Papaverine and Sublingual Microcirculation in Septic Shock

Official title

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

Overview

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

• Drug Papaverine
  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 va

Primary outcome measures

• Change From Baseline in Sublingual Microvascular Flow Index [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Pcc-Pmsf Gradient [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]

Secondary outcome measures (12)

• Change From Baseline in Perfused Vessel Density [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Proportion of Perfused Vessels [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Microcirculatory Heterogeneity Index [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Estimated Critical Closing Pressure [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Estimated Mean Systemic Filling Pressure [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Mean Arterial Pressure [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Cardiac Index [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Norepinephrine Dose [Time frame: Baseline, 3 hours, and 6 hours after initiation of papaverine]
• Change From Baseline in Arterial Lactate [Time frame: Baseline and 6 hours after initiation of papaverine]
• 28-Day Mortality [Time frame: 28 days after enrollment]
• Ventilator-Free Days at Day 28 [Time frame: 28 days after enrollment.]
• Incidence of Prespecified Adverse Events [Time frame: From initiation of papaverine to 6 hours after initiation]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

China · 2 centers

• The First Affiliated Hospital of Bengbu Medical University — Bengbu
• The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medic — Wuhu

Identifiers

NCT: NCT07657741 · 2026-ICU08

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