Milrinone and levosimendan improve microvascular perfusion in septic rats: a randomized, placebo-controlled trial

Microcirculatory dysfunction is a key pathophysiological feature of sepsis and contributes to organ failure and mortality. In the gastrointestinal tract, impaired barrier function due to microcirculatory injury promotes translocation of inflammatory mediators and bacteria, worsening systemic inflammation and multiorgan dysfunction. Inotropic and vasoactive agents may improve microvascular perfusion through vasodilation in addition to their inotropic effects. Milrinone, a phosphodiesterase-3 inhibitor, and levosimendan, a calcium sensitizer, have shown promising but inconsistent effects in sepsis, while data on their direct microcirculatory and mitochondrial effects in abdominal organs remain limited. Sub-therapeutic vasopressin has demonstrated beneficial effects on gut microcirculation in experimental models, but its combination with inotropes has not been investigated. We hypothesized that (1) milrinone and levosimendan increase colonic and hepatic microvascular blood flow and oxygenation, (2) adjunctive low-dose vasopressin further enhances gastrointestinal microcirculation, and (3) mitochondrial respiration does not differ between treatment groups.

Male Wistar rats (n = 105) underwent colon ascendens stent peritonitis (CASP) or sham surgery to induce moderate sepsis. Twenty-four hours later, animals received intravenous infusions of vehicle, milrinone, levosimendan, or the respective inotrope with low-dose vasopressin. Colonic and hepatic microvascular oxygenation and blood flow were assessed using tissue-reflectance spectrophotometry and laser Doppler flowmetry. Mitochondrial respiration in colonic and hepatic tissue homogenates from septic animals was analyzed by respirometry. Statistical analyses included mixed-effects models with Tukey or Dunnett post-hoc tests and Kruskal-Wallis tests with Dunn's correction, using a two-sided significance level of α = 0.05.

In septic animals, milrinone and levosimendan increased colonic and hepatic microvascular blood flow. With adjunctive vasopressin, colonic perfusion remained increased, whereas hepatic blood flow did not increase. Microvascular oxygenation remained unchanged in both organs. In sham-operated animals, microvascular blood flow and oxygenation did not differ between treatment groups. Mitochondrial respiration in colon and liver was unchanged across treatments, as indicated by respiratory control index and ADP/O ratio.

In experimental abdominal sepsis, milrinone and levosimendan increase colonic and hepatic microvascular blood flow without affecting mitochondrial respiration. Adjunctive vasopressin alters hepatic but not colonic microvascular responses during combined inotropic therapy.