Clinical trial NCT03040024
Conditions: Otolaryngeal Cancer
Keywords: Anesthesiology
Sponsor: Emory University
Start date: 2017-03-17; Completion date: 2020-04-24
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this prospective randomized double blinded placebo controlled study is to investigate if a single dose of ketamine in addition to standard anesthesia will reduce the risk of delirium in otolaryngeal cancer patients postoperatively. Ketamine's effect on post-operative pain and opioid use will be measured as well. Electroencephalogram (EEG) will be utilized during the surgical procedure to evaluate its potential as a possible predictive device for delirium.

Detailed description:
This is a single center prospective randomized double blinded placebo controlled study.

The primary aim of the study is to optimize the intraoperative treatment protocol for head and neck cancer patients to reduce the incidence of delirium and associated postoperative cognitive dysfunction. Secondary aims are to determine the dose response relationship for intraoperative ketamine and delirium reduction, determine if a single dose of ketamine will reduce post-operative pain and opioid requirements, determine if raw electroencephalogram (EEG) data can predict postoperative delirium during general anesthesia, and to evaluate length of intensive care unit (ICU) and length of hospital stay.

Participants will be randomized to one of three groups after administration of general anesthesia; one dose of .5 mg/kg intravenous (IV) Ketamine, 1.0 mg/kg of IV Ketamine, or IV placebo.

An EEG will be used during the surgical procedure to gather raw data for off line analysis among patients developing post-operative delirium.

Arms: arm 1: Participants undergoing surgery for otolaryngeal cancer will be randomized to receive one dose of IV ketamine at 0.5 mg/kg. arm 2: Participants undergoing surgery for otolaryngeal cancer will be randomized to receive one dose of IV ketamine at 1.0 mg/kg. arm 3: Participants undergoing surgery for otolaryngeal cancer will be randomized to receive one dose of IV saline/placebo.
Interventions: intervention 1: Ketamine intervention 2: Placebo intervention 3: Electroencephalogram (EEG)
Intervention descriptions: intervention 1: Ketamine will be administered intravenously after administration of general anesthesia and prior to the first surgical incision. intervention 2: Placebo will be administered intravenously after administration of general anesthesia and prior to the first surgical incision. intervention 3: A processed EEG device will be used during the surgical procedure to gather raw EEG data for off line analysis among patients developing post-operative delirium.

Protocol documents:
Prot_SAP_000.pdf: 
October 8, 2019 
Page 1 of 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Prospective, Randomized, Double-Blind, Placebo-controlled Pilot Study of 
Single-dose Intraoperative Ketamine for the Prevention of Delirium in 
Otolaryngeal Cancer Surgery Patients 
 
 
NCT03040024 
 
 
Date: October 8th, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


October 8, 2019 
Page 2 of 27 
 
 
 
Study Title: A Prospective, Randomized, Double-Blind, Placebo-controlled Pilot 
Study of Single-dose Intraoperative Ketamine for the Prevention of Delirium in 
Otolaryngeal Cancer Surgery Patients 
 
 
TABLE OF CONTENTS 
1.  Study Team………………………………………………………………………     1 
2.  Abstract……………………………………………………………………………… 2 
3. Background and Significance………………………………………………………3 
4.  Objectives…………………………………………………………………………… 4 
5.  Innovation, Impact & Leverage……………………………………………………..4 
6. 
Approach………………………………………………………………………………6 
7. Participant Selection………………………………………………………………... 7 
8. 
Procedures……………………………………………………………………………8 
9. 
Risks………………………………………………………………………………….10 
10. Statistical analysis…………………………………………………………………..11 
11. Confidentiality………………………………………………………………………..12 
12. Literature……………………………………………………………………………..13 
 
APPENDIX A- Study Flowchart and Schedule of Assessments……………………15 
APPENDIX B- Study worksheets………………………………………………………16 
1. CAM-ICU Worksheet 
2. The Cognitive Failures Questionnaire 
3. Mini-Mental State Examination (MMSE) 
4. Pain Scale 
5. Provider Instructions-Emory University Hospital Midtown (EUHM) 
6. Mini-Cog 
7. Richmond Agitation Sedation Scale (RASS) 
8. STOP-Bang Scoring Tool, Sleep Apnea Questionnaire 


