Conditions: Cognitive Disorders Delirium Acute Kidney Injury
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: Ketamine induction arm 2: Propofol induction

Interventions: intervention 1: Ketamine intervention 2: Propofol
Intervention descriptions: intervention 1: Ketamine used for induction intervention 2: Propofol for induction

Protocol document:
Prot_SAP_000.pdf: 
 
 
THE IMPACT OF KETAMINE ON POSTOPERATIVE 
COGNITIVE DYSFUNCTION, DELIRIUM, AND RENAL 
DYSFUNCTION IN PATIENTS 70 YEARS OF AGE OR 
OLDER AND UNDERGOING CARDIAC SURGERY. 
 
NCT02554253 
 
8/9/2017 


1 
 
 
THE IMPACT OF KETAMINE ON POSTOPERATIVE COGNITIVE 
DYSFUNCTION, DELIRIUM, AND RENAL DYSFUNCTION IN PATIENTS 70 
YEARS OF AGE OR OLDER AND UNDERGOING CARDIAC SURGERY. 
 
 
IRB Approved 8/9/2017 
 
Principle Investigator: 
Erica D. Wittwer, M.D. 
Assistant Professor of Anesthesiology 
Mayo Clinic College of Medicine 
Email: wittwer.erica@mayo.edu 
 
Co-Principle Investigator: 
William J. Mauermann, M.D. 
Assistant Professor of Anesthesiology  
Mayo Clinic College of Medicine 
Email: Mauermann.william@mayo.edu 
 
Co-Investigator: 
Jane H. Cerhan, Ph.D., L.P. 
Assistant Professor of Psychology 
Mayo Clinic College of Medicine 
Email: Cerhan.Jane@mayo.edu 
 
Statistician:  
Darrell R. Schroeder 
Assistant Professor of Biostatistics 
Mayo Clinic College of Medicine 
Email: schroedd@mayo.edu 
 
Coordinator 
Lavonne Liedl 
Study Coordinator 
Anesthesia Clinical Research Unit 
Mayo Clinic 
Email: liedl.lavonne@mayo.edu 
 
 


2 
 
 
RESEARCH PLAN 
We propose a prospective study in which the effects of ketamine in cardiac 
surgery are investigated in adult patients undergoing cardiac surgical procedures 
requiring cardiopulmonary bypass (CPB). Ketamine has been demonstrated to have an 
anti-inflammatory effect as shown by reductions in Interleukin 6 (IL-6) levels.  
Postoperative dysfunctions in which inflammation has been implicated may be reduced 
by this anti-inflammatory effect.  Use of inotropic and vasopressor support, 
hemodynamic variables, incidence of renal and cognitive dysfunction, and incidence of 
delirium will be assessed. Specifically, we will test the hypothesis that ketamine provides 
anti-inflammatory effects in this population of patients undergoing surgery requiring CPB 
and that the incidence of renal and cognitive dysfunction and delirium will be decreased. 
 
Background and Significance 
Ketamine is an FDA approved nonbarbiturate anesthetic and acts as a N-methyl-
D-aspartate (NMDA) receptor antagonist. This medication is commonly used in the 
induction of anesthesia as well as in the performance of sedation for procedures. 
Ketamine has been demonstrated in several studies to have anti-inflammatory effects.[1-
4]  In cardiac surgical patients, the inflammatory response stimulated by undergoing CPB 
is thought to contribute to postoperative organ system dysfunction and morbidity. A 
reduction in inflammatory mediators has been shown in patients receiving ketamine prior 
to undergoing cardiac surgical procedures, including reductions in IL-6, cardiac troponin 
I (cTnI) and creatine kinase MB (CK-MB). IL-10 has anti-inflammatory effects and has 
been shown to be increased in patients who received preoperative ketamine compared 


3 
 
 
with patients who did not receive ketamine.[1, 4] In a group of patients who did not 
receive ketamine, IL-6 values peaked at 6 hours following aortic cross clamp removal, 
but this rise and peak was not seen in the group of patients who received a continuous 
ketamine infusion.[4]  
A review and meta-analysis examined 14 studies involving 684 patients 
undergoing a variety of surgical procedures including coronary artery bypass graft 
(CABG) surgery. This concluded that ketamine does decrease IL-6 concentration. 
Elevations in IL-6 have been associated with ventricular wall motion abnormalities, 
perioperative complications, postoperative hyperdynamic instability, postoperative 
cognitive dysfunction, renal dysfunction, severity of acute respiratory distress syndrome 
(ARDS), and morbidity and mortality in children after cardiac surgery.[1, 5]  
Results are conflicting regarding the impact of ketamine on CRP. In two reports 
postoperative CRP levels were lower in the group of patients who received pre-operative 
ketamine compared to those who received placebo.[2, 6] However, in a study comparing 
patients receiving a continuous ketamine infusion versus those not receiving ketamine, 
IL-6 and IL-8 levels were reduced in the ketamine group, but CRP levels were not 
different at 24 hours postoperatively.[4] 
Postoperative cognitive dysfunction and postoperative delirium are important 
areas of morbidity following cardiac surgery. Unrelated to cardiac surgery, a systematic 
review confirmed an association between elevated inflammatory markers and poor 
cognitive outcomes.[7] In cardiac surgical patients, elevated IL-6 and CRP levels have 
been shown to be associated with worse cognitive function following CABG surgery.[6] 
Ketamine is thought to be neuroprotective, with multiple possible mechanisms having 


