Efficacy and Safety of Balanced Gelatin Solution for Fluid Infusion in Sepsis Patients Undergoing Emergency Abdominal Surgery: A Multicenter, Adaptive Designed, Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 318
- 试验地点
- 16
- 主要终点
- Primary Outcome 1: Net fluid balance within 24 hours after surgery
研究概览
简要总结
The goal of this randomized clinical trial is to evaluate whether balanced gelatin solution is more effective and safe than balanced crystalloid solution for perioperative fluid management in adults with sepsis undergoing emergency abdominal surgery. Sepsis often causes severe fluid loss from the bloodstream into tissues, leading to low blood pressure, impaired organ function, and the need for urgent fluid resuscitation. Balanced gelatin, a colloid solution, may help maintain intravascular volume more effectively than crystalloid alone.
In this study, participants are randomly assigned in a 1:1 ratio to receive either balanced gelatin or Ringer's acetate during surgery and in the first 24 hours afterward. All patients receive standardized anesthesia care, goal-directed fluid therapy, and protocolized use of vasoactive drugs. The main questions the study aims to answer are:
- Does balanced gelatin reduce positive fluid balance within 24 hours after surgery?
- Does it improve hemodynamic stability during the early postoperative period?
- What effects does balanced gelatin have on kidney function, microcirculation, postoperative recovery, and other clinical outcomes?
Participants will be followed throughout hospitalization and contacted again on postoperative day 28 and day 90 to assess survival, complications, and health-related quality of life. The trial is double-blind, meaning that patients, clinicians, and outcome assessors do not know which fluid is being used. An independent Data and Safety Monitoring Board will oversee patient safety during the study.
The findings of this trial are expected to provide important evidence to guide perioperative fluid resuscitation strategies for septic patients undergoing emergency surgery.
详细描述
Study Background Sepsis is a life-threatening syndrome caused by a dysregulated host response to severe infection, which can rapidly progress to septic shock, multiple organ dysfunction, and death.Despite advances in recognition and treatment in recent years, sepsis remains a major global health challenge, with overall mortality rates still ranging from 18% to 30%.Pathophysiologically, sepsis is characterized by increased capillary permeability and vasodilation, resulting in substantial fluid extravasation into the interstitial space, tissue edema, and intravascular volume depletion. These changes lead to inadequate tissue perfusion, impaired oxygen delivery, and ultimately organ dysfunction. Therefore, timely and appropriate fluid resuscitation remains one of the most fundamental and essential components of sepsis management. Individualized, goal-directed fluid therapy aims to improve systemic perfusion while minimizing the risks associated with fluid overload.
In 2001, Rivers et al. introduced the concept of early goal-directed therapy (EGDT), demonstrating significant mortality reduction (30.5% vs 45%) in patients with severe sepsis and septic shock.This finding prompted widespread adoption of early aggressive fluid resuscitation. However, three large multicenter trials published between 2014 and 2015 (ARISE, ProCESS, and ProMISe) later found no significant mortality differences between EGDT and usual care (approximately 18-25%).These results suggested that with improvements in routine clinical practice, contemporary usual care may already include adequate hemodynamic optimization.
Based on this evidence, the 2016 Surviving Sepsis Campaign (SSC) guidelines recommended administration of at least 30 mL/kg of crystalloid fluid within the first 3 hours for patients with sepsis-induced hypoperfusion, followed by hemodynamic-guided adjustment.Because many participants in these large trials had already received similar volumes before randomization, this dosage became associated with favorable outcomes. The 2021 SSC guideline retained this recommendation, though downgraded from a "strong" to a "weak" recommendation in the absence of new high-quality evidence.This highlights persistent uncertainty and the need for further research on optimal fluid type and strategy in sepsis resuscitation.
Increasing attention has been paid to microcirculation in recent years. While macrocirculatory parameters such as blood pressure may normalize after resuscitation, this does not necessarily indicate restoration of tissue-level perfusion.Persistent microcirculatory dysfunction may contribute to inadequate oxygen delivery and delayed organ recovery. Understanding how different fluid therapies influence both macro- and microcirculation is therefore crucial for optimizing outcomes.
