The Effects of Subanesthetic S-ketamine on Postoperative Delirium and Cognitive Function in the Elderly Undergoing Non-cardiac Thoracic Surgery (SKED)

The Effects of Subanesthetic S-ketamine on Postoperative Delirium and Cognitive Function in the Elderly Undergoing Non-cardiac Thoracic Surgery: a Protocol for Randomized, Double-blinded, Positive-controlled, Non-inferiority Trial

Postoperative delirium (POD) is a common and distressing complication after thoracic surgery. S-ketamine has neuroprotective properties as a dissociative anesthetic. Emerging literature has indicated that S-ketamine can reduce cognitive impairment in depressed patients. However, the role of S-ketamine in preventing postoperative delirium is still unknown. Therefore, this study aims to evaluate the effect of intraoperatively prophylactic S-ketamine compared to dexmedetomidine on the incidence of postoperative delirium in elderly patients undergoing non-cardiac thoracic surgery.

Study Overview

• Status: Completed
• Conditions: Postoperative Delirium; Elderly Patients
• Intervention / Treatment: Drug: S-ketamine; Drug: Dexmedetomidine

Detailed Description

Postoperative delirium (POD) is a common and distressing complication after thoracic surgery. S-ketamine has neuroprotective properties as a dissociative anesthetic. Emerging literature has indicated that S-ketamine can reduce cognitive impairment in depressed patients. However, the role of S-ketamine in preventing postoperative delirium is still unknown. Therefore, this study aims to evaluate the effect of intraoperatively prophylactic S-ketamine compared to dexmedetomidine on the incidence of postoperative delirium in elderly patients undergoing non-cardiac thoracic surgery. This will be a randomized, double-blinded, placebo-and positive-controlled, non-inferiority trial that enrolls patients aged 60 or over undergoing thoracic surgery. The primary outcome will be the incidence of postoperative delirium within 4 days after surgery and assessed using a 3-minute Diagnostic Confusion Assessment Method (3D-CAM) twice a day. Secondary outcomes included postoperative delirium severity, motroic subtypes, episodes, and duration. Additional prespecified outcomes were emergence delirium; time to delirium onset; time to extubation; postoperative pain intensity at rest and during cough at 4, 24, and 48 h postoperatively; postoperative opioid consumption and rescue analgesia requirements; subjective sleep quality within the initial 4 days after surgery; postoperative length of hospital stay; and cognitive function and mortality at 30- and 90-day follow-up.

• Study Type: Interventional
• Enrollment (Actual): 520
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510095
      • Cancer hospital and institute of Guangzhou medical university

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged 60 years or over
• Both genders
• American anesthesiologist association (ASA) physical status classificationⅠ-Ⅲ
• Diagnosed with lung, esophagus, or mediastinum disorders
• Undergoing open or video-assisted thoracic surgery including lobectomy, segmentectomy, pneumonectomy, esophagectomy, or resection of mediastinal tumor
• General anesthesia with one-lung ventilation (OLV) or bronchial blocker.
• An expected operation duration of 2 hours or more.
• Voluntarily participate in the trial and sign informed consent.

Exclusion Criteria:

• History of psychiatric disease or severe depression
• History of glaucoma or hyperthyroidism
• History of severe hepatic (Child-Pugh grade C) or renal (requirement for renal replacement therapy) disorder.
• Body mass index (BMI) greater 35 kg/m2
• Dementia history or baseline Mini-Mental State Examination (MMSE) score less than 23
• Severe audio-visual impairments, or inability to speak Mandarin or Cantonese precluding communication
• Sinus bradycardia (heart rate < 50 beats per minutes, bpm), sick sinus or Wolff- Parkinson-White syndromes, or Ⅱ degree atrioventricular block and over
• Poorly controlled hypertension (resting systolic blood pressure over 180 mm Hg, or resting diastolic blood pressure over 100 mm Hg)
• Allergic to dexmedetomidine, S-ketamine or any of their formulation ingredients;
• Taking sedatives, antidepressants or glucocorticoids
• Alcohol or drug abuser
• Life expectancy of less than 2 months due to extensive tumor metastasis.

