The Impact of Ketamine on Postoperative Cognitive Dysfunction, Delirium, and Renal Dysfunction

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02554253
• Collaborator: (none)
• Enrollment: 52
• Location: 1
• Arms: 2
• Duration (Months): 63
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Ketamine is a commonly used anesthetic medication which is used for induction of anesthesia as well as as an analgesic. It has been shown to have anti-inflammatory properties which may decrease post-operative complications following cardiac surgery with cardiopulmonary bypass that are thought to associated with inflammation. Some studies have shown that ketamine does decrease these complications when compared with anesthetics that are not commonly used in our cardiac anesthesiology practice. Propofol is another commonly used anesthetic medication which is used for induction of anesthesia. Ketamine has not been compared with propofol for potential to reduce post-operative complications associated with the inflammatory process. This study aims to see if ketamine will reduce the incidence of cognitive dysfunction, delirium, and renal dysfunction in comparison with propofol. In addition, the hemodynamic impact of ketamine compared propofol will be investigated.

Condition or Disease	Intervention/Treatment	Phase
Cognitive Disorders; Delirium; Acute Kidney Injury	Drug: Ketamine; Drug: Propofol	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: The Impact of Ketamine on Postoperative Cognitive Dysfunction, Delirium, and Renal Dysfunction in Patients 75 Years of Age or Older and Undergoing Cardiac Surgery
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Dec 1, 2020
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ketamine Ketamine induction	Drug: Ketamine; Ketamine used for induction; Other Names: Ketalar
Active Comparator: Propofol Propofol induction	Drug: Propofol; Propofol for induction; Other Names: Diprivan Propoven

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Postoperative Cognitive Dysfunction [Baseline (preoperative cognitive tests) to hospital discharge or 10 days postoperatively whichever came first.]

   Pre and postoperative cognitive studies will be performed to assess change in cognitive function. Postoperative cognitive dysfunction (POCD) was defined a-priori as a decline of decline of >1 standard deviation (i.e. z-score decline of > 1) on at least 2 neurocognitive tests. The neurocognitive tests utilized include Trail making Test A, Trail making Test B, Hopkins Verbal Learning Test-Revised Learning trials, Hopkins Verbal Learning Test-Revised Delayed Recall, Digit Span, Controlled Oral Word Association Test, Stroop color/word test, and the Mini Mental Status Examination.

Secondary Outcome Measures

1. Number of Patients With Acute Kidney Injury [Baseline (preoperative cognitive tests) to hospital discharge or 10 days postoperatively whichever came first.]

   AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria including an increase in serum creatinine ≥0.3 mg/dL within 48 hours, an increase in serum creatinine to ≥1.5 times baseline within 7 days, and urine output < 0.5 mL/kg/hr for 6 hours.

2. Number of Patients Who Develop Postoperative Delirium [Baseline (preoperative cognitive tests) to hospital discharge or 10 days postoperatively whichever came first.]

   Delirium was defined as a positive CAM (Confusion assessment method) score. CAM score was recorded every 12 hours postoperatively as per routine. The CAM consists of 4 features: 1-Onset, 2-Inattention, 3-Disorganized thinking, and 4-altered level of consciousness. The diagnosis of delirium by CAM is based on the presence of features 1 and 2, and either 3 or 4. The score is either positive or negative. Positive means the patient has delirium and negative indicates the patient is not delirious.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 75 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Scheduled to undergo cardiac surgery.

Inclusion criteria:

• age greater than or equal to 75 years presenting for cardiac surgery at the Mayo Clinic in Rochester, Minnesota;

• schedule to undergo complex cardiac surgery. Complex cardiac surgery will be defined as surgery involving more than one heart valve, redo-sternotomy procedures, or combined valvular and CABG procedures.

Exclusion criteria will include:

• left or right ventricular assist device implantation or explantation,

• procedures not requiring cardiopulmonary bypass,

• active infection or sepsis, severe hepatic disease or ascites,

• pre-operative renal dysfunction including a baseline creatinine equal to or greater than 1.5 mg/dL or requiring dialysis,

• immunosuppressive medication use (including steroid use),

• immunodeficiency syndrome,

• known neurologic or psychiatric disorder, or

• use of drugs for psychosis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Principal Investigator: Erica Wittwer, MD, PhD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 9, 2017

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Erica D. Wittwer, M.D., Ph.D., PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02554253
• Other Study ID Numbers: 14-007148
• First Posted: Sep 18, 2015
• Last Update Posted: Feb 15, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Delirium; Acute Kidney Injury; Renal Insufficiency; Postoperative Cognitive Complications; Cognitive Dysfunction; Cognition Disorders; Ketamine; Propofol

Study Results

Participant Flow

Recruitment Details	Participants who were undergoing complex cardiac surgery at Mayo Clinic were recruited between August 2015 and October 2019.
Pre-assignment Detail	Of the 265 patients assessed for eligibility, 52 were randomized to study groups. 8 did not meet inclusion criteria, 97 declined to participate, 96 were unable to be contacted before surgery, and 12 were unable to coordinate preoperative testing before surgery.