October 8, 2019 
Page 3 of 27 
 
 
 
 
 
Study Title: A Prospective, Randomized, Double-Blind, Placebo-controlled Pilot 
Study of Single-dose Intraoperative Ketamine for the Prevention of Delirium in 
Otolaryngeal Cancer Surgery Patients 
 
Short Title: Delirium Prevention with Ketamine in ENT patients 
Winship EU3268-16 
1. Principal Investigator: Amit Prabhakar, MD 
Assistant Professor 
Department of Anesthesiology 
 
2. Abstract 
The goal of this prospective randomized double blinded placebo controlled study is to 
investigate if a single dose of ketamine in addition to standard anesthesia will reduce the 
risk of delirium in otolaryngeal cancer patients postoperatively. Ketamine’s effect on 
post-operative pain and opioid use will be measured as well. Electroencephalogram 
(EEG) will be utilized during the surgical procedure to evaluate its potential as a possible 
predictive device for delirium. The study will be a single center study at Emory University 
Hospital Midtown (EUHM). 
Up to 100 patients will be consented in order to achieve at least 60 patients who will be 
randomly assigned and administered 0.5 mg/kg, 1mg/kg or placebo intravenous bolus 
after induction of anesthesia. A processed EEG device (SEDline, Masimo Corporation) 
will be used to gather raw EEG data for off line analysis among patients developing post- 
operative delirium. Patients will be screened for delirium with the CAM-ICU once per shift 
(3 times daily) for three days postoperatively. Currently, the CAM- ICU is performed by 
ICU nursing and documented in the electronic medical chart. Both CAM-ICU screens and 
SEDLine monitoring are part of the usual and customary practice associated with these 
cases at EUHM and it would be unusual for a case such as this to be performed    
without this clinical data. Pain will be assessed according to hospital protocol and 
postoperative opioid consumption will be determined from the medical charts. 
Preoperative and postoperative cognitive assessment will be completed at the ENT clinic 
preoperative, and postoperative follow up visit (done by research assistant). Adverse 


October 8, 2019 
Page 4 of 27 
 
 
 
 
effects (e.g., hallucinations or nightmares) will also be evaluated for three days 
postoperatively. 
Chart review, data collection/entry will be done by Candace Stearns, PharmD, research 
assistant and the research staff. 
 
 
 
3. Background and Significance: 
Delirium is a frequent post-operative complication of major surgery with a reported 
incidence of 10-70 % [1] [2] [3]. After major head and neck cancer surgeries the 
incidence of delirium is reported to be over 25% [3]. Delirium is associated with 
increased morbidity and mortality, prolonged length of hospital and intensive care unit 
(ICU) stay and functional and cognitive decline [4] [5] [6] [7]. A history of dementia or 
depression, chronic medical illness, male gender and age>60 years are consistently 
described as risk factors for delirium [8] [9]; in the head and neck cancer patient 
population length of surgery and alcohol consumption have been identified as well [3] 
[10]. Currently there is no effective prophylactic treatment for delirium identified. Even the 
treatment of delirium remains difficult [11]. A Cochrane review on delirium prevention     
in hospitalized patients came to the conclusion that there is a paucity of research in this 
area resulting from difficulties in delirium detection and confounding factors like pre- 
existing cognitive impairment or multiple medical problems [12]. 
Recently a small randomized trial in cardiac surgery patients found a significant 
reduction in postoperative delirium (31% to 3%) when sub-anaesthetic doses of 
ketamine (0.5mg/kg) were given upon induction [13]. The same group further published 
data for improved postoperative cognitive function with ketamine in cardiac patients [13]. 
A follow up randomized prospective study in cardiothoracic patients looking at ketamine 
and delirium is currently recruiting (PODCAST). 
Ketamine’s benefits are thought to be based on its NMDA antagonism, HCN1 inhibitory 
effects and its anti-inflammatory properties [14]. Multiple studies have shown decreased 
post-operative pain with decreased post-operative opioid use when ketamine was 
administered during the surgery [15]. Interestingly a recent study showed that a single 
dose of ketamine had a prolonged two week lasting effect on patients with refractory 
depression [16]. 
Ketamine is a drug that has been in use for more than half a century, is inexpensive and 
has a wide margin of safety. 


