Delirium in Old AgeNCT06817239
Effect of Low-dose EsketaMine on dElirium in High-risk Elderly Patients uNdergoing elecTive Surgery (ELEMENT)
A study testing Esketamine and Normal saline in people with Delirium in Old Age and Delirium, Postoperative, run by Nanfang Hospital, Southern Medical University at 6 sites in China.
Trial summary
Delirium is an acutely occurred neurocognitive disorder characterized by fluctuating symptoms of inattention, altered consciousness and cognitive dysfunction. Delirium is reported to occur in 4% to 65% of postoperative patients depending on the population, and is especially common in older patients. Read more about this study
- Who is it for?
- Ages 65 to 90 years
- Conditions the study is for
- Delirium in Old Age, Delirium, Postoperative, Anesthesia
- What is being tested?
- Esketamine and Normal saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,670 participants
- Where
- 6 sitesChina
- Study dates
- 12 Feb 2025to Jul 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 to 90 years
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- Age ≥65 years and <90 years;
- Scheduled to undergo major non-cardiac surgery.
- Fulfill at least one of risk factors as follows: history of stroke; history of delirium; hypertension; congestive heart failure; coronary artery disease; atrial fibrillation; peripheral artery disease; chronic obstructive pulmonary disease; obstructive sleep apnea; diabetes; chronic kidney disease; anemia; malnutrition; hypoalbuminemia; chronic pain; anxiety and depression; poor sleep quality; smoke; alcoholism.
- Scheduled to receive patient-controlled intravenous analgesia (PCIA).
Who cannot join
- Refuse to participate;
- Preoperative history of epilepsy, myasthenia gravis, Parkinson's disease, intracranial hypertension, delirium, schizophrenia, or other psychiatric diseases;
- Inability to communicate in the preoperative period because of coma, profound dementia, or language barrier;
- Preoperative uncontrolled severe hypertension (baseline SBP>180 mmHg or DBP>110 mmHg);
- Preoperative history of hyperthyroidism and pheochromocytoma;
- Acute cardiovascular event occurring within 30 days before surgery;
Show all 11Show fewer
- Severe hepatic dysfunction (Child-Pugh class C), renal dysfunction (required preoperative dialysis), or expected survival ≤24 hours;
- Scheduled to undergo organ transplantation, vascular surgery, neurosurgery;
- Receiving treatment with ketamine or esketamine;
- Contradiction to ketamine or esketamine;
- Other situations where the investigator or physician considers the patient ineligible for the study.
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
6 sites in 1 country
China6 sites, 4 recruiting
- Recruiting
Fujian Provincial Hospital
Fuzhou, Fujian, 350001
Xiao-Dan Wu, MD
- Active, not recruiting
Ganzhou People's Hospital
Ganzhou, Jiangxi, 341001
- Not yet recruiting
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, 510060
Jing-Dun Xie, MD
- Recruiting
Nanfang Hospital, Southern Medical University
Guangzhou, Guangdong, 510515
Ke-Xuan Liu, MD, +86 13710684096, liukexuan705@163.com
- Active, not recruiting
The First Affiliated Hospital of JiNan University
Guangzhou, Guangdong, 510632
- Recruiting
The Eighth Affliated Hospital of Southern Medical Universily
Guangzhou, Guangdong, 528399
Yi-Wen Zhang, MD
About this study
Official title: Effect of Perioperative Low-dose EsketaMine on dElirium in High-risk Elderly Patients uNdergoing elecTive Major Non-cardiac Surgery: a Multi-center Randomized Trial (ELEMENT Trial)
Delirium is an acutely occurred neurocognitive disorder characterized by fluctuating symptoms of inattention, altered consciousness and cognitive dysfunction. Delirium is reported to occur in 4% to 65% of postoperative patients depending on the population, and is especially common in older patients. Postoperative delirium is disturbing to patients and their families, and it is a strong predictor of both early and long-term worse outcomes including increased non-delirium complications, increased perioperative mortality, shortened overall survival, declined cognitive function, and lowered quality of life.
