Ketamine and Postoperative Cognitive Dysfunction

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.

Eligibility Criteria:
Inclusion Criteria:

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

Exclusion Criteria:

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