October 8, 2019 
Page 5 of 27 
 
 
 
 
We are proposing a prospective randomized placebo controlled study to elucidate the 
effects of ketamine on postoperative delirium in the head and neck cancer population 
receiving “flaps”, administered peri-operatively. 
 
 
 
 
4. Objectives: 
Primary Aim: 
Optimize our intraoperative treatment protocol for head and neck cancer patients to 
reduce the incidence of delirium and associated postoperative cognitive dysfunction. The 
hypothesis is that ketamine decreases delirium postoperatively in this high risk surgical 
patient population. 
Secondary Aims: 
1. Determine the dose response relationship for intraoperative ketamine and delirium 
reduction. Our hypothesis is that higher dose ketamine will lead to a more profound 
reduction in postoperative delirium. 
2. Determine if a single dose of ketamine will reduce post-operative pain and opioid 
requirements. Our hypothesis is that the higher dose of ketamine will lead to a more 
profound decrease in objective pain scores. 
3. Determine if raw EEG data can predict postoperative delirium during general 
anesthesia. Our hypothesis is that EEG patterns will correlate with incidence of post- 
operative delirium. 
4. Evaluate length of ICU and length of hospital stay (done by medical chart review). Our 
hypothesis is that ketamine administration will not increase ICU/hospital stay. 
 
5. Innovation, Impact & Leverage. 
The successful completion of this study will provide critical data on a therapeutic and/or 
prophylactic effect of perioperatively administered ketamine on postoperative delirium. 
Delirium has been associated with increased length of ICU and hospital stay, increased 
cognitive impairment/decline and mortality. Despite increasing evidence of ketamine’s 
ability to reduce postoperative delirium in cardiac patients, its opioid sparing effects and 
decreased postoperative opioid needs, ketamine is not widely used. Clinicians are 
concerned that psychoactive properties (e.g., hallucination and dissociative states) 


October 8, 2019 
Page 6 of 27 
 
 
 
 
interfere with post-operative cognitive function. These side effects however are rarely 
seen when ketamine is used in subanaesthetic doses. 
Additionally, EEG data will be used to determine if this tool can be a possible predictor of 
delirium. 
Currently, the most common way to monitor brain function during surgery is via 
processed electroencephalogram (EEG) monitors (SEDLine). These devices use frontal 
or fronto-temporal EEG electrodes, to measure the electrical activity of the brain. A 
special computer program translates these brain waves into a dimensionless number 
that roughly correlates to the dose of anesthesia administered. A purpose of our 
research is to utilize the electrical information from the raw EEG signals to determine if 
EEG patterns can predict a propensity to develop postoperative delirium. Our approach 
is to probe deeper into the analysis of the EEG signal than simply depth of 
consciousness by developing a taxonomy of specific states leading up to and through 
emergence. 
EEG technology measures the electrical potential generated by synaptic input onto the 
dendrites of cortical neurons. Although higher frequencies are attenuated somewhat by 
the skull, a wide range of frequencies can be observed even with the abbreviated 
montage typical for the commonly available devices. With a minimal amount of effort the 
EEG file is available for download from the device via USB stick. The sensors are pre- 
packaged with gentle adhesive and applied to the patient’s forehead while the patient is 
awake and removed with a minimal amount of discomfort (similar to a Band-Aid). 
Although these EEG devices are not considered an ASA standard monitor for general 
anesthesia, many practitioners elect to place these sensors for routine cases as a 
monitor of depth of anesthesia. Several other benefits of these devices have been 
proven through the use of these devices and their utility as a standard monitor has been 
considered [17].  Previous experiments using abbreviated EEG records in this fashion 
have shown variations in the post-operative pain that correlated with their EEG patterns 
just before emergence from general anesthesia [18]. This is in contrast to the majority of 
the past studies using these devices that have focused on the predictive value of the 
number derived from the proprietary algorithm developed by the manufacturer. These 
algorithms reduce the EEG information into a single dimensionless number which 
roughly correlates with depth of anesthesia, although this concept has come under 
criticism. Our study involves quantitative EEG analysis of multiple electrodes placed over 
frontal brain regions of patients with co-morbid conditions. The value of EEG frequency 


