The generalized Shwartzman reaction is produced experimentally by intravenous administration of two successive doses of endotoxin derived from Gramnegative micro-organisms, spaced approximately 24 hours apart, in susceptible animals, such as rabbits and rats. The initial or preparatory injection of endotoxin given to the animals in producing the generalized Shwartzman reaction can be substituted by administration of reticuloendothelial blocking agents, such as trypan blue, thorotrast, cortisone, and ethyl stearate. Such blocking is also observed in pregnancy. The fundamental pathological change of this interesting but pathogenetically complicated generalized Shwartzman reaction is formation of glomerular fibrin thrombi and renal cortical necrosis. There have been many studies on the prevention of Shwartzman reaction during the past two decades and a variety of preventive agents have been introduced, namely, nitrogen mustard, aminopyrine, dibenamine, streptokinanse, sodium warfarin, hirudin, and heparin. Among the variable results, aminopyrine and heparin were found to be effective to prevent the localized and classical generalized Shwartzman reaction. There has been no report on the inhibitory effect ofheparin on the generalized Shwartzman reaction induced in pregnant rabbits or in the human counterpart. The latter has been reported recently in abortions, predominantly of a criminal nature, with a fatal outcome resulting from the generalized Shwartzmanreaction induced by gram-negative organisms. This investigation is an attempt to evaluate the inhibitory effect of aminopyrine on the generalized Shwartzman reaction induced by a classicaltwo-dose intravenous
injection of E. coli endotoxin into non-pregnant rabbits and that of heparin on the generalized Shwartzman reaction induced by a single intravenous, injection of E. coli endotoxin in pregnant rabbits.
Fifty-two albino rabbits were used in this study,-divided into 3 groups.
Group 1. Twenty non-pregnant rabbits of both sexes were used to determine the endotoxin doses necessary to induce classical generalized Shwartzman reaction by giving two successive intravenous injections, 24 hours apart. Four out of 20 animals were-designated to decide the optimal doses of E. coliendotoxin that can produce the expected generalized. Shwartzman reaction.
Group 2. Twelve non-pregnant rabbits of both sexes were used to evaluate an inhibitory effect of aminopyrine on generalized Shwartzman reaction. The animals were subdivided into an aminopyrine group and a control group. First, the animals of aminopyrine group, 10.0, 0.3 and 0.25 mg. of aminopyrine were administered intravenously 40 minutes before provocative injection of endotoxin. Second, the control group animals were given a two-dose intravenous injection of endotoxin in the same manner that is described in group 1.
Group 3. To observe the preventive effect of heparin against an incipient generalized Shwartzman reaction, 20 pregnant rabbits were used. They were subdivided into a heparin group and a control group. The animals of the control group were given a single intravenous injection of E. coli endotoxin and those of the heparin group were treated as follows: ⓐ An intravenous injection of heparin, simultaneously with the E. coli endotoxin injection. ⓐ An intravenous injection of heparin 2 hours later. ⓑ An intravenous in jection of heparin 4 hours. later.
The results were as follows:
Group 1. The optimal doses of endotoxin that can induce generalized Shwartzman reaction were varied from 2.5 to 4.2 mg. Thirteenout of 16. animals (81%) revealed fibrin thrombi in the glocapillaries and of these, 5 animals (31%) bilateral cortical necrosis occurred. Fibrin thrombi were also observed in the pulmonary capillaries in 12 (75%) of these animals.
Group 2. Aminopyrine failed to demonstrate an inhibitory effect on the generalized Shwartzman reaction, contrary to previous reports that it is capable of preventing Shwartzman reaction of a localized form.
Group 3. Generalized Snwartzman reaction was induced with E. coli endotoxin of 3.5, 3.6 and 5.4mg. given as a single provocative intravenous injection. into the pregnant rabbits in the control group. The counterpart, heparin treated animals, failed to show any evidence of morphological change that can be construed to be a phenomenon of a generalized Shwartzmart reaction. The fall of fibrinogen level in this control group with generalized Shwartzman reaction seems to be in keeping with the concept that intravenous coagulation plays an important role in the pathogenesis of this reaction.
It can be concluded, therefore:
1. Optimal doeses of E. coli endotoxin which induce generalized Shwartzman reaction in non-pregnant rabbits can be varied from 2.5 to 4.2 mg.
2. Aminopyrine which is known to prevent local Shwartzman reaction failed to inhibit generalized Shwartzman reaction in non-pregnant rabbits.
3. Generalized Shwartzman reaction was produced in pregnant rabbits of the control group by a single intravenous injection of E. coli endotoxin and the reaction that was produced in the above was prevented when the animals were treated with heparin. A fall in the fibrinogen level of the pregnant rabwith generalized Shwartzman reaction in the control group appears to be well correlated with the intravenous coagulation phenomenon that took place in the above reaction.
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