Andersson Andreas, Fenhammar Johan, Frithiof Robert, Weitzberg Eddie, Sollevi Alf, Hjelmqvist Hans
Department of Anaesthesiology & Intensive Care, Karolinska University Hospital Huddinge, Sweden.
J Surg Res. 2008 Sep;149(1):138-47. doi: 10.1016/j.jss.2007.12.751. Epub 2008 Jan 11.
Microcirculatory dysfunction is a common feature of sepsis. The potent vasoconstrictor endothelin (ET) is released in sepsis and endotoxemia, potentially contributing to sepsis-induced microcirculatory failure. In this study we tested the hypothesis that mixed ET receptor antagonism with tezosentan would improve splanchnic microcirculatory blood flow in acute porcine endotoxemia.
Sixteen anesthetized and mechanically ventilated pigs received an infusion of endotoxin for 300 min. After 120 min eight pigs received a bolus dose of tezosentan 1 mg/kg followed by an infusion of tezosentan of 1 mg/kg/h throughout the experiment. Eight pigs served as endotoxin controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and in the ileal and colon mucosa. PCO(2) in the ileal mucosa was measured by air tonometry and portal vein flow by an ultrasonic flow probe.
Endotoxin administration induced a state of shock with impaired splanchnic microcirculatory blood flow. Microcirculation in the mucosa of the colon and ileum and mucosal-arterial PCO(2) gap were improved by tezosentan. Portal vein flow was increased, but hepatic microcirculatory blood flow was not significantly improved. Tezosentan preserved cardiac index and decreased pulmonary capillary wedge pressure compared to controls, without causing any differences in the heart rate or mean arterial blood pressure response. Tezosentan also distinctly improved pH and arterial lactate values.
The findings of this study indicate that ET is involved in the microcirculatory dysfunction seen in the ileal and colon mucosa in early endotoxemia. Moreover, this detrimental effect was counteracted by i.v. administration of the mixed ET receptor antagonist tezosentan.
微循环功能障碍是脓毒症的常见特征。强效血管收缩剂内皮素（ET）在脓毒症和内毒素血症中释放，可能导致脓毒症诱导的微循环衰竭。在本研究中，我们检验了以下假设：使用替唑生坦进行混合ET受体拮抗作用可改善急性猪内毒素血症时的内脏微循环血流量。
16只麻醉并机械通气的猪接受了300分钟的内毒素输注。120分钟后，8只猪接受1mg/kg的替唑生坦静脉推注剂量，随后在整个实验过程中以1mg/kg/h的速度输注替唑生坦。8只猪作为内毒素对照组。使用激光多普勒血流仪测量肝脏、回肠和结肠黏膜的微循环血流量。通过气张力测量法测量回肠黏膜中的PCO₂，并通过超声血流探头测量门静脉血流量。
给予内毒素导致休克状态，内脏微循环血流量受损。替唑生坦改善了结肠和回肠黏膜的微循环以及黏膜-动脉PCO₂差值。门静脉血流量增加，但肝脏微循环血流量未得到显著改善。与对照组相比，替唑生坦维持了心脏指数并降低了肺毛细血管楔压，而在心率或平均动脉血压反应方面未引起任何差异。替唑生坦还显著改善了pH值和动脉血乳酸值。
本研究结果表明，ET参与了早期内毒素血症时回肠和结肠黏膜中所见的微循环功能障碍。此外，静脉注射混合ET受体拮抗剂替唑生坦可抵消这种有害作用。