October 8, 2019 
Page 7 of 27 
 
 
 
 
analysis in predicting delirium is unknown, but it has the potential to be an important tool 
in determining risk of delirium. 
 
6. Approach: 
Our aim is to optimize our perioperative treatment protocol for head and neck cancer 
patients in the operating room to positively impact ICU outcomes, by improving the 
incidence of delirium, associated postoperative cognitive dysfunction and pain control. 
This is a single center prospective randomized double blinded placebo controlled study 
that will be conducted at EUHM 
 
Study arms: 
1. 0.5mg/kg pre-incision bolus 
2. 1.0mg/kg pre-incision bolus 
3. Saline placebo pre-incision bolus 
Standard general anesthesia will be applied with following standardized drugs: 
Sevoflurane, fentanyl, hydromorphone, succinylcholine, rocuronium, cis-atracurium, 
lidocaine, propofol. Dosing and choice of above medications is at the discretion of the 
anesthesiologist. 
 
Primary Outcome: 
Delirium (measured by Confusion Assessment Method for Intensive Care Unit criteria, 
CAM-ICU) Measurements: Prior to surgery (baseline assessment upon study enrollment 
in ENT clinic) and postoperative days 0-3 (afternoon/evening on postoperative day 0, 
POD 1-3 measurements per shift as per Emory delirium protocol) 
 
Secondary Outcomes: 
1. Pre- and postoperative cognitive dysfunction (assessed in ENT clinic at pre- and 
post-operative visits or at anesthesia preoperative clinic) with the Mini-Cog, Mini-Mental 
Status Examination (MMSE) and the Cognitive Failure Questionnaire (CFQ). 
2. Pain assessment (Prior to surgery (baseline assessment upon study enrollment in 
ENT clinic) and postoperative days 0-3 (afternoon/evening on postoperative day 0, and 
POD 1-3 per Emory protocol every 4 hours). Assessed by observer-based Behavioral 
Pain Scale or Behavioral Pain Scale (Non-Intubated) with subsequent administration of 
patient-reported Visual Analog Scale. 


October 8, 2019 
Page 8 of 27 
 
 
 
 
3. Post-operative use of narcotics (assessed POD 0-3 from medical chart) 
4. Off line EEG analysis to correlate with postoperative delirium 
 
 
7. Participant Selection 
 
Inclusion criteria: 
 
Inclusion criteria: 
 
1. Patients 18 years of age and older, with otolaryngeal cancer receiving surgery with 
general anesthesia. 
 
(Please note we are purposefully including patients with higher predisposition to delirium 
as we are investigating potential preventive strategies for this diagnosis of multiple 
etiologies. Patients at higher risk of delirium (e.g., advanced age, chronic hypertension) 
will be included in our study. Additionally, other common risk factors that exist in this 
patient population (e.g., alcohol or nicotine use) are thought to contribute to delirium 
postoperatively. [19]) 
 
 
2. Competent to provide informed consent. 
 
 
Exclusion criteria: 
 
1. Emergency surgery 
 
2. Monitored Anesthesia Care (i.e., regional anesthesia alone without plans for general 
anesthesia) 
 
3. Surgery involving the eye, eyebrow, forehead, or frontal scalp near the sensor 
placement 
 
4. Poor health literacy (see next section) 
 
5. Patients with an allergy, or have experienced any drug reaction to ketamine will be 
excluded. 
 
6. Pregnant or lactating patients 
 
7. Patients in active alcohol withdrawal 
 
8. Patients with chronic pain who are taking buprenorphine 
 
Subject Replacement 
 
Subjects who are not admitted to the Intensive Care Unit after surgery, will be replaced, 
but will be followed per protocol through the final visit 2-6 weeks post-operatively. 