Although ketamine/esketamine has anti-inflammatory and neuroprotective effects, evidence on its efficacy in reducing postoperative delirium remains inconsistent and inconclusive. Existing studies are limited by heterogeneity, small sample sizes, single-center designs, and a focus on specific type of surgery. Research on elderly high-risk patients is lacking, and most studies administer the drug intraoperatively, with limited exploration of postoperative use. The optimal dosing and timing for POD prevention are unclear. This study aims to carry out a multicenter, single-blind, placebo-controlled, large-sample randomized controlled trial assessing the effect of low-dose esketamine, given intraoperatively and postoperatively, on delirium in elderly high-risk patients undergoing major non-cardiac surgery.
Read the detailed description
Delirium is an acutely occurred neurocognitive disorder characterized by fluctuating symptoms of inattention, altered consciousness and cognitive dysfunction. Delirium is reported to occur in 4% to 65% of postoperative patients depending on the population, and is especially common in older patients. Postoperative delirium is disturbing to patients and their families, and it is a strong predictor of both early and long-term worse outcomes including increased non-delirium complications, increased perioperative mortality, shortened overall survival, declined cognitive function, and lowered quality of life.
The mechanism of delirium remains unclear, with neuroinflammation playing a significant role. Emerging evidence suggests anesthetic drug selection may influence the incidence of delirium. Ketamine, a non-competitive NMDA receptor antagonist, exhibits anti-inflammatory and neuroprotective properties by reducing TNF-α, IL-6, IL-1β, p-TAU, and S100B levels, mitigating oxidative stress, and inhibiting neuronal autophagy via the PI3K/AKT/mTOR pathway, thereby potentially preserving cognitive function. Clinical studies exploring ketamine's role in postoperative delirium have yielded mixed results. A retrospective study involving ICU patients undergone abdominal surgery found low-dose ketamine reduced delirium risk by 43% after propensity score matching. In cardiac surgery patients, a single dose of ketamine during induction decreased delirium incidence from 31% to 3%. However, a large international multicenter RCT in patients aged ≥60 undergoing major surgery found no reduction in delirium with pre-induction ketamine. A meta-analysis of eight RCTs also reported no preventive effect, though significant heterogeneity and inconsistent diagnostic criteria were noted. Perioperative ketamine use was consistently found safe, with no increase in adverse events such as nausea, vomiting, respiratory depression, or psychiatric symptoms.
Esketamine, the S-(+)-enantiomer of ketamine, has higher bioavailability, a shorter elimination half-life, and fewer side effects. It is effective in general anesthesia, postoperative analgesia, and ICU sedation, and can be used alone for minor procedures or combined with general or regional anesthesia. As an adjunct, it reduces the need for sedatives (e.g., propofol, midazolam) and opioids, minimizes hemodynamic fluctuations and respiratory depression, and improves anesthesia safety. Esketamine may prevent postoperative delirium, as suggested by emerging evidence. A single dose (0.25 mg/kg) before induction reduced delirium incidence in cardiac surgery patients from 44.6% to 23.2%. In elderly patients undergone gastrointestinal cancer surgery, intraoperative infusion (0.25 mg/kg at induction, then 0.125 mg/kg/h until 20 minutes before the end of surgery) decreased delayed neurocognitive recovery but not delirium. Conversely, postoperative esketamine (1 mg/kg) reduced delirium incidence from 40% to 13.3% in another RCT involving elderly patients undergone gastrointestinal surgery. In patients after major abdominal surgery, mini-dose esketamine (0.015 mg/kg/h for 48 hours) significantly lowered ICU delirium scores compared to low-dose esketamine or placebo. Two meta-analyses of 13 and 17 RCTs, respectively, reported reduced delirium incidence with perioperative esketamine usage, though evidence quality was limited by small sample sizes and heterogeneity. Recent studies showed mixed results. A single-center RCT of 426 elderly surgical patients found no reduction in delirium with 0.2 mg/kg esketamine at induction. In 209 patients aged ≥60 undergone tumor resection, 0.5 mg/kg at induction and 2 mg/kg PCIA postoperatively did not reduce delirium but may improve 90-day cognitive function. Similarly, a single-center RCT of 260 elderly patients after arthroplasty surgery found no benefit with esketamine administered at induction (0.2 mg/kg), intraoperatively (0.125 mg/kg/h), and postoperatively (0.5 mg/kg PCIA). Despite inconsistent findings, esketamine is safe in total, with no increased risk of adverse effects such as respiratory depression, nausea, vomiting, or psychiatric symptoms.
