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| Name | Class |
|---|---|
| Asan Medical Center | OTHER |
| Weill Medical College of Cornell University | OTHER |
| Harvard Medical School (HMS and HSDM) | OTHER |
| Medical College of Wisconsin |
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Delirium is a medical term or condition that includes a temporary inability to focus attention and to think clearly. Delirium occurs commonly (10% to 70%) in patients older than 60 undergoing large surgeries. The purpose of this study is to test rigorously whether a drug called ketamine can decrease the chance that patients will experience delirium after their surgery. The investigators are also testing whether ketamine decreases postoperative pain, postoperative opioid consumption, postoperative nausea and vomiting, ICU and hospital length of stay, and adverse outcomes (e.g. hallucinations and nightmares).
Postoperative delirium is one of the most common complications of major surgery, affecting between 10% and 70% of all elderly surgical patients. Delirium manifests as poor attention and inability to think logically, and is associated with longer intensive care unit and hospital stay, long lasting cognitive deterioration, and increased mortality rate. Studies have shown that a low sub-anesthetic dose of ketamine, an anesthetic drug, has the potential to decrease several postoperative complications, including delirium, pain, opioid consumption, and nausea and vomiting. Low dose ketamine would be particularly appealing as a drug to prevent delirium and other postoperative complications, as it is inexpensive and extremely safe. However, these proposed benefits of ketamine in the perioperative setting have not yet been tested in a large clinical trial. The investigators are therefore proposing a pragmatic, exploratory clinical trial to support or refute the contention that low dose ketamine decreases the incidence of postoperative delirium, with the possibility of conducting a larger randomized clinical trial pending the results of this study. At the time of enrollment, patients will undergo the same delirium and pain evaluation that will be used postoperatively. Additionally patients will be screened for functional dependence using the Barthel Index of Activities of Daily Living, for depression using the Geriatric Depression Scale - Short Form, and for obstructive sleep apnea using the STOP-Bang criteria. They will also be asked about any falls they have experienced in the six months prior to surgery. Comorbid conditions, including the components of the Charlson Comorbidity Index, will be obtained by reviewing the patients' medical records. Any available preoperative lab results, including electrolytes and blood counts, will also be recorded.
Patients will be randomized to receive low dose ketamine or placebo following induction of anesthesia and prior to surgical incision. Blinded observers will assess delirium on the afternoon/evening of postoperative day 0 (if feasible) and twice daily (morning and afternoon/evening with at least six hours between assessments) on postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Unit. Acute pain will be assessed via the observer-based Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) with subsequent administration of the patient-reported Visual Analog Scale from postoperative days 0-3. Postoperative opioid consumption will be assessed from the patients' medical charts for postoperative days 0-3. Postoperative nausea and vomiting will be assessed via a patient-reported section of the Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) for postoperative days 0-3. ICU and/or hospital length of stay will be assessed from the patients' medical charts. Adverse outcomes (e.g. hallucinations and nightmares) will be assessed via the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Unit for postoperative days 0-3.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketamine (0.5 mg/kg) | Experimental | Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
|
| Normal saline (placebo) | Placebo Comparator | Intravenous normal saline |
|
| Ketamine (1 mg/kg) | Experimental | Low dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketamine (0.5 mg/kg) | Drug | Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3 | According to Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit criteria the number of patients that had any positive CAM on any day for all patients. The main effect evaluated will be to determine whether ketamine decreases delirium, table 3 of the protocol provides a useful guide for the potential findings of the current study with their implications. To further clarify, delirium will be assessed on the day of surgery, when possible and on the subsequent three days POD 1-3, as long as as patients remain in the hospital and are assessable (i.e., not sedated to a RASS <-3). The assessments on POD 1-3 will be done twice daily, once in the morning and once in the afternoon. The primary outcome of the study includes only the delirium incidence on POD 1-3. The primary comparison will be between the combined ketamine groups and the placebo group. | Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients |
| Measure | Description | Time Frame |
|---|---|---|
| Daily Maximum Pain Recorded | Assessed by observer-based Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) with subsequent administration of patient-reported Visual Analog Scale The behavioral pain scale has three domains and ranges from 3 to 15. The visual analog scale is a continuous scale from 0 to 100 mm. Daily Maximum Pain accounted for pain level in the AM or PM for both the VAS and the BPS/BPS-NI a higher value means a worse outcome. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| George A Mashour, MD PhD | University of Michigan | Principal Investigator |
| Daniel A Emmert, MD PhD | Washington University School of Medicine | Study Director |
| Kane Pryor, MBBS | Cornell | Study Director |
| Eric Jacobsohn, MB ChB | University of Manitoba | Study Director |
| Judith Hudetz, PhD | Medical College of Wisconsin | Study Director |
| Hilary P Grocott, MD | University of Manitoba | Study Chair |
| Michael S Avidan, MBBCh | Washington University School of Medicine | Principal Investigator |
| Sharon Inouye | Harvard Medical School (HMS and HSDM) | Study Director |
| Robert Veselis | Memorial Sloan Kettering Medical Center | Study Director |
| Jayant Aveek |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25231491 | Background | Avidan MS, Fritz BA, Maybrier HR, Muench MR, Escallier KE, Chen Y, Ben Abdallah A, Veselis RA, Hudetz JA, Pagel PS, Noh G, Pryor K, Kaiser H, Arya VK, Pong R, Jacobsohn E, Grocott HP, Choi S, Downey RJ, Inouye SK, Mashour GA. The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial. BMJ Open. 2014 Sep 17;4(9):e005651. doi: 10.1136/bmjopen-2014-005651. | |
| 28576285 |
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746 participants were consented to the study; however only 672 were randomly assigned as 74 participants were determined ineligible after consent. Reasons for ineligibility: operations were cancelled or patients withdrew from the study, etc.
