Effect of heart rate control with ivabradine on hemodynamic in patients with sepsis: study protocol for a prospective, multicenter, randomized controlled trial

Abstract

Introduction

Sepsis, a life-threatening syndrome, is often accompanied by tachycardia in spite of hypovolemia and hypotension have been corrected. Recently, relevant studies have shown that sustained tachycardia in sepsis was related to high mortality, and appropriate control of heart rate (HR) could improve prognosis. Ivabradine reduces HR directly without a negative inotropic effect through inhibition of the I_f ionic current, which is different from the traditional rate control drug (beta-blockers).

Methods and analysis

This is a prospective, multicenter, randomized, open label study designed to investigate the effect of heart rate control with ivabradine on hemodynamic in patients with sepsis. Our study will enroll 172 patients with sepsis as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria with sinus rate of 95 bpm or higher 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 will receive ivabradine to maintain HR between 70 and 94 bpm. The primary outcome is the difference of a reduction in HR below 95 bpm and the effect of ivabradine on hemodynamics between GI and GS group within the first 96 h after randomization. The secondary outcomes include organ function measures, the difference in SOFA score, incidence of adverse events, need for organ support, length of ICU stay, and 28-day overall mortality.

Discussion

There are limited studies on ivabradine to control heart rate in patients with sepsis. Our study aims to evaluate whether direct sinus node inhibition can improve hemodynamics, as well as its impact on organ function and prognosis in patients with sepsis, so as to provide evidence for the safe usage in clinical practice.

Trial registration

ClinicalTrials.gov NCT05882708. Registered on May 11, 2023, https://clinicaltrials.gov/ct2/show/NCT05882708.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-024-08560-5.

Introduction

Sepsis is a syndrome characterized by a dysregulated inflammatory response of the host to infection, resulting in vasodilation and leakage of capillaries [1]. Tachycardia, a common clinical symptom observed in sepsis patients, was previously considered as a compensatory mechanism due to both absolute and relative hypovolemia. However, tachycardia often persists despite adequate fluid resuscitation and appropriate administration of vasopressor drugs for correcting hypovolemia and hypotension, which is referred to as refractory tachycardia. This elevated heart rate (HR) is not only associated with sympathetic overstimulation resulting from dysregulation of the autonomic nervous system, excessive release of catecholamine, myocardial depression, and vascular hyporeactivity but may also be a direct effect of bacterial endotoxin and inflammatory mediators on the sinoatrial node [2–4]. Recent studies have shown that sustained tachycardia is associated with high mortality in patients with sepsis [5, 6]. Furthermore, evidence suggests that refractory tachycardia in patients with septic shock is considered as a critical subtype of sepsis, and these patients may benefit from HR control [7, 8]. Therefore, an adequate and prompt control of tachycardia in sepsis plays an important role in improving treatment outcomes.

Historically, beta-blockers have been regarded as conventional mediations for heart rate control, exerting their effects by antagonizing sympathetic overactivation. There is an increasing interest in the use of ultrashort-acting highly selective β-blockers, particularly esmolol and landiolol, for the treatment of sepsis and septic shock. Although β-blockers have been shown to benefit from reducing heart rate in patients with sepsis, their application in treating individuals with cardiac dysfunction and hemodynamic instability induced by sepsis remains significantly limited due to their negative impact on myocardial contractility and blood pressure [9–11].

Ivabradine, a specific inhibitor of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in sinoatrial node pacemaker cells [12], exerts a rate-dependent heart rate slowing effect by binding to specific sites of HCN channel and inhibiting pacemaker current I_f. Importantly, it does not negatively affect cardiac conduction or contractility, which distinguishes it from β-blockers [13, 14]. Hence, ivabradine may have broader applications and more preponderant for sepsis patients who often present with impaired cardiac function and hemodynamic instability.