Arm/Group Title	Ketamine	Propofol
Arm/Group Description	Ketamine induction Ketamine: Ketamine used for induction	Propofol induction Propofol: Propofol for induction
Period Title: Overall Study
STARTED	26	26
COMPLETED	25	24
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Ketamine	Propofol	Total
Arm/Group Description	Ketamine induction Ketamine: Ketamine used for induction	Propofol induction Propofol: Propofol used for induction	Total of all reporting groups
Overall Participants	25	24	49
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	76.4 (3.5)	76.1 (5.3)	76.3 (4.4)
Sex: Female, Male (Count of Participants)
Female	9 36%	10 41.7%	19 38.8%
Male	16 64%	14 58.3%	30 61.2%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	25 100%	24 100%	49 100%
Trail Making Test A (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	-0.1 (0.8)	0 (1.1)	0.0 (1.0)
Trail Making Test B (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	0.2 (1.0)	-0.1 (1.1)	0.1 (1.1)
Hopkins Verbal Learning Test-Revised (HVLT-R) Learning Trials test (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	-0.7 (0.9)	-0.5 (0.8)	-0.6 (0.9)
Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	-0.9 (1.3)	-0.8 (1.2)	-0.9 (1.2)
Hopkins Verbal Learning Test-Revised (HVLT-R) Digit Span (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	0.2 (0.8)	0.1 (1.0)	0.2 (0.9)
Controlled Oral Word Association Test (COWAT) (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	0.1 (0.8)	0.1 (0.8)	0.1 (0.8)
Stroop color/word test (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	-0.3 (1.0)	-0.6 (1.3)	-0.4 (1.1)
Mini-Mental Status Exam (Z score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Z score]	0.7 (0.9)	0.4 (1.1)	0.6 (1.0)

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Postoperative Cognitive Dysfunction
Description	Pre and postoperative cognitive studies will be performed to assess change in cognitive function. Postoperative cognitive dysfunction (POCD) was defined a-priori as a decline of decline of >1 standard deviation (i.e. z-score decline of > 1) on at least 2 neurocognitive tests. The neurocognitive tests utilized include Trail making Test A, Trail making Test B, Hopkins Verbal Learning Test-Revised Learning trials, Hopkins Verbal Learning Test-Revised Delayed Recall, Digit Span, Controlled Oral Word Association Test, Stroop color/word test, and the Mini Mental Status Examination.
Time Frame	Baseline (preoperative cognitive tests) to hospital discharge or 10 days postoperatively whichever came first.

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Ketamine	Propofol
Arm/Group Description	Ketamine induction Ketamine: Ketamine used for induction	Propofol induction Propofol: Propofol for induction
Measure Participants	25	24
Count of Participants [Participants]	16 64%	10 41.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine, Propofol
	Comments	Raw scores converted to z-scores using published references. Percentage of patients experiencing a decline of > 1 standard deviation was compared between groups using Fisher's exact test. The outcome of postoperative cognitive dysfunction (POCD) was defined a-priori as a decline of decline of >1 standard deviation (i.e. z-score decline of > 1) on at least 2 neurocognitive tests and was compared between groups using Fisher's exact test.
	Type of Statistical Test	Superiority
	Comments	Pilot study
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Number of Patients With Acute Kidney Injury
Description	AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria including an increase in serum creatinine ≥0.3 mg/dL within 48 hours, an increase in serum creatinine to ≥1.5 times baseline within 7 days, and urine output < 0.5 mL/kg/hr for 6 hours.
Time Frame	Baseline (preoperative cognitive tests) to hospital discharge or 10 days postoperatively whichever came first.

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Ketamine	Propofol
Arm/Group Description	Ketamine induction Ketamine: Ketamine used for induction	Propofol induction Propofol: Propofol used for induction
Measure Participants	25	24
Count of Participants [Participants]	6 24%	12 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine, Propofol
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Number of Patients Who Develop Postoperative Delirium
Description	Delirium was defined as a positive CAM (Confusion assessment method) score. CAM score was recorded every 12 hours postoperatively as per routine. The CAM consists of 4 features: 1-Onset, 2-Inattention, 3-Disorganized thinking, and 4-altered level of consciousness. The diagnosis of delirium by CAM is based on the presence of features 1 and 2, and either 3 or 4. The score is either positive or negative. Positive means the patient has delirium and negative indicates the patient is not delirious.
Time Frame	Baseline (preoperative cognitive tests) to hospital discharge or 10 days postoperatively whichever came first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Propofol
Arm/Group Description	Ketamine induction Ketamine: Ketamine used for induction	Propofol induction Propofol: Propofol used for induction
Measure Participants	25	24
Count of Participants [Participants]	0 0%	1 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine, Propofol
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	Surgery to discharge, up to 10 days postoperatively
Arm/Group Title	Ketamine		Propofol
Arm/Group Description	Ketamine induction Ketamine: Ketamine used for induction		Propofol induction Propofol: Propofol used for induction
All Cause Mortality
	Ketamine		Propofol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/24 (0%)
Serious Adverse Events
	Ketamine		Propofol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		1/24 (4.2%)
Cardiac disorders
Complete heart block	0/25 (0%)	0	1/24 (4.2%)	1
RV failure	1/25 (4%)	1	0/24 (0%)	0
Gastrointestinal disorders
Intestinal perforation	1/25 (4%)	1	0/24 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/25 (4%)	1	0/24 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/25 (4%)	1	0/24 (0%)	0
Other (Not Including Serious) Adverse Events
	Ketamine		Propofol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/24 (0%)

Limitations/Caveats

Not powered to detect differences in acute kidney injury. A larger study will be needed.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.