A prospective, multicenter, randomized controlled trial is currently underway in China to evaluate the efficacy of ivabradine in controlling hemodynamic parameters in patients with sepsis who exhibit elevated heart rates. The study, conducted across eight intensive care units (ICUs) in Guangdong, aims to determine whether targeted heart rate reduction with ivabradine can improve outcomes in this critical patient population.
Study Design and Patient Population
The trial is designed as a prospective, multicenter, parallel-group, exploratory randomized controlled study with a 1:1 allocation ratio. Adult patients (aged 18 years or above) admitted to the participating ICUs and diagnosed with sepsis according to Sepsis-3.0 criteria are considered potential candidates. Sepsis-3.0 is defined as a dysregulated host response to infection, resulting in an acute increase of at least 2 points in the Sequential Organ Failure Assessment (SOFA) score.
Eligible patients must have sinus rhythm with a heart rate ≥95 bpm maintained for at least 2 hours but less than 72 hours, despite appropriate volume resuscitation [central venous pressure (CVP) > 8 mmHg, global end-diastolic volume index (GEDI) > 680 ml/m2, and resting inferior vena cava (IVC) diameter > 1.5 cm], or require inotrope application to maintain mean arterial pressure (MAP) ≥65 mmHg. Patients should also be in a relatively stable hemodynamic state, defined as maintaining target MAP with the same dosage of vasopressors for at least 2 hours.
Key exclusion criteria include prior ivabradine therapy, severe liver dysfunction (Child-C grade), pre-existing chronic renal failure (glomerular filtration rate below 15 ml/min/1.73 m2, except patients treated with continuous renal replacement therapy), recent acute myocardial infarction (< 2 months), and other significant cardiac dysfunctions.
Intervention and Treatment Protocol
Following randomization, patients will be allocated to either the standard treatment group (GS) or the ivabradine intervention group (GI). The standard treatment group will receive standard treatments for sepsis in accordance with the 2016 international guidelines, including early and appropriate antibiotic treatment, source control, adequate fluid resuscitation, vasopressors to achieve a target MAP of > 65 mmHg, and life support technologies as necessary. Dobutamine (5-10 μg/kg/min) or levosimendan (0.2 μg/kg/min without a loading bolus dose) may be considered if the cardiac index (CI) < 2.2 L/min/m2.
The ivabradine intervention group will receive the same standard treatments as the GS group, with the addition of enteral ivabradine. The initial dose of ivabradine is 5 mg, administered orally every 12 hours for 96 hours after therapy initiation. The heart rate is assessed before each administration, with dosage adjustments made to maintain a target heart rate between 70 and 94 bpm. If the heart rate falls below 70 bpm, the dosage is reduced to 2.5 mg; if the heart rate remains at or above 95 bpm after 48 hours, the dosage is increased to 7.5 mg. Ivabradine is omitted if the heart rate drops below 60 bpm.
Endpoints and Safety Measures
The primary outcome of the trial is the change in hemodynamic parameters. Safety measures include monitoring for bradycardia, liver impairment, and potential drug interactions. The trial is open-label, meaning that treatment allocation cannot be blinded due to the need to titrate the ivabradine dose to achieve the target heart rate.
This study has started recruitment in June 2023 and is expected to last for 2 years.