Although ketamine/esketamine has anti-inflammatory and neuroprotective effects, evidence on its efficacy in reducing postoperative delirium remains inconsistent and inconclusive. Existing studies are limited by heterogeneity, small sample sizes, single-center designs, and a focus on specific type of surgery. Research on elderly high-risk patients is lacking, and most studies administer the drug intraoperatively, with limited exploration of postoperative use. The optimal dosing and timing for POD prevention are unclear. This study aims to carry out a multicenter, single-blind, placebo-controlled, large-sample randomized controlled trial assessing the effect of low-dose esketamine, given intraoperatively and postoperatively, on delirium in elderly high-risk patients undergoing major non-cardiac surgery.
- Conditions
- Delirium in Old Age, Delirium, Postoperative, Anesthesia, Cognitive Dysfunction, Pain, Postoperative, Esketamine
- Being tested
- Esketamine, Normal saline
- Keywords
- Delirium, Elderly patients, Esketamine, Non-cardiac surgery
- Medical subject headings
- Emergence Delirium, Cognitive Dysfunction, Pain, Postoperative, Delirium
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EsketamineDrug
Esketamine (1mg/ml) will be administered at a loading dose of 0.2 mg/kg, namely at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with a formulation consisting of esketamine 50mg and sufentanil 200 μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes.
Normal salineDrug
Normal saline will be administered at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with sufentanil 200μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes.
| Study group | Role | What they receive |
|---|---|---|
| Esketamine | Experimental | Esketamine (1mg/ml) will be administered at a loading dose of 0.2 mg/kg, namely at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with a formulation consisting of esketamine 50mg and sufentanil 200 μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes. Receives: Drug: Esketamine |
| Normal saline | Placebo comparator | Normal saline will be administered at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with sufentanil 200μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes. Receives: Drug: Normal saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
The incidence of delirium within 5 days after surgery
Delirium is assessed twice daily (8-10 am and 6-8 pm) with The Confusion Assessment Method (CAM) for non-intubated patients or The confusion assessment method for the Intensive Care Unit (CAM-ICU) for intubated patients.
Measured: Up to 5 days after surgery
Quality of recovery on postoperative day 1 (Sub-study)
Quality of recovery is assessed once daily (6-8 pm) with 15-item Quality of Recovery Scale (QoR-15).
Measured: On postoperative day 1
Secondary outcomes (11)
Intensity of pain during the first 3 postoperative days
Intensity of pain will be assessed twice after surgery with the Behavioral Pain Scale and Numeric Rating Scale (an 11- point scale where 0 indicates no pain and 10 the worst pain).
Measured: Up to 3 days after surgery
Use of opioids during the first 3 postoperative days
Include opioids used for PCIA and supplemental analgesics.
Measured: Up to 3 days after surgery
Cognitive function at 30 days after surgery
Cognitive function is assessed with the Telephone-Montreal Cognitive Assessment (T-MoCA) (a 22-point scale, with higher score indicating better function).
Measured: At the end of 30 days after surgery
The incidence of delayed neurocognitive recovery
A decline in the T-MoCA score by 1 standard deviation (SD) or more from the baseline is considered delayed neurocognitive recovery.
Measured: At the end of 30 days after surgery
Death rate at 30 days after surgery
Survival status is followed up at 30 days after surgery.
Measured: At the end of 30 days after surgery
Quality of recovery on postoperative day 3 (Sub-study)
Quality of recovery is assessed once daily (6-8 pm) with QoR-15.
Measured: On postoperative day 3
Postoperative gastrointestinal intolerance during the first 2 postoperative days (Sub-study)
Gastrointestinal intolerance is assessed once daily (6-8 pm) with Intake, Feeling nauseated, Emesis, Exam, and Duration of symptoms scoring system (I-FEED).
