Opioid-free Anesthesia and Postoperative Delirium

Effect of Opioid-free Anesthesia on Postoperative Delirium in Elderly Patients Undergoing Gastrointestinal Surgery

Postoperative delirium (POD) is a common acute and transient form of brain dysfunction in elderly patients following surgery that can lead to serious adverse clinical outcomes and even death. Although existing studies have preliminarily investigated the effects of opioid-free anaesthesia (OFA) on POD, high-quality evidence on these effects for elderly patients undergoing gastrointestinal surgery remains limited. This study aims to investigate the effects of OFA on the development of POD in elderly patients following gastrointestinal surgery. This single-centre, prospective, randomized controlled trial will be conducted at the First Affiliated Hospital of Shandong First Medical University, China. A total of 654 patients aged 65 years or older who are scheduled for elective gastrointestinal surgery will be randomly allocated to receive either opioid-free anaesthesia (OFA; dexmedetomidine, esmolol, and esketamine) or conventional opioid-based anaesthesia (OBA). The primary outcome is the incidence of POD 7 days after surgery. The secondary outcomes are all-cause mortality within 30 days after surgery, intraoperative haemodynamic changes, the 15-item quality of recovery (QoR-15) scores at 24 h, 48 h, and 72 h after surgery, complications during postoperative hospitalization, pain numerical rating scale (NRS) score at 72 h after surgery, incidence of nausea and vomiting at 72 h after surgery, morphine milligram equivalent for analgesics at 72 h after surgery, duration of anaesthesia (from induction to discontinuation), duration of surgery (from skin incision to the last suture), duration of post-anaesthesia care unit (PACU) stay, and length of hospital stay. The results of this study may shed light on the effects of OFA on POD in elderly patients undergoing gastrointestinal surgery. The study is designed on the basis of the following key hypothesis: the use of opioid drugs for anaesthesia may increase the risk of POD through mechanisms such as blood-brain barrier destruction, neuroinflammatory responses, and central nervous system depression. Through the single-centre and prospective design of this randomized controlled trial, this study will directly analyse differences in the effects of OFA and conventional OBA on the incidence of POD, haemodynamic stability and long-term cognitive function in elderly patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Postoperative Delirium; Gastrointestinal Tumors
• Intervention / Treatment: Drug: OFA group; Drug: OBA group

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 174
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Yongtao Sun, PHD. MD.; Phone Number: +8618660795201; Email: science2020@hotmail.com
• Study Contact Backup: Name: Min Zhang; Email: Zhangmin201609@outlook.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients who plan to undergo elective gastrointestinal surgery under general anaesthesia
2. Age ≥65 years
3. American Society of Anaesthesiologists (ASA) grade I-III
4. Body mass index (BMI) of 18.0-30.0 kg/m²
5. Frailty: mFI ≥ 0.27
6. Signed informed consent

Exclusion Criteria:

1. Patients undergoing emergency surgery
2. Patients with language disorders or severe hearing or vision impairment that prevent communication
3. Patients with a history of neurological and psychiatric disorders, including Alzheimer's disease (AD), other types of dementia, stroke, and psychosis
4. Patients with long-term use of psychotropic medications (such as clozapine, risperidone, olanzapine, haloperidol, and chlorpromazine)
5. Patients who have undergone cardiac surgery or craniocerebral surgery within the past year
6. Patients who have participated in other relevant clinical trials within the past 3 months
7. Patients with preoperative cognitive impairment (Telephone Interview for Cognitive Status-modified (TICS-m) score ≤ 27), as determined via the TICS-M test
8. Each patient can be included only once, regardless of whether the reason for the second surgery is related to the primary cause
9. Let me know if you need this in a different bullet style (e.g., asterisks) or with indentation adjustments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Opioid-free anaesthesia group; In the OFA group, anaesthesia will be induced with 1.5-2.5 mg/kg propofol, 0.3-0.5 mg/kg esketamine, and 0.6-1.0 mg/kg rocuronium. Endotracheal intubation or laryngeal mask placement will be performed when the BIS value is observed at 40-60.	Drug: OFA group; In the OFA group, anaesthesia will be induced with 1.5-2.5 mg/kg propofol, 0.3-0.5 mg/kg esketamine, and 0.6-1.0 mg/kg rocuronium. Endotracheal intubation or laryngeal mask placement will be performed when the BIS value is observed at 40-60. Intraoperative continuous intravenous infusion of 2-6 mg/kg/h propofol, 0.5-1.0 μg/kg/h dexmedetomidine, 0.2-0.5 mg/kg/h esketamine, 5-6 μg/kg/min rocuronium bromide, 20-100 μg/kg/min esmolol, and inhaled 1% sevoflurane will be utilized to maintain anaesthesia. At the end of the procedure (after the last suture), all maintenance drugs will be discontinued. Afterwards, 8 mg of ondansetron and 0.2 mg/kg esketamine-assisted sufentanil will be intravenously administered. Postoperative analgesia will be performed by using an intravenous patient-controlled analgesia pump consisting of 1.5 mg/kg esketamine and 16 mg of ondansetron. The volume will be adjusted to 100 mL in 0.9% normal saline; moreover, the continuous infusion rate will be set at 2 mL/h, an; Other Names: Opioid-free anaesthesia
Active Comparator: opioid-based anaesthesia group; In the OBA group, anaesthesia will be induced with 1.5-2.5 mg/kg propofol, 0.6-1.0 mg/kg rocuronium, and 0.3-0.5 μg/kg sufentanil. Endotracheal intubation or laryngeal mask airway insertion will be performed when the BIS value decreases to 40-60.	Drug: OBA group; In the OBA group, anaesthesia will be induced with 1.5-2.5 mg/kg propofol, 0.6-1.0 mg/kg rocuronium, and 0.3-0.5 μg/kg sufentanil. Endotracheal intubation or laryngeal mask airway insertion will be performed when the BIS value decreases to 40-60. During surgery, 2-6 mg/kg/h propofol, 0.2-1.0 μg/kg/min remifentanil, and 5-6 μg/kg/min rocuronium will be continuously pumped to maintain anaesthesia. Both groups will receive inhalation of 1% sevoflurane during anaesthesia maintenance. At the end of the procedure (after the last suture), all maintenance drugs will be discontinued. Afterwards, 8 mg of ondansetron and 0.15 μg/kg sufentanil will be intravenously injected. Postoperative analgesia will be performed by using an intravenous patient-controlled analgesia pump; the formulation will involve 2 μg/kg sufentanil and 16 mg of ondansetron, which will be diluted to 100 mL with 0.9% normal saline. Moreover, the background infusion rate will be set at 2 mL/h, and the lockout interval will be 1; Other Names: opioid-based anaesthesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of postoperative delirium (POD) within 7 days after surgery or at discharge	7 days after surgery or at discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality within 30 days after surgery		30 days after surgery