Ivabradine has been extensively investigated in patients with acute and chronic heart failure, demonstrating favorable safety and tolerability profiles [15]. However, there is currently limited clinical research on the use of ivabradine in patients with sepsis. Although a previous experimental study had shown that ivabradine exerts beneficial effects on microcirculation in septic animals [16], clinical studies have yielded conflicting outcomes. The MODIfY Trial and the study conducted by Datta et al. did not demonstrate improved prognosis for patients with MODS/sepsis following ivabradine administration; however, both studies suggested significant reductions in heart rate as along with potential improvements in hemodynamic parameters and cardiac function without an increased incidence of adverse events [17, 18]. It should be noted that these studies were single-center trials involving a small number of participants, thus providing limited clinical evidence.

The primary objective of this study was to investigate the potential of ivabradine in improving hemodynamics in patients with sepsis and persistent sinus tachycardia. Additionally, it aimed to assess its effect on mortality rates and medication safety. The findings from this trial will contribute valuable evidence for the application of ivabradine in sepsis management.

Methods and analysis

This protocol used the SPIRIT reporting guidelines [19].

Trial design

This is a prospective, multicenter, parallel-group, exploratory randomized (1:1 allocation ratio) controlled clinical study. The study will be conducted in 8 intensive care units (ICUs) in Guangdong, China. Patient enrolment, intervention, and follow-up are performed at the Second Affiliated Hospital of Guangzhou Medical University, Dongguan People’s Hospital, Guangzhou Red Cross Hospital, the First Affiliated Hospital of Jinan University, Guangzhou First People’s Hospital, the Fourth Affiliated Hospital of Guangzhou Medical University, Shunde Hospital of Southern Medical University, and Maoming People’s Hospital. The study is expected to last for 2 years. Recruitment of participants has started in June 2023.

Study setting and informed consent

All patients admitted to the ICUs of participating centers will be considered as potential candidates for the study. Once the patient fulfills the criterion of recruitment described below, the principal investigator or a sub-investigator will explain the experimental procedure and collect a written informed consent (Supplementary Material 1) signed from each patient or responsible surrogate before randomization.

Consent for ancillary studies

There is no plan for additional provisions using participant data and biological specimens in ancillary studies.

Inclusion criteria

Patients who meet the following criteria are eligible to be included in the trial:

1. Adult patients aged 18 years or above.

2. Being treated in intensive care unit (ICU) and diagnosed with sepsis according to Sepsis-3.0 criteria.

3. 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.

4. Patients must have sinus rhythm with a heart rate ≥ 95 bpm maintained for at least 2 h but less than 72 h, 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.

5. Patients should be in a relatively stable period of hemodynamic state, defined as maintaining target MAP with the same dosage of vasopressors for at least 2 h.

6. Informed consent provided by either the patient or his/her legally authorized representative.

Exclusion criteria

The participant is ineligible for trial enrollment if any of the following criteria are met:

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 below 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 who require 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 acute myocardial infarction (< 2 months), 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 [vasoactive inotropic score (VIS) > 120, VIS and the equivalent dose of vasopressors were shown in the Supplementary Material 2], and other regular therapy: (1) worsening hypotension (MAP < 65 mmHg); (2) persistent lactate level > 5 mmol/L (two consecutive measurements with an interval of more than 30 min) showing a progressive upward trend; (3) sustained mixed venous blood oxygen saturation (SvO₂) < 55% for more than two consecutive measurements taken at least 30 min apart indicating progressive deterioration. The above conditions must have lasted for more than 5 h to be considered refractory shock.

12.  Use of beta-blockers within 24 h prior to enrollment.

13.  Pheochromocytoma patients.

14.  Patients who have undergone cardiopulmonary resuscitation.

15.  Patients who have already been enrolled in another interventional clinical study.

Assignment of interventions

Randomization

Research Manager (ResMan) is an internet-based public platform designed for standardized data management of clinical trials. It offers a comprehensive range of functionalities, including central randomization and data management, which can be utilized free of charge. Our internal utilization will involve the randomization system integrated within this platform, enabling investigators at each clinical study branch center to generate randomization allocation with a 1:1 ratio efficiently.

