Trial Outcomes & Findings for The Prevention of Delirium and Complications Associated With Surgical Treatments Multi Center Clinical Trial (NCT NCT01690988)

NCT ID: NCT01690988

Last Updated: 2018-06-06

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 746 participants
• Primary outcome timeframe: Delirium incidence on postoperative days 1-3, calculated by any positive CAM on any day for all patients
• Results posted on: 2018-06-06

Participant Flow

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.

Participant milestones

Measure	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.	Normal Saline (Placebo) Intravenous normal saline Normal Saline (placebo): Normal saline IV 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. Ketamine (1 mg/kg): High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.
Overall Study STARTED	227	222	223
Overall Study COMPLETED	221	217	216
Overall Study NOT COMPLETED	6	5	7

Reasons for withdrawal

Measure	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.	Normal Saline (Placebo) Intravenous normal saline Normal Saline (placebo): Normal saline IV 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. Ketamine (1 mg/kg): High dose (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.
Overall Study Withdrawal by Subject	2	2	3
Overall Study Physician Decision	0	0	1
Overall Study Operation Cancelled	1	1	0
Overall Study Determined ineligible	1	0	0
Overall Study Death	1	1	1
Overall Study Sedated	1	1	2

Baseline Characteristics

The Prevention of Delirium and Complications Associated With Surgical Treatments Multi Center Clinical Trial

Baseline characteristics by cohort

Measure	Ketamine (0.5 mg/kg) n=227 Participants 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.	Normal Saline (Placebo) n=222 Participants Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications	Ketamine (1 mg/kg) n=223 Participants 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.	Total n=672 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	56 Participants n=5 Participants	59 Participants n=7 Participants	61 Participants n=5 Participants	176 Participants n=4 Participants
Age, Categorical >=65 years	171 Participants n=5 Participants	163 Participants n=7 Participants	162 Participants n=5 Participants	496 Participants n=4 Participants
Age, Continuous	70 Years STANDARD_DEVIATION 7.2 • n=5 Participants	70 Years STANDARD_DEVIATION 6.9 • n=7 Participants	70 Years STANDARD_DEVIATION 7.3 • n=5 Participants	70 Years STANDARD_DEVIATION 7.1 • n=4 Participants
Sex: Female, Male Female	83 Participants n=5 Participants	87 Participants n=7 Participants	84 Participants n=5 Participants	254 Participants n=4 Participants
Sex: Female, Male Male	144 Participants n=5 Participants	135 Participants n=7 Participants	139 Participants n=5 Participants	418 Participants n=4 Participants
Region of Enrollment United States	147 Participants n=5 Participants	147 Participants n=7 Participants	149 Participants n=5 Participants	443 Participants n=4 Participants
Region of Enrollment Canada	63 Participants n=5 Participants	61 Participants n=7 Participants	59 Participants n=5 Participants	183 Participants n=4 Participants
Region of Enrollment India	6 Participants n=5 Participants	5 Participants n=7 Participants	5 Participants n=5 Participants	16 Participants n=4 Participants
Region of Enrollment South Korea	11 Participants n=5 Participants	9 Participants n=7 Participants	10 Participants n=5 Participants	30 Participants n=4 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Ketamine (0.5 mg/kg and 1 mg/kg) n=438 Participants Both the 0.5 mg/kg and the 1mg/kg doses groups of Ketamine were combined for analysis) Low dose Ketamine (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Normal Saline (Placebo) n=217 Participants Intravenous normal saline Normal Saline (placebo): Normal saline IV 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. Ketamine (1 mg/kg): High dose (sub-anesthetic) 1 mg/kg ketamine following induction anesthesia or administration of sedative medications.
Number of Patients With Incidence of Delirium Across All Patients at Baseline and Over Post-operative Days 1-3	85 Participants	43 Participants	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Ketamine (0.5 mg/kg and 1 mg/kg) n=227 Participants Both the 0.5 mg/kg and the 1mg/kg doses groups of Ketamine were combined for analysis) Low dose Ketamine (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Normal Saline (Placebo) n=222 Participants Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications	Ketamine (1 mg/kg) n=223 Participants 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 anesthesia or administration of sedative medications.
Daily Maximum Pain Recorded VAS day 1	70 participants Interval 40.0 to 87.0	63.5 participants Interval 43.0 to 82.0	68 participants Interval 37.5 to 90.0
Daily Maximum Pain Recorded VAS day 2	56 participants Interval 30.0 to 80.0	59 participants Interval 31.0 to 80.0	57.5 participants Interval 27.0 to 81.0
Daily Maximum Pain Recorded VAS day 3	46 participants Interval 22.5 to 75.0	52.5 participants Interval 25.5 to 75.0	47 participants Interval 23.0 to 74.0
Daily Maximum Pain Recorded BPS/BPS-NI day 1	4 participants Interval 3.0 to 5.0	4 participants Interval 3.0 to 4.0	4 participants Interval 3.0 to 5.0
Daily Maximum Pain Recorded BPS/BPS-NI 2	4 participants Interval 3.0 to 4.0	3 participants Interval 3.0 to 4.0	3 participants Interval 3.0 to 4.0
Daily Maximum Pain Recorded BPS/BPS-NI 3	3 participants Interval 3.0 to 4.0	3 participants Interval 3.0 to 4.0	3 participants Interval 3.0 to 4.0

SECONDARY outcome

Timeframe: 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)

Outcome measures

Measure	Ketamine (0.5 mg/kg and 1 mg/kg) n=227 Participants Both the 0.5 mg/kg and the 1mg/kg doses groups of Ketamine were combined for analysis) Low dose Ketamine (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Normal Saline (Placebo) n=222 Participants Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications	Ketamine (1 mg/kg) n=223 Participants 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 anesthesia or administration of sedative medications.
Median Opioid Consumption	88.9 mg Interval 46.5 to 175.5	94.7 mg Interval 48.0 to 199.0	78.7 mg Interval 43.8 to 169.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Ketamine (0.5 mg/kg and 1 mg/kg) n=227 Participants Both the 0.5 mg/kg and the 1mg/kg doses groups of Ketamine were combined for analysis) Low dose Ketamine (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Normal Saline (Placebo) n=222 Participants Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications	Ketamine (1 mg/kg) n=223 Participants 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 anesthesia or administration of sedative medications.
Number of Patients With Postoperative Nausea and Vomiting	72 Participants	73 Participants	64 Participants

SECONDARY outcome

Timeframe: Postoperative period

Population: Outcome measure data were not collected.

