Critical Illness, Sepsis, Septic Shock
Conditions
Keywords
dexmedetomidine, septic shock, sublingual microcirculation, microvascular flow index, vascular waterfall, critical closing pressure, mean systemic filling pressure, Pcc, Pmsf, PiCCO, mechanical ventilation, sedation, bradycardia, hypotension, norepinephrine
Brief summary
This prospective, multicenter, single-arm, open-label interventional pilot study aims to evaluate the short-term physiological effects of intravenous dexmedetomidine on sublingual microcirculation and vascular-waterfall parameters in adult patients with septic shock. Eligible patients will have septic shock according to Sepsis-3 criteria, require norepinephrine support after adequate fluid resuscitation, receive invasive mechanical ventilation, and have PiCCO-based hemodynamic monitoring available before dexmedetomidine initiation. After baseline assessment, participants will receive intravenous dexmedetomidine according to the study protocol. Dexmedetomidine will be administered as a continuous intravenous infusion at 0.2-0.7 µg/kg/hour without a loading dose. The infusion rate may be adjusted according to the target sedation level, hemodynamic status, and adverse effects. 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, 3 hours, and 6 hours after initiation of dexmedetomidine. Systemic hemodynamic, perfusion, vasopressor, PiCCO-derived, sedation-related, and safety outcomes will also be collected. The primary objective is to characterize immediate changes in sublingual microcirculation and vascular-waterfall physiology after dexmedetomidine administration and to provide preliminary data for future controlled studies.
Detailed description
Septic shock is characterized by profound circulatory dysfunction involving both the macrocirculation and the microcirculation. Although conventional resuscitation targets such as mean arterial pressure, cardiac output, and serum lactate are widely used, microcirculatory alterations may persist despite apparent stabilization of systemic hemodynamics. Direct evaluation of sublingual microcirculation may therefore provide additional physiological information in patients with septic shock. Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist commonly used for sedation in critically ill patients. Compared with traditional sedatives, dexmedetomidine provides cooperative sedation with limited respiratory depression and may modulate sympathetic tone, inflammation, endothelial function, and regional perfusion. However, dexmedetomidine may also cause bradycardia, hypotension, and changes in vascular tone, which may influence systemic hemodynamics and microcirculatory perfusion. Its immediate effects on directly visualized sublingual microcirculation and vascular-waterfall physiology in patients with septic shock remain insufficiently characterized. The vascular-waterfall phenomenon refers to the concept that tissue perfusion is influenced not only by arterial and venous pressures but also by the relationship between upstream pressure, critical closing pressure, and mean systemic filling pressure. In septic shock, changes in vascular tone, vasopressor exposure, stressed blood volume, venous return, and cardiac output may alter the effective pressure gradient for tissue perfusion. Evaluation of vascular-waterfall variables together with direct sublingual microcirculatory imaging may provide mechanistic insight into the physiological effects of dexmedetomidine beyond conventional macrocirculatory variables. This is a prospective, multicenter, single-arm, open-label, interventional pilot physiological 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, ongoing norepinephrine support, invasive mechanical ventilation with a clinical need for sedation, and PiCCO-based hemodynamic monitoring available before dexmedetomidine initiation. Patients with contraindications to dexmedetomidine, severe bradycardia, high-grade atrioventricular block without a pacemaker, severe uncontrolled arrhythmia, severe hemodynamic instability judged unsuitable for dexmedetomidine, or conditions interfering with sublingual microcirculatory imaging will be excluded. After informed consent is obtained, baseline measurements will be performed immediately before dexmedetomidine administration. Dexmedetomidine will be administered as a continuous intravenous infusion at 0.2-0.7 µg/kg/hour without a loading dose. The dose may be titrated by the treating physician according to the target sedation level, hemodynamic status, heart rate, vasopressor requirement, and adverse effects. The target sedation level will generally be light-to-moderate sedation according to local ICU practice, such as a Richmond Agitation-Sedation Scale score between -2 and 0, unless otherwise clinically indicated. Dose reduction, temporary interruption, or discontinuation will be permitted for safety reasons, including clinically significant hypotension, bradycardia, new-onset or worsening arrhythmia, high-grade atrioventricular block, increased vasopressor requirement, suspected myocardial ischemia, or other clinically significant adverse events. Study assessments will be performed at baseline, 3 hours, and 6 hours after initiation of dexmedetomidine. 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, capillary refill time, Richmond Agitation-Sedation Scale score, and PiCCO-derived variables, will also be recorded. Approximately 20 patients will be enrolled to assess feasibility and generate preliminary estimates of physiological changes after dexmedetomidine administration. The main analyses will describe changes from baseline in sublingual microcirculatory and vascular-waterfall parameters over the 6-hour observation period. Safety events, especially bradycardia, hypotension, high-grade atrioventricular block, and increased vasopressor requirement, will be summarized descriptively to inform the design of subsequent controlled studies.
