Effect of Heart Rate Control With Ivabradine on Hemodynamic in Patients With Sepsis

Sepsis, a life-threatening syndrome, is often accompanied by tachycardia in spite of adequate volume resuscitation to correct hypovolemia and vasopressor medication to correct hypotension. Recently, relevant studies have shown that sustained tachycardia in sepsis was also related to high mortality, and appropriate control of heart rate could improve prognosis. Ivabradine reduces heart rate directly without a negative inotropic effect through inhibition of the If ionic current，which is absent from the traditional rate control drug (beta-blockers). This is a prospective, multicenter, randomized, open label study designed to compare ivabradine with placebo on the difference of heart rate and haemodynamics in patients with sepsis.

This study aims to enroll 172 patients with sepsis as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and sinus tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization. Patients will be randomly assigned to standard treatment group (GS) or ivabradine group (GI，standard treatment for sepsis plus enteral ivabradine). Patients in GI, with a heart rate control target of 70 to 94bpm, received ivabradine within the first 96 hours after randomization, and overall participants are followed up to 28 days. The secondary outcomes include the difference in SOFA score, incidence of serious adverse events, need for organ support, length of ICU stay, and 28-day overall mortality.

Despite recent studies are limited, this study will investigate whether HR control using ivabradine is safe, feasible, and effective, and further enhance the understanding of ivabradine in patients with sepsis.

Eligibility Criteria:
Inclusion Criteria:

1. Adult patients aged 18 years or above.
2. Being treated in an intensive care unit.
3. Sepsis is diagnosed according to Sepsis-3.0 criteria, which is defined as patients requiring antimicrobial agents due to confirmed or suspected infection, acute increase in the SOFA score at least 2 points.
4. Mean arterial pressure (MAP) is maintained ≥65 mmHg with adequate volume resuscitation and vasopressor therapy. Volume resuscitation is considered adequate when Central Venous Pressure (CVP) \> 8mmHg, global end-diastolic volume index (GEDI) \> 680ml/m2 and resting inferior vena cava (IVC) diameter \> 1.5cm.
5. Patients are in a relatively stable period of hemodynamics, as defined that the targe mean arterial pressure are maintained with the same dosage of vasopressors for at least 2 h.
6. Sinus rhythm with heart rate ≥ 95bpm maintain for at least 2 hours but less than 72 hours.

Exclusion Criteria:

1. Patients who had received ivabradine therapy or known allergy to it prior to randomization.
2. Patients with severe liver dysfunction (Child-C grade).
3. Patients with a history of pre-existing chronic renal failure (glomerular filtration rate less than 15 ml/min/1.73 m2), except patients treated with continuous renal replacement therapy (CRRT).
4. Patients with known seizure disorder.
5. Patients with any contraindication to gastrointestinal drug administration.
6. Pregnant or lactating patients.
7. patients requiring the use of potent cytochrome CYP3A4 inhibitors such as antifungals of the azole-type (specifically ketoconazole and itraconazole), macrolide antibiotics (specifically clarithromycin and erythromycin) and HIV protease inhibitors (specifically nelfinavir and ritonavir).
8. Patients with active bleeding;
9. Patients with cardiac dysfunction caused by non-septic causes such as recent (\< 2months) acute myocardial infarction, chronic cardiac dysfunction (NYHA Class Ⅳ), congenital heart disease, pericardial tamponade, severe aortic regurgitation and aortic coarctation before enrollment.
10. Patients with sinoatrial block, sick sinus syndrome, atrioventricular block or heart rate dependence on pacemaker.
11. Patients with refractory shock, which may be considered if one of the following conditions still exists in spite of active volume resuscitation, high doses of vasoactive drugs (VIS score \>120), and other regular therapy: 1) Worsening hypotension (MAP\<65mmHg); 2) Lactate persistence\>5mmol/L (two times in a row with an interval of more than 30min), and a progressive upward trend; 3) Mixed venous blood oxygen saturation (SvO2) sustained \<55% (more than two consecutive times, more than 30min apart), and progressive deterioration. The above conditions lasted for more than 5 hours.
12. Use of beta blockers within 24 hours before enrollment.
13. Pheochromocytoma patients.
14. After cardiopulmonary resuscitation.
15. Patients who have been enrolled in another interventional clinical study.