Currently used resuscitation fluids include crystalloids and colloids. Crystalloids rapidly redistribute into the interstitial space and may exacerbate tissue edema-particularly in sepsis where capillary permeability is increased-potentially impairing microcirculatory flow.Colloids contain larger molecules that remain intravascular for longer periods, generating oncotic pressure and maintaining circulating volume more effectively, which may theoretically support microcirculatory perfusion and oxygen delivery. Clinically used colloids include albumin, hydroxyethyl starch (HES), and gelatin. Albumin is effective but costly and limited in availability. HES has fallen out of favor due to its association with kidney injury and increased mortality in sepsis.Gelatin, derived from bovine collagen hydrolysates, is now the only artificial colloid still recommended by guidelines for hypovolemia in sepsis patients.Nevertheless, high-quality randomized controlled evidence comparing gelatin with crystalloids in sepsis remains insufficient.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
This trial uses a double-blind design. Participants, treating clinicians, investigators, outcome assessors, and statisticians are all blinded to treatment allocation. To ensure masking, study fluids are packaged in identical opaque containers, prepared and labeled by independent unblinded coordinators who are not involved in subject recruitment, clinical intervention, follow-up, or data analysis. A double-check system involving an independent witness is implemented during the drug packaging and labeling process. Strict role isolation is maintained throughout the study to prevent any bias in treatment execution or outcome assessment. Emergency unblinding is strictly limited to patient safety emergencies and must be documented.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years.
- •Diagnosis of sepsis according to the Sepsis-3 definition, caused by intra-abdominal infection, and requiring emergency abdominal surgery for source control.
- •Sequential Organ Failure Assessment (SOFA-2) score ≥ 2 (determined by the most recent available clinical data) and blood lactate > 2 mmol/L (measured within 6 hours prior to enrollment).
- •Subject or legal representative can understand the study purpose and provide written informed consent.
排除标准
- •Received any dose of artificial colloids within 24 hours prior to randomization.
- •Predicted mortality within 48 hours (ASA physical status class ≥ V).
- •Atrial fibrillation or congestive heart failure.
- •Severe Acute Respiratory Distress Syndrome (ARDS).
- •Preoperative coagulation dysfunction or receiving anticoagulant therapy.
- •Preoperative requirement for renal replacement therapy (long-term or intermittent, including hemodialysis or peritoneal dialysis).
- •Acute burns exceeding 10% of the total body surface area.
- •Severe hepatic impairment.
- •Severe electrolyte disturbance.
- •Pregnancy or breastfeeding.
- •Known allergy to gelatin.
- •Current participation in other interventional clinical trials.
- •Other conditions that the investigator considers inappropriate for inclusion.
研究组 & 干预措施
Balanced Gelatin Solution
Patients randomized to the balanced gelatin group receive balanced gelatin solution (4% succinylated gelatin in a balanced crystalloid carrier) for volume expansion during the surgical procedure, guided by a stroke volume (SV) monitoring protocol. The study fluid management may continue for up to 24 hours post-randomization according to clinical needs. The cumulative dose of balanced gelatin is capped at 30 mL/kg (ideal body weight) within the first 24 hours; once reached or when the study fluid is unavailable, Ringer's acetate is used for subsequent resuscitation.
干预措施: Balanced Gelatin Solution (Drug)
Crystalloid Solution
Patients randomized to the crystalloid group receive acetate Ringer's solution as the sole resuscitation fluid during emergency abdominal surgery for sepsis, according to the same goal-directed protocol guided by stroke volume monitoring. No gelatin solution or lactate-containing crystalloids will be administered within the first 24 hours post-randomization. The total volume of crystalloid infusion is not limited.