Interventions
Dexmedetomidine will be administered as a continuous intravenous infusion at 0.2-0.7 µg/kg/hour without a loading dose. The infusion rate may be adjusted according to the target sedation level, heart rate, mean arterial pressure, vasopressor requirement, PiCCO-derived hemodynamic variables, and adverse effects. Dose reduction, temporary interruption, or discontinuation is permitted for safety reasons, including clinically significant hypotension, bradycardia, new-onset or worsening arrhythmia, high-grade atrioventricular block, suspected myocardial ischemia, increased vasopressor requirement, or other clinically significant adverse events. The actual dose, infusion duration, and reasons for dose adjustment or discontinuation will be recorded.
Sponsors
First Affiliated Hospital of Wannan Medical College
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
All enrolled participants will receive intravenous dexmedetomidine and undergo repeated physiological assessments before and after treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-85 years. * Diagnosis of septic shock according to Sepsis-3 criteria, defined as suspected or documented infection with vasopressor requirement to maintain mean arterial pressure ≥65 mmHg and serum lactate \>2 mmol/L after adequate fluid resuscitation. * Enrollment within 24 hours after diagnosis of septic shock in the ICU. * Receiving invasive mechanical ventilation. * Receiving continuous intravenous sedative and/or analgesic therapy other than dexmedetomidine before enrollment, with a clinical decision to add dexmedetomidine for sedation management. * Continuous norepinephrine infusion at enrollment. * PiCCO catheter in place and PiCCO-based hemodynamic monitoring available before dexmedetomidine initiation. * Written informed consent obtained from the patient or legally authorized representative.
Exclusion criteria
* Shock primarily caused by non-septic etiologies, including cardiogenic, hypovolemic, obstructive, hemorrhagic, or anaphylactic shock. * Expected death or withdrawal of life-sustaining treatment within 24 hours. * Known allergy or hypersensitivity to dexmedetomidine. * Severe bradycardia or clinically significant conduction abnormality before enrollment, including heart rate \<50 beats/min, second-degree or third-degree atrioventricular block, sick sinus syndrome, or other conduction abnormality without a functioning pacemaker. * Severe uncontrolled arrhythmia, acute coronary syndrome, or clinically significant myocardial ischemia before enrollment. * Severe hemodynamic instability judged unsuitable for dexmedetomidine by the treating physician, including refractory hypotension or rapidly escalating vasopressor requirement. * Severe hepatic dysfunction judged by the investigator to substantially increase the risk of dexmedetomidine accumulation or adverse effects. * Conditions interfering with sublingual microcirculatory assessment, including major oral or sublingual lesions, active oral bleeding, inability to access the sublingual area, or poor baseline image quality. * Pregnancy or lactation. * Participation in another interventional clinical trial that may affect study outcomes or safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pcc-Pmsf Gradient | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | The vascular-waterfall pressure gradient will be calculated as the difference between estimated critical closing pressure and estimated mean systemic filling pressure. The outcome is the change in Pcc-Pmsf from baseline to 3 and 6 hours after dexmedetomidine initiation. |
| Change From Baseline in Sublingual Microvascular Flow Index | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Microvascular flow index will be assessed using sublingual microcirculatory imaging. Three to five sublingual video fields will be recorded at each time point, and MFI will be calculated according to standard microcirculatory scoring methods. The outcome is the change in MFI from baseline to 3 and 6 hours after dexmedetomidine initiation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Perfused Vessel Density | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Perfused vessel density will be measured from sublingual microcirculatory images. The outcome is the change in PVD from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Proportion of Perfused Vessels | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine. | Proportion of perfused vessels will be measured from sublingual microcirculatory images. The outcome is the change in PPV from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Microcirculatory Heterogeneity Index | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Microcirculatory heterogeneity index will be calculated from sublingual microcirculatory measurements. The outcome is the change in HI from baseline to 3 and 6 hours after dexmedetomidine initiation. |