Blinding

This is an open-label trial where the treatment allocation cannot be blinded due to the necessity of titrating the ivabradine dose to achieve a target heart rate.

Intervention

After randomization, included patients are allocated to either standard treatment (standard group, GS) or standard treatment and enteral ivabradine (intervention group, GI). The study flow chart is detailed in Fig. 1.

Fig. 1.

Flow chart of the trial. HR, heart rate; MAP, mean arterial pressure

Standard group (GS)

In this arm, patients will receive standard treatments for sepsis in accordance with the 2016 international guidelines [20]. These include:

1. Administering early and appropriate antibiotic treatment.

2. Promptly dealing with the source of sepsis.

3. Adequate fluid resuscitation to correct hypovolemia. In addition, repeated fluid challenge will be allowed to evaluate fluid responsiveness and guide effective circulating volume targets (CVP > 8 mmHg or GEDI > 680 ml/m² or IVC > 1.5 cm) during the trial observation period (within 96 h after grouping).

4. Utilizing vasopressors to achieve a target MAP of > 65 mmHg.

5. Employing life support technologies such as ventilators and CRRT as necessary.

6. Considering administration of dobutamine 5–10 μg/kg/min or levosimendan (at a dose of 0.2 μg/kg/min without a loading bolus dose) when the cardiac index (CI) < 2.2 L/min/m².

Because a heart rate target was not specified in the guideline, it is not mandated for patients in this group who had sinus tachycardia.

Ivabradine intervention group (GI)

The principles of basic treatment are consistent with those in GS, and ivabradine will be introduced. Previous studies have shown that heart rate reduction below 95 beats per minute was safe and had survival benefits in patients with sepsis [21, 22]. Furthermore, the drug usage instruction specifies that it should not be administered to individuals with a resting heart rate below 70 bpm prior to treatment. Therefore, our study determined that participants randomized to this arm achieved heart rate control ranging from 70 to 94 beats per minute.

The initial dose of ivabradine, 5 mg, is immediately administered orally. Throughout the intervention period, ivabradine will be given every 12 h until 96 h after therapy initiation. Heart rate is assessed before each administration. 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 h, the dosage is increased to 7.5 mg. Ivabradine is omitted if the heart rate drops below 60 bpm. Beyond this timeframe, the decision to continue with ivabradine rests with the treating intensivist’s discretion. Once severe symptomatic bradycardia (heart rate < 60 bpm, accompanied by worsening hypotension and an increased requirement for norepinephrine support) develops in a patient, ivabradine administration ceases and intravenous infusion of isoproterenol starts. The dose of isoproterenol gradually decreases until withdrawal when the heart rate is maintained above 70/min. If a heart rate of 95 bpm or higher recurs after discontinuation of ivabradine during the intervention period (within 96 h after grouping), treatment with ivabradine can be resumed at a dose that is 2.5 mg lower than the previous dose, followed by subsequent titration based on the heart rate. Furthermore, cessation of ivabradine therapy is warranted in cases of severe liver impairment, malignant arrhythmia, cardiac conduction block, allergic reactions, concurrent use of medications with potentially harmful effects when combined with ivabradine (such as azole antifungal drugs, macrolide antibiotics, HIV protease inhibitors), or in the view of the intensivist that ivabradine treatment is harmful to the patient’s well-being.

The intervention process for each group is shown in Fig. 2. In both groups, the following treatments should be noted upon inclusion or during the trial observation (or intervention) period:

1. It is suggested to maintain a hemoglobin level of ≥ 70 g/L.

2. Remifentanil and propofol are preferred for analgesia and sedation, with the aim of achieving a Richmond agitation-sedation scale (RASS) score between 0 and − 3. Dexmedetomidine is contraindicated.

