Joseph H. Lang

Activation of Serum Complement by Contrast Media

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.

Histamine Release by Contrast Media

The blood draining organs with a high histamine content was sampled and elevation of plasma histamine was found to result from injections of certain contrast media. All methylglucamine contrast media tested to date (acetrizoate, diatrizoate, and iodipamide) produced such elevations. Methylglucamine chloride also caused elevation of plasma histamine. Some “allergic” reactions to contrast media may be explained on this basis.

Steroids: theoretical and experimental basis for utilization in prevention of contrast media reactions.

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.

An experimental basis for histamine release in contrast material reactions.

Perfusion of the canine liver or lung with methylglucamine contrast media or methylglucamine chloride alone will produce elevated histamine plasma levels in the effluent vascular channels from these organs. The sodium salts of the contrast media were less effective than the methylglucamine salts in producing histamine release. These studies suggest a threshold effect for contrast-media-induced histamine release as well as a potentiating effect for sequential injections. Using equal quantities of contrast media, injections over a 39-second period produced greater histamine release than 2-second injections.

Complement and contrast material reactors

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.

Binding of roentgenographic contrast media to serum albumin.

As part of an investigation of the molecular basis of the phystologic properties of organic contrast media, the binding to serum albumin of diatrizoate, acetrizoate, iodipamide, iopanoate and-MP-231 was measured by the method of equilibrium dialysis. Binding to other serum proteins was not detected

Changes in complement and coagulation factors in a patient suffering a severe anaphylactoid reaction to injected contrast material: some considerations of pathogenesis.

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 total hemolytic complement (CH50) and in the concentration of the C1 esterase inhibitor (C1 INH) 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.

The Role of the Y and Z Hepatic Proteins in the Excretion of Radiographic Contrast Materials

The Y and Z proteins, found only in the liver and the mucosa of the small intestine, bind bilirubin, bromosulfophthalein, and certain other organic anions and may be responsible for the preferential hepatic uptake and biliary excretion of these compounds. Experiments show that two cholecystographic contrast media, iopanoic acid and iodipamide, bind to the Y and Z proteins, while iothalamate, a representative urographic contrast agent, does not, indicating that these proteins may be important in determining the pathway of excretion of contrast material.

The plasma contact system in atopic asthma

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.

Development of Contrast Media Idiosyncrasy in the Dog

A laboratory dog exhibited an altered response to injections of sodium iothalamate. This idiosyncratic response may have been predicated on an earlier series of iothalamate injections. The overt manifestations of the reactions in this dog were vomiting, hypotension, and hyperreflexia. Significant changes in several electrolyte components and serum complement levels were noted when the dog reacted to the contrast material.