Background and objective This study involved an investigation into the pharmacokinetic and pharmacodynamic behavior of esmolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study of 16 healthy subjects with each receiving an infusion of dobutamine sufficient to increase heart rate (HR) by 30 beats per minute (bpm) followed by a 60-minute infusion of 50 µg/kg/min esmolol. Pharmacokinetics, HR, and blood pressure were evaluated for 180 minutes. Results In the presence of dobutamine, esmolol elimination was substantially faster than without dobutamine, Esmolol infusion reduced dobutamine-induced elevation of HR reversibly whereas the dobutamine-induced systolic blood pressure (SBP) reduction did not recover after the termination of the esmolol infusion. No serious adverse events (AEs) were observed. Conclusions The accelerated elimination of esmolol was likely due to higher cleavage through tissue esterases induced by dobutamine-induced increased tissue passage cycles per time unit. The HR effect was characteristic of a beta-blocker, whereas the blood pressure effect was likely due to a mechanism other than direct beta-blockade. HR remained elevated after the infusion of esmolol and dobutamine, most likely due to persistent blood pressure reduction.

• Keywords
• cardioselective β-blocker, dobutamine, esmolol, pharmacodynamics, pharmacokinetics,
• Publication type
• Journal Article MeSH

BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017-002138-22 . Registered on 8 August 2017.

• Keywords
• Beta-blocker, Landiolol, Randomized controlled trial, Sepsis, Septic shock, Tachycardia,
• MeSH
• Anti-Arrhythmia Agents adverse effects   therapeutic use   MeSH
• Adrenergic beta-Antagonists adverse effects   therapeutic use   MeSH
• Time Factors MeSH
• Intensive Care Units * MeSH
• Clinical Trials, Phase IV as Topic MeSH
• Blood Pressure drug effects   MeSH
• Humans MeSH
• Urea adverse effects   analogs & derivatives   therapeutic use   MeSH
• Morpholines adverse effects   therapeutic use   MeSH
• Multicenter Studies as Topic MeSH
• Prospective Studies MeSH
• Randomized Controlled Trials as Topic MeSH
• Shock, Septic diagnosis   drug therapy   physiopathology   MeSH
• Heart Rate drug effects   MeSH
• Vasoconstrictor Agents therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Anti-Arrhythmia Agents MeSH
• Adrenergic beta-Antagonists MeSH
• landiolol MeSH Browser
• Urea MeSH
• Morpholines MeSH
• Vasoconstrictor Agents MeSH