Delirium
Conditions
Keywords
Delirium, ketamine, surgery, neurological complications
Brief summary
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).
Detailed description
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.
Interventions
Low dose (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications.
DRUGNormal Saline (placebo)
Normal saline IV following induction of anesthesia or administration of sedative medications
DRUGKetamine (1 mg/kg)
Low dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.
Sponsors
Asan Medical Center
Weill Medical College of Cornell University
Harvard Medical School (HMS and HSDM)
Medical College of Wisconsin
Memorial Sloan Kettering Cancer Center
Post Graduate Institute of Medical Education and Research, Chandigarh
University of Bern
University of Michigan
University of Manitoba
University Health Network, Toronto
Virginia Mason Hospital/Medical Center
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients 60 and older * Competent to provide informed consent * Undergoing major surgery (e.g., open cardiac surgery, open or thoracoscopic thoracic surgery, abdominal surgery, open urological surgery, open gynecological surgery, major orthopedic surgery, major vascular surgery including endovascular procedures, major ear, nose and throat surgery).
Exclusion criteria
* Patients with an allergy to ketamine * Those in whom a significant elevation of blood pressure would constitute a serious hazard (e.g., pheochromocytoma, aortic dissection) * Unable to provide informed consent * Patients with drug misuse history (e.g., ketamine, cocaine, heroin, amphetamine, methamphetamine, MDMA, phencyclidine, lysergic acid, mescaline, psilocybin) * Patients taking anti-psychotic medications (e.g., chlorpromazine, clozapine, olanzapine, risperidone, haloperidol, quetiapine, risperidone, paliperidone, amisulpride, sertindole) * Patients with a weight outside the range 50 kg - 200 kg (110 lbs - 440 lbs)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3 | Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Opioid Consumption | Postoperative days 0-3 | 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) |
| Number of Patients With Postoperative Nausea and Vomiting | Postoperative days 1-3 | 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. |
| Daily Maximum Pain Recorded | Postoperative days 1-3, two assessment daily (morning and afternoon), with at least six hours between assessments | 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. |
| Adverse Outcomes (Number of Patients With Hallucinations) | Postoperative days 1-3 | Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit |
| Adverse Outcomes (Number of Patients With Nightmares) | Postoperative days 1-3 | Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive care Unit |
| ICU and/or Hospital Length of Stay | Postoperative period | Assessed from patients' medical charts |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 227 |
| Normal Saline (Placebo) Intravenous normal saline
Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications | 222 |
| 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. | 223 |
| Total | 672 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 1 |
| Overall Study | Determined ineligible | 1 | 0 | 0 |
| Overall Study | Operation Cancelled | 1 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Sedated | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 3 |
Baseline characteristics
| Characteristic | Ketamine (0.5 mg/kg) | Normal Saline (Placebo) | Ketamine (1 mg/kg) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 171 Participants | 163 Participants | 162 Participants | 496 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants | 59 Participants | 61 Participants | 176 Participants |
| Age, Continuous | 70 Years STANDARD_DEVIATION 7.2 | 70 Years STANDARD_DEVIATION 6.9 | 70 Years STANDARD_DEVIATION 7.3 | 70 Years STANDARD_DEVIATION 7.1 |
| Region of Enrollment Canada | 63 Participants | 61 Participants | 59 Participants | 183 Participants |
| Region of Enrollment India | 6 Participants | 5 Participants | 5 Participants | 16 Participants |
| Region of Enrollment South Korea | 11 Participants | 9 Participants | 10 Participants | 30 Participants |
| Region of Enrollment United States | 147 Participants | 147 Participants | 149 Participants | 443 Participants |
| Sex: Female, Male Female | 83 Participants | 87 Participants | 84 Participants | 254 Participants |
| Sex: Female, Male Male | 144 Participants | 135 Participants | 139 Participants | 418 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 227 | 2 / 220 | 0 / 223 |
| other Total, other adverse events | 90 / 227 | 82 / 222 | 86 / 223 |
| serious Total, serious adverse events | 0 / 227 | 0 / 222 | 0 / 223 |
Outcome results
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.
