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Ketamine and Postoperative Cognitive Dysfunction (POCK)

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ClinicalTrials.gov Identifier: NCT02892916
Recruitment Status : Completed
First Posted : September 8, 2016
Last Update Posted : September 10, 2019
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE July 31, 2016
First Posted Date  ICMJE September 8, 2016
Last Update Posted Date September 10, 2019
Actual Study Start Date  ICMJE March 20, 2017
Actual Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
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
Original Primary Outcome Measures  ICMJE
 (submitted: September 1, 2016)
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2019)
  • 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).
  • 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).
  • 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.
  • 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
  • Depression [ Time Frame: Days 7 and 90 after surgery ]
    Depression assessed using the Geriatric Depression Scale (GDS)
  • Anxiety [ Time Frame: Days 7 and 90 after surgery ]
    Anxiety assessed using the Hospital and Anxiety Depression Scale.
  • 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.
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • Hospital length of stay [ Time Frame: Day 90 ]
    Hospital length of stay assessed from patients' medical administrative data in days
  • Cause of death [ Time Frame: Day 90 ]
    Cause of death as postoperative cardio-respiratory arrest and degradation of the general condition
  • Hospital readmission [ Time Frame: Day 90 ]
    Hospital readmission during the follow up, whatever the etiology
  • 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
  • Quality of life evaluated thanks to the SF-36 scale [ Time Frame: Day 90 ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: September 1, 2016)
  • Postoperative cognitive dysfunction (POCD) [ 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
  • Depression [ Time Frame: Days 7 and 90 after surgery ]
    Depression assessed using the Geriatric Depression Scale (GDS)
  • Anxiety [ Time Frame: Days 7 and 90 after surgery ]
    Anxiety assessed using the Hospital and Anxiety Depression Scale.
  • Pain status [ 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.
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • Hospital length of stay [ Time Frame: Day 90 ]
  • Cause of death [ Time Frame: Day 90 ]
  • Hospital readmission [ Time Frame: Day 90 ]
  • 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
  • Quality of life [ Time Frame: Day 90 ]
    Quality of life with SF-36 (the 36-Item Short Form Health Survey) scale and the Modified Fatigue Impact Scale
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine and Postoperative Cognitive Dysfunction
Official Title  ICMJE The Prevention of Post Operative Cognitive Dysfunction by Ketamine: a Prospective Multicenter Randomized Blinded Placebo-controlled Trial in Elderly Patients Undergoing Elective Orthopaedic Surgery
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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Post Operative Cognitive Dysfunction
Intervention  ICMJE
  • Drug: Ketamine
    A bolus of low intravenous dose (sub-anaesthetic) 0.5 mg/kg ketamine following induction of anaesthesia.
    Other Name: Ketamine hydrochloride
  • Drug: Placebo
    A bolus of an intravenous normal saline solution following induction of anaesthesia.
    Other Name: Normal saline solution
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Ketamine
  • Placebo Comparator: Placebo
    Patients in this control group will receive a bolus of an intravenous normal saline solution following induction of anaesthesia.
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 9, 2019)
307
Original Estimated Enrollment  ICMJE
 (submitted: September 1, 2016)
900
Actual Study Completion Date  ICMJE August 31, 2019
Actual Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02892916
Other Study ID Numbers  ICMJE P150910
2016-000691-16 ( EudraCT Number )
PHRC-15-15-0534 ( Other Grant/Funding Number: French Ministry of Health )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Ministry of Health, France
Investigators  ICMJE
Principal Investigator: Franck Verdonk, MD, PhD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP