Ketamine and Postoperative Cognitive Dysfunction

NCT02892916 | Completed Phase 3 DMC

• 3 other identifiers: P1509102016-000691-16PHRC-15-15-0534
• Study Type: interventional
• Target: 307
• Locations: 1 country
• Sites: 1

Brief Summary

Over 30 million patients require a major surgery annually in the US alone and more than half of them are performed in patients over 60 years of age. Post-operative cognitive dysfunction (POCD) is a keystone complication of these surgeries and affects up to 40% of surgical patients aged over 60 years on discharge from the hospital. Despite controlled longitudinal studies have shown that POCD is transient, it is associated with delirium, higher mortality, earlier retirement, and greater utilization of social financial assistance The pathophysiology of persistent postoperative cognitive dysfunction and causal relationship between POCD and delirium remain incompletely understood. Identified clinical risk factors for both include advanced age, type of surgery, preexisting cognitive impairment, and drug addiction. We and others have provided evidence that the inflammatory response triggered by surgical trauma and pain may contribute to the development of delirium and cognitive impairment after surgery. Ketamine, a N-methyl-D-aspartic acid receptor antagonist, is commonly used in anaesthesia and postoperative analgesia. By reducing both pain and glutamate excitotoxic effects on neuronal and microglial brain cells, it contributes to tone down the neuroinflammatory process associated with surgery. A recent body of evidence has shown that ketamine reduces the depressive-like behavior induced by inflammatory or stress-induced stimuli in mice. Ketamine was also found to reduce levels of inflammatory biomarkers in cardiac surgical patients. Orthopaedic surgery is a high-risk situation for developing postoperative cognitive dysfunction. In patients undergoing non-cardiac surgery, the prevalence of POCD is 26% one week after surgery and decreased to 10% at 3 months postoperatively, and a similar prevalence is found 12 months after the operation. Postoperative delirium is associated with an increased risk of POCD. Hundred thousands of patients \> 60 years undergo elective orthopaedic procedures per year around the world.

Conditions

Post Operative Cognitive Dysfunction

Keywords

Post-operative cognitive dysfunction (POCD); Delirium; Ketamine; Elective orthopaedic surgery

Outcome Measures

Primary Outcomes (1)

• Proportion of early postoperative cognitive dysfunction

  POCD assessed using MoCA (Montreal Cognitive Assessment) test and others cognitive tests included in the calculation of the combined Z-score

  Days 7 and 90 after surgery

Secondary Outcomes (17)

• Post-operative cognitive dysfunction type

  Days 7 and 90 after surgery

• Post-operative cognitive dysfunction severity

  Days 7 and 90 after surgery

• The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)

  Days 7 before surgery or discharge from the hospital

• Early postoperative delirium

  7 days after surgery

• Depression

  Days 7 and 90 after surgery

Study Arms (2)

Ketamine

EXPERIMENTAL

Patients in this experimental group will receive a bolus of low intravenous dose (sub-anaesthetic) 0.5 mg/kg ketamine following induction of anaesthesia.

Drug: Ketamine

Placebo

PLACEBO COMPARATOR

Patients in this control group will receive a bolus of an intravenous normal saline solution following induction of anaesthesia.

Drug: Placebo

Interventions

Ketamine DRUG

A bolus of low intravenous dose (sub-anaesthetic) 0.5 mg/kg ketamine following induction of anaesthesia.

Also known as: Ketamine hydrochloride

Ketamine

Placebo DRUG

A bolus of an intravenous normal saline solution following induction of anaesthesia.

Also known as: Normal saline solution

Placebo

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients 60 years and older
• Competent to provide informed consent
• Undergoing major elective orthopaedic surgery under general anaesthesia
• Patients with and without pre-existing neurodegenerative disease

You may not qualify if:

• Moribund patient or patient under palliative care
• Expected length of stay at hospital \< 48 hours
• Patient under tutorship or curatorship
• Surgical procedure performed under spinal or epidural anaesthesia without general anaesthesia
• Emergency surgery (i.e. emergency hip fracture)
• Patients with a known allergy to ketamine
• Contraindication for ketamine: severe, uncontrolled arterial hypertension or severe heart (FEVG\<25%)
• Patient with glaucoma or history of thyrotoxicosis
• Severe audition or vision disorder
• Patients with drug misuse history (e.g., ketamine, cocaine, heroin, amphetamine, methamphetamine, MDMA (methylenedioxymethamphetamine), phencyclidine, lysergic acid, mescaline, psilocybin)
• Patients taking anti-psychotic medications (e.g., chlorpromazine, clozapine, olanzapine, risperidone, haloperidol, quetiapine, risperidone, paliperidone, amisulpride, sertindole)
• Patients with severe alcohol liver disease (TP\<50% and or bilirubin \> 50 µmol/L)
• Pregnant or breast-feeding woman
• Patient not speaking French
• Absence of informed consent or request to not participate to the study

