Hemodynamic Instability, Microcirculatory Dysfunction, Septic Shock, Sublingual Microcirculation
Conditions
Keywords
Septic shock, Papaverine, Sublingual microcirculation, Microcirculatory dysfunction, Vascular waterfall phenomenon, Critical closing pressure, Perfused vessel density, Microvascular flow index, Proportion of perfused vessels, Pilot physiological study
Brief summary
This is a prospective, multicenter, single-arm, open-label, pilot physiological study designed to evaluate the effects of intravenous papaverine on sublingual microcirculation and the vascular waterfall phenomenon in adult patients with septic shock. Eligible patients will have septic shock according to Sepsis-3 criteria, require norepinephrine support after adequate fluid resuscitation, and have PiCCO-based hemodynamic monitoring available before papaverine administration. Papaverine will be administered as an intravenous infusion of 30 mg over 10 minutes, followed by a continuous infusion of 2-5 mg/hour. Sublingual microcirculatory variables, vascular-waterfall-related indices, PiCCO-derived hemodynamic variables, macrocirculatory parameters, tissue perfusion variables, vasopressor dose, and safety outcomes will be assessed before and after papaverine administration. The study aims to explore whether papaverine can improve microvascular perfusion and reduce microcirculatory flow impairment in septic shock, and to provide preliminary physiological and safety data for future controlled trials.
Detailed description
Septic shock is characterized by profound circulatory and metabolic abnormalities, including systemic vasodilation, endothelial dysfunction, altered vascular tone, impaired tissue perfusion, and microcirculatory heterogeneity. Sublingual microcirculatory alterations, such as reduced perfused vessel density, decreased proportion of perfused vessels, impaired microvascular flow index, and increased flow heterogeneity, have been associated with organ dysfunction and adverse outcomes in septic shock. In addition to global hemodynamic derangements, septic shock may involve abnormal regulation of the effective downstream pressure of the circulation. The vascular waterfall phenomenon refers to a physiological condition in which blood flow is limited by a critical closing pressure or effective downstream pressure that exceeds venous pressure, resulting in impaired flow despite an apparently adequate macrocirculatory pressure gradient. This phenomenon may contribute to the dissociation between macrocirculation and microcirculation observed in septic shock. Papaverine is a non-selective phosphodiesterase inhibitor and direct smooth muscle relaxant with vasodilatory properties. It has been used clinically to relieve vascular spasm and improve regional blood flow in different vascular beds. By reducing vascular smooth muscle tone, papaverine may improve microvascular perfusion and influence vascular-waterfall-related physiology. However, its effects on sublingual microcirculation and vascular waterfall phenomenon in septic shock remain unclear. In this study, patients with septic shock will undergo baseline measurements before papaverine initiation. Papaverine will then be administered intravenously at 30 mg over 10 minutes, followed by continuous infusion at 2-5 mg/hour. The infusion rate may be adjusted according to mean arterial pressure, heart rate, vasopressor requirement, PiCCO-derived hemodynamic variables, and adverse events. Sublingual microcirculation will be assessed using handheld vital microscopy. PiCCO-derived hemodynamics, arterial pressure, central venous pressure, lactate, urine output, vasopressor dose, and safety variables will be recorded at predefined time points. This pilot physiological study is intended to generate preliminary data regarding the microcirculatory effects, vascular-waterfall-related effects, feasibility, and safety of papaverine in patients with septic shock.
Interventions
DRUGPapaverine
Papaverine will be administered intravenously as 30 mg infused over 10 minutes, followed by continuous infusion at 2-5 mg/hour. The maintenance infusion rate may be adjusted according to the patient's hemodynamic status, mean arterial pressure, heart rate, vasopressor requirement, PiCCO-derived variables, and adverse events. Dose reduction, temporary interruption, or discontinuation of papaverine is permitted for safety reasons, including clinically significant hypotension, rapidly increasing vasopressor requirement, new-onset or worsening arrhythmia, myocardial ischemia, severe liver function abnormality, or any other clinically significant adverse event judged by the treating physician or investigator.
