Background and Rationale Frailty, defined as reduced physiological reserve and stress tolerance, affects a growing proportion of elderly surgical patients. Among frail individuals undergoing gastrointestinal surgery, the incidence of postoperative delirium (POD) is reported to be as high as 54%, compared with 20% in non-frail peers. Opioid-based anaesthesia (OBA) may contribute to POD through mechanisms including prefrontal cortex inhibition, cholinergic dysfunction, and sleep-wake cycle disruption. Opioid-free anaesthesia (OFA) utilises multimodal non-opioid drugs (e.g., dexmedetomidine, esketamine, esmolol) to achieve anaesthesia and analgesia while avoiding opioid exposure. However, high-quality randomised controlled trials specifically targeting frail elderly patients are lacking.
Study Design and Setting
This is a single-centre, prospective, parallel-group, superiority randomised controlled trial conducted at the First Affiliated Hospital of Shandong First Medical University, China. The protocol follows the SPIRIT 2025 guidelines. Participant enrolment is scheduled to begin on 1 May 2026.
Randomisation, Allocation Concealment, and Blinding Participants are randomised 1:1 to the OFA or OBA group using block randomisation with variable block sizes (2, 4, and 6) generated by Stata software. Allocation concealment is achieved using sequentially numbered, sealed, opaque envelopes. The envelope for a given participant is opened by the attending anaesthesiologist only after the participant enters the operating room. This is a single-blind trial: participants, surgeons, ward nurses, outcome assessors (postoperative delirium evaluators), and the statistician remain blinded to group assignment. Anaesthesiologists are not blinded because the intraoperative drug regimens differ substantially, and unblinding is necessary for safe management. Blinding of outcome assessors is reinforced by separate research personnel who perform all postoperative delirium and quality-of-recovery assessments.
Detailed Intervention Specifications Common procedures (both groups)
No premedication. General anaesthesia with tracheal intubation or laryngeal mask airway.
Monitoring: ECG, SpO₂, non-invasive/invasive blood pressure, end-tidal CO₂, bispectral index (BIS) target 40-60.
Preoxygenation with 100% oxygen for 5 min.
Ventilation settings: tidal volume 6-8 mL/kg, respiratory rate 10-14 breaths/min, I:E ratio 1:1.5-2, PEEP 5 cmH₂O (adjusted to maintain PₑₜCO₂ 35-45 mmHg).
Bilateral ultrasound-guided transversus abdominis plane block: 40 mL of 0.375% ropivacaine after induction.
Reversal of neuromuscular blockade at the end of surgery: sugammadex 2-4 mg/kg IV.
OBA group (control)
Induction: propofol 1.5-2.5 mg/kg, rocuronium 0.6-1.0 mg/kg, sufentanil 0.3-0.5 μg/kg.
Maintenance (continuous infusion): propofol 2-6 mg/kg/h, remifentanil 0.2-1.0 μg/kg/min, rocuronium 5-6 μg/kg/min, plus inhaled sevoflurane 1%.
End of surgery (after last suture): discontinue all maintenance drugs, then administer ondansetron 8 mg IV and sufentanil 0.15 μg/kg IV.
Postoperative patient-controlled analgesia (PCA): sufentanil 2 μg/kg + ondansetron 16 mg in 100 mL normal saline; background 2 mL/h, bolus 0.5 mL, lockout 15 min.
OFA group (experimental)
Induction: propofol 1.5-2.5 mg/kg, esketamine 0.3-0.5 mg/kg, rocuronium 0.6-1.0 mg/kg. No opioid.
Maintenance (continuous infusion): propofol 2-6 mg/kg/h, dexmedetomidine 0.5-1.0 μg/kg/h, esketamine 0.2-0.5 mg/kg/h, rocuronium 5-6 μg/kg/min, esmolol 20-100 μg/kg/min, plus inhaled sevoflurane 1%.
End of surgery: discontinue all maintenance drugs, then ondansetron 8 mg IV + esketamine 0.2 mg/kg (mixed with a small dose of sufentanil, total sufentanil dose ≤5 μg for procedural pain only).
Postoperative PCA: esketamine 1.5 mg/kg + ondansetron 16 mg in 100 mL normal saline; same pump settings as OBA group. No opioid in the PCA.
Haemodynamic management Intraoperative hypotension (systolic blood pressure <90 mmHg) or hypertension (>160 mmHg) and bradycardia (<50 bpm) or tachycardia (>100 bpm) are recorded as adverse events. Vasopressors (phenylephrine or ephedrine) and atropine may be used at the discretion of the anaesthesiologist; their doses are recorded.
Outcome Assessment Procedures (Technical Description)
Primary outcome - POD incidence POD is assessed twice daily (between 08:00-10:00 and 18:00-20:00) from postoperative day 1 to day 7 or until hospital discharge, whichever occurs first. For non-intubated ward patients, the 3-Minute Diagnostic Interview for CAM (3D-CAM) is used. For patients remaining in the intensive care unit or requiring mechanical ventilation, the CAM-ICU is applied. All assessors undergo a standardised training session including video-based case scenarios and inter-rater reliability testing (kappa ≥0.85 required).
