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X-ray contrast media are individually injected into human blood vessels in greater quantities than any other pharmacological substance. Adverse reactions to these substances have heretofore been considered anaphylactoid in nature. Others and we have demonstrated that the mechanisms involved are multifactorial and may involve activation of mast cells and basophils, activation of the complement system, activation of the contact system, and the conversion of L-arginine into nitric oxide. Appropriate pretreatment with corticosteriods will diminish the incidence of reactions. Most recently we have demonstrated that the contrast media function as 'pseudoantigens' (PsA). They can combine with antibodies, but cannot themselves produce antibodies. This property appears to be dependent on aggregation in high concentrations and varies with the individual media. It furthermore appears to be non-specific in relation to antibodies, and suggests that binding occurs to the Fc portion of immunoglobulins. We have now demonstrated that the least toxic of current media demonstrate the best antibody binding and in sufficient concentration can inhibit contrast induced mast cell activation and/or non-contrast antigen induced mast cell activation, apparently due to in vivo pseudoantigen excess. In lesser concentrations and/or lesser binding, the media can trigger mast cell activation.

Rationale and Objectives: The authors performed this study to determine whether adverse reactions similar to those that occur in patients receiving antipsychotic medication may occur after inadvertent intrathecal injections of some contrast material., Materials and Methods: Recombinant human dopamine-2 (D-2) receptors were incubated together with tritiated (hydrogen 3) spiperone, a D-2 receptor agonist commonly used in binding studies, and three types of contrast material (sodium/meglumine diatrizoate; meglumine iothalamate; and iohexol) in different concentrations to determine competitive binding potentials. Nonspecific binding was also assessed. Membranes were washed, filtered, and counted in a scintillation counter., Results: At several different concentrations, diatrizoate demonstrated a potential to displace the binding of spiperone to the D-2 receptors, whereas the other two contrast materials tested (iothalamate meglumine and iohexol) showed only weak binding potentials., Conclusion: Diatrizoate, which has been incriminated in most adverse reactions resulting from the inadvertent intrathecal injection of a contrast material, may produce symptoms similar to those of the neuroleptic malignant syndrome by blocking neurotransmission through dopamine receptors. Although antipsychotic drugs produce this parkinsonism-like effect only after prolonged use, it is probable that diatrizoate produces the effect immediately by virtue of the high concentrations that may accumulate at the base of the brain after myelography. Also worthy of note is the fact that the two other contrast materials that have produced a number of reported adverse reactions share a molecular similarity to diatrizoate that is not found with other contrast materials.

Background: X-ray contrast media (CM) toxicity resembles IgE-antigen-based anaphylaxis, and CM-related histamine release has been demonstrated in vitro and in vivo. While nobody has succeeded in producing antibodies against injections of neat CM, the ability of CM to compete with a series of antigens against their respective antibodies has recently been demonstrated. However, there is a paradox, since the CM with the strongest antibody binding are nevertheless the least likely to provoke antigen-antibody-related mast cell/basophil release., Methods: Two strains of rats were subjected to (a) passive cutaneous anaphylaxis (PCA) studies in the presence of various concentrations of CM, (b) blood pressure (BP) tracings following bolus administrations of various prototypical CM and (c) BP tracings in ovalbumin (OVA)-sensitized rats, challenged with OVA plus CM, vs. OVA plus CM-equivalent saline., Results: In the PCA studies, and the OVA challenge studies, the CM appear to act in an antigen excess mode, limiting the potential of the OVA to elicit anaphylactic changes, as demonstrated by permeability studies or by BP levels. The bolus CM studies demonstrate that the more potent CM 'antigens' actually produce an increase in BP and the less potent CM 'antigens', a drop in BP. These changes can be related to the CM acting in an 'antigen' excess mode vs. an 'antigen' equivalent mode., Conclusions: The CM have the potential to act in an 'antigen' excess or 'antigen'-equivalent mode. The potential to express an 'antigen'-excess mode in vivo, may be unique to CM because of the high concentrations injected., (Copyright 2000 S. Karger AG, Basel)

