Sublingual Microcirculatory Effects of Enalaprilat in an Ovine Model of Septic Shock

Severe sepsis is frequently associated with microcirculatory abnormalities despite seemingly adequate hemodynamic resuscitation. As increased serum angiotensin II levels may play a role in this dysfunction, we evaluated the microcirculatory effects of enalaprilat in an experimental model of septic shock. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, 16 adult female anesthetized, mechanically ventilated sheep were randomized to receive 2.5 mg enalaprilat or saline. When fluid-resistant hypotension (mean arterial pressure, <65 mmHg) developed, norepinephrine was given up to a maximal dose of 3 μg·kg(-1)·min(-1). The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. A cutoff of 20 μm was used to differentiate small and large vessels. Experiments were pursued until the sheep's spontaneous death or for a maximum of 30 h. There were progressive and significant reductions in the proportion of small perfused vessels and in the microvascular flow index for small vessels (both P < 0.01 for trend) during shock and the first 2 h of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat. There were no differences between treated and placebo groups in global hemodynamic variables, time to shock or median survival time (21.8 [18.6-28.8] vs. 22.9 [21.8-30.0] h; P = 0.45). However, oxygen exchange was worse (PaO2/FiO2 ratio, 224 [128-297] vs. 332 [187-450]; P < 0.05), and creatinine concentrations increased more in the treated group (from 0.51 [0.42-0.75] to 1.19 [0.64-1.50] mg·dL(-1); P = 0.04) than in the control group (from 0.55 [0.45-0.62] to 0.78 [0.46-1.78] mg·dL(-1); P = 0.12), Enalaprilat therefore prevented the worsening of sublingual microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock, without significant effect on arterial pressure, but with a possible deleterious effect on renal and lung function.