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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.

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.

Maximal complexing of alpha 2-macroglobulin (alpha 2M) and kallikrein (KK) occurs at a temperature of 22-24 rather than at 37 degrees C. The protease expressivity of the complex is also maximal at 22-24 degrees C. alpha 2M-KK complex, sustained permeability changes in guinea pig skin. These findings suggest that the complex, rather than free KK, could play a role in the kinin release reported in some late-phase reactions, some instances of delayed-type hypersensitivity and some cold-induced reactions.

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.

Earlier studies suggest that adverse reactions to injected radiographic contrast media are idiosyncratic. In an attempt to gain a better understanding of pathophysiologic events underlying these reactions, rabbit models injected with lethal dose ranges of a cholangiographic contrast material were studied. These animals showed activation of both the complement and coagulation systems. Externally applied heat potentiated complement consumption and increased mortality. Depleting complement components C3-C9 by cobra venom factor did not prevent activation of coagulation or diminish mortality. However, depleting fibrinogen diminished complement activation and markedly diminished mortality. Heparin, administered at several hourly intervals after contrast challenge, also diminished mortality. These studies suggest that the adverse effects of contrast media in this model system are mediated chiefly by the coagulation system, and that complement, if it participates deleteriously, must involve components up to, but not including, C3. A logical role for the inhibitor of C1 esterase in adverse contrast reactions is considered.

Since complement activation is sharply temperature-dependent, we have examined the effects of fever produced by a very small dose of endotoxin on contrast media lethality in rabbits. After the injection of 8.2 ml/kg of 52% methylglucamine iodipamide, a group of rabbits exhibiting an average temperature elevation of 1.5 degrees C had a 100% mortality rate. This was contrasted to a 30% mortality in control rabbits receiving contrast alone, and no mortality in rabbits receiving endotoxin alone. The rabbits with fever and increased mortality exhibited increased activation of serum complement. From this preliminary data it appears that caution should be observed in performing a contrast examination in a patient with endotoxemia and/or a fever.

An in vitro test for the rate of appearance of kallikrein in plasma due to contact system activation by dextran sulfate at 0 degree C was applied to plasmas of 19 atopic asthma patients and 19 age- and sex-matched controls without atopy. The average prekallikrein activation rate was markedly higher in the plasmas of the atopic patients. Mean endogenous heparin levels were also elevated.

In a previous study, and in the present study, we have found that the baseline plasma samples of patients with asthma contain average levels of an endogenous heparin-like material (EHM) that is significantly higher than that noted in non-allergic, non-asthmatic controls. This material appears to have properties of both heparin and heparan sulfate. Three out of six patients responding to inhalational antigen challenge displayed an acute increment in EHM concentration that coincided with a fall in FEV values. The relation of EHM concentration to provoked asthma, or to asthma in general, remains to be determined.

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.

Rabbits pretreated with methylprednisolone acquired significant protection against an intravenous challenge of meglumine iodipamide. In comparison to controls, the pretreated rabbits showed moderate elevations of Factor XII, and rather striking elevations of C1-esterase inhibitor. Treated rabbits also showed significantly less granulocytosis. It is believed that the protective effect can be ascribed to the modulation of acute phase reactants by increased concentrations of C1-esterase inhibitor.

A modification of an anti-Xa assay for plasma heparin has been devised using a low molecular weight dextran sulfate that competitively binds protein heparin neutralizers and displaces masked heparin. The addition of 0.12 mg dextran sulfate per ml of plasma permits heparin, neutralized by the products of platelet aggregation, to recover full functional activity against Xa. The assay will permit a more accurate assessment of both exogenous plasma heparin and endogenous heparin-like activity in blood samples collected with varying techniques. A further modification is proposed employing polybrene to neutralize the plasma heparin-like material providing a concurrent control for each sample that increases accuracy by eliminating the effect of varying AT-III levels which have anti-Xa activity.

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.

Bradykinin release, an end product of contact system activation, is thought to play a significant role in the pathophysiology of asthma. We have found an increased level of native alpha 2-macroglobulin-kallikrein (alpha 2M-KK) in asthma plasmas, and have demonstrated increased levels of contact system activity in these plasmas under certain laboratory conditions. We investigated the possible role of alpha 2M-KK as a modulator of the contact system activity. Alpha 2M-KK potentiated the factor XII activation on kaolin and the kallikrein production in a dextran-sulfate-mediated assay. This potentiation presumably involves a proteolytic effect of alpha 2M-KK on high molecular weight kininogen.

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.