Sponsors
First Affiliated Hospital of Wannan Medical College
The First Affiliated Hospital of Bengbu Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
All enrolled patients will receive intravenous papaverine in addition to standard care for septic shock. Physiological measurements will be performed before and after papaverine administration.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-85 years. * Septic shock according to Sepsis-3 criteria, defined as suspected or documented infection requiring vasopressors 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 continuous norepinephrine infusion at enrollment. * Receiving invasive mechanical ventilation at enrollment, allowing assessment of vascular waterfall-related hemodynamic variables. * PiCCO-based hemodynamic monitoring, invasive arterial pressure monitoring, and central venous access available before papaverine administration. * 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 primarily caused by non-septic etiologies, including cardiogenic, hypovolemic, obstructive, hemorrhagic, or anaphylactic shock. * Expected death or planned withdrawal of life-sustaining treatment within 24 hours. * Known allergy or hypersensitivity to papaverine. * Severe hemodynamic instability judged unsuitable for papaverine by the treating physician, including refractory hypotension or rapidly escalating vasopressor requirement. * Clinically significant arrhythmia, high-grade atrioventricular block, acute coronary syndrome, or active myocardial ischemia before enrollment. * Severe hepatic dysfunction judged by the investigator to substantially increase the risk of papaverine-related adverse effects. * Conditions preventing reliable 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 Sublingual Microvascular Flow Index | Baseline, 3 hours, and 6 hours after initiation of papaverine | 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 each post-papaverine time point. |
| Change From Baseline in Pcc-Pmsf Gradient | Baseline, 3 hours, and 6 hours after initiation of papaverine | 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 each post-papaverine time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Perfused Vessel Density | Baseline, 3 hours, and 6 hours after initiation of papaverine | Perfused vessel density will be measured from sublingual microcirculatory images. The outcome is the change in PVD from baseline to each post-papaverine time point |
| Change From Baseline in Proportion of Perfused Vessels | Baseline, 3 hours, and 6 hours after initiation of papaverine | Proportion of perfused vessels will be measured from sublingual microcirculatory images. The outcome is the change in PPV from baseline to each post-papaverine time point |
| Change From Baseline in Microcirculatory Heterogeneity Index | Baseline, 3 hours, and 6 hours after initiation of papaverine | Microcirculatory heterogeneity index will be calculated from sublingual microcirculatory measurements. The outcome is the change in HI from baseline to each post-papaverine time point. |
| Change From Baseline in Estimated Critical Closing Pressure | Baseline, 3 hours, and 6 hours after initiation of papaverine | Estimated critical closing pressure will be calculated using predefined hemodynamic methods. The outcome is the change in Pcc from baseline to each post-papaverine time point. |
| Change From Baseline in Estimated Mean Systemic Filling Pressure | Baseline, 3 hours, and 6 hours after initiation of papaverine | Estimated mean systemic filling pressure will be calculated using predefined hemodynamic methods. The outcome is the change in Pmsf from baseline to each post-papaverine time point |
| Change From Baseline in Mean Arterial Pressure | Baseline, 3 hours, and 6 hours after initiation of papaverine | 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 each post-papaverine time point. |
| Change From Baseline in Cardiac Index | Baseline, 3 hours, and 6 hours after initiation of papaverine | Cardiac index will be measured using PiCCO-based transpulmonary thermodilution and/or pulse contour analysis. The outcome is the change in cardiac index from baseline to each post-papaverine time point. |
| Change From Baseline in Norepinephrine Dose | Baseline, 3 hours, and 6 hours after initiation of papaverine | 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 each post-papaverine time point. |
| Change From Baseline in Arterial Lactate | Baseline and 6 hours after initiation of papaverine | Arterial lactate concentration will be measured according to routine clinical practice. The outcome is the change in lactate from baseline to 6 hours after initiation of papaverine. |
| 28-Day Mortality | 28 days after enrollment | All-cause mortality within 28 days after enrollment. |
| Ventilator-Free Days at Day 28 | 28 days after enrollment. | Number of days alive and free from invasive mechanical ventilation within 28 days after enrollment |
| Incidence of Prespecified Adverse Events | From initiation of papaverine to 6 hours after initiation | Prespecified adverse events include clinically significant hypotension, new-onset or worsening arrhythmia, suspected myocardial ischemia, reduction in cardiac index requiring treatment modification, escalation of vasopressor or inotropic support, interruption or discontinuation of papaverine for safety reasons, cardiac arrest, or other clinically significant events during the observation period |
Countries
China
Contacts
CONTACTqiancheng xu, PhD
Outcome results
None listed