3. Treatments known to significantly prolong the QT interval, such as class I (e.g., quinidine, procaine) and class IV (e.g., diltiazem, verapamil) antiarrhythmics, are not permitted.

4. Initiation of β-blockers and amiodarone during the 96-h treatment period is prohibited unless deemed necessary for managing adverse events (AEs).

Fig. 2.

Study drug administration protocol. HR, heart rate; bpm, beats per minute

Strategies to improve adherence to interventions

Not applicable. Most of the participants in this study required analgesic and sedative treatment and nasal nutrition due to critical illness, and intervention can be completed without cooperation of patients. Persuasion is necessary to obtain cooperation for conscious patients.

Outcomes

Patients will be followed up to 28 days after enrolment. The primary outcomes are the difference of a reduction in heart rate between the two groups and the effect of ivabradine on hemodynamics during the first 96 h after randomization. Hemodynamic assessment parameters comprise MAP, CI, stroke volume index (SVI), left ventricular ejection function (LVEF), and VIS. Secondary outcomes include the difference in SOFA score, incidence of adverse events, need for organ support (defined as need for vasopressors, mechanical ventilation, or renal replacement therapy), length of stay in ICU, and 28-day overall mortality.

Sample size and recruitment

Although multiple outcome parameters are used as the primary end point, improvement of only one of these measures is considered to be required for the intervention to be effective. The primary focus of this study is to assess the difference in the area under the curve (AUC) of the subthreshold heart rate. According to previous study, the median difference in AUC between ivabradine and placebo was − 25.6 (95%CI − 31.4 to − 15.9) bpm [18]. We assume that differences between two groups will be detected with a power of 90% at a bilateral α risk of 0.05. Additionally, we have considered potential loss to follow-up and withdrawals, estimating it at 10% for patients. Hence, a total sample size of 172 subjects will be assigned equally to GI and GS groups in order to meet these requirements. Power calculations were performed using Power Analysis & Sample Size (PASS) V.14.0 software.

Since the recruitment period is 18 months, furthermore, the centers participating in this study are high-volume tertiary hospitals in China, and it was estimated that only one or two patients per month would be enrolled at each centers to meet the required sample size.

Data collection and management

Data collection

The schedule of events for the trial is summarized in Table 1. The patient’s medical history (main diagnosis and site of infection) and demographic information will be recorded. In addition to echocardiography for cardiac function evaluation, all patients need to be monitored for arterial pressure, electrocardiogram, and CVP. Pulse indicator Continuous Cardiac Output (PiCCO) is recommended to monitor hemodynamics in study centers with equipment.

Table 1.

The schedule of events for the trial

	Screening	Inclusion (D0)	Study period (D1–D4)	Death/D28
Baseline information
Demographic data and history	√	√
Inclusion and exclusion criteria	√
Written informed consent	√
Main diagnosis and site of infection	√	√	√	√
ECG	√	√
Vital signs		√	√
CVP		√	√
APCHE-II/SOFA		√	√
Efficacy observation
Ivabradine application		√	√
Echocardiography (CO, VTI, SV, LVEF, TAPSE, E/e’ ratio, diameter and variation of IVC)		√	√ (D2, D4)
PiCCO (if applicable, recommended)		√	√
Use of vasopressors and VIS		√	√
Mechanical ventilation		√	√
CRRT		√	√
In/out fluids			√
Laboratory tests
Blood routine examination, liver, renal, coagulation, serum electrolyte levels, PCT, lactate		√	√
Arterial blood gas (BG)/central venous BG		√	√
Myocardial enzymology, BNP		√	√ (D2, D4)
Inflammatory factors (IL-6, CRP)		√	√ (D2, D4)
Safety observation
Adverse events		√	√
Additional observation
ICU and hospital LOS			√	√
Alive or dead status			√	√

APCHEII Acute Physiology and Chronic Health Evaluation II, CRRT continuous renal replacement therapy, LOS length of stay, SOFA Sequential Organ Failure Assessment, ECG electrocardiogram, IL Interleukin CRP C-reactive protein, PiCCO Pulse indicator Continuous Cardiac Output, CVP Central Venous Pressure, PCT Procalcitonin

Baseline assessments performed at the inclusion visits which labeled D0 include vital signs, CVP, echocardiographic parameters for cardiac function, results of laboratory tests, Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, and SOFA score.

