Remimazolam Versus Propofol for Early Recovery After Cytoreductive Surgery

N/ANot Yet RecruitingNCT07785557

Beijing Tsinghua Chang Gung Hospital320 enrolled

Overview

The REPAIR Trial is a single-center, prospective, randomized, parallel-group superiority trial enrolling 320 adults scheduled for elective cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC). Participants will be assigned 1:1 to bispectral index-guided remimazolam- or propofol-based general anesthesia under standardized perioperative care. The primary objective is to determine whether remimazolam improves patient-reported recovery 48 ± 4 hours after surgery, measured by the Chinese 15-item Quality of Recovery score (QoR-15; range, 0 to 150; higher scores indicate better recovery). The investigators hypothesize that remimazolam will produce a higher 48-hour QoR-15 score than propofol. Secondary outcomes will characterize recovery at 24 and 72 hours, intraoperative hypotension burden and vasopressor use, acute kidney injury, infection, delirium, respiratory complications, other safety events, and 30-day mortality.

Cytoreductive surgery for peritoneal surface malignancies often involves extensive peritoneal stripping, multivisceral resection, major fluid shifts, and prolonged anesthesia. Some patients also receive HIPEC. Propofol may cause vasodilation and cardiovascular depression, whereas remimazolam may provide greater hemodynamic stability. Whether this difference translates into clinically meaningful improvement in overall postoperative recovery remains uncertain. After written informed consent and completion of baseline assessments, eligible participants will be randomized 1:1 using variable block sizes of 4, 6, or 8, stratified by whether HIPEC is planned. Allocation will be obtained from a permission-controlled electronic randomization system after eligibility is reconfirmed in the operating room and immediately before the first assigned study hypnotic. Participants, postoperative QoR-15 assessors, complication adjudicators, and the primary statistician will remain masked. Anesthesia clinicians cannot be masked because they must titrate the assigned drug. Both groups will receive bispectral index-guided total intravenous anesthesia with a target BIS of 40 to 60 and standardized principles for analgesia, hemodynamic rescue, temperature management, neuromuscular monitoring, extubation, and intensive care. Surgery end is defined as completion of skin closure, and all postoperative assessment windows are anchored to that time. The primary outcome is the Chinese QoR-15 total score 48 ± 4 hours after surgery. The primary analysis will use analysis of covariance or an equivalent general linear model with treatment group, baseline QoR-15 score, and planned HIPEC stratum as covariates. The adjusted between-group mean difference, 95% confidence interval, and two-sided P value will be reported. The sample size of 320 provides 90% power to detect a 6-point difference assuming a common standard deviation of 15 and allowing 15% for an unavailable primary outcome or loss to follow-up.

Interventions

RemimazolamDRUG

Remimazolam is infused intravenously at 6 mg/kg/hour for induction. If a Modified Observer's Assessment of Alertness/Sedation score of 1 or lower is not reached after 3 minutes, the rate is increased to 12 mg/kg/hour. After loss of consciousness, maintenance starts at 1.0 mg/kg/hour and is adjusted in steps of 0.2 mg/kg/hour at intervals of at least 5 minutes within an allowed range of 0.5 to 2.0 mg/kg/hour to maintain BIS 40 to 60. Infusion stops at completion of skin closure. Dosing weight is actual body weight for BMI below 30 kg/m² and adjusted body weight for BMI of 30 kg/m² or higher. Flumazenil is not used routinely and is reserved for clinically indicated rescue.