Measured: Up to 2 days after surgery
Postoperative gastrointestinal dysfunction during the first 2 postoperative days (Sub-study)
Gastrointestinal dysfunction is assessed once daily (6-8 pm) with Intake, Feeling nauseated, Emesis, Exam, and Duration of symptoms scoring system (I-FEED).
Measured: Up to 2 days after surgery
Quality of recovery at 30 days after surgery (Sub-study)
Quality of recovery is assessed with QoR-15.
Measured: At the end of 30 days after surgery
HADS score at 30 days after surgery (Sub-study)
Anxiety and depression are assessed with Hospital Anxiety and Depression Scale (HADS).
Measured: At the end of 30 days after surgery
Sleep quality at 30 days after surgery (Sub-study)
Sleep quality is assessed with Pittsburgh Sleep Quality Index (PSQI).
Measured: At the end of 30 days after surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Feb 2025
- Study start12 Feb 2025
- Primary completionJun 2027 (estimated)
- Study completionJul 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (31)Papers the sponsor has linked to this study.
- Other trials for Delirium in Old AgeStudies of the same condition, open and under way.
- More trials run by Nanfang Hospital, Southern Medical UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 1,670 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Nanfang Hospital, Southern Medical University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ke-Xuan Liu, MD, Principal investigator, Nanfang Hospital, Southern Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06817239
- Sponsor's protocol ID
- NFEC-2025-016
- Status last verified
- Apr 2025
- First submitted
- 4 Feb 2025
- Last updated
- 27 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA. 2017 Sep 26;318(12):1161-1174. doi: 10.1001/jama.2017.12067.
PubMed 28973626Rudolph JL, Marcantonio ER. Review articles: postoperative delirium: acute change with long-term implications. Anesth Analg. 2011 May;112(5):1202-11. doi: 10.1213/ANE.0b013e3182147f6d. Epub 2011 Apr 7.
PubMed 21474660Lindroth H, Bratzke L, Purvis S, Brown R, Coburn M, Mrkobrada M, Chan MTV, Davis DHJ, Pandharipande P, Carlsson CM, Sanders RD. Systematic review of prediction models for delirium in the older adult inpatient. BMJ Open. 2018 Apr 28;8(4):e019223. doi: 10.1136/bmjopen-2017-019223.
PubMed 29705752Balas MC, Happ MB, Yang W, Chelluri L, Richmond T. Outcomes Associated With Delirium in Older Patients in Surgical ICUs. Chest. 2009 Jan;135(1):18-25. doi: 10.1378/chest.08-1456. Epub 2008 Nov 18.
PubMed 19017895Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, Serafim RB, Stevens RD. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015 Jun 3;350:h2538. doi: 10.1136/bmj.h2538.
PubMed 26041151Moskowitz EE, Overbey DM, Jones TS, Jones EL, Arcomano TR, Moore JT, Robinson TN. Post-operative delirium is associated with increased 5-year mortality. Am J Surg. 2017 Dec;214(6):1036-1038. doi: 10.1016/j.amjsurg.2017.08.034. Epub 2017 Sep 20.
PubMed 28947274Crocker E, Beggs T, Hassan A, Denault A, Lamarche Y, Bagshaw S, Elmi-Sarabi M, Hiebert B, Macdonald K, Giles-Smith L, Tangri N, Arora RC. Long-Term Effects of Postoperative Delirium in Patients Undergoing Cardiac Operation: A Systematic Review. Ann Thorac Surg. 2016 Oct;102(4):1391-9. doi: 10.1016/j.athoracsur.2016.04.071. Epub 2016 Jun 22.
PubMed 27344279Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008 Sep;65(3):229-38. doi: 10.1016/j.jpsychores.2008.05.019.
PubMed 18707945Zhao J, Zhang R, Wang W, Jiang S, Liang H, Guo C, Qi J, Zeng H, Song H. Low-dose ketamine inhibits neuronal apoptosis and neuroinflammation in PC12 cells via alpha7nAChR mediated TLR4/MAPK/NF-kappaB signaling pathway. Int Immunopharmacol. 2023 Apr;117:109880. doi: 10.1016/j.intimp.2023.109880. Epub 2023 Feb 27.
