Impact of Esketamine on Delayed Neurocognitive Recovery in Older Patients

Official title

Impact of Esketamine on Delayed Neurocognitive Recovery in Older Patients Undergoing Non-cardiac Surgery: a Two-center, Dose-exploring Pilot Trial

Overview

Esketamine is frequently used during the perioperative period for supplemental analgesia. Small sample size trials showed that subanesthetic dose esketamine may decrease postoperative neurocognitive complications. However, conflicting results exist and optimal dose of esketamine remains to be determined. This dose-exploring pilot trial is designed to evaluate the safety and efficacy of three different perioperative esketamine dosing regimens in older patients undergoing major non-cardiac surgery. The primary purpose is to explore the optimal dosing strategy that produce maximal neurocognitive benefits with minimal adverse neuropsychiatric symptoms.

Detailed description

Postoperative neurocognitive complications including delirium and delayed neurocognitive recovery are common in older patients after major surgery and associated with worse early and long-term outcomes. Risk factors of neurocognitive complications are multiple. Predisposing factors include older age, low education, and cognitive decline. Precipitating factors include major surgery, high dose opioids, severe pain, and sleep disturbances. The underlying mechanisms are not totally clear but may include surgery-related stress response and inflammation.

Ketamine is a noncompetitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist and has been used as an anesthetic and analgesic for decades. Esketamine is the S-enantiomer of ketamine and has an analgesic potent of approximately 2 times of that of ketamine. Available studies showed that subanesthetic dose ketamine/esketamine may reduce delirium and/or delayed neurocognitive recovery. However, conflicting results exist. Furthermore, even subanesthetic dose ketamine/esketamine may produce neuropsychiatric symptoms which are harmful for neurocognitive recovery.

This dose-exploring pilot trial is designed to evaluate the safety and efficacy of three different perioperative esketamine dosing regimens in older patients undergoing major non-cardiac surgery. The primary purpose is to explore the optimal dosing strategy that produce maximal neurocognitive benefits with minimal adverse neuropsychiatric symptoms.

Interventions

• Drug Esketamine 1
  During anesthesia, a loading dose esketamine (0.5 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.1 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.05 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.25 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (0.5 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.25 mg/h esketa
• Drug Esketamine 2
  During anesthesia, a loading dose esketamine (1.0 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.2 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.1 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.5 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (1 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.5 mg/h esketamine)
• Drug Esketamine 3
  During anesthesia, a loading dose esketamine (1.5 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.3 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.15 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.75 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (1.5 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.75 mg/h esketa
• Drug Normal saline
  During anesthesia, a loading dose placebo (normal saline) 0.4 ml/kg will be infused over 30 minutes after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with sufentanil (1 ug/ml), programmed to deliver 2-ml bolus with a 8-10-minute lock-out time and a 1-ml/h background infusion, and used for up to 48 hours.

Primary outcome measures

• Incidence of dissociative symptoms [Time frame: Up to 4 days after surgery]

Secondary outcome measures (3)

• Incidence of emergence delirium [Time frame: At 30 minutes after extubation]
• Incidence of postoperative delirium [Time frame: Up to 4 days after surgery]
• Incidence of delayed neurocognitive recovery [Time frame: Up to 5 days after surgery]

Eligibility criteria

Inclusion criteria

• Aged >=65 but <= 90 years;
• Scheduled to undergo non-cardiac surgery with an expected duration of >= 2 hours under general anesthesia;
• Requiring patient-controlled intravenous analgesia (PCIA) after surgery.

Exclusion criteria

• Unable to communicate preoperatively due to visual or auditory impairment, language barrier, or severe dementia;
• Comorbid with schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis;
• Traumatic brain injury or neurosurgery;
• Severe hepatic dysfunction (Child-Pugh Class C), severe renal dysfunction (receiving dialysis preoperatively), or American Society of Anesthesiologists physical status classification >= Ⅳ;
• Expected admission to the Intensive Care Unit with endotracheal intubation after surgery;
• Anaphylaxis to esketamine;
• Participation in other clinical studies, or any other conditions that are considered unsuitable to be involved in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

China · 2 centers

• Peking University First Hospital — Beijing
• Tianjin Medical University General Hospital — Tanjing

Publications

• Brodier EA, Cibelli M. Postoperative cognitive dysfunction in clinical practice. BJA Educ. 2021 Feb;21(2):75-82. doi: 10.1016/j.bjae.2020.10.004. Epub 2020 Dec 24. No abstract available. PMID 33889433
• Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K, Kuipers HM, Hanning CD, Siersma VD, Kristensen D, Canet J, Ibanaz MT, Moller JT; ISPOCD2 Investigators. Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology. 2002 Jun;96(6):1351-7. doi: 10.1097/00000542-200206000-00014. PMID 12170047
• Zhang ZR, Li YZ, Wu XQ, Chen WJ, Xu J, Zhao WH, Gong XY. Postoperative cognitive dysfunction in elderly postcardiac surgery patients: progress in rehabilitation application research. Front Rehabil Sci. 2024 Dec 17;5:1525813. doi: 10.3389/fresc.2024.1525813. eCollection 2024. PMID 39741908
• Liu Y, Fu H, Wang T. Neuroinflammation in perioperative neurocognitive disorders: From bench to the bedside. CNS Neurosci Ther. 2022 Apr;28(4):484-496. doi: 10.1111/cns.13794. Epub 2022 Jan 6. PMID 34990087
• Li YL, Huang HF, Le Y. Risk factors and predictive value of perioperative neurocognitive disorders in elderly patients with gastrointestinal tumors. BMC Anesthesiol. 2021 Jul 19;21(1):193. doi: 10.1186/s12871-021-01405-7. PMID 34281529
• Charipova K, Urits I, Viswanath O, Urman RD. Preoperative assessment and optimization of cognitive dysfunction and frailty in the ambulatory surgical patient. Curr Opin Anaesthesiol. 2020 Dec;33(6):732-739. doi: 10.1097/ACO.0000000000000901. PMID 32769745
• Amado LA, Perrie H, Scribante J, Ben-Israel KA. Preoperative cognitive dysfunction in older elective noncardiac surgical patients in South Africa. Br J Anaesth. 2020 Sep;125(3):275-281. doi: 10.1016/j.bja.2020.04.072. Epub 2020 Jun 10. PMID 32532428
• Mahanna-Gabrielli E, Schenning KJ, Eriksson LI, Browndyke JN, Wright CB, Culley DJ, Evered L, Scott DA, Wang NY, Brown CH 4th, Oh E, Purdon P, Inouye S, Berger M, Whittington RA, Price CC, Deiner S. State of the clinical science of perioperative brain health: report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018. Br J Anaesth. 2019 Oct;123(4):464-478. doi: 10.10 PMID 31439308

Identifiers

NCT: NCT07523334 · 2026-0166

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