Serum tumour necrosis factor-α (TNF-α, pg/mL) concentration	Blood samples are collected at 5 predefined perioperative time points: 10 minutes after anaesthesia induction (baseline), 10 minutes after pneumoperitoneum, 1 hour after pneumoperitoneum, 24 hours post-surgery, and 48 hours post-surgery. Serum TNF-α concentration is measured in duplicate by enzyme-linked immunosorbent assay (ELISA). Each time point yields a separate value; these values are not aggregated into a single composite measure. All five time-specific values will be analysed separately using repeated measures models to compare changes over time between the two treatment groups.	10 minutes after anaesthesia induction; 10 minutes and 1 hour after pneumoperitoneum; and 24 hours and 48 hours after surgery
Serum cortisol concentration (nmol/L)		10 minutes after anaesthesia induction; 10 minutes and 1 hour after pneumoperitoneum; and 24 hours and 48 hours after surgery
Quality of Recovery-15 (QoR-15) score	The QoR-15 is a 15-item patient-reported questionnaire that measures quality of recovery after surgery and anesthesia. Each item is scored from 0 (none of the time) to 10 (all of the time). Total scores range from 0 (worst possible recovery) to 150 (best possible recovery). Higher scores indicate a better outcome.	24 hours, 48 hours, and 72 hours after surgery
Postoperative complications during hospitalization	Postoperative complications are defined according to [specify criteria, e.g., Clavien-Dindo classification, or list specific complications such as surgical site infection, pneumonia, deep vein thrombosis, etc.]. The number of participants experiencing one or more complications during the specified time frame will be reported. No scale is used; this is a binary (yes/no) outcome per participant.	During the index hospitalization, from the end of surgery until hospital discharge (assessed daily; reported for the entire hospitalization period) Alternative specific phrasing: "Up to 30 days" if discharge may occur earlier.
Numeric Rating Scale (NRS) Pain Score	Pain intensity is assessed using the 11-point Numeric Rating Scale (NRS), where 0 = no pain and 10 = worst imaginable pain. The assessment is performed at rest and on movement (e.g., coughing or deep breathing) by a trained research assistant blinded to group allocation. The score at 72 hours post-surgery (with an allowable window of 72 ± 6 hours) is recorded as the primary pain outcome. If the 72-hour assessment coincides with hospital discharge before that time point, the assessment is performed at discharge (up to 72 hours). The single score at this specified time point is reported; no aggregation across multiple time points is performed.	Day 1 (day of surgery, assessed within 6 hours after arrival to the post-anaesthesia care unit) Day 2 (postoperative day 2, assessed at 48 ± 6 hours after surgery) Day 3 (postoperative day 3, assessed at 72 ± 6 hours after surgery)
Incidence and Severity of Postoperative Nausea and Vomiting (PONV) as Assessed by a 4-Point Categorical Scale	PONV is measured using a 4-point categorical scale: 0 = no nausea or vomiting; = mild nausea without vomiting; = moderate nausea with retching or one episode of vomiting; = severe nausea with multiple episodes of vomiting Minimum value = 0, maximum value = 3. Higher scores indicate a worse outcome (more severe PONV). The primary metrics reported will be: Incidence = proportion of participants with any PONV (score ≥1) during the time frame Severity = mean (or median) score at each time point, plus the proportion with a score of 3	From the end of surgery up to 72 hours postoperatively
Total Postoperative Opioid Consumption in Morphine Milligram Equivalents (MME)	All opioid analgesics administered intravenously, orally, or via patient-controlled analgesia (PCA) during the specified time frame are converted to MME using standard conversion factors (e.g., CDC or equianalgesic reference). Minimum value = 0 MME (no opioid use) Maximum value = no theoretical upper limit (reported as range observed) Higher MME indicates greater opioid consumption, which is generally considered a worse outcome (e.g., more pain or greater analgesic requirement) The primary metric reported will be mean (or median) total MME per participant during the time frame, along with standard deviation or interquartile range.	From the end of surgery up to 72 hours postoperatively
Duration of anaesthesia (in minutes)	Duration of anaesthesia is defined as the time from the start of anaesthesia induction (first administration of induction agent) to the withdrawal of all anaesthetic maintenance medications at the end of surgery. The duration is recorded in minutes and calculated from intraoperative anaesthesia records. A single value is reported per participant.	during anaesthesia
