Effects of Anisodamine on Sublingual Microcirculation and Vascular Waterfall Phenomenon in Patients With Septic Shock: A Prospective, Multicenter, Single-arm, Open-label, Pilot Physiological Study
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 20
- 试验地点
- 1
研究概览
简要总结
This prospective, multicenter, single-arm, open-label interventional pilot study aims to evaluate the short-term physiological effects of intravenous anisodamine on sublingual microcirculation and vascular-waterfall parameters in adult patients with septic shock.
Eligible patients will have septic shock according to Sepsis-3 criteria, will require norepinephrine support after adequate fluid resuscitation, and will be receiving invasive mechanical ventilation and PiCCO-based hemodynamic monitoring. After baseline assessment, participants will receive intravenous anisodamine according to the study protocol. Anisodamine will be administered as a loading dose of 0.5 mg/kg within 3 minutes, with a minimum dose of 20 mg and a maximum dose of 40 mg, followed by continuous infusion at 0.02-0.1 mg/kg/hour, with a maximum total daily dose of 200 mg.
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 anisodamine. Systemic hemodynamic, perfusion, vasopressor, PiCCO-derived variables, and safety outcomes will also be collected.
The primary objective is to characterize immediate changes in sublingual microcirculation and vascular-waterfall physiology after anisodamine administration and to provide preliminary data for future controlled studies.
详细描述
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.
Anisodamine is a non-specific muscarinic cholinoceptor antagonist that has been used in China as an adjunctive therapy in septic shock. Previous clinical studies suggest that anisodamine may improve microcirculatory perfusion, reduce lactate levels, and decrease vasopressor requirements in selected patients with septic shock. However, its immediate effects on directly visualized sublingual microcirculation and vascular-waterfall physiology 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, vascular closing pressure, and stressed blood volume 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 anisodamine 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, and PiCCO-based hemodynamic monitoring before anisodamine initiation. Patients with contraindications to anisodamine, major conditions interfering with sublingual microcirculatory imaging, severe uncontrolled arrhythmia, or expected death or withdrawal of life-sustaining treatment within 24 hours will be excluded.
After informed consent is obtained, baseline measurements will be performed immediately before anisodamine administration. Anisodamine will be given as an intravenous loading dose of 0.5 mg/kg within 3 minutes, with a minimum dose of 20 mg and a maximum dose of 40 mg, followed by continuous intravenous infusion at 0.02-0.1 mg/kg/hour. The total daily dose will not exceed 200 mg. The maintenance dose may be adjusted by the treating physician according to the patient's microcirculatory status, serum lactate level, capillary refill time, hemodynamics, and adverse effects. Dose reduction, temporary interruption, or discontinuation will be permitted for safety reasons, including clinically significant hypotension, tachycardia, new-onset or worsening arrhythmia, prolonged QT interval, myocardial ischemia, mental status changes, urinary retention, ileus, or other clinically significant adverse events.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 or within 24 hours after ICU admission for septic shock.
- •Receiving invasive mechanical ventilation at the time of enrollment.
- •PiCCO catheter in place and PiCCO-based hemodynamic monitoring available before anisodamine initiation.
- •Continuous norepinephrine infusion at enrollment.
- •Adequate initial fluid resuscitation and hemodynamic optimization as judged by the treating physician, with volume status assessed by dynamic indices, echocardiography, or PiCCO-derived variables.
- •Ability to obtain sublingual microcirculatory images of acceptable quality at baseline.
- •Written informed consent obtained from the patient or legally authorized representative.
排除标准
- •Shock mainly 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 contraindications to anisodamine or anticholinergic therapy, including glaucoma, acute phase of intracranial hemorrhage, elevated intracranial pressure, untreated bowel obstruction, or prostatic enlargement without urinary catheterization.
- •Known allergy or hypersensitivity to anisodamine or any component of the study drug.
- •Severe or uncontrolled arrhythmia before enrollment, including sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes, uncontrolled supraventricular tachycardia, or atrial fibrillation/flutter with uncontrolled ventricular response.
- •Acute coronary syndrome, clinically significant myocardial ischemia, or cardiac arrest before enrollment during the current ICU stay.
- •Severe cardiac dysfunction judged unsuitable for anisodamine by the treating physician, including severe ventricular dysfunction, cardiogenic shock, or need for high-dose inotropic support.
- •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.
- •Immunocompromised status or agranulocytosis, including long-term immunosuppressive therapy, chemotherapy-associated severe neutropenia, or other severe immune suppression judged by the investigator.
- •Pregnancy, planned pregnancy, or lactation.
- •Participation in another interventional clinical trial that may affect study outcomes or safety.
- •Inability to obtain informed consent.
研究者
Qiancheng Xu
Principal Investigator
First Affiliated Hospital of Wannan Medical College