Regional release of tissue-type plasminogen activator in sepsis: effects of volume resuscitation

Background

Septic shock is characterised by increased systemic fibrinolytic activity. This study in endotoxemic pigs was designed to: 1) describe regional tPA (tissue-type plasminogen activator) activity; 2) assess changes in tPA activity following aggressive volume resuscitation.

Materials and methods

Anesthetised, mechanically ventilated pigs (24–29 kg) were instrumented to monitor cardiac output (CO), portal- (Q_MES), hepatic- (Q_HEP), and renal (Q_REN) blood flow. Aortic arterial and renal, portal and hepatic venous blood samples were collected. Total tPA (ng/ml) in plasma was analysed by ELISA and together with blood flow data enabled the calculation of net flux of tPA across the pulmonary (PULM), mesenteric (MES), hepatic (HEP) and renal (REN) circulation. Following baseline sampling, endotoxin (E. Coli 0111:B4) was infused for 2 hours. Animals were then volume resuscitated with albumin and saline and observed another 3 hours. Statistical analyses were made by ANOVA and Fisher's PLSD. ^*P < 0.05. Values are mean ± SEM, n = 8.

Results

CO decreased from 4.1 ± 0.3 l/min to 2.7 ± 0.1^* during sepsis and was restored to 4.7 ± 0.1 by volume resuscitation. Parallel changes were observed in Q_MES from 0.9 ± 0.1 l/min to 0.5 ± 0.1^*, and back to 1.1 ± 0.2) and Q_REN (from 135 ± 15 ml/min, to 62 ± 20^*, and back to 124 ± 25). Q_HEP was maintained at 1.1 ± 0.1 to 1.3 ± 0.1 l/min by an effective hepatic arterial buffer response. Net regional plasma fluxes of tPA are shown in the Table.

Table

Conclusions

Fibrinolytic activity increases early in sepsis shown by a net pulmonary and mesenteric release of tPA. Increased net hepatic uptake would mask the pre-hepatic changes in tPA. Early volume resuscitation in sepsis is able to completely reverse all these changes. The findings demonstrate the dynamics of hemostasis during sepsis. Early interventions to restore hemodynamic stability are important to maintain normal fibrinolytic activity.