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Ketamine and Postoperative Cognitive Dysfunction (POCK)

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ClinicalTrials.gov Identifier: NCT02892916
Recruitment Status : Recruiting
First Posted : September 8, 2016
Last Update Posted : May 29, 2019
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.


Condition or disease Intervention/treatment Phase
Post Operative Cognitive Dysfunction Drug: Ketamine Drug: Placebo Phase 3

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 274 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: The Prevention of Post Operative Cognitive Dysfunction by Ketamine: a Prospective Multicenter Randomized Blinded Placebo-controlled Trial in Elderly Patients Undergoing Elective Orthopaedic Surgery
Actual Study Start Date : March 20, 2017
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : September 30, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Ketamine

Arm Intervention/treatment
Experimental: Ketamine
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
A bolus of low intravenous dose (sub-anaesthetic) 0.5 mg/kg ketamine following induction of anaesthesia.
Other Name: Ketamine hydrochloride

Placebo Comparator: Placebo
Patients in this control group will receive a bolus of an intravenous normal saline solution following induction of anaesthesia.
Drug: Placebo
A bolus of an intravenous normal saline solution following induction of anaesthesia.
Other Name: Normal saline solution




Primary Outcome Measures :
  1. Proportion of early postoperative cognitive dysfunction [ Time Frame: Days 7 and 90 after surgery ]
    POCD assessed using MoCA (Montreal Cognitive Assessment) test and others cognitive tests included in the calculation of the combined Z-score


Secondary Outcome Measures :
  1. Post-operative cognitive dysfunction type [ Time Frame: Days 7 and 90 after surgery ]
    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).

  2. Post-operative cognitive dysfunction severity [ Time Frame: Days 7 and 90 after surgery ]
    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).

  3. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) [ Time Frame: Days 7 before surgery or discharge from the hospital ]
    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.

  4. Early postoperative delirium [ Time Frame: 7 days after surgery ]
    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

  5. Depression [ Time Frame: Days 7 and 90 after surgery ]
    Depression assessed using the Geriatric Depression Scale (GDS)

  6. Anxiety [ Time Frame: Days 7 and 90 after surgery ]
    Anxiety assessed using the Hospital and Anxiety Depression Scale.

  7. Pain status: Visual Analog Scale [ Time Frame: Day prior to surgery, at days 7 and 90 after surgery ]
    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.

  8. Time from surgery to POCD. [ Time Frame: Days 7 and 90 after surgery ]
    Time of occurrence of POCD (early or late) and his association with postoperative delirium

  9. Pre-existing cognitive status [ Time Frame: Days 7 and 90 after surgery ]
    Pre-existing cognitive status measured by the preoperative combined Z-score for cognitive functions and his association with the occurrence of postoperative delirium

  10. Preoperative Charlson's score for comorbidities [ Time Frame: Days 7 and 90 after surgery ]
    Preoperative Charlson's sore for comorbidities and his association with the occurrence of postoperative delirium

  11. Intraoperative serious adverse events [ Time Frame: Day 7 ]
    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.

  12. Postoperative adverse events [ Time Frame: Day 7 ]
    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.

  13. Hospital length of stay [ Time Frame: Day 90 ]
    Hospital length of stay assessed from patients' medical administrative data in days

  14. Cause of death [ Time Frame: Day 90 ]
    Cause of death

  15. Hospital readmission [ Time Frame: Day 90 ]
    Hospital readmission during the follow up, whatever the etiology

  16. Inflammatory biomarkers [ Time Frame: Day 90 ]
    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

  17. Quality of life evaluated thanks to the SF-36 scale [ Time Frame: Day 90 ]
    Quality of life evaluated thanks to the SF-36 scale



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02892916


Contacts
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Contact: Franck Verdonk, MD, PhD +33 1 49 28 23 62 franck.verdonk@aphp.fr

Locations
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France
AP-HP - Hôpital Saint-Antoine Recruiting
Paris, Île-de-France, France, 75012
Contact: Franck Verdonk, MD       franck.verdonk@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Ministry of Health, France
Investigators
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Principal Investigator: Franck Verdonk, MD, PhD Assistance Publique - Hôpitaux de Paris

Publications:

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02892916     History of Changes
Other Study ID Numbers: P150910
2016-000691-16 ( EudraCT Number )
PHRC-15-15-0534 ( Other Grant/Funding Number: French Ministry of Health )
First Posted: September 8, 2016    Key Record Dates
Last Update Posted: May 29, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Post-operative cognitive dysfunction (POCD)
Delirium
Ketamine
Elective orthopaedic surgery

Additional relevant MeSH terms:
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Ketamine
Cognitive Dysfunction
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action