During the trial observation (or intervention) period, which is defined as the first 96 h after randomization, vital signs and CVP are recorded every 12 h, laboratory tests are monitored every 24 h, SOFA score is evaluated daily, and echocardiographic assessment is performed every 48 h.

Vital signs include heart rate and rhythm, blood pressure, respiratory rate, body temperature, peripheral oxygen saturation (SpO₂), and state of consciousness (evaluated by Glasgow Coma Scale), as well as RASS.

The items of laboratory tests include blood routine examination, liver function tests, renal function tests, coagulation profile evaluation, serum electrolyte levels assessment, arterial blood gas analysis, and myocardial enzyme measurement. Superior vena cava blood gasses can be measured at the same time if a deep venous catheter is present. Procalcitonin, lactate, and biomarkers of inflammatory [e.g., interleukin (IL)-6, C-reactive protein (CRP)] are also required.

Importantly, some measurements [velocity time integral (VTI), stroke volume (SV), cardiac output (CO), LVEF, diameter and variation of IVC, tricuspid annular plane systolic excursion (TAPSE), E/e’ ratio] are obtained through echocardiography. If PiCCO is applicable, corresponding parameters, such as GEDI, systemic vascular resistance index (SVRI), extravascular lung water index (ELWI), CI, SVI, and cardiac power index (CPI), should be recorded at baseline and every 12 h for the following 96 h. Moreover, vasopressor requirement during above periods ought to be recorded as VIS.

Other clinical data to be collected will encompass ventilator support, daily intravenous fluid intake, and urine output, as well as the need for renal replacement therapy. Participants will also be followed up to ascertain survival status at 28 days post-randomization. The information will be acquired by telephone. Severe adverse events (SAEs) occurring within a span of 96 h following randomization will be reported.

Data management

Data will be collected using the electronic case record form (eCRF) and stored within the ResMan platform (http://www.medresman.org.cn/login.aspx). Each research center possesses an account granting access to the system. All study members will receive protocol and device training (if necessary) before participating in the study to ensure protocol adherence. Data will be stored for at least 3 years after trial termination and publication of the final report. Any data required to support the protocol can be supplied on request.

Confidentiality

All records of trial participants will be stored anonymously in eCRF using identification numbers and initials and remain confidential to the public.

Statistical analysis

Multiple imputation is performed for missing data. For descriptive analyses, continuous variables are expressed as mean and standard deviation (SD) or median and interquartile range (IQR), depending on their type of distribution. Categorical variables are presented as proportions (%). Statistical comparisons between variables were conducted using chi-square tests for categorical data, t-test for normally distributed continuous data, and Kruskal–Wallis test for non-normally distributed continuous data, respectively.

All analyses are performed according to the intention-to-treat principle. To mitigate the issue of multiple comparisons, we calculated areas under the curve (AUCs) relative to baseline values for continuous variables with repeated measurements as primary factors, as suggested by Matthews et al. [23]. Subsequently, AUCs between groups were compared using the Wilcoxon-Mann–Whitney test. Additionally, ICU and 28-day overall mortality are compared through a multivariable Cox regression model. This model is built by using stepwise forward inclusion based on likelihood ratio P values for factors interpreted as significant effects in univariate or descriptive analysis, which are considered as covariables. Survival curves are plotted by Kaplan–Meier and log-rank analyses.