4 
 
 
been proposed, although the exact mechanism has not yet been elucidated.[2]  
Interestingly, ketamine has been shown to be associated with a decreased incidence of 
delirium and these patients also had lower postoperative CRP levels. In this study the 
incidence of delirium was reduced from 31% in the control group to 3% in the ketamine 
group.[2] In patients undergoing cardiac surgery polymorphisms in the 5HT2a receptor 
gene and NMDA receptor 3A and 2B subunits genes were investigated for association 
with postoperative delirium. A genetic variation, the presence of the AG haplotype of the 
GRIN3A gene, of the NMDA receptor was independently associated with postoperative 
delirium.[8] Additionally, when examining patients who developed delirium those with 
the AG haplotype suffered from delirium longer than patients with the GG haplotype. 
This may be a potential avenue by which ketamine impacts delirium. Postoperative 
delirium is associated with increased morbidity and mortality as well as increased 
hospital length of stay.[9, 10] If ketamine administration does prove to reduce delirium, it 
could make a significant impact on morbidity and mortality following cardiac surgery as 
delirium has proven difficult to prevent and treat. 
Renal dysfunction is another significant area of morbidity in patients following 
cardiac surgery and has been associated with increased mortality.[11] Although no data 
has demonstrated an association between ketamine and a decrease in renal dysfunction, 
elevated postoperative IL-6 levels, measured 12 hours following surgery, have been 
associated with an increased incidence of renal dysfunction following surgery utilizing 
CPB.[5] One study demonstrated a decreased incidence of acute kidney injury (AKI) in 
patients who received propofol compared to those who received sevoflurane and another 
study demonstrated a decreased incidence of AKI in patients receiving a post-CPB 


5 
 
 
dexmedetomidine infusion.[12, 13] It is reasonable to postulate that the anti-
inflammatory properties of ketamine as revealed by decreased levels of the inflammatory 
marker IL-6 may be associated with a decrease in postoperative renal dysfunction.  
Patient age (> 65 years) and increased surgical complexity (with longer operative 
times) are known risk factors for postoperative cognitive dysfunction, delirium, and renal 
dysfunction.[14-16] These higher risk patients would be the population that would benefit 
most from the potential decrease in these important areas of morbidity.  
Specific Aims/Hypotheses: 
We aim to determine the impact of ketamine administration at induction of 
anesthesia on delirium, postoperative cognitive dysfunction, renal dysfunction, intra and 
postoperative hemodynamics, requirement for inotropic and vasopressor support, and 
postoperative mortality. 
 
Specific Aim 1:  1. Determine the incidence of cognitive dysfunction and delirium in 
patients who receive ketamine for induction compared with those who receive propofol.     
 
Specific Aim 2:  Determine the impact of ketamine on patient hemodynamics as well as 
the dose of vasopressor and inotropes used during the intra and postoperative periods. 
 
Specific Aim 3: Determine the incidence of renal dysfunction, defined by AKIN criteria, 
in patients who receive ketamine for induction compared with those who receive 
propofol. 


6 
 
 
 
 
STUDY DESIGN 
We propose a prospective study in which patients will be randomized for 
induction with ketamine versus propofol (another regularly used anesthesia induction 
agent). Hemodynamics before, during and after cardiopulmonary bypass and use of 
inotropic and vasopressor medications will be recorded as per usual charting.  The 
incidence of delirium, cognitive dysfunction, and renal dysfunction will be compared 
between the ketamine and propofol groups.   
Inclusion/Exclusion Criteria 
We will include patients age greater than or equal to 70 years presenting for 
cardiac surgery at the Mayo Clinic in Rochester, Minnesota.  Patients will be eligible for 
inclusion if they are 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  2.0  mg/dL or requiring dialysis, immunosuppressive medication use (including 
steroid use), immunodeficiency syndrome, known neurologic or psychiatric disorder, or 
use of drugs for psychosis.  
Number of Subjects 


7 
 
 
 