PropofolDRUG

Propofol 1.5 to 2.5 mg/kg is administered intravenously over 60 to 90 seconds for induction. After loss of consciousness, maintenance starts at 6 mg/kg/hour and is adjusted in steps of 1 mg/kg/hour at intervals of at least 5 minutes. The usual range is 4 to 10 mg/kg/hour and the allowed range is 3 to 12 mg/kg/hour to maintain BIS 40 to 60. Infusion stops at completion of skin closure. Dosing weight is actual body weight for BMI below 30 kg/m² and adjusted body weight for BMI of 30 kg/m² or higher.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria 1.Age 18 to 75 years. 2.American Society of Anesthesiologists physical status class II or III. 3.Pathologically confirmed primary peritoneal surface malignancy or peritoneal metastasis from colorectal, gastric, ovarian, or appendiceal malignancy. 4.Scheduled for elective cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy under general anesthesia. 5.Expected surgical duration of at least 2 hours and planned postoperative admission to the intensive care unit. 6.Able to understand and independently complete the Chinese Quality of Recovery-15 questionnaire. 7.Willing to participate and able to provide written informed consent. Exclusion Criteria 1. Emergency surgery. 2. Uncontrolled bacterial, fungal, or viral infection requiring systemic anti-infective treatment within 14 days before surgery, or temperature of 38.0 °C or higher at post-consent eligibility confirmation with corresponding clinical, imaging, microbiological, or laboratory evidence. Perioperative antimicrobial prophylaxis is not an exclusion. 3. Child-Pugh class C, total bilirubin greater than 3 times the upper limit of normal, or alanine or aspartate aminotransferase greater than 5 times the upper limit of normal. 4. Estimated glomerular filtration rate below 30 mL/min/1.73 m² or maintenance renal replacement therapy. 5. Known allergy to remimazolam, benzodiazepines, propofol, or their excipients, or a contraindication to either study drug. 6. Continuous or near-daily opioid use for at least 90 days before surgery, or benzodiazepine or Z-drug use on at least 5 days per week for at least 4 weeks. 7. Severe cognitive, psychiatric, hearing, speech, or language impairment that prevents understanding and independent completion of the QoR-15 after standardized explanation. 8. Pregnancy or breastfeeding. 9. A preoperative plan for continuous epidural analgesia or another continuous regional analgesic technique that is incompatible with the study's standardized intravenous analgesia pathway. 10. A specific clinical condition that, in the investigator's judgment, would make participation pose an unacceptable risk.

Outcomes

Primary Outcomes

Quality of Recovery-15 total score at 48 hours

The validated Chinese QoR-15 contains 15 items scored from 0 to 10. The total score ranges from 0 to 150, with higher scores indicating better recovery. The first valid assessment within the prespecified window is used. If any item cannot be completed, the total score is missing rather than prorated. Participants who die before the assessment window are not assigned a score of zero; mortality is reported separately and addressed in prespecified sensitivity analyses.

Time frame: 48 ± 4 hours after the end of surgery, defined as completion of skin closure (allowable window, 44 to 52 hours)

Secondary Outcomes

Quality of Recovery-15 total score at 24 hours

Chinese QoR-15 total score, ranging from 0 to 150, with higher scores indicating better recovery. The first valid assessment in the prespecified window is used.

Time frame: 24 ± 2 hours after completion of skin closure (allowable window, 22 to 26 hours)

Cumulative duration of mean arterial pressure below 65 mmHg

Total number of valid monitored minutes with mean arterial pressure below 65 mmHg.

Time frame: From initiation of the assigned study hypnotic until completion of skin closure during the index surgery

Time-weighted average of mean arterial pressure below 65 mmHg

TWA-MAP65 is calculated as the area under the threshold of 65 mmHg divided by valid arterial-pressure monitoring time. It reflects both depth and duration of hypotension and is reported in mmHg. Invasive arterial pressure data are summarized as one-minute medians after prespecified artifact handling.

Time frame: From initiation of the assigned study hypnotic until completion of skin closure during the index surgery

Quality of Recovery-15 total score at 72 hours

Chinese QoR-15 total score, ranging from 0 to 150, with higher scores indicating better recovery. Participants discharged before the visit may complete the assessment by a masked telephone interview.

Time frame: 72 ± 6 hours after completion of skin closure (allowable window, 66 to 78 hours)

Proportion of valid monitoring time with mean arterial pressure below 65 mmHg

Percentage of valid invasive arterial-pressure monitoring time during which mean arterial pressure is below 65 mmHg.

Time frame: From initiation of the assigned study hypnotic until completion of skin closure during the index surgery

Lowest intraoperative mean arterial pressure

Lowest valid one-minute median mean arterial pressure, reported in mmHg, after application of prespecified artifact rules.