Ketamine and Postoperative Cognitive Dysfunction (POCK)

The Prevention of Post Operative Cognitive Dysfunction by Ketamine: a Prospective Multicenter Randomized Blinded Placebo-controlled Trial in Elderly Patients Undergoing Elective Orthopaedic Surgery

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.

The design consists in a prospective multicenter randomized blinded placebo-controlled trial in elderly patients undergoing elective orthopaedic surgery. Patients will be informed at the pre-anaesthetic consultation, 7 to 30 days before surgery. They will be randomized the day before surgery. Cognitive and depressive status at baseline will be assessed precisely the day pior to surgery with cognitive tests. Self-administered scores will be recorded to evaluate depression, anxiety, and quality of life. At the day of surgery, patients in the experimental group will receive a bolus of low intravenous dose (sub-anaesthetic) 0.5 mg/kg ketamine following induction of anaesthesia. Patients in the control group will receive a bolus of an intravenous normal saline solution following induction of anaesthesia. From D0 (2 hours after surgery end) to D7 or discharge from the hospital if earlier, delirium, pain, adverse clinical and psychiatric events will be measured and recorded. Cognitive functions, neuropathic pain, depression, anxiety and quality of life will be assessed at D7 or discharge from the hospital if earlier and D90. Inflammatory markers will be measured before surgery, at D1, D7 or discharge from the hospital if earlier and D90.

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

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

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

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

The evaluation should be based on differences between pre- and postoperative performance (7 days or at discharge from the hospital if earlier and 3 months or earlier at the surgical follow-up visit depending on the practices of the different centers).

The evaluation should be based on differences between pre- and postoperative performance (7 days or at discharge from the hospital if earlier and 3 months or earlier at the surgical follow-up visit depending on the practices of the different centers).

Measurements will start from postoperative day 0 two hours after the end of surgery to day 7 or discharge from the hospital if earlier, twice daily (morning and evening) with at least 6 hours between two consecutive measurements.

Patients with at least one episode of delirium measured by CAM (Confusion Assessment Method) or CAM-ICU (adaptation used in Intensive Care Unit) scores between day 0 and day 7

Pain scores assessed by the patient-reported Visual Analog Scale. Neuropathic pain at 3 months measured by the DN4 (Douleur Neuropathique en 4 questions) questionnaire.

Pre-existing cognitive status measured by the preoperative combined Z-score for cognitive functions and his association with the occurrence of postoperative delirium

Preoperative Charlson's sore for comorbidities and his association with the occurrence of postoperative delirium

Intraoperative serious adverse events such as bleeding requiring at least 2 red cell units or unexpected prolonged duration of surgery and their association with postoperative delirium.

Early post-operative complications (reoperation, hospital readmission, bleeding, transfusion, sepsis, hypoxemia, sodium disorders, specific medications, presence or absence of a specific rehabilitation program) recorded from patients' charts and their association with postoperative delirium.

Inflammatory biomarkers (C Reactive Protein, Interleukin-6, Interleukin-2, TNFalpha, B-type natriuretic peptide and Troponin) levels and their association with the occurrence of postoperative delirium and long term POCD

Quality of life evaluated thanks to the SF-36 scale is a 36-item patient-reported questionnaire that covers eight health domains: physical functioning (10 items), bodily pain (2 items), role limitations due to physical health problems (4 items), role limitations due to personal or emotional problems (4 items), emotional well-being (5 items), social functioning (2 items), energy/fatigue (4 items), and general health perceptions (5 items). Scores for each domain range from 0 to 100, with a higher score defining a more favorable health state

Inclusion Criteria: 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 Exclusion Criteria: 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 Non affiliation to the social security

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