The incidence of renal dysfunction in patients following cardiac surgery has been 
reported to be anywhere from 21% to 38%.[13, 17, 18] The incidence of delirium after 
cardiac surgery has been reported over a broad range including 18% to 31%.[2, 14] 
Assuming a reduction in the incidence of renal dysfunction and delirium of 
approximately 10%, an appropriate sample size would be approximately 20 patients per 
group. We will plan to recruit 26 patients in each group.   
Randomization and Consent 
 
Written, informed consent will be obtained.  The study will be minimal risk and 
non-invasive.  Ketamine and propofol are both standard and commonly used medications 
for the induction of anesthesia. All aspects of care will be as per usual for patients 
undergoing these operations at The Mayo Clinic.  Subjects will be recruited by letter via 
review of the surgical listing and scheduled for a preoperative appointment to review the 
study and obtain consent. Randomization will occur via delivery of a sealed envelope by 
a member of the study staff who is not directly involved with patient care on the morning 
of surgery to the consultant anesthesiologist assigning the patient to the ketamine or 
propofol group.  
Human Subjects 
Detailed Description: The human subjects will be prospectively studied after being 
randomized to receive one of two commonly used anesthesia induction agents. 
Population:  The subject population in this study will include all patients admitted to 
Mayo Clinic Rochester for cardiac surgery that meet the inclusion criteria.  No 
specific populations (regardless of race, ethnicity or gender) will be excluded from 
this study aside from those who meet the exclusion criteria described above. 


8 
 
 
Research Materials: Electronic data will be stored securely and only accessed by 
those authorized on the IRB application. 
The study will be minimal risk and written, informed consent will be obtained.  
Potential Risks: This study compares two commonly used anesthetic agents. This 
study will not increase the risk of physical harm beyond what the surgical procedure 
naturally caries. The only potential risk is a breach of confidentiality, but this is 
thoroughly addressed as described below. 
Protection:  Data will be collected and stored on a secure Mayo server in a password-
locked folder.  No patient names will be stored, and the only identifiers included in 
the data will be clinic number, date of birth and date of admission.  Only investigators 
authorized by the IRB will be allowed access to the study data. 
   
Protocol/Methods 
 
After written, informed consent is obtained the following baseline cognitive 
function studies will be administered by the anesthesia clinical research unit: Trail-
making test, the Mini-Mental State Examination, Hopkins Verbal Learning Test (Revised 
forms 1 and 2), Digit Span forward and backward, Controlled Oral Word Association, 
and Stroop Test.  
Anesthetic management will be directed by the consultant anesthesiologist as per 
routine aside from the following: Patients will be randomized to ketamine (1-2 mg/kg) 
versus propofol (0.5-1 mg/kg) induction with additional medication administered as 
needed to achieve intubating conditions. Inhalation anesthetic for induction in 


9 
 
 
combination with either propofol or ketamine will be permitted. The ketamine group will 
not receive propofol and vice versus. Maximum fentanyl bolus dosing will be 10 µg/kg, 
consistent with the currently implemented cardiac surgery rapid recovery protocol. 
Albumin administration will be avoided, but ultimately left to the discretion of the 
consultant anesthesiologist.   Invasive monitoring techniques will be left to the discretion 
of the consultant anesthesiologist as per routine. 
 
All other aspects of patient care will be as per routine including administration of 
inotropic or vasopressors as needed at the discretion of the anesthesiologist and /or 
cardiac surgical team. Administration of inotropic or vasopressors will be recorded in the 
anesthesia record as per usual practice. Propofol or dexmedetomidine infusions will be 
utilized for sedation at the end of the procedure as per usual practice.  
 
The Confusion Assessment method for the ICU (CAM ICU) score will be 
recorded every 12 hours in the ICU as per routine. After dismissal from the ICU, a CAM 
score will be reviewed until hospital discharge. Prior to hospital discharge or within 1- 2 
days prior to discharge,  the patient will undergo post-intervention cognitive function 
studies administered by the anesthesia clinical research unit: Trail-making test, the Mini-
Mental State Examination, Hopkins Verbal Learning Test (Revised forms 1 and 2), Digit 
Span forward and backward, Controlled Oral Word Association, and Stroop Test.  
Outcome measurements 
 
After inclusion in the study, demographic and medical data from all patients 
including age, height, weight, medical co-morbidities and current medications will be 
recorded and saved in the database.  In addition, information regarding the planned 
procedure and the specifics of each patient’s cardiac disease including ventricular 


10 
 
 
function, current cardiac anatomy and details of previous cardiac repairs will be recorded. 
Liver and renal function will be assessed by recording liver function tests and renal 
indices if available in the preoperative medication record. 
 