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
Experimental: S-ketamine; S-ketamine (50 mg, 2 ml) is diluted to 50 ml (1 mg/ml) with 48 ml normal saline;	Drug: S-ketamine; Loading dose: 0.25mg/kg in 10 minutes Maintenance dose: 0.1mg/kg/h
Active Comparator: Dexmedetomidine; Dexmedetomidine (200 ug, 2 ml) is diluted to 100 ml (2 ug/ml) with 98 ml normal saline;	Drug: Dexmedetomidine; Loading dose: 0.2 ug/kg in 10 minutes Maintenance dose: 0.2 ug/kg/h

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Post-operative Delirium in 4 Days After Surgery	3-minute Diagnostic Confusion Assessment Method (3D-CAM)	Within 4 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of Delirium	Confusion Assessment Method- Severity (CAM-S, Mild-to-moderate delirium will be defined as a CAM-S score of 3 to 5, while severe delirium will be defined as a CAM-S score of 6 to 7)	Within 4 days after surgery
Duration of postoperative delirium	Positive days of postoperative delirium	Within 4 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain severity	Numeric rating scale (NRS)0 = [no pain], 0 < NRS < 4 [mild pain], 4 ≤ NRS < 7 [moderate pain], 7 ≤ NRS <10 [severe pain], NRS = 10 [worst pain imaginable]	Within 2 days after surgery
Quality of sleep	Numeric rating scale(0 = best-quality sleep, 10 = worst-quality sleep)	Within 4 days after surgery
Cognitive function	Telephone interview for cognitive status-40 (TICS-40); A score below 21 will be defined as mild cognitive impairment, the higher scores mean a worse outcome.	On postoperative day 30
Cognitive function	Telephone interview for cognitive status-40 (TICS-40); A score below 21 will be defined as mild cognitive impairment, the higher scores mean a worse outcome.	On postoperative day 90
Emergence delirium	Richard Agitation-Sedation Scale (RASS) (RASS score ≥ 1 indicates emergency delirium, the higher scores mean a worse outcome.)	From 30 minutes after the arrival in the post anesthesia care unit (PACU) until the time-point of PACU discharge, assessed up to 2 hours
Postoperative opioid consumption and rescue analgesia requirements	MME	Postoperative 48 hours
Postoperative length of hospital stay		Postoperative length of hospital stay
Hypotension (MAP < 65 mmHg)	min	Intraoperative
Hypertension	percent	Intraoperative
Hypertension MAP > 120 % of baseline		Intraoperative
Hypoxemia	SpO2 < 90%	Intraoperative
Bradycardia	HR<55 bpm	Intraoperative
Tachycardia	HR > 100 bpm	Intraoperative
S-ketamine-related psychomimetic side effects	dizziness, nightmares, and hallucinations	Postoperative days 4

Collaborators and Investigators

• Sponsor: Affiliated Cancer Hospital & Institute of Guangzhou Medical University
• Investigators: Study Chair: Yihua Li, PhD, Cancer hospital and institute of Guangzhou medical university

Publications and helpful links

General Publications

• Wei W, Zhang A, Liu L, Zheng X, Tang C, Zhou M, Gu Y, Yao Y. Effects of subanaesthetic S-ketamine on postoperative delirium and cognitive function in elderly patients undergoing non-cardiac thoracic surgery: a protocol for a randomised, double-blinded, placebo-controlled and positive-controlled, non-inferiority trial (SKED trial). BMJ Open. 2022 Aug 1;12(8):e061535. doi: 10.1136/bmjopen-2022-061535.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2022
• Primary Completion (Actual): August 31, 2025
• Study Completion (Actual): August 31, 2025

Study Registration Dates

• First Submitted: December 23, 2021
• First Submitted That Met QC Criteria: February 15, 2022
• First Posted (Actual): February 16, 2022

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: S-ketamine; Dexmedetomidine; Postoperative delirium; elderly patients
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Emergence Delirium; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Esketamine; Dexmedetomidine
• Other Study ID Numbers: ATHGuangzhou

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No