Operation time (in minutes)		from skin incision to the last suture
Length of PACU stay (in minutes)		From PACU admission (immediately after surgery) to PACU discharge, assessed at the time of discharge.
Length of Hospital Stay (days)	Length of stay is calculated as the total number of calendar days from admission (or surgery) to discharge. If discharge occurs on the same day as admission/surgery, length of stay is recorded as 0 days. This is a continuous outcome measure; shorter length of stay is generally considered a better outcome (indicating faster recovery and fewer complications). The primary metric reported will be the mean (or median) length of stay in days, with standard deviation or interquartile range.	From the date of hospital admission to the date of hospital discharge, assessed through hospital discharge (average expected stay of 7 days).
Intraoperative Systolic Blood Pressure (SBP， mmHg)	Systolic blood pressure (SBP) is recorded in mmHg from the anaesthesia information management system (invasive arterial line or non-invasive cuff as per clinical routine) at each of the 8 specified time points. Each time point yields a separate absolute value. No aggregation (e.g., average, area under the curve) is performed across time points. The 8 time-specific values will be analysed separately using repeated measures models to compare changes between treatment groups.	before intubation, immediately after intubation, at incision, at 30 min (±5 min) after pneumoperitoneum, at 60 min (±5 min) after pneumoperitoneum, at 120 min (±5 min) after pneumoperitoneum, at 5 min before end of surgery, and at extubation.
Intraoperative Diastolic Blood Pressure (DBP, mmHg)	Diastolic blood pressure (DBP) is recorded in mmHg at each of the 8 specified time points. Each time point provides an independent absolute value. No aggregation across time points is performed. The eight values will be analysed using repeated measures methods.	before intubation, immediately after intubation, at incision, at 30 min (±5 min) after pneumoperitoneum, at 60 min (±5 min) after pneumoperitoneum, at 120 min (±5 min) after pneumoperitoneum, at 5 min before end of surgery, and at extubation.
Intraoperative Mean Arterial Pressure (MAP, mmHg)	Mean arterial pressure (MAP) is recorded in mmHg at the 8 specified time points (either directly measured from an arterial line or calculated as (SBP + 2×DBP)/3 if non-invasive cuff is used). Values are reported separately for each time point; no composite summary measure is created. Repeated measures analysis will compare MAP trajectories between the two randomised groups.	before intubation, immediately after intubation, at incision, at 30 min (±5 min) after pneumoperitoneum, at 60 min (±5 min) after pneumoperitoneum, at 120 min (±5 min) after pneumoperitoneum, at 5 min before end of surgery, and at extubation.
Intraoperative Heart Rate (HR, bpm)	Heart rate (HR) is recorded in beats per minute from continuous ECG monitoring at each of the 8 specified time points. Each time point yields a separate absolute value. No aggregation across time points is performed. The eight time-specific HR values will be analysed using repeated measures models to assess group differences and time-by-group interactions.	before intubation, immediately after intubation, at incision, at 30 min (±5 min) after pneumoperitoneum, at 60 min (±5 min) after pneumoperitoneum, at 120 min (±5 min) after pneumoperitoneum, at 5 min before end of surgery, and at extubation.
Serum interleukin-6 (IL-6, pg/mL) concentration	Blood samples are collected at the same 5 perioperative time points as described for TNF-α (baseline, 10 min after pneumoperitoneum, 1 h after pneumoperitoneum, 24 h post-surgery, 48 h post-surgery).	10 minutes after anaesthesia induction; 10 minutes and 1 hour after pneumoperitoneum; and 24 hours and 48 hours after surgery
Serum epinephrine concentration (pg/mL)		10 minutes after anaesthesia induction; 10 minutes and 1 hour after pneumoperitoneum; and 24 hours and 48 hours after surgery
Serum norepinephrine concentration (pg/mL)		10 minutes after anaesthesia induction; 10 minutes and 1 hour after pneumoperitoneum; and 24 hours and 48 hours after surgery

