Aprotinin Prevents the Development of the Trauma-Induced Multiple Organ Failure in a Chronic Sheep Model

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Abstract
Trauma-induced multiple organ failure in sheep was prevented by aprotinin therapy. Multiple organ failure was induced in 16 female merino sheep by initial haemorrhagic shock and intramedullary femoral nailing (day 0), and 12 hourly injections of 0.75 micrograms/kg Escherichia coli endotoxin +0.7 ml/kg zymosan-activated plasma (days 1-5). In addition, the aprotinin group (n = 6) received simultaneous injections of 5 mg/kg (35 695 KIU/kg) aprotinin, whereas ten animals did not receive aprotinin and served as the control group (n = 10). Organ functions were monitored for a total of 11 days by measuring haemodynamic, cardio-respiratory and biochemical quantities of blood, urine and epithelial lining fluid. During the subsequent eleven day period, aprotinin induced a significant (p < 0.05) reduction of the pathological changes (development of multiple organ failure) seen in the control group. Thus, aprotinin prevented an alteration of cardiac function (cardiac index for control/aprotinin groups at day 1: 6.5/6.2, and at day 10: 10.47/7.0 1/min x m2), an impairment of lung function (mean pulmonary arterial pressure at day 1: 2.26/1.86, and at day 10: 3.83/2.13 kPa; epithelial lining fluid/plasma ratio of albumin concentrations as a direct marker of lung capillary permeability damage at day 0: 0.18/0.16, and at day 10: 0.45/0.15), a deterioration of liver function (plasma sorbitol dehydrogenase at day 0: 7.9/7.6, and at day 10: 29.6/7.4 U/1), but not of renal function (creatinine clearance at day 1: 91.4/66.1, and at day 10: 53.1/59.2 ml/min). Urinary aprotinin excretion increased up to day 3, then decreased rapidly despite further aprotinin administration. As a non-specific marker of cell damage, plasma lactate dehydrogenase indicated an aprotinin-induced organ protection (day 0: 501/409, and at day 10: 719/329 U/1). The neutrophil count and the measured chemiluminescence of neutrophils from the blood and epithelial lining fluid showed that aprotinin reduced the in vivo neutrophil activation, the alveolar neutrophil invasion, the production of inflammatory mediators, and the production of reactive oxygen metabolites during the passage of the capillary-interstitial-alveolar space by neutrophils.