PubMed 36842233Chen M, Han Y, Que B, Zhou R, Gan J, Dong X. Prophylactic Effects of Sub-anesthesia Ketamine on Cognitive Decline, Neuroinflammation, and Oxidative Stress in Elderly Mice. Am J Alzheimers Dis Other Demen. 2022 Jan-Dec;37:15333175221141531. doi: 10.1177/15333175221141531.
PubMed 36474365Faisal H, Qamar F, Hsu ES, Xu J, Lai EC, Wong ST, Masud FN. Prevalence of Delirium After Abdominal Surgery and Association With Ketamine: A Retrospective, Propensity-Matched Cohort Study. Crit Care Explor. 2024 Jan 11;6(1):e1032. doi: 10.1097/CCE.0000000000001032. eCollection 2024 Jan.
PubMed 38222873Hudetz JA, Patterson KM, Iqbal Z, Gandhi SD, Byrne AJ, Hudetz AG, Warltier DC, Pagel PS. Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2009 Oct;23(5):651-7. doi: 10.1053/j.jvca.2008.12.021. Epub 2009 Feb 23.
PubMed 19231245Avidan MS, Maybrier HR, Abdallah AB, Jacobsohn E, Vlisides PE, Pryor KO, Veselis RA, Grocott HP, Emmert DA, Rogers EM, Downey RJ, Yulico H, Noh GJ, Lee YH, Waszynski CM, Arya VK, Pagel PS, Hudetz JA, Muench MR, Fritz BA, Waberski W, Inouye SK, Mashour GA; PODCAST Research Group. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet. 2017 Jul 15;390(10091):267-275. doi: 10.1016/S0140-6736(17)31467-8. Epub 2017 May 30.
PubMed 28576285Fellous S, Dubost B, Cambriel A, Bonnet MP, Verdonk F. Perioperative ketamine administration to prevent delirium and neurocognitive disorders after surgery: a systematic review and meta-analysis. Int J Surg. 2023 Nov 1;109(11):3555-3565. doi: 10.1097/JS9.0000000000000619.
PubMed 37526094Pfenninger EG, Durieux ME, Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology. 2002 Feb;96(2):357-66. doi: 10.1097/00000542-200202000-00022.
PubMed 11818769
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Perioperative Low-dose EsketaMine on dElirium in High-risk Elderly Patients uNdergoing elecTive Major Non-cardiac Surgery: a Multi-center Randomized Trial (ELEMENT Trial)
- ClinicalTrials.gov ID
- NCT06817239
- Acronym / sponsor ID
- NFEC-2025-016
- Conditions
- Delirium in Old Age, Delirium, Postoperative, Anesthesia, Cognitive Dysfunction, Pain, Postoperative, Esketamine
- Keywords
- Delirium, Elderly patients, Esketamine, Non-cardiac surgery
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 1,670 participants (estimated)
- Lead sponsor
- Nanfang Hospital, Southern Medical UniversityUniversity, hospital or other
- Study start
- 12 Feb 2025 (actual)
- Primary completion
- Jun 2027 (estimated)
- Study completion
- Jul 2027 (estimated)
- First posted
- 10 Feb 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Delirium is an acutely occurred neurocognitive disorder characterized by fluctuating symptoms of inattention, altered consciousness and cognitive dysfunction. Delirium is reported to occur in 4% to 65% of postoperative patients depending on the population, and is especially common in older patients. Postoperative delirium is disturbing to patients and their families, and it is a strong predictor of both early and long-term worse outcomes including increased non-delirium complications, increased perioperative mortality, shortened overall survival, declined cognitive function, and lowered quality of life.
Although ketamine/esketamine has anti-inflammatory and neuroprotective effects, evidence on its efficacy in reducing postoperative delirium remains inconsistent and inconclusive. Existing studies are limited by heterogeneity, small sample sizes, single-center designs, and a focus on specific type of surgery. Research on elderly high-risk patients is lacking, and most studies administer the drug intraoperatively, with limited exploration of postoperative use. The optimal dosing and timing for POD prevention are unclear. This study aims to carry out a multicenter, single-blind, placebo-controlled, large-sample randomized controlled trial assessing the effect of low-dose esketamine, given intraoperatively and postoperatively, on delirium in elderly high-risk patients undergoing major non-cardiac surgery.