October 8, 2019 
Page 9 of 27 
 
 
 
 
Recruitment Plan/Eligibility Screening: 
Patients undergoing surgical procedures requiring general anesthesia will first be 
approached for participation during the patient’s preoperative visit, at the preoperative 
ENT clinic visit or on the day of surgery. A clinical research coordinator or other research 
personnel will be available to answer questions and obtain informed consent from the 
patient. It will be made clear to the patient that study participation is optional and that 
they can "opt out" at any time even if they have signed a consent form. In order to assure 
that our study participants are capable of understanding the information provided           
in the informed consent a single question screen will be used to detect inadequate health 
literacy: "How confident are you filling out medical forms by yourself?". This has been 
used in previous hospitals to detect poor health literacy [20]). 
We intend on enrolling up to 100 male and female patients that meet eligibility criteria in 
order to have 60 patients who complete all study assessments. In addition to examining 
the potential effects of age, anesthetic drugs, and other patient and clinical factors on 
cognitive trajectories post-anesthesia, gender will be recorded and statistically examined 
as a potential contributor to different EEG patterns among our patients in this 
observational study. 
 
8. Procedures: 
 
Upon enrollment, demographic data and medical history will be collected, 
subjects will be questioned about obstructive sleep apnea (OSA) using the 
STOP-Bang Questionnaire [21]). They will also be screened for cognitive 
impairment using Mini-Cog, Mini-Mental Status Examination (MMSE) and the 
Cognitive Failure Questionnaire (CFQ). A baseline pain assessment will be 
performed using the Visual Analog Scale. A baseline assessment of delirium will 
be obtained using the Confusion Assessment Method for Intensive Care Unit 
(CAM-ICU) criteria. 
 
Patients will be randomized to one of three groups on the morning of surgery by 
the Investigational Drug Service, before they enter the operating room.  A 
randomization table will be provided and the subject assignment will be the next 
available number on the list. The study staff will be blinded to the list and the 
assignment.  Group 1 will be given 0.5mg/kg of ketamine pre-incision as an 
intravenous (IV) bolus. Group 2 will receive 1.0mg/kg of ketamine pre-incision as 


October 8, 2019 
Page 10 of 
 
 
 
 
an IV bolus. Group 3. Will be administered saline/ placebo pre-incision an IV 
bolus. The provider will be blinded to the treatment assignment. 
 
Upon arrival in the operating room, before the induction of anesthesia, 
disposable EEG sensors (SEDLine) will be applied over the forehead according 
to the manufacturer's instructions. 
 
The pads will be placed out of the surgical field. For surgical cases where patient 
positioning or surgical skin preparation may interfere with good sensor contact, 
tape or Tegaderm® patches will be applied over the sensors to ensure they stay 
dry and in place. 
 
The patient will then be induced according to standard of care at the 
anesthesiologist’s discretion. After induction a single bolus dose of ketamine 
(0.5mg/kg or 1mg/kg) or saline placebo will be given intravenously. 
 
The operation itself will proceed in the usual fashion using the standard monitors 
placed in all such cases according to institutional practice. Operative 
characteristics will be recorded. 
 
At the conclusion of the operation, the anesthesia practitioner will press the event 
marker button to aid in synchronizing the EEG raw data. The provider will adhere 
to specific guidelines (Provider Instructions), data will be recorded and the EEG 
file (without patient identifiers) will be downloaded and stored securely. 
 
The sensor will be removed and EEG data will cease to be collected before 
transport to the recovery room. 
 
While in the recovery room, the patient’s pain level will be assessed (observer- 
based Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) with 
subsequent administration of patient-reported Visual Analog Scale) as standard 
of care. The patient will be screened for post–operative delirium using the CAM- 
ICU delirium score and the Richmond Agitation and Sedation Score (CAM-ICU; 
RASS) 30 minutes after arrival and at discharge. 
 
