Overview

Septic shock is a major health problem, with several million cases annually worldwide and a mortality approaching 45%. Tachycardia is associated with excess mortality during septic shock. This pejorative effect could be related to the increase in cardiac metabolic demand, impaired cardiac diastolic function, and/or poorer tolerance of administered exogenous catecholamines. Recent studies suggest that controlling the heart rate with the use of beta blockers has beneficial effects on the morbidity and mortality of septic shock. However, the negative effects of beta-blockers on cardiac contractility and blood pressure complicate their use during septic shock, particularly because about one-half of patients exhibit a septic-associated systolic dysfunction, which often requires the use of inotropes.

Ivabradine is a selective inhibitor of If channels in the sinoatrial node. It is a pure bradycardic agent with no deleterious effect on other aspects of cardiac function (contractility, conduction and repolarization) nor on blood pressure. Ivabradine can therefore alleviate sinus tachycardia without negative inotropic effects nor hypotension. Moreover, the improvement in diastolic function (ventricular filling) with ivabradine may increase stroke volume, even in case of severe impairment of systolic function. Controlling sinus tachycardia with ivabradine during septic shock would allow reducing cardiac metabolic demand (and potentially associated ischemic events) and improving the chronotropic tolerance of exogenous catecholamines. The effectiveness of ivabradine in controlling the heart rate was demonstrated in various clinical settings such as coronary artery disease, chronic heart failure and cardiogenic shock. Encouraging preliminary data are reported in critically ill patients.

Eligibility

Inclusion Criteria:

• 18 years of age or older,
• Proven or suspected site of infection,
• Septic shock (defined as hypotension unresponsive to fluid resuscitation and requiring vasopressor treatment to maintain adequate blood pressure in the context of proven or suspected site of infection) for at least 2 hours and less than 24 hours (inclusion is possible before 2 hours in case of increasing doses of norepinephrine),
• In sinus rhythm with heart rate ≥ 95 bpm at time of randomization,
• Informed consent obtained in accordance with local regulations,
• Affiliation to a social security regime.

Exclusion Criteria:

• Age < 18 years,
• Cardiac arythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"), sino-atrial block; 3rd degree atrioventricular block, "IRISS" protocol, version 6.0 of 30/10/2023 7/47 This document is the property of DRCD / APHP. All reproduction is strictly prohibited.
• Cardiogenic shock or unstable or acute heart failure without proven or suspected infection,
• Acute myocardial infarction with angiographic documentation; CCS class

  ≥ II angina pectoris;

• Septic shock requiring vasopressor treatment for more than 24 hours,
• Refractory shock with systolic arterial pressure <90 mm Hg) despite the use of high doses of vasopressors (norepinephrine BASE or epinephrine BASE > 2.4 µg/kg/min; these doses should be multiplied by two for noradrenaline salt (tartrate or bitartrate),
• Co-treatment with drugs inducing bradycardia, QT lengthening or strong inhibition of CYP4503A4, pacemaker, defibrillator, kalemia <3 mM,
• Co-treatment with verapamil or diltiazem (which are moderate CYP4503A4 inhibitors with heart rate reducing properties)
• Known pregnancy, breast feeding, women with childbearing potential will be tested for pregnancy and excluded if pregnant,
• Known allergy to ivabradine or to any of the excipients, retinitis pigmentosa, congenital galactosemia, lactase deficiency, glucose or galactose malabsorption,
• Severe chronic renal failure (creatinine clearance <15 ml/min) or hepatic failure (prothrombin time <20%),
• Enteral feeding impossible, vomiting, congenital galactosemia, lactase deficiency, glucose-galactose malabsorption syndrome,
• Tachycardia due to hyperthyroidism, pheochromocytoma or severe anemia (<7 g/dL),
• Prior enrolment in the trial, participation in another interventional study on septic shock,
• Known legal incapacity (patients under guardianship or curatorship),
• Decision to limit full care taken before obtaining informed consent,
• Patient under AME (state emergency medical help),
• Lack of affiliation to social security.