Purpose: To compare U.S. Food and Drug Administration (FDA) and manufacturer data about patient reactions to ionic and nonionic, low- and high-osmolar contrast media from 1990 through 1994., Materials and Methods: Reactions to all available high-osmolar and four low-osmolar contrast media (ioxaglate, iohexol, iopamidol, and ioversol) were compared. Ioxaglate is composed of charged particles, and data are reported separately. Reactions were also compared with data from 1980 to 1984, when only high-osmolar contrast media were available., Results: With high-osmolar contrast media compared with the three noncharged low-osmolar media, the incidence (per million examinations) was highest for all reported reactions (193.8 vs 44.4), severe reactions (37.4 vs 10.5), and deaths (3.9 vs 2.1). With high-osmolar media compared with ioxaglate, respectively, the incidence of total reactions was higher (193.8 vs 142.5), of severe reactions was almost the same (37.4 vs 33.6), and of death was lower (3.9 vs 6.4). The incidence of severe reactions to total reactions was higher with nonionic media (23.7%) and ioxaglate (23.6%) than with ionic media (19.3%). The incidence of death to severe reactions was 19.7% with nonionic media, 19.0% with ioxaglate, and 10.4% with high-osmolar media. The incidence of renal failure (as a percentage of total reports) was approximately 3.6 times higher with all low-osmolar contrast media (2.3%) than with high-osmolar media (0.6%), usually in patients with pathologic cardiac conditions., Conclusion: All of these factors merit consideration in the evaluation of the utility of a given contrast medium.

Rationale and Objectives: We assessed the role that nitric oxide (NO) plays in contrast media (CM) toxicity, using 100% lethal dose (LD100) studies in hyperimmune Brown Norway (BN) rats., Methods: Ninety-two BN rats and 41 Sprague-Dawley (SD) rats underwent CM LD100 tail vein injections with methylglucamine iothalamate or sodium iothalamate to the point of cessation of respiration. Methylglucamine hydrochloride also was injected. The injections were accompanied by L-arginine (L-Arg) or D-arginine (D-Arg) analogues or by an H1 blocker. L-Arg analogues inhibit NO formation, and D-Arg analogues do not., Results: An L-Arg analogue, but not a D-Arg analogue, increased the tolerance of BN rats (p < .005) for methylglucamine iothalamate but not for sodium iothalamate. The L-Arg analogue also protected BN rats against methylglucamine chloride injections (p < .002). H1 blockade protected BN rats against methylglucamine iothalamate (p < .0005) and methylglucamine chloride (p < .005) injections. None of these measures altered the CM tolerance of SD rats. In SD rats, injections of either methylglucamine iothalamate or sodium iothalamate along with a D-Arg analogue or normal saline were better tolerated than similar injections in BN rats (p < .01 and .002 for methylglucamine iothalamate and sodium iothalamate, respectively). In SD rats but not BN rats, sodium iothalamate was better tolerated than was methylglucamine iothalamate (p < .0005)., Conclusion: NO appears to play a significant role in BN rats LD100 CM toxicity and has been implicated by others in the blood pressure fall characterizing some forms of antigen-induced anaphylaxis [1, 2]. The results of the current study and the literature suggest that methylglucamine-modulated release of histamine from mast cells may underlie the NO production.

Objective: The purpose of this study was to determine whether patients receiving a two-dose corticosteroid regimen before IV injection of nonionic contrast medium gain protection against adverse reactions to contrast material., Subjects and Methods: A randomized, blinded study involving three institutions was initiated in 1988. Patients were divided into two groups. One group received a 32-mg oral dose of methylprednisolone administered 6-24 hr before and again 2 hr before injection of contrast material. The other group received placebo tablets administered in the same time periods. During a 3-year period, 1155 patients and control subjects successfully completed the protocol. Demographic characteristics, including histories of previous reactions and histories of asthma or allergy, did not differ in the two groups. All signs and symptoms that appeared after injection of contrast material were carefully recorded and graded according to an earlier scheme [1]. Patients, control subjects, and all attending personnel were blinded regarding the premedication., Results: Corticosteroid pretreatment conferred protection for overall reactions (1.7% vs 4.9%, p = .005) and grade I (mild) reactions (0.2% vs 1.9%, p = .004). Subjects receiving corticosteroids also had fewer grade II (moderate) (p = .63) and grade III (severe) (p = .11) reactions, but the total numbers involved were small, and the differences were not significant., Conclusion: A rigidly controlled study of the potential protective effects of a two-dose oral corticosteroid regimen preceding IV injection of nonionic contrast medium indicates that corticosteroid pretreatment confers significant protection, at least for overall reactions and grade I reactions.

