TREATMENT THE RESISTANT CASE Is there a place for proteinase inhibition? A review of the literature

The evidence demonstrating excessive proteinase activity in states of shock is reviewed. The capacity of extrinsic inhibitors to control such activity is indicated and the literature showing the value of inhibitors in treating shock is summarized. Three principles to be observed in the use of exogenous inhibitors are proposed. PROTEINASE is the generic term for proteolytic enzymes. Proteolysis occurs in the processes of digestion and during autolysis. In more controlled form, it is the basis of certain homeostatic processes in which the proteinases are activators and pro-activators, the control being exercised by inhibitor systems. In disease or following trauma, the activity of these systems increases as an essential part of the attempt to restore the physiological state. This is desirable, but on occasion activity increases to an extent which overwhelms the intrinsic inhibitor mechanisms. This is highly undesirable as it results, separately or in combination, in acute haemostatic defects, intravascular coagulation, redistribution of the blood volume and, as a result, in profound disturbances of haemodynamics which contribute to inadequate tissue perfusion. In such circumstances of excessive, harmful proteinase activity, the temporary redress of the disturbed intrinsic balance by the administration of exogenous proteinase in-hibitors would be a desirable therapeutic step. Many such extrinsic inhibitors, ranging from aspirin to certain amino acids, are available and they have been reviewed by Back (1966). Their very varied activity has been analysed, with particular reference to fibrinolysis, by McNicol & Douglas (1964) who showed that only six are of practical value: s-Amino caproic acid (EACA). Tranexamic acid. 1-(Aminomethyl)cyclohexane-4-carboxylic acid (AMCHA). p-Aminomethyl benzoic acid (PAMBA). Parotid proteinase inhibitor (Trasylol). Pancreatic proteinase inhibitor (Iniprol). Of these, only EACA and parotid proteinase inhibitor appear sufficiently frequently in the literature to warrant review. In order to present the evidence for the involvement of proteinase systems in the state of shock and to examine the value of extrinsic inhibition in controlling those systems and in treating shock, the three hinted at above, namely coagulation, fibrino-lysis and vasoactivity, will be considered. Hardaway (1965) and his group of workers (Rutherford, West & Hardaway, 1966) have shown that intravascular coagulation is a feature of haemorrhagic, endotoxin and traumatic shock; Nordstrom, Olsson & Blom-back (1965) have demonstrated increased circulating thromboplastin after surgery and shown experimentally that equivalent levels lead to massive intra-vascular thrombus formation; such thrombi have been observed by electron microscopy in endotoxin shock by McKay, Margaretten & Csavossy (1967). The anticoagulant …