Effect of nonsteroidal anti-inflammatory drugs in endotoxin shock

Abstract

Our interest in the nonsteroidal anti-inflammatory drugs was generated by reports that described blocking of the effects of bradykinin and the inhibition of kallikrein by these agents. Since plasma kinins are released during shock, these drugs were tested in this pathological condition. Although, on closer inspection, the antibradykinin effect turned out to be rather unspecific in most tests and the significance of kinin release during shock can be questioned, administration of nonsteroidal anti-inflammatory drugs protects dogs against the effects of injected endotoxin. This was proved by Hinshaw, Erdös, and collaborators in 200 dogs. They pretreated dogs with acetylsalicylic acid, indomethacin, or phenylbutazone. The animals were subsequently shocked by i.v. injection of a ld 80 dose of Escherichia coli endotoxin. Injection of endotoxin to dogs elicits a biphasic hemodynamic response. Immediately after the injection, the mean systemic arterial blood pressure decreases for a short time and then increases; this is followed by a longer lasting hypotension in the second phase of shock. The first decrease in systemic arterial blood pressure in shock is explained by hepatic pooling of blood as indicated by the increasing portal venous pressure. Aspirin blocked both the primary and the secondary decrease in mean systemic arterial blood pressure and the increase in portal venous pressure in the shocked animals. Pretreatment with aspirin also significantly increased the rate of survival. The administration of indomethacin or phenylbutazone led to somewhat different results. Indomethacin diminished the decrease in blood pressure in the first phase of shock but did not block the increase in portal venous pressure. After this short period of hypotension, the dogs treated with indomethacin maintained a normal blood pressure for the duration of the experiments, in contrast to the control group. Phenylbutazone, in a smaller number of studies, protected the animals in the second phase of shock only. Although all three drugs used in these studies abolished the hypotension in the second phase of shock, their modes of action on the splanchnic circulation might be different.