| Change From Baseline in Estimated Critical Closing Pressure | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Estimated critical closing pressure will be calculated using predefined hemodynamic methods based on arterial pressure waveform-derived parameters and PiCCO-based cardiac output measurements. The outcome is the change in Pcc from baseline to 3 and 6 hours after dexmedetomidine initiation. |
| Change From Baseline in Estimated Mean Systemic Filling Pressure | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Estimated mean systemic filling pressure will be calculated using predefined hemodynamic methods based on PiCCO-derived cardiac output and systemic vascular resistance-related variables. The outcome is the change in Pmsf from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Mean Arterial Pressure | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Mean arterial pressure will be recorded from invasive arterial monitoring at each study time point. The outcome is the change in MAP from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Heart Rate | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Heart rate will be recorded from bedside monitoring at each study time point. The outcome is the change in heart rate from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Cardiac Index | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Cardiac index will be measured using PiCCO-based hemodynamic monitoring. The outcome is the change in cardiac index from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Norepinephrine Dose | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Norepinephrine dose will be recorded in µg/kg/min at each study time point. The outcome is the change in norepinephrine dose from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Arterial Lactate | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Arterial lactate concentration will be measured according to routine clinical practice. The outcome is the change in lactate from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Capillary Refill Time | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine | Capillary refill time will be assessed according to local clinical practice. The outcome is the change in capillary refill time from baseline to 3 and 6 hours after dexmedetomidine initiation |
| Change From Baseline in Richmond Agitation-Sedation Scale Score | Baseline, 3 hours, and 6 hours after initiation of dexmedetomidine. | Sedation depth will be assessed using the Richmond Agitation-Sedation Scale. The outcome is the change in RASS score from baseline to 3 and 6 hours after dexmedetomidine initiation. |
| Incidence of Clinically Significant Bradycardia | From initiation of dexmedetomidine to 6 hours after initiation. | Clinically significant bradycardia will be recorded during the observation period. Bradycardia is defined as heart rate less than 50 beats per minute, or any decrease in heart rate requiring dose reduction, temporary interruption, discontinuation of dexmedetomidine, atropine administration, pacing, or other clinical intervention |
| Incidence of Clinically Significant Hypotension | From initiation of dexmedetomidine to 6 hours after initiation. | Clinically significant hypotension will be recorded during the observation period. Hypotension is defined as mean arterial pressure less than 65 mmHg, or any decrease in blood pressure requiring fluid bolus, escalation of vasopressor or inotropic support, dose reduction, temporary interruption, or discontinuation of dexmedetomidine |
| ICU Length of Stay | From ICU admission to ICU discharge, assessed up to 28 days after enrollment. | Number of days from ICU admission to ICU discharge. |
| 28-Day Mortality | 28 days after enrollment. | All-cause mortality within 28 days after enrollment. |
Countries
China
Contacts
CONTACTqiancheng xu
Outcome results
None listed