Comparative safety of high-osmolality and low-osmolality radiographic contrast agents.
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Biomedical subjects
Publications and source records attributed to E C Lasser.
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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.
Activation of the plasma contact system with the production of bradykinin appears to play a role in X-ray contrast material reactions and in some forms of anaphylaxis. We have noted that the plasmas of contrast material reactors and some asthmatics show an accelerated rate of contact activity when exposed to exogenous contact activators at low temperatures, and we have identified two plasma priming substances (endogenous contact activators; ECA) that contribute to this potential activity. One primer appears to be a sulfated polysaccharide or proteoglycan that resembles heparin and/or heparan sulfate in its properties. Plasmas containing this primer show a cold-promoted activation of factor VII (CPA) as described by Gjonnaess (Thromb. Diathes. Haemorrh. 1972; 28: 169-181) and found particularly in high estrogen states. These plasmas also show spontaneous amidolytic (contact system) activity on cold incubation, and potentiated amidolytic activity when exposed to exogenous sulfated negative surfaces. A consideration of these findings and data in the literature suggest that these surfaces may originate on endothelial linings, may be increased in concentration by immunization and estrogens, and decreased by corticosteroid pretreatment. These considerations merit further study and may be the basis for the observed increase in asthma/allergy symptoms in some females during high estrogen periods.
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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.
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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.
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.
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.
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.
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.
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.
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.
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.
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