The levels of contaminant, free inorganic iodide and iodine were determined in several commonly used ionic and nonionic intravenous contrast media to gain a better understanding of the roles of these compounds in radioactive iodine uptake inhibition. The method, which involved a reduction-oxidation reaction using sodium nitrite, yielded accurate and precise data for the iothalomate based ionic contrast media as well as the nonionic contrast media. There was no free iodine in any of the contrast media tested. There was considerable variation in free iodide levels, ranging from 1.38 microgram/ml to 20.84 microgram/ml among the different contrast media, although significant differences between the ionic and nonionic media were not found. These levels of contaminant iodide are thought to play a role in the short-term inhibition of radioactive iodine uptake.

There is increasing evidence that activation of the plasma contact system that results in the production of bradykinin plays an important role in contrast material systemic reactions. The effects of bradykinin in anaphylaxis depend on its rate of destruction and its rate of production. The highest percentage of contrast material reactions occur after intravenous injections, and the major enzyme hydrolyzing bradykinin (kininase II; angiotensin-converting enzyme) is found on pulmonary vascular endothelial surfaces. The inhibitory effects of numerous ionic and nonionic contrast material solutions on the enzyme have been determined. Additionally, the role in this inhibition of the chelators found in all commercial contrast material vials has been studied. In vitro, all such preparations combined with their chelators inhibit angiotensin-converting enzyme. Whether this inhibition plays a role in vivo remains to be established.

In vitro inhibition of adenosine triphosphatase and carbonic anhydrase by several radiographic contrast media and other compounds was measured. The concentrations required for 50% inhibition were, in general, similar to those obtained for other enzymes. The effect of methylglucamine could not be determined for either enzyme because of interference with the assays.

Lymphangiography was performed on 40 adult cats, 39 dogs, 20 rabbits, and 12 rats of mixed sex using Ethiodol or radiopaque perfluorocarbon (BPC). Ethiodol was more radiodense than RPC, but imaging of lymph channels and nodes was satisfactory with the latter. RPC could be infused rapidly, while Ethiodol infusion was time consuming. RPC was biologically inert; Ethiodol produced both local and systemic inflammatory reactions. The lymph node distribution with RPC was more uniform and persisted for longer periods. It was concluded that RPC was an improvement over Ethiodol for lymphangiography.

Bradykinin, the end product of activation of the plasma contact system, may play a significant role in reactions to contrast material and in other forms of anaphylactoid and anaphylactic responses to drugs or antigens. Activation of factor XII initiates activity in the plasma contact system, and we have identified factors (negatively charged surfaces) present in elevated concentrations in the plasma of patients who are asthmatic or allergic that can "prime" their plasma for the initiation and/or potentiation of factor XII activation. In other studies, we have shown that persons who react to contrast material and persons who are asthmatic or allergic share both a potential for accelerated contact system activity and evidence of an increased mean concentration of low-level contact system products. Recently, we have found that contrast media can inhibit angiotensin-converting enzyme, the substance that hydrolyzes bradykinin and limits its systemic effects. Thus, a number of factors suggest that it is the potential for increased production of bradykinin in persons who are allergic or asthmatic that may account for the greatly increased susceptibility of these patients to contrast material. This susceptibility may be critically triggered by the contrast media-induced inhibition of angiotensin converting enzyme. In view of these findings, the possibility exists that most, if not all, significant reactions to contrast material require an underlying allergic diathesis that may, or may not, be apparent by history and conventional diagnostic testing.

An in vitro is described that attempts to detect patients with a potential for adverse systemic reactions to contrast material. This test involves measuring the rate of conversion of prekallikrein to kallikrein under certain standard conditions. In a preliminary retrospective study, the test could be used to identify such patients with a sensitivity of 88%, a specificity of 82%, and a predictive value of 79%.

A patient, suffering a severe anaphylactoid reaction to contrast material injected for an intravenous pyelogram, developed a consumption coagulopathy and evidence of complement activation. Precontrast complement values suggested that the patient had been processing complement via the classical pathway, perhaps as a consequence of an earlier protracted Klebsiella infection. Following contrast injection, a precipitous fall in hemolytic complement (CH50) and in the concentration of the C1 esterase inhibitor (C1INH) developed, as well as a diminution in C4 and C3 with the evolution of C3 conversion products. The possible role that these changes might play in the pathogenesis of idiosyncratic reactions to contrast media is considered.

