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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
172
After randomization, the starting dose of ivabradine, 5mg, is given via the gastrointestinal tract every 12 hours. Heart rate control ranged from 70 to 94 bpm. Ivabradine was maintained until 96 hours after initiation of therapy. Beyond this period, the decision to continue ivabradine is left to the discretion of the treating intensivist. During the drug intervention period, heart rate is assessed before each dose. Ivabradine is tapered or discontinued if the heart rate is lower than the target rate; If the heart rate remains ≥95 bpm after 48 hours, the dose is increased to 7.5mg. If a heart rate of 95 or more bpm recurs after discontinuation during the intervention period, treatment with ivabradine can be resumed. Furthermore, Ivabradine is also discontinued at any time in the presence of severe liver impairment, malignant arrhythmia, cardiac conduction block, allergy, the need to take drugs with potentially harmful effects of ivabradine.
the Affiliated Panyu central Hospital of Guangzhou Medical University
Guangzhou, Guangdong, China
RECRUITINGthe Second Affiliated Hospital of Guangzhou Medical University
Guangzhou, Guangdong, China
RECRUITINGthe Third Affiliated Hospital of Guangzhou Medical University
Guangzhou, Guangdong, China
RECRUITINGThe difference of a reduction in heart rate
Heart rate is a continuous variable with repeated measurements during the first 96 hours after enrollment, the area under the curve (AUC) relative to baseline are calculated for each group, and then difference in AUC are compared.
Time frame: 96 hours
The difference in MAP
MAP will be recorded every 12 hours for each patient during the first 96 hours after enrollment. The area under the curve (AUC) relative to baseline are calculated for each group, and then difference in AUC are compared. The change in this index will be used to evaluate the hemodynamic effects of ivabradine.
Time frame: 96 hours
The difference in CI
Cardiac index (CI) will be recorded every 12 hours for each patient during the first 96 hours after enrollment. The area under the curve (AUC) relative to baseline are calculated for each group, and then difference in AUC are compared. The change in this index will be used to evaluate the hemodynamic effects of ivabradine.
Time frame: 96 hours
The difference in LVEF
Left ventricular ejection fraction (LVEF),measured by bedside ultrasound, will be recorded every 12 hours for each patient during the first 96 hours after enrollment. The area under the curve (AUC) relative to baseline are calculated for each group, and then difference in AUC are compared. The change in this index will be used to evaluate the hemodynamic effects of ivabradine.
Time frame: 96 hours
The difference in SVI
Stroke volume index (SVI), obtained through PiCCO, will be recorded every 12 hours for each patient during the first 96 hours after enrollment. The area under the curve (AUC) relative to baseline are calculated for each group, and then difference in AUC are compared. The change in this index will be used to evaluate the hemodynamic effects of ivabradine.
Time frame: 96 hours
The difference in VIS
Vasopressor requirement during the trial observation (or intervention) period ought to be recorded as vasoactive inotropic score (VIS) according to the formula. The area under the curve (AUC) relative to baseline are calculated for each group, and then difference in AUC are compared. The change in this index will be used to evaluate the hemodynamic effects of ivabradine.
Time frame: 96 hours
28-day overall mortality
Overall survival measured from randomization to death or day 28
Time frame: 28 days
difference of the Sequential Organ Failure Assessment score
Difference of the Sequential Organ Failure Assessment (SOFA) score (0\~24) at day 1, 2, 3, 4 between groups. Higher score means more illness. SOFA score include organ function measure, which can reflect the functional status of organs.
Time frame: 96 hours
length of ICU stay
average length of ICU stay will be compared
Time frame: 28 days
The percentage of need for organ support
the percentage of receipt of CRRT, vasopressors and mechanical ventilation. It can reflect the functional status of organs, especially renal and pulmonary.
Time frame: 28 days
length of in-hospital stay
average length of in-hospital stay will be compared
Time frame: 28 days
Incidence of adverse events
The incidence of adverse events will be compared between the two groups
Time frame: 96 hours
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