P4605Landiolol, a beta-blocker, optimizes cardiac energetics and peripheral microhemodynamics better than ivabradine while reducing heart rate at hemodynamic resuscitation of experimental septic shock

Background Septic shock is associated with sympathetic over-activation characterized by tachycardia, which is associated with poor survival. Though several kinds of drugs are available to reduce heart rate (HR), it is not clear which drug should be used to reduce HR effectively in initial hemodynamic resuscitation in septic shock. Purpose The aim of this study was to experimentally investigate comparative effects of landiolol (a β-blocker) and ivabradine (an If-channel inhibitor) on initial hemodynamic resuscitation in a canine model of endotoxin shock. Methods We used 19 anesthetized dogs. Seven dogs were allocated to control (CT) group, six dogs to landiolol (BB) group, and six dogs to ivabradine (IVA) group. In all the groups, endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide (4 mg/kg) over 1 h. After induction of endotoxin shock, we started hemodynamic resuscitation to restore mean arterial pressure (AP) and cardiac output (CO) by infusing noradrenaline (NA) and Ringer acetate solution (RiA). Dose of NA and RiA were automatically titrated with use of a computer-controlled drug infusion system that we developed previously. Hemodynamic resuscitation was continued for 4 h. During resuscitation, the BB group was given landiolol infusion at a low-dose range (1–10 μg/kg/min, manually titrated), while the IVA group was given ivabradine at 0.25 mg/kg bolus-injected every 2 h. Results The drug infusion system automatically restored AP to 70 mmHg and CO to greater than 90% of baseline level in all the groups. The restored AP and CO were not significantly different among the three groups (Figure A, B). There were no significant differences in the computer-controlled infusion rate of NA and cumulated volume of RiA infused among the three groups (Figure C). During the first 2 h of resuscitation, HR was significantly reduced in the BB and IVA groups in comparison to the CT group (Figure D). However, only in the BB group, cardiac oxygen consumption was significantly lower than that in the CT group (Figure E). Blood lactate level decreased significantly after hemodynamic resuscitation only within the BB group (Figure F). Figure 1 Conclusions In the initial hemodynamic resuscitation of septic shock, both low-dose landiolol infusion and ivabradine injection may be used to reduce HR. However, to optimize cardiac energetics and peripheral microhemodynamics, low-dose landiolol infusion may be preferable to ivabradine injection. Acknowledgement/Funding This work was supported by JSPS KAKENHI Grant Number 15K01307, 18K12126.