Time frame: Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine (0.5 mg/kg and 1 mg/kg) | Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3 | 85 Participants |
| Normal Saline (Placebo) | Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3 | 43 Participants |
Comparison: The primary analysis was a comparison between the placebo control group and the combined ketamine groupsp-value: 0.91295% CI: [-6.07, 7.38]Chi-squared
Secondary
Adverse Outcomes (Number of Patients With Hallucinations)
Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit
Time frame: Postoperative days 1-3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine (0.5 mg/kg and 1 mg/kg) | Adverse Outcomes (Number of Patients With Hallucinations) | 45 Participants |
| Normal Saline (Placebo) | Adverse Outcomes (Number of Patients With Hallucinations) | 40 Participants |
| Ketamine (1 mg/kg) | Adverse Outcomes (Number of Patients With Hallucinations) | 62 Participants |
Comparison: Frequency of patients reporting hallucinations using the DSAQ instrument.p-value: 0.01Chi-squared
Secondary
Adverse Outcomes (Number of Patients With Nightmares)
Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive care Unit
Time frame: Postoperative days 1-3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine (0.5 mg/kg and 1 mg/kg) | Adverse Outcomes (Number of Patients With Nightmares) | 27 Participants |
| Normal Saline (Placebo) | Adverse Outcomes (Number of Patients With Nightmares) | 18 Participants |
| Ketamine (1 mg/kg) | Adverse Outcomes (Number of Patients With Nightmares) | 34 Participants |
p-value: 0.03Chi-squared
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.
Time frame: Postoperative days 1-3, two assessment daily (morning and afternoon), with at least six hours between assessments
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ketamine (0.5 mg/kg and 1 mg/kg) | Daily Maximum Pain Recorded | BPS/BPS-NI 2 | 4 participants |
| Ketamine (0.5 mg/kg and 1 mg/kg) | Daily Maximum Pain Recorded | VAS day 3 | 46 participants |
| Ketamine (0.5 mg/kg and 1 mg/kg) | Daily Maximum Pain Recorded | BPS/BPS-NI 3 | 3 participants |
| Ketamine (0.5 mg/kg and 1 mg/kg) | Daily Maximum Pain Recorded | VAS day 1 | 70 participants |
| Ketamine (0.5 mg/kg and 1 mg/kg) | Daily Maximum Pain Recorded | BPS/BPS-NI day 1 | 4 participants |
| Ketamine (0.5 mg/kg and 1 mg/kg) | Daily Maximum Pain Recorded | VAS day 2 | 56 participants |
| Normal Saline (Placebo) | Daily Maximum Pain Recorded | BPS/BPS-NI day 1 | 4 participants |
| Normal Saline (Placebo) | Daily Maximum Pain Recorded | BPS/BPS-NI 2 | 3 participants |
| Normal Saline (Placebo) | Daily Maximum Pain Recorded | BPS/BPS-NI 3 | 3 participants |
| Normal Saline (Placebo) | Daily Maximum Pain Recorded | VAS day 2 | 59 participants |
| Normal Saline (Placebo) | Daily Maximum Pain Recorded | VAS day 1 | 63.5 participants |
| Normal Saline (Placebo) | Daily Maximum Pain Recorded | VAS day 3 | 52.5 participants |
| Ketamine (1 mg/kg) | Daily Maximum Pain Recorded | BPS/BPS-NI 3 | 3 participants |
| Ketamine (1 mg/kg) | Daily Maximum Pain Recorded | VAS day 1 | 68 participants |
| Ketamine (1 mg/kg) | Daily Maximum Pain Recorded | VAS day 2 | 57.5 participants |
| Ketamine (1 mg/kg) | Daily Maximum Pain Recorded | VAS day 3 | 47 participants |
| Ketamine (1 mg/kg) | Daily Maximum Pain Recorded | BPS/BPS-NI day 1 | 4 participants |
| Ketamine (1 mg/kg) | Daily Maximum Pain Recorded | BPS/BPS-NI 2 | 3 participants |
Comparison: We compared the combined average pain level (pain level at rest, taking a deep breath, and/or when moving) over the entire day (AM and PM).p-value: 0.964ANOVA
Secondary
ICU and/or Hospital Length of Stay
Assessed from patients' medical charts
Time frame: Postoperative period
Population: Outcome measure data were not collected.
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)
Time frame: Postoperative days 0-3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ketamine (0.5 mg/kg and 1 mg/kg) | Median Opioid Consumption | 88.9 mg |
| Normal Saline (Placebo) | Median Opioid Consumption | 94.7 mg |
| Ketamine (1 mg/kg) | Median Opioid Consumption | 78.7 mg |
Comparison: 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)p-value: 0.476ANOVA
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.
Time frame: Postoperative days 1-3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine (0.5 mg/kg and 1 mg/kg) | Number of Patients With Postoperative Nausea and Vomiting | 72 Participants |
| Normal Saline (Placebo) | Number of Patients With Postoperative Nausea and Vomiting | 73 Participants |
| Ketamine (1 mg/kg) | Number of Patients With Postoperative Nausea and Vomiting | 64 Participants |
Comparison: 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 1-3p-value: 0.572Chi-squared