Assessed from patients' medical charts

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Postoperative days 1-3

Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive Care Unit

Outcome measures

Measure	Ketamine (0.5 mg/kg and 1 mg/kg) n=227 Participants Both the 0.5 mg/kg and the 1mg/kg doses groups of Ketamine were combined for analysis) Low dose Ketamine (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Normal Saline (Placebo) n=222 Participants Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications	Ketamine (1 mg/kg) n=223 Participants 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 anesthesia or administration of sedative medications.
Adverse Outcomes (Number of Patients With Hallucinations)	45 Participants	40 Participants	62 Participants

SECONDARY outcome

Timeframe: Postoperative days 1-3

Assessed via Confusion Assessment Method or Confusion Assessment Method for Intensive care Unit

Outcome measures

Measure	Ketamine (0.5 mg/kg and 1 mg/kg) n=227 Participants Both the 0.5 mg/kg and the 1mg/kg doses groups of Ketamine were combined for analysis) Low dose Ketamine (sub-anesthetic) 0.5 mg/kg ketamine following induction of anesthesia or administration of sedative medications. Ketamine (1 mg/kg): (sub-anesthetic) 1 mg/kg ketamine following induction of anesthesia or administration of sedative medications.	Normal Saline (Placebo) n=222 Participants Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications	Ketamine (1 mg/kg) n=223 Participants 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 anesthesia or administration of sedative medications.
Adverse Outcomes (Number of Patients With Nightmares)	27 Participants	18 Participants	34 Participants

Adverse Events

Ketamine (0.5 mg/kg)

Serious events: 0 serious events

Other events: 90 other events

Deaths: 0 deaths

Normal Saline (Placebo)

Serious events: 0 serious events

Other events: 82 other events

Deaths: 2 deaths

Ketamine (1 mg/kg)

Serious events: 0 serious events

Other events: 86 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Ketamine (0.5 mg/kg) n=227 participants at risk 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.	Normal Saline (Placebo) n=222 participants at risk Intravenous normal saline Normal Saline (placebo): Normal saline IV following induction of anesthesia or administration of sedative medications	Ketamine (1 mg/kg) n=223 participants at risk 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.
Nervous system disorders Atrial Fibriliation	9.3% 21/227 • Number of events 21 • Assessed up to 3 days (POD 0-3).	8.6% 19/222 • Number of events 19 • Assessed up to 3 days (POD 0-3).	6.7% 15/223 • Number of events 15 • Assessed up to 3 days (POD 0-3).
Blood and lymphatic system disorders Anaemia/Bleeding	8.4% 19/227 • Number of events 19 • Assessed up to 3 days (POD 0-3).	5.9% 13/222 • Number of events 13 • Assessed up to 3 days (POD 0-3).	9.0% 20/223 • Number of events 20 • Assessed up to 3 days (POD 0-3).
Infections and infestations Infection	7.0% 16/227 • Number of events 16 • Assessed up to 3 days (POD 0-3).	8.1% 18/222 • Number of events 18 • Assessed up to 3 days (POD 0-3).	6.7% 15/223 • Number of events 15 • Assessed up to 3 days (POD 0-3).
Renal and urinary disorders Renal	5.7% 13/227 • Number of events 13 • Assessed up to 3 days (POD 0-3).	5.0% 11/222 • Number of events 11 • Assessed up to 3 days (POD 0-3).	3.6% 8/223 • Number of events 8 • Assessed up to 3 days (POD 0-3).
Vascular disorders Hypotension	4.8% 11/227 • Number of events 11 • Assessed up to 3 days (POD 0-3).	5.0% 11/222 • Number of events 11 • Assessed up to 3 days (POD 0-3).	4.0% 9/223 • Number of events 9 • Assessed up to 3 days (POD 0-3).
Cardiac disorders Tachycardia	3.5% 8/227 • Number of events 8 • Assessed up to 3 days (POD 0-3).	3.6% 8/222 • Number of events 8 • Assessed up to 3 days (POD 0-3).	3.6% 8/223 • Number of events 8 • Assessed up to 3 days (POD 0-3).
Gastrointestinal disorders Gastrointestinal	4.0% 9/227 • Number of events 9 • Assessed up to 3 days (POD 0-3).	3.6% 8/222 • Number of events 8 • Assessed up to 3 days (POD 0-3).	2.7% 6/223 • Number of events 6 • Assessed up to 3 days (POD 0-3).
Vascular disorders Hypertension	0.44% 1/227 • Number of events 1 • Assessed up to 3 days (POD 0-3).	1.4% 3/222 • Number of events 3 • Assessed up to 3 days (POD 0-3).	2.2% 5/223 • Number of events 5 • Assessed up to 3 days (POD 0-3).

Additional Information

Dr. Michael Avidan

Washington University School of Medicine

Phone: 314-747-4155

Email: avidanm@wustl.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place