Microcirculatory effects of enalaprilat in an ovine model of severe sepsis

AbstractINTRODUCTION. Patients with severe sepsis present high levels of angiotensin II (ang II), a hormone with vasoactive, proinflammatory, and procoagulant properties. Despite seemingly adequate hemodynamic resuscitation, microcirculatory abnormalities are frequently observed. Increased serum levels of ang II may play a role in this microcirculatory dysfunction during severe sepsis.OBJECTIVES. To evaluate the microcirculatory effects of enalaprilat in an experimental model of severe sepsis.METHODS. Prospective, randomized, double-blind, placebo controlled study including 16 adult female anesthetized, mechanically ventilated sheep. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, animals were randomized to receive either enalaprilat 2.5 mg or saline. A combination of Ringer's lactate (RL) and hydroxyethyl starch solutions was titrated to prevent hypovolemia. When fluid-resistant hypotension (MAP < 65 mmHg) developed, the animals were given norepinephrine up to a maximal dose of 3 µg/kg/min. The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy (Microscan, MicroVision Medical) at baseline (just before feces injection), before drug administration, before norepinephrine infusion (shock), and after the 1st and 2nd hour of norepinephrine infusion. Capillary density, proportion of perfused vessels, and microvascular flow index (MFI) were calculated. A cut-off of 20µm was used to differentiate small and large vessels. Experiments were pursued until the sheep's spontaneous death or a maximum of 30 hours. Results are presented as mean±SE.RESULTS. There were progressive and significant reductions in the proportion of small perfused vessels (p=0.006 for trend) and in the MFI (p=0.003 for trend) during shock and the first 2 hours of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat (p=0.83 and p=0.85 for trend in the proportion of small perfused vessels and MFI, respectively) (Figure). There were no differences between treated and placebo groups in global hemodynamic variables, time to shock (18.1±2.4 hours vs 17.6±2.1 hours, p=1.0) or median survival time (23±1.7 hours vs 24±1.9 hours, p=0.49). However creatinine concentrations increased more in the treated group (from 0.60±0.09 to 1.15±0.19, p=0.04) than in the control group (from 0.62±0.10 to 1.01±0.23, p=0.12).[figure]CONCLUSIONS. Enalaprilat prevented the worsening of microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock without significant effect on arterial pressure, but possibly associated with an earlier impairment of renal function.