Bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock

Introduction

Endothelin (ET), the most potent endogenous vasoconstrictor known, is highly produced in septic states. High plasma levels of ET are associated with morbidity and mortality in septic patients. Being a potent vasoactive peptide produced in sepsis, ET may be involved in the pathophysiology of the markedly deteriorated splanchnic circulation seen in septic shock. In this study, bosentan, a non-peptide mixed ET receptor antagonist was utilised in order to attenuate splanchnic blood flow disturbances and counteract intestinal mucosal acidosis in a porcine model of endotoxin shock.

Materials and methods

Sixteen landrace pigs were anesthetised and catheterised for monitoring of regional and central hemodynamics. A tonometer (sigmoid catheter, Tonometrics Inc, MA, USA) was introduced into the ileum and a magnetic flow probe placed around the portal vein. All animals received 20 ml/kg/h of Ringer's glucose throughout the experiment. After baseline measurements, onset of endotoxin challenge (20 μg/kg/h for 3 h) was followed by bosentan administration (n = 8) 2 h later. Eight animals receiving only endotoxin served as controls. The experiments were terminated 5 h after onset of endotoxin challenge.

Results and discussion

As endotoxin infusion reduced cardiac index and systemic oxygen delivery, bosentan treatment restored these parameters to baseline levels. The endotoxin-induced reduction in mean arterial blood pressure remained unaffected by bosentan. The profound reduction in gut oxygen delivery and portal blood flow in response to endotoxin was completely abolished by bosentan administration. Further, bosentan significantly improved a markedly reduced calculated pHi. The endotoxemia induced mucosal-arterial PCO₂ gap was also significantly reduced in response to bosentan administration. There were no apparent differences when monitoring tonometry data as calculated pHi or mucosal-arterial PCO₂ gap, in terms of significance between or within groups. The PCO₂ gap between the mucosa and portal vein was utilised as a monitor of the mucosa in relation to total portal drainage. The mucosal-portal PCO₂ gap was increased in response to endotoxin challenge, illustrating mucosal susceptibility to shock. Mucosal-portal PCO₂ gap was also reduced by bosentan.

Conclusion

Bosentan restored the markedly reduced gut oxygen delivery induced by endotoxin, in parallel with marked improvement of intestinal mucosal acidosis. These findings suggest that endothelin is involved in the microcirculatory disturbances of the gut in endotoxin shock. Bosentan may prove useful in reducing gut ischemia in septic shock conditions.