Comparison of Landiolol Versus Standard of Care for Prevention of Mortality in Patients Hospitalized for a Septic Shock With Hypercontractility

Study Overview
=================
Brief Summary
-----------------
Several data emphasize the relation between tachycardia (>90/min) and high mortality during septic shock. The investigators previously demonstrated the high mortality associated with hypercontractility, tachycardia and the presence of a left ventricular obstruction. A severe hypovolemia, a hyper adrenergic stimulation or a severe vasoplegia can all explain this relation between tachycardia, hypercontractility and the mortality during septic shock. Landiolol is another short-term acting beta-blocker with a half-life of 4 minutes without any beta 2 activity or membrane stabilizing effect. The landiolol has been used in critically ill patients to control supraventricular tachycardia but not in this context of tachycardia and septic shock. The investigators hypothesize that landiolol by reducing the heart rate may improve the survival of patients treated for a septic shock and presenting with an hypercontractility state.

Official Title
-----------------
Comparison of Landiolol Versus Standard of Care for Prevention of Mortality in Patients Hospitalized for a Septic Shock With Hypercontractility: an Open Label Prospective Randomized Study

Conditions
-----------------
Septic Shock, Tachycardia, Mortality During Septic Shock, Beta-blocker

Intervention / Treatment
-----------------
* Other: echocardiography
* Drug: Landiolol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years old Patient admitted for a septic shock (according to the SEPSIS3 definition: sepsis with persisting hypotension (MAP<65mmHg or SAP <90mmHg) requiring vasopressors to maintain MAP>65mmHg and having a serum lactate level >2 mmol/L Patient who received at least 30ml/kg of fluid and absence of fluid responsiveness Left ventricular ejection fraction >65% (visual or Simpson method using echocardiography) Tachycardia >100 bpm in sinus rhythm with a MAP 65mmHg for more than 1 hour Patient receiving invasive mechanical ventilation Patients adapted to the ventilator under sedation and analgesia Written informed consent Patient covered by French national health insurance Exclusion Criteria: Patients with inclusion criteria already present for more than 36 hours Patient treated with Dobutamine, adrenaline or isoprenaline Patient currently treated with beta blockers (previous home betablocker treatment is not an exclusion criteria) Supra ventricular (atrial fibrillation or flutter) or ventricular arrhythmias Patients with any form of cardiac pacing Sick sinus syndrome Severe atrioventricular (AV) nodal conductance disorders (without pacemaker): 2nd or 3rd degree AV block Known pulmonary hypertension ScVO2 <70% Moribund Cardiac arrest Non-treated phaeochromocytoma Acute asthmatic attack Pregnant or breastfeeding woman Patient deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision), Age <18 years Hypersensitivity to the active substance or to any of the excipients Severe bradycardia (less than 50 beats per minute) Cardiogenic shock Severe hypotension Decompensated heart failure when considered not related to the arrhythmia Severe, uncorrectable metabolic acidosis Presence of significant bleeding, or Acute respiratory distress defined by increased oxygen dependency, polypnea > 30 /min, signs of struggle (pulling, thoraco-abdominal sway) if the patient is not intubated and ventilated.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>2 days with landiolol IV + usual care | Drug: Landiolol<br>* Patients randomized to the experimental group will be treated according to the standard of care plus for 2 days with landiolol IV started at a dose of 1 microgram/kg/min and progressively increased every 10 minutes to a maximum of 40 micrograms/kg/min.<br>|
| Active Comparator: Control group<br>usual care according to the attending physician and following the guidelines of surviving sepsis campaign. | Other: echocardiography<br>* Full echocardiography will be performed at baseline and during the follow-up at H1, H3, H6 and H12.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variation of mortality rate in landiolol group compared to control group |  | day 28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tachycardia, Septic Shock, mortality during septic shock, beta-blocker