Peritoneal Neoplasms, Postoperative Recovery
Conditions
Keywords
Cytoreductive surgery, Hyperthermic intraperitoneal chemotherapy, Remimazolam, Propofol, Quality of Recovery-15, Postoperative quality of recovery, Intraoperative hypotension, Total intravenous anesthesia, Peritoneal surface malignancy
Brief summary
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.
Detailed description
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
DRUGRemimazolam
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.
DRUGPropofol
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.
Sponsors
Beijing Tsinghua Chang Gung Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Recovery-15 total score at 48 hours | 48 ± 4 hours after the end of surgery, defined as completion of skin closure (allowable window, 44 to 52 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of serious adverse events | From the first dose of assigned study hypnotic through postoperative day 30 | Number and proportion of participants with at least one serious adverse event, classified and reported according to the approved protocol and ethics requirements. |
| All-cause mortality | Within 30 days after completion of skin closure | Death from any cause. |
| Quality of Recovery-15 total score at 24 hours | 24 ± 2 hours after completion of skin closure (allowable window, 22 to 26 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. |
| Cumulative duration of mean arterial pressure below 65 mmHg | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery | Total number of valid monitored minutes with mean arterial pressure below 65 mmHg. |
| Time-weighted average of mean arterial pressure below 65 mmHg | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery | 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. |
| Quality of Recovery-15 total score at 72 hours | 72 ± 6 hours after completion of skin closure (allowable window, 66 to 78 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. |
| Proportion of valid monitoring time with mean arterial pressure below 65 mmHg | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery | Percentage of valid invasive arterial-pressure monitoring time during which mean arterial pressure is below 65 mmHg. |
| Lowest intraoperative mean arterial pressure | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery. | Lowest valid one-minute median mean arterial pressure, reported in mmHg, after application of prespecified artifact rules. |
| Time to first vasopressor administration | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery. | Elapsed time from initiation of the assigned study hypnotic to the first vasopressor dose, reported in minutes. Participants who do not receive a vasopressor are described separately. |
| Cumulative dose of vasopressors | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery. | Cumulative dose of each vasopressor is reported using the original drug units. A norepinephrine-equivalent dose may also be reported using a conversion rule finalized in the data dictionary before enrollment begins. |
| Maximum vasopressor infusion rate | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery. | Maximum recorded continuous infusion rate for each vasopressor, using drug-specific units. |
| Number of hypotension rescue episodes | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery. | Count of prespecified hypotension rescue episodes triggered by mean arterial pressure below 65 mmHg for at least 1 minute or any mean arterial pressure below 55 mmHg, after verification of the arterial waveform and clinical context. |
| Number of study-hypnotic dose reductions due to hypotension | From initiation of the assigned study hypnotic until completion of skin closure during the index surgery | Count of dose reductions of the assigned study hypnotic documented as being prompted by hypotension. |
| Incidence of acute kidney injury | From completion of skin closure through postoperative day 7 or hospital discharge, whichever occurs first. | Acute kidney injury is defined by any KDIGO criterion: serum creatinine increase of at least 0.3 mg/dL (26.5 µmol/L) within 48 hours, increase to at least 1.5 times baseline within the observation window, or urine output below 0.5 mL/kg/hour for 6 hours. KDIGO stage is also recorded. |
| Incidence of postoperative infection | Within 30 days after completion of skin closure | Occurrence of surgical-site, intra-abdominal, pulmonary, urinary-tract, catheter-related, or bloodstream infection adjudicated by masked assessors using applicable CDC/NHSN definitions and clinical, imaging, microbiological, and treatment data. |
| Incidence of postoperative delirium | Postoperative days 1 to 3 or until transfer out of the ICU, whichever occurs first. | Delirium is assessed twice daily. CAM-ICU is administered when the Richmond Agitation-Sedation Scale score is -3 or higher. Any positive CAM-ICU assessment counts as delirium for that day; reasons for inability to assess are recorded. |
| Incidence of postoperative hypoxemia | Within 7 days after completion of skin closure | Oxygen saturation below 90% or arterial oxygen tension below 60 mmHg lasting at least 10 minutes and requiring escalation of oxygen therapy. |
| Use of noninvasive ventilation | Within 7 days after completion of skin closure. | Any postoperative use of noninvasive positive-pressure ventilation for a clinical indication. |
| Use of high-flow nasal cannula oxygen | Within 7 days after completion of skin closure | Any postoperative use of high-flow nasal cannula oxygen for a clinical indication. |
| Incidence of respiratory failure | Within 7 days after completion of skin closure | Postoperative respiratory failure adjudicated according to the prespecified perioperative respiratory outcome definitions. |
| Incidence of reintubation | Within 7 days after the first planned extubation | Reinsertion of an endotracheal tube for a clinical indication after the first planned extubation. |
| Incidence of pneumonia | Within 7 days after completion of skin closure | Postoperative pneumonia adjudicated using the prespecified clinical, imaging, microbiological, and treatment criteria. Pneumonia may also satisfy the postoperative infection definition and will be reported in both relevant outcome domains without summing event counts into a new composite outcome. |
| Incidence of study-drug allergic reactions | From the first dose of assigned study hypnotic through postoperative day 30 | Any clinically diagnosed allergic or hypersensitivity reaction attributed as possibly, probably, or definitely related to a study hypnotic. |
| Incidence of bradycardia | From the first dose of assigned study hypnotic through postoperative day 30 | Heart rate below 45 beats per minute for at least 1 minute or bradycardia requiring pharmacologic treatment. |
Countries
China
Contacts
CONTACTYi Duan, MD
Outcome results
None listed