While in the ICU pain assessment will be performed on postoperative days 0-3 
(afternoon/evening on postoperative day 0, and POD 1-3 per Emory protocol, 
that is typically recorded by staff every 4 hours). Assessed by observer-based 
Behavioral Pain Scale or Behavioral Pain Scale (Non-Intubated) with subsequent 
administration of patient-reported Visual Analog Scale. Available data will be 


October 8, 2019 
Page 10 of 27 
 
 
 
 
gathered from the medical chart including vasopressor use, ICU and hospital 
length of stay. 
 
The patient will be screened for post-operative delirium using the CAM-ICU 
delirium score and the RASS during the ICU stay, typically recorded three times 
a day per Emory SOC. Available data will be gathered from the medical record 
for POD 1-3. 
 
 
At the routine outpatient ENT clinic postoperative visit that may occur from 2 to 6 
weeks after surgery, cognitive impairment again will be screened with the Mini- 
Cog, Mini-Mental Status Examination  (MMSE) and the Cognitive Failure 
Questionnaire (CFQ). Pain assessment will be performed using the Visual 
Analog Scale. 
 
This will be done by our research assistant. 
 
Post-operative use of narcotics will be assessed POD 0-3 from medical chart and 
at postop clinic visits at the ENT clinic visit postoperatively. The subject’s study 
participation will end at the postoperative ENT clinic visit. 30 day readmissions, 
as well as mortality will be captured. 
 
9. Risks 
 
a. Risks regarding EEG sensors: 
 
There is a very small chance of minor skin irritation from applying sensor strips (as the 
conductive gel has a minimal amount of latex-free adhesive similar to EKG leads); these 
skin reactions typically go away in 30 minutes without treatment. There is no more risk of 
skin irritation or discomfort from application or removal of these sensors than occurs 
during the removal of a Band-Aid. It should be noted that SEDLine sensors are routinely 
placed on the forehead of surgical patients without adverse effects. However, an 
information sheet with general instructions on care for minor skin problems after sensor 
removal will be made available. This sheet will also have recommendations for 
recognizing and treating minor skin irritation (i.e., mild soap and water) and the contact 
information for the study coordinator. 
b. Risks regarding ketamine are as follows: 


October 8, 2019 
Page 11 of 27 
 
 
 
 
According to the manufacturer the anesthesia induction dose is as follows: the initial 
dose of ketamine administered intravenously may range from 1 to 4.5 mg/kg. The 
average amount required to produce 5–10 min of surgical anesthesia has been 2 mg/kg. 
The short-term side effects of ketamine at higher doses (>1–2 mg/kg) than the dosages 
proposed for this study (0.5 or 1 mg/kg) include tachycardia, nystagmus, hypersalivation, 
euphoria, emergence reactions, hallucinations and nightmares [22] In the doses used in 
this study (low dose ketamine at 0.5 and 1mg/kg after induction), it is very unlikely that 
these side effects will happen. [23] 
 
 
c. ADE reporting and Data Safety Monitoring Plan: 
The Emory School of Medicine, section of Anesthesiology Research, will conduct this 
study according to the national rules, regulations and guidelines governing human 
clinical research. In addition, procedures cited by the US Code of Federal Regulations 
(Title 21) will be followed as these apply to the principles of Good Clinical Practices and 
approval by the Emory Institutional Review Board (IRB). Investigators will complete 
Emory University required research training. All individuals involved in the study and 
data collection will be made aware of the unanticipated event reporting policy. 
 
The research team will monitor subjects randomized and treated in the study for adverse 
events related to the research through the final study visit in the ENT clinic.  If the 
change from baseline is considered by the investigator to be part of the normal 
fluctuations of an underlying disease process, this shall not be reported as an adverse 
event (AE). If the change in baseline is considered by the investigator to be an untoward 
medical occurrence different from the standard of care, this medical occurrence shall be 
reported as an AE.  Any event meeting serious adverse event criteria will be reported by 
the research team immediately to the PI via email or telephone and will be reported to 
the Institutional Review Board (IRB) per policy. The PI will also inform all investigators of 
the event via email. The common grading system will be used for adverse event 
reporting where Grade 1 is mild, Grade 2 moderate, Grade 3 severe, Grade 4 life- 
threatening or disabling, and Grade 5 death related to AE. Should emergency unblinding 
be required for the safety of the patient, the PI will contact the Investigational Drug 
Service responsible for the preparation and dispensing of the study medication. 