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Ministry of Health, France: collaborator

Study Sites (1)

AP-HP - Hôpital Saint-Antoine

Paris, Île-de-France Region, 75012, France

Location

Related Publications (10)

• Kurdi MS, Theerth KA, Deva RS. Ketamine: Current applications in anesthesia, pain, and critical care. Anesth Essays Res. 2014 Sep-Dec;8(3):283-90. doi: 10.4103/0259-1162.143110.

  PMID: 25886322 BACKGROUND

• Jabre P, Combes X, Lapostolle F, Dhaouadi M, Ricard-Hibon A, Vivien B, Bertrand L, Beltramini A, Gamand P, Albizzati S, Perdrizet D, Lebail G, Chollet-Xemard C, Maxime V, Brun-Buisson C, Lefrant JY, Bollaert PE, Megarbane B, Ricard JD, Anguel N, Vicaut E, Adnet F; KETASED Collaborative Study Group. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009 Jul 25;374(9686):293-300. doi: 10.1016/S0140-6736(09)60949-1. Epub 2009 Jul 1.

  PMID: 19573904 BACKGROUND

• Riou B, Lecarpentier Y, Viars P. Inotropic effect of ketamine on rat cardiac papillary muscle. Anesthesiology. 1989 Jul;71(1):116-25. doi: 10.1097/00000542-198907000-00020.

  PMID: 2751123 BACKGROUND

• Riou B, Viars P, Lecarpentier Y. Effects of ketamine on the cardiac papillary muscle of normal hamsters and those with cardiomyopathy. Anesthesiology. 1990 Nov;73(5):910-8. doi: 10.1097/00000542-199011000-00019.

  PMID: 2240681 BACKGROUND

• Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016 May 26;533(7604):481-6. doi: 10.1038/nature17998. Epub 2016 May 4.

  PMID: 27144355 BACKGROUND

• Harraz MM, Tyagi R, Cortes P, Snyder SH. Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry. 2016 Mar;21(3):313-9. doi: 10.1038/mp.2015.211. Epub 2016 Jan 19.

  PMID: 26782056 BACKGROUND

• Zorumski CF, Nagele P, Mennerick S, Conway CR. Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy. Front Psychiatry. 2015 Dec 9;6:172. doi: 10.3389/fpsyt.2015.00172. eCollection 2015.

  PMID: 26696909 BACKGROUND

• Hudetz 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.

  PMID: 19231245 BACKGROUND

• Arrowsmith JE, Harrison MJ, Newman SP, Stygall J, Timberlake N, Pugsley WB. Neuroprotection of the brain during cardiopulmonary bypass: a randomized trial of remacemide during coronary artery bypass in 171 patients. Stroke. 1998 Nov;29(11):2357-62. doi: 10.1161/01.str.29.11.2357.

  PMID: 9804648 BACKGROUND

• Verdonk F, Lambert P, Gakuba C, Nelson AC, Lescot T, Garnier F, Constantin JM, Saurel D, Lasocki S, Rineau E, Diemunsch P, Dreyfuss L, Tavernier B, Bezu L, Josserand J, Mebazaa A, Coroir M, Nouette-Gaulain K, Macouillard G, Glasman P, Lemesle D, Minville V, Cuvillon P, Gaudilliere B, Quesnel C, Abdel-Ahad P, Sharshar T, Molliex S, Gaillard R, Mantz J. Preoperative ketamine administration for prevention of postoperative neurocognitive disorders after major orthopedic surgery in elderly patients: A multicenter randomized blinded placebo-controlled trial. Anaesth Crit Care Pain Med. 2024 Aug;43(4):101387. doi: 10.1016/j.accpm.2024.101387. Epub 2024 May 6.

  PMID: 38710325 DERIVED

MeSH Terms

Conditions

Delirium

Interventions

Ketamine; Saline Solution

Condition Hierarchy (Ancestors)

Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Franck Verdonk, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2016
• First Posted: September 8, 2016
• Study Start: March 20, 2017
• Primary Completion: August 31, 2019
• Study Completion: August 31, 2019
• Last Updated: September 10, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)