A Randomized Porcine Study in Low Cardiac Output of Vasoactive and Inotropic Drug Effects on the Gastrointestinal Tract

Abstract

Background: Splanchnic vasodilation by inodilators is an argument for their use in critical cardiac dysfunction. To isolate peripheral vasoactivity from inotropy, such drugs were investigated, and contrasted to vasopressors, in a fixed low cardiac output (CO) model resembling acute cardiac dysfunction effects on the gastrointestinal tract. We hypothesized that inodilators would vasodilate and preserve the aerobic metabolism in the splanchnic circulation in low CO.

Methods: In anesthetized pigs, CO was lowered to 60% of baseline by partial inferior caval vein balloon inflation. The animals were randomized to placebo (n = 8), levosimendan (24 μg kg-1 bolus, 0.2 μg kg-1 min-1, n = 7), milrinone (50 μg kg-1 bolus, 0.5 μg kg-1 min-1, n = 7), vasopressin (0.001, 0.002 and 0.006 U kg-1 min-1, 1 h each, n = 7) or norepinephrine (0.04, 0.12, and 0.36 μg kg-1 min-1, 1 h each, n = 7). Hemodynamic variables including mesenteric blood flow were collected. Systemic, mixed-venous, mesenteric-venous, and intraperitoneal metabolites were analyzed.

Results: Cardiac output was stable at 60% in all groups, which resulted in systemic hypotension, low superior mesenteric artery blood flow, lactic acidosis, and increased intraperitoneal concentrations of lactate. Levosimendan and milrinone did not change any circulatory variables, but levosimendan increased blood lactate concentrations. Vasopressin and norepinephrine increased systemic and mesenteric vascular resistances at the highest dose. Vasopressin increased mesenteric resistance more than systemic, and the intraperitoneal lactate concentration and lactate/pyruvate ratio.

Conclusion: Splanchnic vasodilation by levosimendan and milrinone may be negligible in low CO, thus rejecting the hypothesis. High-dose vasopressors may have side effects in the splanchnic circulation.

Fig. 1

Animal inclusion by randomization and animal exclusions in the different study groups.

Fig. 2

Cardiac indices in animals subjected to partial inflation of an occlusion balloon in the inferior caval vein immediately after time point 0 h. Starting at 1 h, the animals were randomized to intravenous infusion of either placebo (5% glucose, 0.2 mL kg⁻¹ h⁻¹), vasopressin (0.001 U kg⁻¹ min⁻¹ for the first hour, 0.002 U kg⁻¹ min⁻¹ for the second hour, and 0.006 U kg⁻¹ min⁻¹ for the last hour), norepinephrine (0.04 μg kg⁻¹ min⁻¹ for the first hour, 0.12 μg kg⁻¹ min⁻¹ for the second hour, and 0.36 μg kg⁻¹ min⁻¹ for the last hour), levosimendan (bolus 24 μg kg⁻¹ in 10 min, thereafter continuous infusion of 0.2 μg kg⁻¹ min⁻¹) or milrinone (bolus 50 μg kg⁻¹ in 10 min, thereafter continuous infusion of 0.5 μg kg⁻¹ min⁻¹). Data are presented as means and 95% confidence intervals. See Figure 1 for the exact number of animals in each group at each time point.

Fig. 3

Mean arterial pressure (MAP, panel A), mesenteric and systemic vascular resistance indices, and their ratio (MVRI, panel D; SVRI, panel B; MVRI/SVRI ratio, panel F), superior mesenteric artery blood flow (SMA flow, panel C), and heart rate (panel E) in animals subjected to partial inflation of an occlusion balloon in the inferior caval vein immediately after time point 0 h. Starting at 1 h, the animals were randomized to intravenous infusion of either placebo (5% glucose, 0.2 mL kg⁻¹ h⁻¹), levosimendan (bolus 24 μg kg⁻¹ in 10 min, thereafter continuous infusion of 0.2 μg kg⁻¹ min⁻¹) or milrinone (bolus 50 μg kg⁻¹ in 10 min, thereafter continuous infusion of 0.5 μg kg⁻¹ min⁻¹). ^a: statistical difference between the indicated time point and baseline in the placebo group. Data are presented as means and 95% confidence intervals. See Figure 1 for the exact number of animals in each group at each time point.

Fig. 4

Mean arterial pressure (MAP, panel A), mesenteric and systemic vascular resistance indices, and their ratio (MVRI, panel D; SVRI, panel B; MVRI/SVRI ratio, panel F), superior mesenteric artery blood flow (SMA flow, panel C), and heart rate (panel E) in animals subjected to partial inflation of an occlusion balloon in the inferior caval vein immediately after time point 0 h. Starting at 1 h, the animals were randomized to intravenous infusion of either placebo (5% glucose, 0.2 mL kg⁻¹ h⁻¹), vasopressin (0.001 U kg⁻¹ min⁻¹ for the first hour, 0.002 U kg⁻¹ min⁻¹ for the second hour, and 0.006 U kg⁻¹ min⁻¹ for the last hour) or norepinephrine (0.04 μg kg⁻¹ min⁻¹ for the first hour, 0.12 μg kg⁻¹ min⁻¹ for the second hour, and 0.36 μg kg⁻¹ min⁻¹ for the last hour). ^a: statistical difference between the indicated time point and baseline in the placebo group. ^b and ^c: statistical difference between the norepinephrine or vasopressin and placebo group, respectively, at the indicated time points. Data are presented as means and 95% confidence intervals. See Figure 1 for the exact number of animals in each group at each time point.