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| ID | Title | Description |
|---|---|---|
| FG000 | Ketamine (0.5 mg/kg) | Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (0.5 mg/kg): Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
| FG001 | Normal Saline (Placebo) | Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications |
| FG002 | Ketamine (1 mg/kg) | High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Ketamine (0.5 mg/kg) | Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (0.5 mg/kg): Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3 | According to Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit criteria the number of patients that had any positive CAM on any day for all patients. The main effect evaluated will be to determine whether ketamine decreases delirium, table 3 of the protocol provides a useful guide for the potential findings of the current study with their implications. To further clarify, delirium will be assessed on the day of surgery, when possible and on the subsequent three days POD 1-3, as long as as patients remain in the hospital and are assessable (i.e., not sedated to a RASS <-3). The assessments on POD 1-3 will be done twice daily, once in the morning and once in the afternoon. The primary outcome of the study includes only the delirium incidence on POD 1-3. The primary comparison will be between the combined ketamine groups and the placebo group. | Of all 672 participants, data were analyzed AM and PM and post operative day 1 through day 3 for screened participants with a CAM. The overall incidence of delirium were compared, Ketamine 0.5 mg/kg and 1 mg/kg groups were combined as per-specified in the study protocol. | Posted | Count of Participants | Participants | Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients |
Assessed up to 3 days (POD 0-3).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ketamine (0.5 mg/kg) | Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (0.5 mg/kg): Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial Fibriliation | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Michael Avidan | Washington University School of Medicine | 314-747-4155 | avidanm@wustl.edu |
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| ID | Term |
|---|---|
| D003693 | Delirium |
| ID | Term |
|---|---|
| D003221 | Confusion |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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| OTHER |
| Memorial Sloan Kettering Cancer Center | OTHER |
| Post Graduate Institute of Medical Education and Research, Chandigarh | OTHER |
| University of Bern | OTHER |
| University of Michigan | OTHER |
| University of Manitoba | OTHER |
| University Health Network, Toronto | OTHER |
| Virginia Mason Hospital/Medical Center | OTHER |
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|
| Normal Saline (placebo) | Drug | Normal saline IV following induction of anesthesia or administration of sedative medications |
|
|
| Ketamine (1 mg/kg) | Drug | Low dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
|
|
| Postoperative days 1-3, two assessment daily (morning and afternoon), with at least six hours between assessments |
| Median Opioid Consumption | Assessed from patients' medical charts. All morphine equivalent drugs consumed by patients perioperatively Opioid Drugs included: * Postoperatively while still in hospital, the list of pain medication used included Morphine, Hydromorphone, Meperidine, Nalbuphine, Oxycodone,Oxymorphone, Tramadol, bupivacaine, (Codeine, Fentanyl, Naloxone) Total Opiates (Morphine Equivalent) in milligrams The median(IQR) opioid consumption was compared across the three study groups Placebo vs. Lo-K (0.5 mg/kg) vs. Hi-K (1 mg/kg) | Postoperative days 0-3 |
| Number of Patients With Postoperative Nausea and Vomiting | Assessed from patient-reported postoperative nausea and vomiting section of Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) Patients where asked whether they "currently have nausea/vomiting" AM & PM the response choices: None, Mild, Moderate, Severe Incidence of nausea\vomiting accounted for any positive reporting(Mild, moderate, or sever) Daily incidence accounted for any positive incidence AM/PM in each POD Any POD nausea/vomiting reports the incidence across day 1-3 The incidence of nausea and or vomiting was compared across the three study groups Placebo vs. Lo-K (0.5 mg/kg) vs. Hi-K (1 mg/kg) for POD 1-3 and overall. | Postoperative days 1-3 |
| ICU and/or Hospital Length of Stay | Assessed from patients' medical charts | Postoperative period |
| Adverse Outcomes (Number of Patients With Hallucinations) | Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit | Postoperative days 1-3 |
| Adverse Outcomes (Number of Patients With Nightmares) | Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive care Unit | Postoperative days 1-3 |
| Post Graduate Institute of Medical Education and Research, Chandigarh |
| Study Director |
| Heiko Kaiser | University of Bern | Study Director |
| Stephen Choi | University of Toronto | Study Chair |