Our primary outcomes will be the incidence of cognitive dysfunction and delirium 
as well as the incidence of renal dysfunction.  Secondary outcomes will include assessing 
differences in hemodynamics, inotropic use and vasopressor use between the ketamine 
and propofol group. Mortality during admission for cardiac surgery will be assessed, 
however, the study will not be powered for this to be a primary outcome measure. 
Data Analysis 
 
Incidence of renal and cognitive dysfunction and delirium will be expressed as a 
percentage. Values will be compared between ketamine and non-ketamine groups using t-
tests and ANOVA. A P value of less than 0.05 will be considered significant. Secondary 
outcomes will be analyzed using a t-test or ANOVA. All comparisons will be completed 
adjusting for multiple comparisons using the Bonferroni method.  
 
References 
 
 
 
1. 
Dale, O., et al., Does intraoperative ketamine attenuate inflammatory reactivity 
following surgery? A systematic review and meta-analysis. Anesthesia and 
analgesia, 2012. 115(4): p. 934-43. 
2. 
Hudetz, J.A., et al., Ketamine attenuates delirium after cardiac surgery with 
cardiopulmonary bypass. Journal of cardiothoracic and vascular anesthesia, 2009. 
23(5): p. 651-7. 
3. 
Riha, H., et al., Comparison of the effects of ketamine-dexmedetomidine and 
sevoflurane-sufentanil anesthesia on cardiac biomarkers after cardiac surgery: 
an observational study. Physiological research / Academia Scientiarum 
Bohemoslovaca, 2012. 61(1): p. 63-72. 


11 
 
 
4. 
Welters, I.D., et al., Continuous S-(+)-ketamine administration during elective 
coronary artery bypass graft surgery attenuates pro-inflammatory cytokine 
response during and after cardiopulmonary bypass. British journal of anaesthesia, 
2011. 106(2): p. 172-9. 
5. 
Musleh, G.S., et al., Association of IL6 and IL10 with renal dysfunction and the 
use of haemofiltration during cardiopulmonary bypass. European journal of 
cardio-thoracic surgery : official journal of the European Association for Cardio-
thoracic Surgery, 2009. 35(3): p. 511-4. 
6. 
Hudetz, J.A., et al., Elevated postoperative inflammatory biomarkers are 
associated with short- and medium-term cognitive dysfunction after coronary 
artery surgery. Journal of anesthesia, 2011. 25(1): p. 1-9. 
7. 
Whiteley, W., et al., Inflammatory markers and poor outcome after stroke: a 
prospective cohort study and systematic review of interleukin-6. PLoS medicine, 
2009. 6(9): p. e1000145. 
8. 
Kazmierski, J., et al., The assessment of the T102C polymorphism of the 5HT2a 
receptor gene, 3723G/A polymorphism of the NMDA receptor 3A subunit gene 
(GRIN3A) and 421C/A polymorphism of the NMDA receptor 2B subunit gene 
(GRIN2B) among cardiac surgery patients with and without delirium. General 
hospital psychiatry, 2014. 
9. 
Ely, E.W., et al., The impact of delirium in the intensive care unit on hospital 
length of stay. Intensive care medicine, 2001. 27(12): p. 1892-900. 
10. 
van den Boogaard, M., et al., Incidence and short-term consequences of delirium 
in critically ill patients: A prospective observational cohort study. International 
journal of nursing studies, 2012. 49(7): p. 775-83. 
11. 
Tolpin, D.A., et al., Subclinical changes in serum creatinine and mortality after 
coronary artery bypass grafting. The Journal of thoracic and cardiovascular 
surgery, 2012. 143(3): p. 682-688 e1. 
12. 
Ji, F., et al., Post-bypass dexmedetomidine use and postoperative acute kidney 
injury in patients undergoing cardiac surgery with cardiopulmonary bypass. PloS 
one, 2013. 8(10): p. e77446. 
13. 
Yoo, Y.C., et al., Anesthetics influence the incidence of acute kidney injury 
following valvular heart surgery. Kidney international, 2014. 86(2): p. 414-22. 
14. 
Li, H.C., et al., Delirium, Subsyndromal Delirium, and Cognitive Changes in 
Individuals Undergoing Elective Coronary Artery Bypass Graft Surgery. The 
Journal of cardiovascular nursing, 2014. 
15. 
Krzych, L.J., et al., Complex assessment of the incidence and risk factors of 
delirium in a large cohort of cardiac surgery patients: a single-center 6-year 
experience. BioMed research international, 2013. 2013: p. 835850. 
16. 
Bahar, I., et al., Acute renal failure following open heart surgery: risk factors and 
prognosis. Perfusion, 2005. 20(6): p. 317-22. 
17. 
Garg, A.X., et al., Kidney function after off-pump or on-pump coronary artery 
bypass graft surgery: a randomized clinical trial. JAMA : the journal of the 
American Medical Association, 2014. 311(21): p. 2191-8. 
18. 
Schopka, S., et al., Impact of cardiopulmonary bypass on acute kidney injury 
following coronary artery bypass grafting: a matched pair analysis. Journal of 
cardiothoracic surgery, 2014. 9(1): p. 20. 


12