EFFECTS OF ANTI-C5A MONOCLONAL-ANTIBODIES ON OXYGEN USE IN A PORCINE MODEL OF SEVERE SEPSIS

Methods We analysed the effects of complement depletion and of C5a inh ibition on haemodynamic parameters, oxygen delivery (Do(2)), oxygen co nsumption (Vo(2)), oxygen extraction ratio (OER) and blood lactate lev els after live bacteria infusion in pigs. Results In the first series of experiments, animals were decomplemented by cobra venom factor (CVF ; 125 mu g kg(-1)) and challenged with 1.3 x 10(9) Escherichia coli kg (-1). In a second series, animals were treated with neutralizing anti- C5a monoclonal antibodies (mAb) T13/9 before infusion of an increased E. coli dosage (1 x 10(10) E. coli kg(-1)). Administration of Gramnega tive bacteria resulted in hypotension, tachycardia, pulmonary hyperten sion and decreased cardiac output typical for severe sepsis. These alt erations were more pronounced in animals challenged with a higher bact eria concentration (1 x 10(10) E. coli kg(-1), n = 5) than with a lowe r dosage (1.3 x 10(9) E. coil kg(-1), n = 4). Complement depletion by CVF injection 24 h before E. coli infusion (n = 4), or anti-C5a mAb T1 3/9 administration (It = 4) had no effect on the changes in haemodynam ic parameters and in Do(2) associated with E. coli challenge. Applicat ion of either 1.3 x 10(9) or 1 x 10(10) E. coli kg(-1) resulted in a m arked decrease in Vo(2) and an increase in blood lactate levels, where as the OER did not change throughout the experiment. In contrast, pret reatment with CVF 24 h before low-dose E. coti (1.3 x 10(9) kg(-1)) ad ministration resulted in a significant increase in Vo(2) (P < 0.05) an d in OER (P < 0.05) compared with untreated septic animals (n = 4). No hyperlactaemia occurred in complement-depleted septic animals compare d with complement-sufficient animals (P < 0.05). Animals challenged wi th a high E. coli dose (1 x 10(1) kg(-1)) and treated with anti-C5a mA bs showed a pronounced increase in Vo(2) and OER (P < 0.05) accompanie d by an attenuated increase in lactate levels (P < 0.05) compared with untreated septic animals. Conclusion The results demonstrate an impro ved oxygen use after complement depletion in this model of severe Gram -negative sepsis. Furthermore, a similar effect was seen after specifi cally neutralizing C5a by mAbs, indicating a role of C5a in the underl ying mechanism.