Radiopaque fluorocarbon (RFC) emulsions were prepared with small particle size and high concentration of the fluorocarbon. When RFC emulsions were injected intravenously in hamsters, rats, and mice with eight types of malignant tumors, the tumors became radiopaque, except in the mice with spontaneous teratoma of the ovaries. Tumors as small as 3 to 4 mm could be defined radiographically using routine x-ray techniques. The tumors remained radiopaque for days to weeks after injection. Light and electron microscopy revealed characteristic fluorocarbon vacuoles primarily in the tumor macrophages. Thus RFC emulsions may be useful in detection of malignant tumors.

An accelerated prekallikrein transformation is present at 4 degrees C in plasmas obtained from asthmatic patients (asthma plasmas) and in prereaction plasmas from contrast material (CM) reactors. Preliminary data show that (1) higher levels of alpha 2-macroglobulin bound kallikrein (alpha 2M-KK) may be found in asthma plasmas and pre-contrast medium reactor plasmas in comparison with control plasmas. In the asthma plasmas, these differences approach, but do not quite attain, significance; (2) complexes of alpha 2M-KK potentiate prekallikrein activation in buffer (BA) and dextran sulfate activation (DSA) assays; and (3) polybrene (factor XII inhibitor) induces an early blockage in the production of kallikrein activity in BA and DSA, indicating the presence in these plasmas of cryptic surfaces with a function analogous to dextran sulfate. These results indicate that, in asthma and probably in CM reactors plasmas, cryptic surfaces and alpha 2M-KK may each contribute to contact system activity induced at 4 degrees C.

Emulsions of radiopaque perfluorocarbon with small particle size were prepared by sonication and concentrated by centrifugation. The emulsions were well tolerated when given intravenously to rats in a dose up to 20 ml/kg. Whole-body angiograms were obtained for up to 6 hours after injection with visualization of vessels smaller then 1 mm. Hepatosplenograms were obtained after 2 hours and for several days after injections of radiopaque perfluorocarbon. Contrast enhancement was also seen in the myocardium, ovaries, adrenal glands, and intestines with brominated perfluorocarbon emulsions.

Metrizamide was employed in six patients who, during angiography, had had severe anaphylactoid reactions to conventional ionic contrast media. Five of these patients had received corticoid premedication before injection of both conventional contrast medium and metrizamide; anaphylaxis occurred only after administration of conventional contrast media. Four patients had no detectable reaction whatsoever after metrizamide; a fifth had only transient tachycardia. In the sixth patient, delayed edema developed in the region of his cerebral arteriovenous malformation. These observations suggest a marked decrease in the incidence and severity of anaphylactoid reactions when metrizamide is substituted in patients who have reacted to ionic contrast media. Metrizamide, or a comparable nonionic contrast agent, should be strongly considered in patients who have had a severe reaction to conventional contrast medium.

A prospective, randomized study of the potential protective effects of corticosteroids administered as pretreatment against contrast material (CM) reactions is reported. Patients (n = 6,763) from multiple institutions received either a single dose of steroids (32 mg of oral methylprednisolone, approximately 2 hours before CM challenge), a double dose (32 mg approximately 12 hours and 2 hours before CM challenge), or placebo. All contrast injections were with ionic media and were given intravenously. The two-dose (but not the one-dose) corticosteroid regimen provided significant protection. The effect on reaction incidences of a number of historical variables is also tabulated.

Evidence is presented for the activation of serum complement by contrast media, in vitro and in vivo. Activation as a function of concentration was measured and the increasing order of effectiveness was found to be metrizamide, iothalamate, diatrizoate, acetrizoate, iodipamide and iopanoate. This order is the same as for protein binding and enzyme inhibition. The activation mechanism for iodipamide, and by inference for the other compounds, does not involve gamma-globulin aggregation. Serial daily injections in normal dogs resulted in substantial declines in serum complement over several days. Guinea pigs which were depleted of serum complement with cobra venom factor were found to be no less sensitive to lethal doses of iodipamide than those with normal complement. Implications of these findings are discussed.

A new compound, di-iodo-triglucosyl benzene (DTB), was synthesized and tested for contrast medium potential. It is stable and soluble in water, with a molecular weight of 864 and a viscosity of 33.3 cps at 40degrees C for a 66.6% w/v solution. It is rapidly excreted unchanged by the kidneys. Its estimated LD50 in mice at an intravenous injection rate of 330 mg l/min is 34.0 g/kg. It is highly hydrophilic and not epileptogenic, but its low iodine content (29.4%) makes it unfavorable for clinical use.

