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

Sponsor

Affiliated Cancer Hospital & Institute of Guangzhou Medical University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05242692

Collaborator

(none)

780

Enrollment

Location

Arms

23.7

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Postoperative Delirium Elderly Patients	Drug: S-ketamine Drug: Dexmedetomidine Drug: Normal saline	Early Phase 1

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. The main secondary outcomes will be the severity and duration of postoperative delirium. Other prespecified secondary outcomes will be the incidence of emergency delirium, postoperative pain, quality of sleep, cognitive function, and the plasm concentration of acetylcholine, brain-derived neurotrophic factor, and tumor necrosis factor.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

780 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

The labeled "Study medication" syringes (50ml) in identical appearance, and the infusion regimen formulated by the pharmacist based on the randomization, will be distributed to the attending anesthesiologists responsible for anesthetic management as soon as the research team informs the central pharmacy about the patient heading for surgery. To avoid anesthesiologists' speculation about the randomized assignment, the study drugs will be infused at a similar rate. The anesthesiologists, the patients, the investigators responsible for follow-up, and the statisticians are all masked to randomized allocations until the final statistical analyses are completed. The blindness will be unmasked by the primary investigator in a medical emergency including deterioration of patient's condition intraoperatively or adverse events postoperatively.

Primary Purpose:

Prevention

Official Title:

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, placebo-and Positive-controlled, Non-inferiority Trial

Actual Study Start Date :

Mar 10, 2022

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Feb 28, 2024

Arms and Interventions

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
Placebo Comparator: Normal saline Control group only contains 50 ml normal saline in light of blindness	Drug: Normal saline Refer to either S-ketamine or Dexmedetomidine

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

Placebo Comparator: Normal saline

Control group only contains 50 ml normal saline in light of blindness

Drug: Normal saline

Refer to either S-ketamine or Dexmedetomidine

Outcome Measures

Primary Outcome Measures

Number of Patients With Post-operative Delirium in 4 Days After Surgery [Within 4 days after surgery]
3-minute Diagnostic Confusion Assessment Method (3D-CAM)

Secondary Outcome Measures

Severity of Delirium [Within 4 days after surgery]
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)
Duration of postoperative delirium [Within 4 days after surgery]
Positive days of postoperative delirium

Other Outcome Measures

Emergency delirium [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]
Richard Agitation-Sedation Scale (RASS) (RASS score ≥ 1 indicates emergency delirium, the higher scores mean a worse outcome.)
Pain severity [Within 2 days after surgery]
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]
Quality of sleep [Within 4 days after surgery]
Numeric rating scale(0 = best-quality sleep, 10 = worst-quality sleep)
Cognitive function [On postoperative day 30]
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.
Cognitive function [On postoperative day 60]
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.
Concentration of plasma acetylcholine (ACh) [Within 5 minutes before induction]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma acetylcholine (ACh) [Within 5 minutes after the end of skin closure]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma acetylcholine (ACh) [On postoperative day 4]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma brain deprived neurotrophic factor (BDNF) [Within 5 minutes before induction]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma brain deprived neurotrophic factor (BDNF) [Within 5 minutes after the end of skin closure]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma brain deprived neurotrophic factor (BDNF) [On postoperative day 4]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma tumor necrosis factor (TNF) [Within 5 minutes before induction]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma tumor necrosis factor (TNF) [Within 5 minutes after the end of skin closure]
Enzyme-linked immunosorbent assay (ELISA) method
Concentration of plasma tumor necrosis factor (TNF) [On postoperative day 4]
Enzyme-linked immunosorbent assay (ELISA) method

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.