*’ All such high-risk patients should receive this pretreat- ment regimen.

The efficacy of the suggested pretreatment program might be enhanced further by the addition of an H2

antihistamine, such as cimetidine. A recent study sup- ports this suggestion. A pretreatment regimen evalu- ating the combination of the H 1 antagonist clemastine plus cimetidine was found to reduce significantly the number of patients who experienced RCM-~-induced side effects when these patients were compared to patients who had received clemastine or prednisolone alone.“,” This finding is not surprising, It is known that when histamine is infused intravenously. the consequent cardiopulmonary responses (tachycardia, reduced diastolic blood pressure, widened pulse pres- sure, headache, cutaneous flushing, and bronchocon- striction) are all significantly reduced by pretreatment with a combination of Hl and t-12 antihistamines.“J Furthermore, anaphylactoid reactions to plasma sub- stitutes have been effectively inhibited by pretreat- ment with a combination of HI and I-E receptor an- tagonists.“5 Addition of the cimetidine to the above treatment protocol could be accomplished by the ad- ministration of 300 mg of cimetidine orally I to 2 hr before the procedure. The observation has been made that the administration of 25 mg of ephedrine 1 hr before the procedure (in addition to the prednisone and diphenhydramine) will also reduce further the in- cidence of recurrent reactions.“”

When the procedure is perfonned, emergency re- suscitation equipment and trained personnel should be in the x-ray room. The fact that the suggested pre- treatment is not universally protective in high-risk pa- tients underscores the importance of the above pre- cautions,x7. ”

Situations may occur in which a high risk patient must undergo a radiographic contrast procedure on an emergency basis. Although no data are available to document efficacy, a pretreatment regimen for such emergency contrast studies has been proposed.“’ This regimen also stresses the need for documenting the indication for the emergency procedure and informing the patient of the risks involved. Medications used in this regimen are intravenous hydrocortisone, 200 mg administered immediately and every 4 hr until the procedure is completed, and diphenhydramine, 50 mg administered intramuscularly 1 hr before the proce- dure.” Again, resuscitation equipment and personnel should be present.

The pretreatment regimen is also indicated for the patient at risk when RCM is administered by other than the intravascular route. Reactions can occur with other routes of administration.9X Thus high-risk pa- tients undergoing procedures such as hysterosalpin- gography and retrograde urography with RCM should be pretreated. Subjects undergoing myelography with older, oil-based agents such as iophendylate need not be pretreated. since these agents are not tri-iodinated

408 EtfFmeyer et al. J. ALLERGY CLIN. IMMUNOL. MARCH 1995

benzene rings. However, patients having myelogra- phy performed with newer isotonic RCM such as metrizamideW should be pretreated. Although the fre- quency of reactions to isotonic RCM appears to be reduced as compared to hypertonic agents,57, ‘O” such reactions still occur, and it is possible that previous reactors may still be at a significantly increased risk.

Should a RCM-induced anaphylactoid reaction oc- cur, the treatment is the same as for a classic ana- phylactic reaction. The mainstay of treatment is epinephrine. Antihistamines, corticosteroids , volume replacement, vasopressors, and other measures should be used as dictated by the severity of the individual episode.

Before treatment the anaphylactoid reaction must be distinguished from a vasovagal reaction with hy- potension and bradycardia. Such reactions do occur as a result of various radiologic procedures, including those with the use of RCM.“’ Manifestations of an anaphylactoid reaction may include hypotension and tachycardia. Thus, when a hypotensive patient is eval- uated immediately after the administration of RCM, the pulse rate is a critical distinguishing feature. Ap- propriate treatment of the vagal reaction would require atropine.

Ideally, the patients at risk of experiencing an anaphylactoid reaction would be identified before un- dergoing any radiocontrast study. Unfortunately, as of this date, no means are available to identify such high-risk patients. In the future perhaps accurate in vitro tests will be able to identify these patients. Ef- forts to develop such tests are in the investigational state. *‘, 48, 68 Alternatively, it may be possible to de- velop new radiographic contrast agents that do not have the propensity to cause anaphylactoid reactions.57

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