Two different radiographic contrast media (RCM), iothalamate and iodipamide, induced the activation of several complement (C) components in normal, genetically C2-deficient and agammaglobulinemic human sera in vitro. This activation was dose dependent and demonstrable by a reduction in whole C as well as C4, C2, C3, and C5 hemolytic activities. C6, C8, and C9 hemolytic activities were unaffected. Concommitant with the loss of C3 hemolytic activity was the appearance of C3 proteolytic cleavage products that were identified by immunoelectrophoresis. Both the loss of C3 hemolytic activity and the production of C3 fragments occurred in the presence of 10 mM EDTA, indicating RCM-induced C3 cleavage occurred without participation of the multicomponent C3/C5 convertases of either the classical or alternative C pathways. Furthermore, loss of C3 hemolytic activity was not due to the direct alteration of the C3 molecule by RCM because purified C3 was unaffected upon incubation with RCM at a concentration that induced 80% reduction in the C3 hemolytic activity in normal human serum. Serum samples obtained from 40 patients, before and 30 min after undergoing i.v. pyelography, revealed no significant change in total hemolytic C activity; 34 patients received sodium and methylglucamine diatrizoate and six received sodium iothalamate. Hemolytic C3 levels were also determined for the six patients before and 30 min after administration of sodium iothalamate and no significant change in activity was detectable.

Adverse reactions to intravascular administration of contrast media, while low in incidence, merit serious consideration in view of increased utilization of these substances all over the world. Evidence for involvement of soluble mediators, antibody-antigen reactions, psychogenic factors, and the acute activation systems, is reviewed. As a group, the pre-contrast challenge plasmas of reactors are characterized by slightly diminished concentrations of Cl-esterase inhibitor and total hemolytic complement, and by an accelerated rate of conversion of prekallikrein to kallikrein on exposure to contact activators. The role of intravenous pretesting and pretreatment is considered. A rationale for pretreatment with adrenocorticosteroids is presented.

Both animal and human data suggest the possibility that the C1 esterase inhibitor may play an important controlling role in contrast media systemic reactions. This critical controlling protein has a major inhibitory effect on C1, kallikrein, activated factor XII of the intrinsic coagulation system, and on plasmin. In addition, it probably has other inhibitory effects not so well documented. Any circumstance that contributes to a continuing activation of the complement, coagulation, kinin, or fibrinolytic systems may result in partial consumption of the inhibitor and predispose the individual to adverse reactions to contrast challenge.

In vitro and in vivo studies were done to examine the effects of methylprednisolone on the adverse reactions induced by contrast media. At very high concentrations, the steroid potentiated the complement-activating effect produced in vitro by iodipamide, but inhibited the immune and nonimmune mechanisms of hemolysis. Rabbits pretreated for 3 days with intramuscular methylprednisolone (at high or low dosages) were significantly protected against an LD47 challenging dose of iodipamide. Those treated once with a low intravenous dose immediately prior to iodipamide challenge were protected to a lesser degree. Rabbits treated once with a very high intravenous dose of steroid evidenced no protection. A hyper-responsive dog was consistently protected against adverse reactions to injected sodium iothalamate by a 3-day steroid pretreatment.

Patients showing systemic reactions to intravascular contrast media and patients receiving contrast media without reaction have significantly different mean values (p is less than 0.05) for functionally determined serum C1-esterase inhibitor (C1 INH) and total hemolytic complement (CH50). The lower concentration of these components in reactors appears in baseline serum samples (as well as after injection), and suggests that many anaphylactoid reactions to contrast media are conditioned by earlier complement consumption, and result directly from contrast-induced activation of complement, and other activation system components in the presence of inhibitor depression.

Though the precise etiology of anaphylactoid contrast media reactions is unknown, recent investigations have contributed important insight into their pathogenesis. Explorations of the complement and coagulation systems, the basophil histamine release system, and antigen-IgE interactions are summarized. Current investigations focusing on the contact system are discussed. Patients with asthma and patients who are contrast material reactors show increased prekallikrein transformation rates indicating increased contact system activity. Increased endogenous heparin-like material was found in asthmatic patients and in 50% of prechallenge citrated plasmas of patients who later developed contrast reactions, suggesting partial explanation of increased incidence of reactions in asthmatics. Elevated heparin-like material may have pathogenic significance; it may potentiate prekallikrein transformation and inhibit adenylate cyclase to induce release of inflammatory mediators and produce bronchospasm. When appropriately administered, glucocorticoids appear to protect against contrast reactions. Incidence of systemic anaphylaxis with nonionic contrast media is unknown but is expected to be less than that with ionic media. Additional experience is needed to assess this potential benefit of nonionics.