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Introduction

The liver is essential for bacterial elimination, preventing intestinal bacteria from entering the systemic circulation, and for producing inflammatory cytokines. Glucocorticoids have been reported to exert heterogeneous effects on bacterial clearance in sepsis. Using a porcine model of gram-negative abdominal sepsis, we investigated how portal venous administration of budesonide, a glucocorticoid with extensive hepatic first-pass metabolism, affects hepatic bacterial and endotoxin elimination as well as the systemic inflammatory response, in comparison with systemic administration and no treatment.

Methods

The Portal Steroid-Sepsis (Sep-Port, n = 8) and Systemic Steroid-Sepsis (Sep-Syst, n = 8) groups were administered budesonide in the portal vein or systemically, followed by an E. coli infusion for 3 h in the portal vein. The Septic Controls (Sep-Ctrl, n = 8) received saline instead of budesonide. Non-septic Controls (NSep-Port, n = 3) were treated only with portal budesonide. Portal, arterial, and hepatic venous bacterial counts were analyzed hourly during the bacterial infusion. The levels of endotoxin and inflammatory cytokines were measured.

Results

There was no difference in hepatic/portal venous bacterial count ratios. However, the arterial and hepatic venous bacterial counts were higher in the Sep-Syst compared to Sep-Port group (p < 0.001 and p < 0.01, respectively), while microbiological findings were similar in the Sep-Port and Sep-Ctrl groups. Hepatic endotoxin elimination did not differ between the groups. IL-10 levels were higher in the Sep-Port compared to the Sep-Syst group at 1 h (p < 0.01), and IL-6 levels were lower in the Sep-Port compared to the Sep-Ctrl after the bacterial infusion (p < 0.05).

Conclusions

In this experimental sepsis model, hepatic bacterial elimination was unaffected by portal or systemic budesonide, whereas systemic administration was associated with increased systemic bacterial levels. Endotoxin clearance was unaffected by budesonide. Portal budesonide elicited a more pronounced anti-inflammatory response compared to systemic administration. These findings suggest that hepatic exposure to budesonide may modulate the inflammatory response while limiting adverse effects on systemic bacterial clearance.

Editorial Comment

Glucocorticoids are widely used in sepsis management, yet their effects on bacterial clearance is incompletely understood. In this porcine model of gram-negative abdominal sepsis, portal venous delivery of budesonide (which has ~90% hepatic first-pass metabolism) preserved bacterial elimination and enhanced the early anti-inflammatory response, without the increase in systemic bacterial levels seen with systemic administration. These results demonstrate that route of delivery as a potentially important determinant of the risk-benefit balance of glucocorticoid therapy in sepsis, and support further investigation of hepatic-targeting strategies.