Additional analyses will be performed according to the per-protocol principle. A 2-sided significance level of α = 0.05 is considered statistically significant. All analyses were performed using the statistical software packages R version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS 26.0 (SPSS Inc., Chicago, IL, USA).

Oversight and monitoring

Composition of the data monitoring committee, its role, and reporting structure

Not applicable. There is no data monitoring committee in this study. To ensure patient safety and data integrity, the study sponsor has specially designated two clinical trial monitors to continuously supervise data management activities, and the senior scientific project leader and investigators performed field visits on a regular basis.

Safety and adverse outcomes

All AEs and suspected unexpected AEs that occurring during the study period have to be recorded on the CRF. The occurrence time, severity, duration, treatment measures, and outcomes of AEs should be faithfully reported. The experimental group should also judge the relationship between AEs and interventions. In case of any AE identification by research staff, immediate notification to the center monitor is required followed by reporting to the sponsor, principal investigator, and ethics committee within 24 h via telephone or fax. The management recommendations for AEs are outlined below while Fig. 3 illustrates a flowchart depicting AE processing.

1. Malignant sinus tachycardia: sinus rhythm ≥ 140 bpm with significant hemodynamic compromise (e.g., markedly lower blood pressure, signs of shock), short-acting β-blockers, such as esmolol and landiolol, are recommended.

2. New supraventricular arrhythmias (atrial fibrillation, atrial flutter): amiodarone is recommended for cardioversion.

3. Severe symptomatic bradycardia: considering worsening hypotension or increasing norepinephrine requirement due to a heart rate < 60 bpm. Ivabradine is discontinued, and intravenous infusion of isoproterenol is given when necessary.

4. Other arrhythmias and conduction abnormalities: the study will be terminated and patients are treated with drugs according to the type of arrhythmia, and pacemaker is used if necessary.

5. Severe liver dysfunction: serum bilirubin increases more than 5 times, or serum ALT and AST increase more than 10 times. The study will be terminated and liver protective drugs are given.

Fig. 3.

Process for managing adverse events

It is referred to as an SAE if any of the following occurs:

1. Death or prolonging the length of hospital stay (considered by the investigator to be related to the intervention).

2. AE that may directly cause the death of the subject.

3. Permanent or significant disability, or dysfunction.

4. Major medical events.

Frequency and plans for auditing trial conduct

The department of research office and the ethics committee of each center will audit the study annually. And the principal investigator will check the appropriateness of the data and conduction of the trial every month.

Ethics approval and dissemination

The study protocol has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (Reference number: 2022-hs-53). Any protocol amendments will be written into a formal substantial amendment reviewed by the institutional review board of the Second Affiliated Hospital of Guangzhou Medical University before application. In addition, this trial had registered on https://www.clinicaltrials.gov/, with the identifier NCT05882708. The study will be reported in accordance with the CONSORT guidelines [24]. All information from the participants will not be made publicly available and will not be provided to any company or institution.

The results dissemination will be carried out by investigators of the study. The study findings will be disseminated in research journals and through conference presentations and/or posters. After publication, it could be published via dedicated websites/forums and/or social media. The datasets analyzed during the current study and statistical code are available from the corresponding author on reasonable request, as is the full protocol. The sponsor played no part in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.

Discussion

Tachycardia is a prevalent occurrence in sepsis patients, and it often persists even after resuscitation. Previous studies have shown that persistent tachycardia is independently associated with an increased risk of mortality in sepsis. Although controlling the heart rate may bring survival benefits to patients, tachycardia involves multiple factors and may be a compensatory response of the body. Therefore, selecting appropriate medications for effectively controlling the heart rate has become a major concern.