October 8, 2019 
Page 12 of 27 
 
 
 
 
All enrolled subjects will be followed and monitored per Emory standard of care for 
postoperative surgery. Subject data will be evaluated on an ongoing basis during the 
study visits to ensure continued subject safety. There will be no pre-specified formal 
stopping rule for safety. An interim safety analysis will be performed after 10 participants 
are enrolled in each arm to ensure ongoing subject safety. 
 
 
 
This monitoring plan is appropriate, since ketamine, an anesthetic drug, has an excellent 
safety profile and is commonly used in anesthetic practice. In addition, the doses used  
in this study are unlikely to cause major or minor side effects (e.g., emergence reactions, 
hallucinations). 
10. Statistical analysis 
a. Sample size: 
It was assumed about 30% delirium incidence in our population by standard care [1] [2] 
[3]. 
Estimating 5-8 oropharyngeal cancer surgeries per week with a conservative enrollment 
rate of 50%, we will be able to recruit 130-208 patients in 12 months. We plan to enroll 
about 85 eligible patients in order to achieve 20 completed patients in each randomized 
group. For this pilot study, with this sample size we will have 85% statistical power under 
significant level of 0.05 to detect delirium incidence rate drop at least 30$ (placebo) to 
5% (two treatment arms combined) by one-sized Mantel Haenszel test, and such effect 
size is supported by an existing trial [13]. 
 
b. Data analysis: 
For primary aim, the incidence of delirium will be calculated in each of three randomized 
group with 95% confidence interval (CI), and compared between each ketamine treated 
group with placebo group through Fisher’s exact test. For secondary aims, the dose 
response effect of ketamine on delirium reduction will be tested by Cochran-Armitage 
trend test. For other outcomes, such as pain (and/or change from baseline), MMSE 
(and/or change from baseline), EEG data, length of stay (LOS), and use of narcotics will 
be first described by summary statistics (mean, median, standard deviation, frequency, 
and etc.) by three randomized groups and then compared by Chi-square test/Fisher’s 
exact test, ANOVA, or Krusal-Wallis test wherever appropriate. The analysis will be 


October 8, 2019 
Page 13 of 27 
 
 
 
 
conducted by the Biostatistics and Bioinformatics Shared Resource at Winship Cancer 
Institute. 
The Winship OnCore system will be used for data entry and analysis. 
11. Confidentiality 
The privacy of the research subjects will be ensured through standard procedures for 
securing research data. Whenever possible, a study number, rather than a name, will be 
used on study records.  Identifying information will not appear when we present or 
publish the study results. All interactions with subjects during the study will occur in a 
private setting. Only Emory owned computers will be utilized to store data with any 
identifiers and these are compliant with the Emory disc encryption policy. 
 
 
 
 
12. Literature: 
1. 
Pandharipande, P., et al., Prevalence and risk factors for development of delirium 
in surgical and trauma intensive care unit patients. J Trauma, 2008. 65(1): p. 34- 
41. 
2. 
Radtke, F.M., et al., Remifentanil reduces the incidence of post-operative 
delirium. J Int Med Res, 2010. 38(4): p. 1225-32. 
3. 
Yamagata, K., et al., Risk factors for postoperative delirium in patients 
undergoing head and neck cancer surgery. Int J Oral Maxillofac Surg, 2005. 
34(1): p. 33-6. 
4. 
Gottesman, R.F., et al., Delirium after coronary artery bypass graft surgery and 
late mortality. Ann Neurol, 2010. 67(3): p. 338-44. 
5. 
Bickel, H., et al., High risk of cognitive and functional decline after postoperative 
delirium. A three-year prospective study. Dement Geriatr Cogn Disord, 2008. 
26(1): p. 26-31. 
6. 
Koster, S., et al., Consequences of delirium after cardiac operations. Ann Thorac 
Surg, 2012. 93(3): p. 705-11. 
7. 
Mangusan, R.F., et al., Outcomes associated with postoperative delirium after 
cardiac surgery. Am J Crit Care, 2015. 24(2): p. 156-63. 
8. 
Inouye, S.K., Delirium in older persons. N Engl J Med, 2006. 354(11): p. 1157- 
65. 