Detailed description
Delirium is an acutely occurred neurocognitive disorder characterized by fluctuating symptoms of inattention, altered consciousness and cognitive dysfunction. Delirium is reported to occur in 4% to 65% of postoperative patients depending on the population, and is especially common in older patients. Postoperative delirium is disturbing to patients and their families, and it is a strong predictor of both early and long-term worse outcomes including increased non-delirium complications, increased perioperative mortality, shortened overall survival, declined cognitive function, and lowered quality of life.
The mechanism of delirium remains unclear, with neuroinflammation playing a significant role. Emerging evidence suggests anesthetic drug selection may influence the incidence of delirium. Ketamine, a non-competitive NMDA receptor antagonist, exhibits anti-inflammatory and neuroprotective properties by reducing TNF-α, IL-6, IL-1β, p-TAU, and S100B levels, mitigating oxidative stress, and inhibiting neuronal autophagy via the PI3K/AKT/mTOR pathway, thereby potentially preserving cognitive function. Clinical studies exploring ketamine's role in postoperative delirium have yielded mixed results. A retrospective study involving ICU patients undergone abdominal surgery found low-dose ketamine reduced delirium risk by 43% after propensity score matching. In cardiac surgery patients, a single dose of ketamine during induction decreased delirium incidence from 31% to 3%. However, a large international multicenter RCT in patients aged ≥60 undergoing major surgery found no reduction in delirium with pre-induction ketamine. A meta-analysis of eight RCTs also reported no preventive effect, though significant heterogeneity and inconsistent diagnostic criteria were noted. Perioperative ketamine use was consistently found safe, with no increase in adverse events such as nausea, vomiting, respiratory depression, or psychiatric symptoms.
Esketamine, the S-(+)-enantiomer of ketamine, has higher bioavailability, a shorter elimination half-life, and fewer side effects. It is effective in general anesthesia, postoperative analgesia, and ICU sedation, and can be used alone for minor procedures or combined with general or regional anesthesia. As an adjunct, it reduces the need for sedatives (e.g., propofol, midazolam) and opioids, minimizes hemodynamic fluctuations and respiratory depression, and improves anesthesia safety. Esketamine may prevent postoperative delirium, as suggested by emerging evidence. A single dose (0.25 mg/kg) before induction reduced delirium incidence in cardiac surgery patients from 44.6% to 23.2%. In elderly patients undergone gastrointestinal cancer surgery, intraoperative infusion (0.25 mg/kg at induction, then 0.125 mg/kg/h until 20 minutes before the end of surgery) decreased delayed neurocognitive recovery but not delirium. Conversely, postoperative esketamine (1 mg/kg) reduced delirium incidence from 40% to 13.3% in another RCT involving elderly patients undergone gastrointestinal surgery. In patients after major abdominal surgery, mini-dose esketamine (0.015 mg/kg/h for 48 hours) significantly lowered ICU delirium scores compared to low-dose esketamine or placebo. Two meta-analyses of 13 and 17 RCTs, respectively, reported reduced delirium incidence with perioperative esketamine usage, though evidence quality was limited by small sample sizes and heterogeneity. Recent studies showed mixed results. A single-center RCT of 426 elderly surgical patients found no reduction in delirium with 0.2 mg/kg esketamine at induction. In 209 patients aged ≥60 undergone tumor resection, 0.5 mg/kg at induction and 2 mg/kg PCIA postoperatively did not reduce delirium but may improve 90-day cognitive function. Similarly, a single-center RCT of 260 elderly patients after arthroplasty surgery found no benefit with esketamine administered at induction (0.2 mg/kg), intraoperatively (0.125 mg/kg/h), and postoperatively (0.5 mg/kg PCIA). Despite inconsistent findings, esketamine is safe in total, with no increased risk of adverse effects such as respiratory depression, nausea, vomiting, or psychiatric symptoms.