| Ryan Pong | Virginia Mason Medical Center | Study Chair |
| Gyujeong Noh | Asan Medical Center | Study Director |
| Result |
| Avidan MS, Maybrier HR, Abdallah AB, Jacobsohn E, Vlisides PE, Pryor KO, Veselis RA, Grocott HP, Emmert DA, Rogers EM, Downey RJ, Yulico H, Noh GJ, Lee YH, Waszynski CM, Arya VK, Pagel PS, Hudetz JA, Muench MR, Fritz BA, Waberski W, Inouye SK, Mashour GA; PODCAST Research Group. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet. 2017 Jul 15;390(10091):267-275. doi: 10.1016/S0140-6736(17)31467-8. Epub 2017 May 30. |
| 30768457 | Derived | Vlisides PE, Thompson A, Kunkler BS, Maybrier HR, Avidan MS, Mashour GA; PODCAST Research Group. Perioperative Epidural Use and Risk of Delirium in Surgical Patients: A Secondary Analysis of the PODCAST Trial. Anesth Analg. 2019 May;128(5):944-952. doi: 10.1213/ANE.0000000000004038. |
| 30336852 | Derived | Mashour GA, Ben Abdallah A, Pryor KO, El-Gabalawy R, Vlisides PE, Jacobsohn E, Lenze E, Maybrier HR, Veselis RA, Avidan MS; PODCAST Research Group. Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Br J Anaesth. 2018 Nov;121(5):1075-1083. doi: 10.1016/j.bja.2018.03.030. Epub 2018 Sep 19. |
| Operation Cancelled |
|
| Determined ineligible |
|
| Death |
|
| Sedated |
|
| Normal Saline (Placebo) |
Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications |
| BG002 | Ketamine (1 mg/kg) | High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants | No |
|
|
|
|
|
| Secondary | Daily Maximum Pain Recorded | Assessed by observer-based Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) with subsequent administration of patient-reported Visual Analog Scale The behavioral pain scale has three domains and ranges from 3 to 15. The visual analog scale is a continuous scale from 0 to 100 mm. Daily Maximum Pain accounted for pain level in the AM or PM for both the VAS and the BPS/BPS-NI a higher value means a worse outcome. | Posted | Median | Inter-Quartile Range | participants | Postoperative days 1-3, two assessment daily (morning and afternoon), with at least six hours between assessments |
|
|
|
|
| Secondary | Median Opioid Consumption | Assessed from patients' medical charts. All morphine equivalent drugs consumed by patients perioperatively Opioid Drugs included: * Postoperatively while still in hospital, the list of pain medication used included Morphine, Hydromorphone, Meperidine, Nalbuphine, Oxycodone,Oxymorphone, Tramadol, bupivacaine, (Codeine, Fentanyl, Naloxone) Total Opiates (Morphine Equivalent) in milligrams The median(IQR) opioid consumption was compared across the three study groups Placebo vs. Lo-K (0.5 mg/kg) vs. Hi-K (1 mg/kg) | Posted | Median | Full Range | mg | Postoperative days 0-3 |
|
|
|
|
| Secondary | Number of Patients With Postoperative Nausea and Vomiting | Assessed from patient-reported postoperative nausea and vomiting section of Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) Patients where asked whether they "currently have nausea/vomiting" AM & PM the response choices: None, Mild, Moderate, Severe Incidence of nausea\vomiting accounted for any positive reporting(Mild, moderate, or sever) Daily incidence accounted for any positive incidence AM/PM in each POD Any POD nausea/vomiting reports the incidence across day 1-3 The incidence of nausea and or vomiting was compared across the three study groups Placebo vs. Lo-K (0.5 mg/kg) vs. Hi-K (1 mg/kg) for POD 1-3 and overall. | Posted | Count of Participants | Participants | Postoperative days 1-3 |
|
|
|
|
| Secondary | ICU and/or Hospital Length of Stay | Assessed from patients' medical charts | Outcome measure data were not collected. | Posted | Postoperative period |
|
|
| Secondary | Adverse Outcomes (Number of Patients With Hallucinations) | Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit | Posted | Count of Participants | Participants | Postoperative days 1-3 |
|
|
|
|
| Secondary | Adverse Outcomes (Number of Patients With Nightmares) | Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive care Unit | Posted | Count of Participants | Participants | Postoperative days 1-3 |
|
|
|
|
| 0 |
| 227 |
| 0 |
| 227 |
| 90 |
| 227 |
| EG001 | Normal Saline (Placebo) | Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications | 2 | 220 | 0 | 222 | 82 | 222 |
| EG002 | Ketamine (1 mg/kg) | High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications. | 0 | 223 | 0 | 223 | 86 | 223 |
| Anaemia/Bleeding | Blood and lymphatic system disorders | Systematic Assessment |
|
| Infection | Infections and infestations | Systematic Assessment |
|
| Renal | Renal and urinary disorders | Systematic Assessment |
|
| Hypotension | Vascular disorders | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | Systematic Assessment |
|
| Gastrointestinal | Gastrointestinal disorders | Systematic Assessment |
|
| Hypertension | Vascular disorders | Systematic Assessment |
|
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| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
|
| VAS day 3 |
|
| BPS/BPS-NI day 1 |
|
| BPS/BPS-NI 2 |
|
| BPS/BPS-NI 3 |
|