EARLY AND CONCOMITANT ADMINISTRATION OF NOREPINEPHRINE AND ILOMEDIN IMPROVES MICROCIRCULATORY PERFUSION WITHOUT IMPAIRING MACROCIRCULATION IN AN INTESTINAL ISCHEMIA-REPERFUSION INJURY SWINE MODEL: A RANDOMIZED EXPERIMENTAL TRIAL

ABSTRACT Background: Intestinal ischemia-reperfusion injury is associated with both macrocirculatory and microcirculatory failure. Association of a vasoconstrictor in combination with a vasodilator such as ilomedin may improve macrocirculation parameters, microcirculation perfusion and reduce endothelial dysfunction. The primary objective was to demonstrate a difference in mean arterial pressure (MAP) after intestinal reperfusion with the concomitant administration of norepinephrine and ilomedin during ischemia compared with traditional hemodynamic treatment strategies (fluid resuscitation and vasopressors only). Secondary objectives were to demonstrate an improvement in peripheral and intestinal microcirculatory perfusion and endothelial dysfunction after intestinal reperfusion using this association. Methods: We conducted a randomized preclinical trial in 21 large white pigs, in which a 2-h small bowel ischemia was performed using a segmental mesenteric occlusion model, followed by a 2-h reperfusion. Pigs were randomized into the following three groups: goal-directed fluid therapy, early administration of norepinephrine before reperfusion and early administration of ilomedin and norepinephrine before reperfusion. Macrocirculatory (MAP and Cardiac Index (CI), microcirculatory (Sublingual with SideStream Dark Field system and intestinal hemoglobin oxygen saturation with hyperspectral imaging) measurements and biological analysis (biomarkers of endothelial dysfunction) were performed. Results: There were no significant differences in the MAP ( P = 0.499) and the CI ( P = 0.659) between the three groups. Perfused vessel density in sublingual microcirculation was significantly higher immediately after reperfusion and 2 h after reperfusion in the early administration of ilomedin and norepinephrine group compared with the other two groups ( P < 0.05). Hemoglobin oxygen saturation measured at the intestinal level was significantly higher immediately after reperfusion in the early administration of ilomedin and norepinephrine group compared with the other two groups ( P < 0.01). There were no significant differences in biomarkers of endothelial dysfunction between the three groups. Creatinine, AST and alkaline phosphatases increased significantly 2 h after reperfusion in the early administration of ilomedin and norepinephrine group compared with baseline ( P < 0.05). Conclusions: Early administration of norepinephrine and ilomedin during ischemia improved short-term postreperfusion sublingual and intestinal microcirculation without worsening macrocirculatory parameters in an intestinal ischemia-reperfusion injury model. However, use of this strategy seemed to worsen both liver and kidney function.