Although ketamine/esketamine has anti-inflammatory and neuroprotective effects, evidence on its efficacy in reducing postoperative delirium remains inconsistent and inconclusive. Existing studies are limited by heterogeneity, small sample sizes, single-center designs, and a focus on specific type of surgery. Research on elderly high-risk patients is lacking, and most studies administer the drug intraoperatively, with limited exploration of postoperative use. The optimal dosing and timing for POD prevention are unclear. This study aims to carry out a multicenter, single-blind, placebo-controlled, large-sample randomized controlled trial assessing the effect of low-dose esketamine, given intraoperatively and postoperatively, on delirium in elderly high-risk patients undergoing major non-cardiac surgery.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Esketamine | Experimental | Drug: EsketamineEsketamine (1mg/ml) will be administered at a loading dose of 0.2 mg/kg, namely at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with a formulation consisting of esketamine 50mg and sufentanil 200 μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes. |
| Normal saline | Placebo comparator | Drug: Normal salineNormal saline will be administered at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with sufentanil 200μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes. |
Who may qualify
- Ages
- 65 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (4 listed)
- Age ≥65 years and <90 years;
- Scheduled to undergo major non-cardiac surgery.
- Fulfill at least one of risk factors as follows: history of stroke; history of delirium; hypertension; congestive heart failure; coronary artery disease; atrial fibrillation; peripheral artery disease; chronic obstructive pulmonary disease; obstructive sleep apnea; diabetes; chronic kidney disease; anemia; malnutrition; hypoalbuminemia; chronic pain; anxiety and depression; poor sleep quality; smoke; alcoholism.
- Scheduled to receive patient-controlled intravenous analgesia (PCIA).
Key exclusion criteria (11 listed)
- Refuse to participate;
- Preoperative history of epilepsy, myasthenia gravis, Parkinson's disease, intracranial hypertension, delirium, schizophrenia, or other psychiatric diseases;
- Inability to communicate in the preoperative period because of coma, profound dementia, or language barrier;
- Preoperative uncontrolled severe hypertension (baseline SBP>180 mmHg or DBP>110 mmHg);
- Preoperative history of hyperthyroidism and pheochromocytoma;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EsketamineEsketamine (1mg/ml) will be administered at a loading dose of 0.2 mg/kg, namely at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with a formulation consisting of esketamine 50mg and sufentanil 200 μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes. | Drug | Esketamine |
| Normal salineNormal saline will be administered at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with sufentanil 200μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes. | Drug | Normal saline |
Primary outcome
The incidence of delirium within 5 days after surgery
Time frame: Up to 5 days after surgery
Delirium is assessed twice daily (8-10 am and 6-8 pm) with The Confusion Assessment Method (CAM) for non-intubated patients or The confusion assessment method for the Intensive Care Unit (CAM-ICU) for intubated patients.
Quality of recovery on postoperative day 1 (Sub-study)
Time frame: On postoperative day 1
Quality of recovery is assessed once daily (6-8 pm) with 15-item Quality of Recovery Scale (QoR-15).
11 secondary outcomes
Intensity of pain during the first 3 postoperative days
Time frame: Up to 3 days after surgery
Use of opioids during the first 3 postoperative days
Time frame: Up to 3 days after surgery
Cognitive function at 30 days after surgery
Time frame: At the end of 30 days after surgery
The incidence of delayed neurocognitive recovery
Time frame: At the end of 30 days after surgery
Death rate at 30 days after surgery
Time frame: At the end of 30 days after surgery
Quality of recovery on postoperative day 3 (Sub-study)
Time frame: On postoperative day 3
Postoperative gastrointestinal intolerance during the first 2 postoperative days (Sub-study)
Time frame: Up to 2 days after surgery
Postoperative gastrointestinal dysfunction during the first 2 postoperative days (Sub-study)
Time frame: Up to 2 days after surgery
Quality of recovery at 30 days after surgery (Sub-study)
Time frame: At the end of 30 days after surgery
HADS score at 30 days after surgery (Sub-study)
Time frame: At the end of 30 days after surgery
Sleep quality at 30 days after surgery (Sub-study)
Time frame: At the end of 30 days after surgery
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2025.
- Background: PubMed 28973626Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA. 2017 Sep 26;318(12):1161-1174. doi: 10.1001/jama.2017.12067.
