Quantitative aspects of blood coagulation in the generalized Shwartzman reaction. II. Effect of cortisone.

Abstract

Extract: In the previous paper quantitative changes in the coagulation mechanism accompanying each of the two injections of endotoxin required for the production of the generalized Shwartzman reaction (GSR) were described. It was demonstrated that the development of cortical necrosis of the kidneys was dependent both on the induction of intravascular clotting and on the state of preparation of the rabbits in response to the first dose of endotoxin. Conversely, the adequacy of preparation could be assessed by the response to a standard dose of endotoxin measured by the degree of intravascular clotting induced and the incidence of cortical necrosis of the kidneys.In 1952 THOMAS and GOOD reported that the GSR could be produced by a single injection of Serratia marcesens or meningococcus endotoxin if rabbits were pre-treated with ACTH or cortisone. It was the purpose of the present investigations to compare the degree of preparation induced by cortisone and by Thorotrast with that induced by E. coli endotoxin employing a provocative dose of endotoxin which had heen shown capable of inducing intravascular clotting and cortical necrosis of the kidneys in adequately prepared rabbits.Rabbits were pre-treated with cortisone 25 mg IM for four days and given a single dose of endotoxin on the third day according to the regimen of THOMAS and GOOD. With provocation using the standard dose of endotoxin (0.100 mg/kg), renal cortical necrosis was not observed in any of 20 animals. In contrast this same provocative dose induced renal cortical necrosis in 74 and 77 % of animals prepared with 0.01 and 0.1 mg/kg of endotoxin. With the same regimen of cortisone preparation provocative doses of endotoxin of 0.2 and 0.5 mg/kg likewise failed to induce cortical necrosis. With a provocative dose of 1.0 mg/kg two of fifteen animals developed cortical necrosis of the kidneys. Five animals receiving 2.0 mg/kg of endotoxin exhibited no GSR. With cortisone preparation of I00 and 250 mg/day for four days provocation with 1.0 mg/kg of endotoxin resulted in cortical necrosis in only 1 of 6 animals in each group (table I). Coagulation studies were carried out in animals prepared with cortisone, 25 mg/day for four days, and provoked with the standard dose of endotoxin of 0.1 mg/kg. Significant decreases were noted in white cells, platelets, Factors II and VIII, but no significant changes occurred in Factor V or fibrinogen concentrations (table II). These changes are almost identical to those found with saline preparation.Thorotrast was given to eleven rabbits in a dose of 3.0 ml/kg intravenously and eighteen hours later 0.1 ml/kg of endotoxin was given. Five of the animals developed cortical necrosis of the kidneys. With Thorotrast preparation the coagulation mechanism was activated in its entirety, with highly significant falls in all of the measured coagulation factors observed (table III).Conclusions: Cortisone preparation, even in doses ten times those employed by THOMAS and GOOD did not lead to development of intravascular clotting or cortical necrosis of the kidneys following a single injection of E. coli endotoxin. This held true even when the provocative dose of endotoxin was raised to ten times the standard dose or forty times the minimum effective dose with endotoxin preparation. Thorotrast preparation, on the other hand, was followed by intravascular clotting and cortical necrosis of the kidneys as response to a single injection of endotoxin in the standard amount.Speculation: The ability to prepare animals for intravascular clotting and the development of the generalized Shwartzman phenomenon does not seem to be an inherent property of cortisone but appears to be dependent upon the type of endotoxin used in provocation. The implications that others have drawn from the data of THOMAS and GOOD that the use of cortisone may be hazardous in treatment of Shwartzman-like clinical conditions in the human appear to be premature in the present state of knowledge.