干预措施: Acetate Ringer's Solution (Drug)
结局指标
主要结局
Primary Outcome 1: Net fluid balance within 24 hours after surgery
时间窗: Intraoperative period and postoperative 24 hours
\[Hierarchical Testing Sequence: 1st\] This is the first primary endpoint in the hierarchical testing sequence. Net fluid balance is defined as the difference between total infused volume and total output volume during surgery and the first 24 postoperative hours. Input volume includes all study fluids (balanced gelatin solution or acetate Ringer's), albumin, blood products, and maintenance crystalloid infusion. Excluded are solvent volumes \<50 mL and non-therapeutic fluids such as irrigation or enteral/oral intake. Albumin is recorded in mL of solution administered. Blood product volumes are standardized: packed red blood cells 1 unit = 200 mL; plasma = actual volume; apheresis platelets 1 therapeutic dose = 250 mL; cryoprecipitate 1 unit = 25 mL (with center-specific adjustment allowed). Output volume includes intraoperative blood loss, urine output, and measurable drainage (thoracic, abdominal, nasogastric, etc.), excluding insensible or unmeasurable losses.
Primary Outcome 2: Proportion of patients achieving hemodynamic stability within 24 hours after surgery
时间窗: Postoperative 24 hours
\[Hierarchical Testing Sequence: 2nd\] This is the second primary endpoint in the hierarchical testing sequence. Hemodynamic stability (HDS) is defined as meeting all of the following three criteria at postoperative 24 hours: 1. Mean arterial pressure (MAP) ≥65 mmHg without vasopressor support, sustained ≥1 hour after discontinuation of vasopressors, with all subsequent MAP measurements ≥65 mmHg. 2. Blood lactate ≤2 mmol/L, based on the most recent venous or arterial sample. 3. Urine output ≥1 mL/kg/h, based on the average over the preceding 6 hours. The outcome measure is the percentage of patients in each group who fulfill all three criteria.
次要结局
- Secondary Outcome 1.1: Intensity of study drug use within 24 hours after surgery(Randomization to postoperative 24 hours)
- Secondary Outcome 1.2: Blood product utilization rate within 24 hours after surgery(Randomization to postoperative 24 hours)
- Secondary Outcome 1.3: Vasopressor load within 24 hours after surgery(Randomization to postoperative 24 hours)
- Secondary Outcome 1.4: Proportion of patients receiving inotropic drugs within 24 hours after surgery(Randomization to postoperative 24 hours)
- Secondary Outcome 2.1: Intraoperative lactate reduction magnitude(Baseline to end of surgery)
- Secondary Outcome 2.2: 24-hour lactate reduction magnitude(Baseline to postoperative 24 hours)
- Secondary Outcome 2.3: Normalization rate of capillary refill time (CRT) at end of surgery(From baseline to end of surgery)
- Secondary Outcome 3.1: Proportion of patients with decrease in SOFA score at postoperative day 3 compared with baseline(Baseline (preoperative) to postoperative day 3)
- Secondary Outcome 3.2: Proportion of patients with severe organ dysfunction within 3 days after surgery(Postoperative day 1 to day 3)
- Secondary Outcome 3.3: Incidence of acute kidney injury within 3 days after surgery(Baseline to postoperative day 3)
- Secondary Outcome 3.4: Cumulative duration of renal replacement therapy within 28 days after surgery(Postoperative day 1 to day 28)
- Secondary Outcome 3.5: Incidence of coagulopathy within 3 days after surgery(Baseline to postoperative day 3)
- Secondary Outcome 3.6: Duration of ventilator-free time within 24 hours after surgery(Postoperative 24 hours)
- Secondary Outcome 3.7: Duration of ventilator-free time within 7 days after surgery(Postoperative day 1 to day 7)
- Secondary Outcome 3.8: Duration of vasopressor-free time within 24 hours after surgery(Postoperative 24 hours)
- Secondary Outcome 3.9: Duration of vasopressor-free time within 72 hours after surgery(Postoperative day 1 to day 3)
- Secondary Outcome 4.1: Length of ICU stay(From ICU admission to ICU discharge)
- Secondary Outcome 4.2: Length of total hospital stay(From hospital admission to discharge)
- Secondary Outcome 5.1: All-cause mortality within 28 days after surgery(Postoperative day 1 to day 28)
- Secondary Outcome 5.2: All-cause mortality within 90 days after surgery(Postoperative day 1 to day 90)