- Background: PubMed 21474660Rudolph JL, Marcantonio ER. Review articles: postoperative delirium: acute change with long-term implications. Anesth Analg. 2011 May;112(5):1202-11. doi: 10.1213/ANE.0b013e3182147f6d. Epub 2011 Apr 7.
- Background: PubMed 29705752Lindroth H, Bratzke L, Purvis S, Brown R, Coburn M, Mrkobrada M, Chan MTV, Davis DHJ, Pandharipande P, Carlsson CM, Sanders RD. Systematic review of prediction models for delirium in the older adult inpatient. BMJ Open. 2018 Apr 28;8(4):e019223. doi: 10.1136/bmjopen-2017-019223.
- Background: PubMed 19017895Balas MC, Happ MB, Yang W, Chelluri L, Richmond T. Outcomes Associated With Delirium in Older Patients in Surgical ICUs. Chest. 2009 Jan;135(1):18-25. doi: 10.1378/chest.08-1456. Epub 2008 Nov 18.
- Background: PubMed 26041151Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, Serafim RB, Stevens RD. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015 Jun 3;350:h2538. doi: 10.1136/bmj.h2538.
- Background: PubMed 28947274Moskowitz EE, Overbey DM, Jones TS, Jones EL, Arcomano TR, Moore JT, Robinson TN. Post-operative delirium is associated with increased 5-year mortality. Am J Surg. 2017 Dec;214(6):1036-1038. doi: 10.1016/j.amjsurg.2017.08.034. Epub 2017 Sep 20.
- Background: PubMed 27344279Crocker E, Beggs T, Hassan A, Denault A, Lamarche Y, Bagshaw S, Elmi-Sarabi M, Hiebert B, Macdonald K, Giles-Smith L, Tangri N, Arora RC. Long-Term Effects of Postoperative Delirium in Patients Undergoing Cardiac Operation: A Systematic Review. Ann Thorac Surg. 2016 Oct;102(4):1391-9. doi: 10.1016/j.athoracsur.2016.04.071. Epub 2016 Jun 22.
- Background: PubMed 18707945Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008 Sep;65(3):229-38. doi: 10.1016/j.jpsychores.2008.05.019.
- Background: PubMed 36842233Zhao J, Zhang R, Wang W, Jiang S, Liang H, Guo C, Qi J, Zeng H, Song H. Low-dose ketamine inhibits neuronal apoptosis and neuroinflammation in PC12 cells via alpha7nAChR mediated TLR4/MAPK/NF-kappaB signaling pathway. Int Immunopharmacol. 2023 Apr;117:109880. doi: 10.1016/j.intimp.2023.109880. Epub 2023 Feb 27.
- Background: PubMed 36474365Chen M, Han Y, Que B, Zhou R, Gan J, Dong X. Prophylactic Effects of Sub-anesthesia Ketamine on Cognitive Decline, Neuroinflammation, and Oxidative Stress in Elderly Mice. Am J Alzheimers Dis Other Demen. 2022 Jan-Dec;37:15333175221141531. doi: 10.1177/15333175221141531.
- Background: PubMed 38222873Faisal H, Qamar F, Hsu ES, Xu J, Lai EC, Wong ST, Masud FN. Prevalence of Delirium After Abdominal Surgery and Association With Ketamine: A Retrospective, Propensity-Matched Cohort Study. Crit Care Explor. 2024 Jan 11;6(1):e1032. doi: 10.1097/CCE.0000000000001032. eCollection 2024 Jan.
- Background: PubMed 19231245Hudetz JA, Patterson KM, Iqbal Z, Gandhi SD, Byrne AJ, Hudetz AG, Warltier DC, Pagel PS. Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2009 Oct;23(5):651-7. doi: 10.1053/j.jvca.2008.12.021. Epub 2009 Feb 23.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Ke-Xuan Liu, MD principal investigator
Nanfang Hospital, Southern Medical University
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Esketamine and Normal saline in people with Delirium in Old Age and Delirium, Postoperative, run by Nanfang Hospital, Southern Medical University at 6 sites in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Ke-Xuan Liu, MD (+86 13710684096, liukexuan705@163.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The incidence of delirium within 5 days after surgery (time frame: Up to 5 days after surgery). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06817239, which also lists 31 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2025.