Effects of Esmolol on Sublingual Microcirculation and Vascular Waterfall Phenomenon in Patients With Septic Shock

Effects of Esmolol on Sublingual Microcirculation and Vascular Waterfall Phenomenon in Patients With Septic Shock: A Prospective, Multicenter, Single-arm, Open-label, Pilot Physiological Study

This prospective, multicenter, single-arm interventional pilot study aims to evaluate the short-term physiological effects of intravenous esmolol on sublingual microcirculation and vascular-waterfall parameters in adult patients with septic shock. Eligible patients will have septic shock according to Sepsis-3 criteria, persistent tachycardia after initial hemodynamic optimization, ongoing norepinephrine support, adequate volume status or absence of significant fluid responsiveness, and preserved or hyperdynamic cardiac function.

Approximately 20 patients will be enrolled from participating intensive care units. After baseline assessment, participants will receive continuous intravenous esmolol infusion according to the study protocol and clinical safety criteria. Sublingual microcirculatory variables, including microvascular flow index, perfused vessel density, proportion of perfused vessels, and heterogeneity index, as well as vascular-waterfall parameters, including estimated critical closing pressure, estimated mean systemic filling pressure, and the Pcc-Pmsf gradient, will be measured at baseline and at 3, and 6 hours after esmolol initiation. Additional systemic hemodynamic, perfusion, vasopressor, and safety variables will also be collected.

The primary objective is to characterize immediate changes in sublingual microcirculation and vascular-waterfall physiology after esmolol administration and to provide preliminary data for the design of future controlled studies.

Septic shock is characterized by profound circulatory dysfunction involving both systemic hemodynamics and the microcirculation. Persistent tachycardia is common in septic shock and may reflect sympathetic overactivation, high catecholamine exposure, fever, pain, hypovolemia, or ongoing circulatory stress. After adequate fluid resuscitation, vasopressor support, analgesia and sedation, and correction of reversible causes, persistent tachycardia may contribute to increased myocardial oxygen consumption, impaired diastolic filling, reduced ventriculo-arterial coupling, and altered tissue perfusion.

Esmolol is an ultra-short-acting β1-selective adrenergic blocker that can be titrated rapidly and discontinued promptly if adverse hemodynamic effects occur. Previous studies suggest that heart rate control with esmolol in selected patients with septic shock may reduce catecholamine requirements and improve cardiovascular efficiency. However, its immediate effects on sublingual microcirculation and vascular-waterfall physiology remain insufficiently characterized.

The vascular-waterfall phenomenon refers to the concept that tissue perfusion may depend not only on arterial and venous pressures but also on the relationship between upstream pressure, critical closing pressure, and mean systemic filling pressure. In septic shock, changes in vascular tone, vasopressor exposure, and microvascular regulation may alter critical closing pressure and the effective pressure gradient for tissue perfusion. Evaluating these parameters together with direct sublingual microcirculatory imaging may provide mechanistic insight into the physiological effects of esmolol beyond conventional macrocirculatory variables.

This is a prospective, multicenter, single-arm interventional pilot study conducted in adult intensive care unit patients with septic shock. Patients will be screened after initial hemodynamic optimization. Eligible patients must have septic shock according to Sepsis-3 criteria, persistent tachycardia, ongoing norepinephrine support, adequate volume status or no significant fluid responsiveness, and preserved or hyperdynamic cardiac function before esmolol initiation. Patients with shock predominantly due to non-septic causes, severe cardiac dysfunction, contraindications to β-blockade, or inability to obtain acceptable sublingual microcirculatory images will be excluded.

After informed consent is obtained, baseline measurements will be performed immediately before esmolol initiation. Participants will then receive continuous intravenous esmolol infusion. The infusion may be started at a low dose and titrated according to heart rate, mean arterial pressure, cardiac output or cardiac index, vasopressor requirement, and clinical safety criteria. Temporary dose reduction, interruption, or discontinuation of esmolol will be permitted for safety reasons, including clinically significant hypotension, bradycardia, reduced cardiac output, worsening shock, new or worsening arrhythmia, or other adverse events judged by the treating physician or investigator.

Study assessments will be performed at baseline and at 3, and 6 hours after initiation of esmolol. Sublingual microcirculatory imaging will be used to assess microvascular flow index, perfused vessel density, proportion of perfused vessels, and microcirculatory heterogeneity index. Vascular-waterfall related variables will include estimated critical closing pressure, estimated mean systemic filling pressure, and the Pcc-Pmsf gradient. Systemic hemodynamic and perfusion variables, including heart rate, mean arterial pressure, cardiac index, norepinephrine dose, arterial lactate, urine output, and predefined adverse events, will also be recorded.

Approximately 20 patients will be enrolled to assess feasibility and generate preliminary estimates of physiological changes after esmolol administration. The main analyses will describe changes from baseline in sublingual microcirculatory and vascular-waterfall parameters over the 6-hour observation period. Safety events and exploratory clinical outcomes may be summarized descriptively to inform the design of subsequent controlled trials.

Inclusion Criteria:

Age 18-85 years. Diagnosis of septic shock according to Sepsis-3 criteria, requiring norepinephrine to maintain MAP ≥65 mmHg after adequate fluid resuscitation.

Persistent tachycardia after initial hemodynamic optimization, adequate analgesia/sedation, and correction of reversible causes, defined as heart rate ≥95 beats/min.

Continuous norepinephrine infusion for ≥6 hours, with norepinephrine dose ≥0.10 μg/kg/min at enrollment.

Adequate volume status or absence of fluid responsiveness assessed by dynamic indices, echocardiography, or advanced hemodynamic monitoring; if PiCCO is used, GEDVI >700 mL/m² and/or ITBVI >850 mL/m² may be used as supportive criteria.

Preserved or hyperdynamic cardiac function before esmolol initiation, defined as cardiac index >3.0 L/min/m² or absence of severe septic cardiomyopathy.

Ability to obtain sublingual microcirculatory images of acceptable quality at baseline.

Written informed consent obtained from the patient or legally authorized representative.

Exclusion Criteria:

Shock mainly caused by non-septic etiologies, including cardiogenic, hypovolemic, obstructive, hemorrhagic, or anaphylactic shock.

Severe cardiac dysfunction or severe septic cardiomyopathy, including cardiac index <2.2 L/min/m² despite adequate preload, severe ventricular dysfunction, or need for inotropic agents at enrollment.

Use of β-blockers before ICU admission or within 24 hours before enrollment. Contraindications to esmolol or β-blockade, including high-grade atrioventricular block without pacing, severe bradycardia, sick sinus syndrome, severe bronchospasm/asthma, or known allergy to esmolol.

Severe structural heart disease or major pulmonary conditions affecting hemodynamics or safety, including severe valvular disease, significant congenital heart disease, cardiomyopathy, severe pulmonary bullae, or untreated pneumothorax.

Acute coronary syndrome, life-threatening arrhythmia, or cardiac arrest before enrollment during the current ICU stay.

Conditions interfering with sublingual microcirculatory assessment, including major oral/sublingual lesions, active oral bleeding, inability to access the sublingual area, or poor baseline image quality.

Pregnancy or lactation, expected death or withdrawal of life-sustaining treatment within 24 hours, expected ICU stay <48 hours, or inability to obtain informed consent.