Secondary outcome - blood sampling for inflammatory and stress markers Blood samples are drawn from an indwelling arterial catheter (if present) or by venipuncture at five predefined time points: (1) 10 min after anaesthesia induction (baseline), (2) 10 min after pneumoperitoneum creation, (3) 1 h after pneumoperitoneum, (4) 24 h post-surgery, (5) 48 h post-surgery. Serum is separated within 30 min, aliquoted, and stored at -80°C. Tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are measured by enzyme-linked immunosorbent assay (ELISA); cortisol, epinephrine and norepinephrine are measured by high-performance liquid chromatography with electrochemical detection.
Secondary outcome - haemodynamic data collection Vital signs (heart rate, systolic/diastolic/mean arterial pressure) are recorded from the anaesthesia information management system at eight specified time points: before intubation, immediately after intubation, at surgical incision, at 30 min (±5 min), 60 min (±5 min) and 120 min (±5 min) after pneumoperitoneum, at 5 min before the end of surgery, and at extubation.
Secondary outcome - quality of recovery The 15-item Quality of Recovery (QoR-15) questionnaire is administered by a blinded research assistant via face-to-face interview at 24, 48, and 72 hours post-surgery. The total score ranges 0-150 (higher = better recovery).
Secondary outcome - pain and opioid consumption Pain at rest and on movement is measured using the 11-point Numerical Rating Scale (0 = no pain, 10 = worst imaginable pain) at 24, 48, and 72 hours. Cumulative opioid consumption (converted to oral morphine milligram equivalents, MME) from the PCA device log and any rescue analgesics is calculated for the first 72 hours.
Sample Size Calculation
The sample size was computed using PASS 2021 software for a superiority trial with a dichotomous primary outcome. Assumptions: expected POD incidence 54.8% in OBA group (based on our centre's previous observational cohort) and 32.6% in OFA group (a clinically meaningful absolute risk reduction of 22.2%). Two-sided α = 0.05, power (1-β) = 0.80, allocation ratio 1:1. The required evaluable sample size is 78 participants per group (156 total). Accounting for a 10% drop-out or incomplete primary outcome data, the final enrolment target is 174 participants (87 per group). No interim analysis is planned.
Statistical Analysis Plan
All analyses follow the intention-to-treat (ITT) principle, including all randomised participants in their originally assigned groups. The primary outcome (POD incidence) is compared using the chi-square test; relative risk (RR) and 95% confidence interval (CI) are reported. If baseline characteristics show clinically meaningful imbalance (e.g., age, sex, or comorbidities), a multivariable logistic regression model will be performed as a sensitivity analysis.
Continuous secondary outcomes (e.g., QoR-15, NRS, MME, length of stay) are tested for normality using the Shapiro-Wilk test. Normally distributed data are compared using independent samples t-tests; non-normally distributed data are compared using the Mann-Whitney U test. Categorical secondary outcomes (e.g., PONV, complications, 30-day mortality) are analysed by chi-square or Fisher's exact test. Repeated measures (inflammatory markers, haemodynamics) are analysed using linear mixed models for repeated measures (MMRM) with unstructured covariance, including group, time, and group-by-time interaction as fixed effects, and participant as random effect. Missing data are handled by multiple imputation (20 imputed datasets) under the missing at random assumption, with sensitivity analysis using complete-case analysis.
Statistical significance is defined as two-sided P < 0.05. No multiplicity adjustment is applied because the primary outcome is single, and secondary outcomes are considered exploratory. All analyses are performed using SPSS version 29.0 (IBM Corp.) or R version 4.3 (R Foundation).
Data Monitoring and Safety
An independent Data Safety Monitoring Board (DSMB) comprising three members (an anaesthesiologist, a geriatrician, and a biostatistician) not involved in the trial conducts reviews after every 50 enrolled participants. The DSMB evaluates serious adverse events (SAEs; grade ≥2 according to the CTCAE v5.0) and any pattern of unexpected harm. SAEs are reported to the principal investigator within 24 hours, to the ethics committee within 72 hours, and to the DSMB within 7 days. The trial may be paused or terminated if the DSMB identifies a significantly higher incidence of severe adverse events in either group (prespecified stopping rule: ≥20% absolute excess of grade ≥3 events in the OFA group compared with OBA). All participants are covered by clinical trial liability insurance and travel accident insurance.
Protocol Version and Amendments
The current protocol version is V4.0 dated 8 April 2025. Any amendments that alter the study design, inclusion/exclusion criteria, interventions, or primary outcome will be submitted to the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University for approval prior to implementation. Approved amendments will be updated on ClinicalTrials.gov (NCT05935540) and, where applicable, re-consent will be obtained from enrolled participants.
Dissemination Policy
The results will be submitted for publication in a peer-reviewed journal irrespective of whether the findings are positive, negative, or inconclusive. Authorship will follow ICMJE guidelines. The complete de-identified individual participant data will be made available upon reasonable request to the corresponding author after publication.