Collaborators and Investigators

• Sponsor: Qianfoshan Hospital
• Investigators: Principal Investigator: Yongtao Sun, Shandong First Medical University; Study Chair: Min Zhang, Shandong First Medical University

Publications and helpful links

General Publications

• Scholz AF, Oldroyd C, McCarthy K, Quinn TJ, Hewitt J. Systematic review and meta-analysis of risk factors for postoperative delirium among older patients undergoing gastrointestinal surgery. Br J Surg. 2016 Jan;103(2):e21-8. doi: 10.1002/bjs.10062. Epub 2015 Dec 16.
• Hoogendijk EO, Afilalo J, Ensrud KE, Kowal P, Onder G, Fried LP. Frailty: implications for clinical practice and public health. Lancet. 2019 Oct 12;394(10206):1365-1375. doi: 10.1016/S0140-6736(19)31786-6.
• Dilmen OK, Meco BC, Evered LA, Radtke FM. Postoperative neurocognitive disorders: A clinical guide. J Clin Anesth. 2024 Feb;92:111320. doi: 10.1016/j.jclinane.2023.111320. Epub 2023 Nov 8.
• Liu J, Wang T, Song J, Cao L. Effect of esketamine on postoperative analgesia and postoperative delirium in elderly patients undergoing gastrointestinal surgery. BMC Anesthesiol. 2024 Feb 1;24(1):46. doi: 10.1186/s12871-024-02424-w.
• Aldecoa C, Bettelli G, Bilotta F, Sanders RD, Aceto P, Audisio R, Cherubini A, Cunningham C, Dabrowski W, Forookhi A, Gitti N, Immonen K, Kehlet H, Koch S, Kotfis K, Latronico N, MacLullich AMJ, Mevorach L, Mueller A, Neuner B, Piva S, Radtke F, Blaser AR, Renzi S, Romagnoli S, Schubert M, Slooter AJC, Tommasino C, Vasiljewa L, Weiss B, Yuerek F, Spies CD. Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients. Eur J Anaesthesiol. 2024 Feb 1;41(2):81-108. doi: 10.1097/EJA.0000000000001876. Epub 2023 Aug 30.
• Kreutzmann HPMMR, Palm P, Rasmussen TB, Ahlehoff O, Helmark C, Instenes I, Larsen JKP, Lassen JF, Ryg J, Jensen LO, Norekval TM, Borregaard B; CONCARD Investigators. The association between self-reported frailty status and 1-year all-cause mortality and readmission following PCI: A prospective multi-centre cohort study, CONCARDPCI. Int J Cardiol. 2026 Mar 1;446:134072. doi: 10.1016/j.ijcard.2025.134072. Epub 2025 Dec 5.
• Howell SJ, Dhesi JK. Frailty in the perioperative setting: lessons from SNAP-3. Br J Anaesth. 2025 Aug;135(2):296-299. doi: 10.1016/j.bja.2025.05.024. Epub 2025 Jun 24.
• Desrochers RM, Lynch LJ, Gates JD, Ricaurte D, Wade JT, Dicks RS, Keating JJ. Outcomes in Post-operative Delirium Following Bowel Resection: A Single Center Retrospective Review. J Surg Res. 2022 Dec;280:163-168. doi: 10.1016/j.jss.2022.07.009. Epub 2022 Aug 13.
• Li H, Liu C, Yang Y, Wu QP, Xu JM, Wang DF, Sun JJ, Mao MM, Lou JS, Liu YH, Cao JB, Duan CY, Mi WD. Effect of Intraoperative Midazolam on Postoperative Delirium in Older Surgical Patients: A Prospective, Multicenter Cohort Study. Anesthesiology. 2025 Feb 1;142(2):268-277. doi: 10.1097/ALN.0000000000005276. Epub 2024 Oct 29.
• Sim JH, Kim KM, Lee U, Lee EK, Noh GJ, Choi BM. Incidence of postoperative delirium and quality of recovery in older patients undergoing gastrectomy under general anaesthesia with remimazolam vs. propofol: a randomised non-inferiority study. Anaesthesia. 2025 Nov;80(11):1370-1380. doi: 10.1111/anae.16684. Epub 2025 Jul 14.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: April 6, 2026
• First Submitted That Met QC Criteria: May 16, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 16, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: postoperative delirium; elderly patients; gastrointestinal surgery; opioid-free anaesthesia
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Neoplasms by Site; Neoplasms; Digestive System Diseases; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Emergence Delirium; Digestive System Neoplasms
• Other Study ID Numbers: YXLL-KY-2025（079）

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

This study aims to investigate the effect of OFA on the occurrence of POD in frail elderly patients after gastrointestinal surgery.

This single-centre, prospective, randomized controlled trial (RCT) will be conducted at the First Affiliated Hospital of Shandong First Medical University, China. A total of 44 frail elderly patients aged 65 years or older who plan to undergo elective gastrointestinal surgery (modified frailty index (mFI > 0.27) will be randomly assigned to either the OFA group (receiving dexmedetomidine, esmolol, and ketamine) or the opioid-based anaesthesia (OBA) group. The primary outcome is the incidence of POD within 7 days after surgery or at discharge. Secondary outcome measures include the perioperative stress response, inflammation, intraoperative haemodynamics, postoperative 30-day all-cause mortality, intraoperative haemodynamic changes, 15-item quality of recovery (QoR-15), and postoperative complications during hospitalization.

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years after the publication of results.

IPD Sharing Access Criteria

Who Qualified researchers from academic, non-profit, or commercial institutions with an approved research proposal; regulatory authorities; and direct collaborators.

What Anonymized IPD, data dictionary, protocol, SAP, and ICF summary. No direct or indirect participant identifiers.

How

Submit proposal via online portal.

Independent review committee approval.

Sign data use agreement (non-identification, non-commercial, no third-party sharing).

Access via secure virtual research environment or encrypted download; time-limited (e.g., 12 months); audit logs kept.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No