Historically, beta-blockers have been considered relatively contraindicated for sepsis due to their cardiac suppressive effects. However, a meta-analysis summarizing multiple high-quality studies showed that the use of ultrashort-acting β-blockers such as esmolol and landiolol in patients with sepsis was associated with reduced mortality [25]. Beta-blockers are recognized for their ability to effectively control heart rate across various types of tachycardia. However, they may present challenges in terms of negative myocardial contractility and excessive inhibition, which could potentially restrict their utilization and dosage among patients with septic shock [26]. On the other hand, ivabradine has a specific site of action, whether it is more appropriate for rate control in sepsis patients with sinus tachycardia has not been determined. Previous studies on ivabradine and heart rate control in patients with sepsis are limited, most of them are single-center studies, with small sample size and also have problems such as ignoring the type of tachycardia. To the best of our knowledge, this is the first multicenter, prospective, randomized controlled study of ivabradine in sepsis patients with sinus tachycardia, which is of great significance for broadening the drug application population and improving the prognosis of sepsis.

For the safety and ethical considerations of the trial, it is anticipated that a limited number of patients may receive amiodarone or β-blockers when occurring adverse events. However, given the rapid metabolic clearance of these drugs, their impact on the results is expected to be minimal. Nevertheless, a sensitivity analysis can be conducted during post-trial analysis to maximally reduce the impact of confounding factors. Moreover, extensive exclusion criteria have resulted in a significant proportion of patients being excluded from the study. The exclusion criteria related to potential adverse effects of ivabradine and were deemed necessary to ensure patient safety.

Recently, studies have also indicated that ivabradine may improve microcirculatory function parameters by reducing the level of inflammatory factors in the blood [16, 27, 28]. Our study will also use the collected data to calculate oxygen delivery, combined with lactate to evaluate microcirculation status, and further explore the effect of ivabradine on inflammatory factors with the help of PCT and CRP, which is more comprehensive and may fill the gap in this aspect of previous research.

In conclusion, our study aims to evaluate the potential of direct sinus node inhibition in improving hemodynamics in patients with sepsis. Besides, it may have many other effects worth exploring and more high-quality clinical trials are warranted to provide evidence.

Trial status

The study used the 3.0 version of the protocol (date: 20 September 2022). The recruitment began in June 2023 and is expected to complete recruitment in December 2024. Recruitment status is recruiting.

Abbreviations

HR

Heart rate

ICU

Intensive care unit

SOFA

Sequential Organ Failure Assessment

CVP

Central venous pressure

GEDI

Global end-diastolic volume index

IVC

Inferior vena cava

MAP

Mean arterial pressure

CRRT

Continuous renal replacement therapy

VIS

Vasoactive inotropic score

CI

Cardiac index

RASS

Richmond agitation-sedation scale

AEs

Adverse events

SVI

Stroke volume index

LVEF

Left ventricular ejection function

AUC

Area under the curve

PiCCO

Pulse indicator Continuous Cardiac Output

APACHE

Acute Physiology and Chronic Health Evaluation

IL

Interleukin

CRP

C-reactive protein

VTI

Velocity time integral

SV

Stroke volume

CO

Cardiac output

SVRI

Systemic vascular resistance index

ELWI

Extravascular lung water index

CPI

Cardiac power index

ECG

Electrocardiogram

Authors’ contributions

Weiyan Chen and Zhenhui Zhang, as principal corresponding person of the project, designed the trial and had ultimate authority over the collection, management, analysis, and interpretation of the data, as well as the decision to submit the report for publication. Zhenhui Zhang obtained funding for the trial. Jiezhao Zheng and Deliang Wen helped to improve the trial design and drafted the manuscript. All authors read and approved the final manuscript.

Funding

This project was funded by the Second Affiliated Hospital of Guangzhou Medical University (Project Number: 2022-LCYJ-DZX-02). The foundation had no influence over the design of the study, the collection, analysis, and interpretation of the data or the writing of the manuscript.

Data availability

The study investigators will have access to the final dataset, and they will not have any contractual agreement that limits such access. Any data required to support the protocol can be supplied on request.

Declarations

Consent for publication

Not applicable—no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. The informed consent form of participant is attached.

Competing interests

The authors declare that they have no competing interests.