Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock

Abstract

Introduction: The present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20% in the microvascular flow index of small vessels among groups.

Methods: The design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 μg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization.

Results: TP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 μg/kg/minute (0.29 to 1.04) vs. 0.16 μg/kg/minute (0.03 to 0.37) for TP and 0.40 μg/kg/minute (0.20 to 1.05) vs. 0.23 μg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7% (2.6 to 19.8) for TP, 8.9% (0.0 to 17.8) for AVP, and 6.9% (3.5 to 10.1) for placebo (P < 0.05 vs. baseline for each comparison), as well as perfused vessel density 18.6% (8.6 to 36.9) for TP, 20.2% (-3.0 to 37.2) for AVP, and 11.4% (-3.0 to 19.4) for placebo (P < 0.05 vs. baseline for each comparison).

Conclusions: The present study suggests that to achieve a MAP of 65 to 75 mmHg in septic patients treated with NE, the addition of continuously infused low-dose TP or AVP does not affect sublingual microcirculatory blood flow. In addition, our results suggest that microcirculatory flow abnormalities are mainly related to other factors (for example, volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se.

Trial registration: ClinicalTrial.gov NCT00995839.

Figure 1

Absolute changes in microcirculatory variables. AVP, arginine vasopressin; BL, baseline; DBS, De Backer Score; HI, heterogenity index; MFI, microvascular flow index of small vessels (Ø < 20 μm); NE, norepinephrine; CTRL, control; PPV, proportion of perfused vessels; PVD, perfused vessel density; TP, terlipressin; VD, vessel density. Solid lines, median; dashed lines, mean; boxes, 25th and 75th percentiles; whisker caps, 10th and 90th percentiles. ^aP < 0.05, ^aaP < 0.01, ^aaaP < 0.001 vs. BL; ^bP < 0.05 vs. CTRL.

Figure 2

Norepinephrine requirements. The upper panel shows norepinephrine (NE) infusion rates in the terlipressin (TP), arginine vasopressin (AVP) and control (CTRL) groups at baseline (BL) and at 6 hours. The lower panel shows relative NE changes (dNE) after 6 hours compared to baseline in each study group. Solid lines, median; dashed lines, mean; boxes, 25th and 75th percentiles; whisker caps, 10th and 90th percentiles. ^aaP < 0.01, ^aaaP < 0.001 vs. BL; ^bP < 0.05, ^bbbP < 0.001 vs. controls.

Figure 3

Relative changes in microcirculatory variables. Data represent relative changes from baseline (BL) at 6 hours. AVP, arginine vasopressin; dDBS, relative changes in De Backer Score; dHI, relative changes in heterogeneity index; dMFI, relative changes in microvascular flow index of small vessels (Ø < 20 μm); dPPV, relative changes in proportion of perfused vessels; dPVD, relative changes in perfused vessel density; dVD, relative changes in vessel density; CTRL, control; TP, terlipressin. Solid lines, median; dashed lines, mean; boxes, 25th and 75th percentiles; whisker caps, 10th and 90th percentiles.