LANdiolol MIcrocirculatory Effects During Septic chOc (MILANOS)

Study Overview
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Brief Summary
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The objectives of this study are to evaluate the effect of continuous intravenous Landiolol injection (from 0.5 to 10 µg/kg/min during 12 hours ) up to a 15% decrease in Heart Rate (HR) on microcirculatory vascular reactivity vs. usual tachycardia management and evaluate the hemodynamic effects of Landiolol vs. usual management in patients with septic shock.

Detailed Description
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This is a Phase 3, prospective, randomized, open label, evaluation of the efficacy of continuous intravenous Landiolol injection up to a 15% decrease in HR on microcirculatory vascular reactivity vs. usual tachycardia management. Design: A monocentric, open-label, randomised, superiority clinical trial Sample size : 44 patients, 22 in each group Treatments groups: Continuous intravenous Landiolol injection ( from 0.5 to 10 µg/kg/min during 12 hours ) up to a 15% decrease in HR on microcirculatory vascular reactivity vs usual tachycardia management Treatment duration : 24 hours Assessement: Landiolol (Rapibloc)'s perfusion will be started at T0 at 0.5 mcg/kg/min and increased by 0.5 mcg/kg/min every 30 minutes in order to achieve a 15% (T1) decrease in HR, within the limit of 10 mcg/kg/min. Then the dosage will be maintained for 2 hours (T2) then the drug will be stopped gradually over 2 hours. Maximum duration of Landiolol infusion will be 12 hours. No interim analysis is planned. Analysis will be performed at the end of the study after data review and freezing of database.

Official Title
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LANdiolol MIcrocirculatory Effects During Septic chOc

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Landiolol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sinus tachycardia not compensatory, if the doctor considers that the heart rate acceleration should be treated. The study will be carried out in reanimated and stabilized septic shock defined as: Septic shock is tachycardic (HR>100/min) patients with sepsis (suspected infection + 2 SOFA points) according to the latest international definition and the need to receive noradrenaline to maintain an average blood pressure above 65 mmHg Patient supported for at least 6 hours, necessary for diagnostic management and hemodynamic optimization according to international standards and for less than 24 hours to limit confounding factors related to prolonged reanimation (sedation) and empowerment of organ failure in general and vascular in particular. Hemodynamic stabilization will be defined as the absence of increased doses of norepinephrine in the previous two hours to limit the risk of hypotension induced by Landiolol infusion. Age >18 years Patient (or family member) informed consent signature or emergency consent Affiliation to a social security system Exclusion Criteria: Asthma Patients treated with the following bradycardizing drugs: Digitalis Bradycardizing calcium channel blockers Cordarone Other beta-blocker Hypersensitivity to Landiolol or to one of its excipients (Mannitol E421, sodium hydroxide) Sinus disease Cardiogenic shock Decompensated heart failure when considered unrelated to arrhythmia Pregnant or nursing woman, Participation in another interventional research involving the human person or being in the exclusion period following a previous research involving the human person, if applicable Ward or curative patient Moribund patient Estimated life expectancy less than 1 month

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Landiolol injection<br>Intravenous Landiolol injection (from 0.5 to 10 µg/kg/min during 12 hours) up to a 15% decrease in HR on microcirculatory vascular reactivity. | Drug: Landiolol<br>* Intravenous Landiolol injection (from 0.5 to 10 µg/kg/min during 12 hours) up to a 15% decrease in HR on microcirculatory vascular reactivity.<br>* Other names: Rapibloc;|
| No Intervention: Usual tachycardia management<br>No treatment, usual tachycardia management. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of decrease in heart rate (HR) on microcirculatory vascular reactivity | The objectives of this study are to evaluate the effect of continuous intravenous Landiolol injection (from 0.5 to 10 µg/kg/min during 12 hours ) up to a 15% decrease in HR on microcirculatory vascular reactivity vs. usual tachycardia management in patients with septic shock. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac flow | Measure of the cardiac flow to evaluate the hemodynamic effects of Landiolol vs. usual tachycardia management | 24 hours | 
| marbling score | Measure of the marbling score to evaluate the effects of Landiolol vs. usual tachycardia management | 24 hours | 
| skin recoloration time | Measure of skin recoloration time to evaluate the effects of Landiolol vs. usual tachycardia management | 24 hours | 
| Arterial lactate clearance | Measure of sarterial lactate clearance to evaluate the effects of Landiolol vs. usual tachycardia management | 24 hours | 
| Measure of Systemic and endothelial inflammation parameters | Evaluate the hemodynamic effects of Landiolol vs. usual tachycardia management on Systemic and endothelial inflammation parameters: Plasma cytokines (Procartaplex) VCAM-1 (vascular endothelial cell adhesion molecule), Soluble Endocan (ELISA) | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Landiolol, Microcirculatory effects, Heart rate, Hemodynamic effects, Microvascular reactivity