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9. 
Zhang, W.Y., et al., Risk factors for postoperative delirium in patients after 
coronary artery bypass grafting: A prospective cohort study. J Crit Care, 2015. 
10. 
Shah, S., et al., Alcohol-related predictors of delirium after major head and neck 
cancer surgery. Arch Otolaryngol Head Neck Surg, 2012. 138(3): p. 266-71. 
11. 
Siddiqi, N., et al., Interventions for preventing delirium in hospitalised patients. 
Cochrane Database Syst Rev, 2007(2): p. CD005563. 
12. 
Siddiqi N, Holt R, Britton AM, Holmes J The Cochrane Collaboration. 2009. 
Interventions for preventing delirium in hospitalised patients 2007 Apr 18; 
(2):CD005563. 
 
13. 
Hudetz, J.A., et al., Ketamine attenuates delirium after cardiac surgery with 
cardiopulmonary bypass. J Cardiothorac Vasc Anesth, 2009. 23(5): p. 651-7. 
14. 
Hudetz, J.A., et al., Ketamine attenuates post-operative cognitive dysfunction 
after cardiac surgery. Acta Anaesthesiol Scand, 2009. 53(7): p. 864-72. 
15. 
Bell, RF; Dahl, J.B.; Moore, R.A.; Kalso, E. Perioperative ketamine for acute 
postoperative pain. Cochrane Database Syst Rev. 2006 Jan 251): CD004603. 
 
16. 
Price RB, Nock MK, Charney DS, Mathew SJ Effects of intravenous ketamine on 
explicit and implicit measures of suicidality in treatment-resistant depression. Biol 
Psychiatry 2009;66:522-6.17. 
 
17. 
Klopman, M.A., Sebel, P.S. Cost-effectiveness of bispectral index monitoring. 
Curr Opin Anaesthesiol. 2011 Apr; 24(2):177-81. 
18. 
Chander, D. et al. Electroencephalographic variation during end maintenance 
and emergence from surgical anesthesia. PLoS One. 2014 Sep 29; 
9(9):e106291. 
19. 
Zaal IJ, Devlin JW, Peelen LM, Slooter AJ. A Systematic Review for Delirium in 
the Intensive Care Unit. Crit Care Med. 2015 Jan;43(1):40-7 
20. 
Chew, LD, Griffin, JM et al. validation of screening questions for limited health 
literacy in a large VA outpatient population. J Gen Intern Med. 2008 May; 
23(5):561-6 
 
21. 
Chung, F, Elsaid H, Screening for obstructive sleep apnea before surgery: why is 
it important? Curr Opin Anaesthesiol. 2009 Jun;22(3):405-11. 


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22. 
Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural 
sedation in adults. Am J Emerg Med 2008; 26:985–1028 
 
23. 
Elia N, Tramer MR. Ketamine and postoperative pain—a quantitative systematic 
review of randomised trials. Pain 2005; 113:61–70. 


October 8, 2019 
Page 16 of 27 
 
 
 
 
Assessments 
Screening 
(up to 6 
weeks 
prior to 
surgery) 
Treatment 
Visit/DOS 
Recovery 
Room 
POD 0 
POD 1 
POD 2 
POD 3 
ENT 
clinic 
visit 2-6 
weeks 
after 
surgery 
Inclusion/Exclusion Criteria 
Review 
X 
Informed Consent 
X 
Randomization 
X 
Treatment with 
Ketamine/Placebo 
X1 
Connection to EEG Device 
(SEDLine Monitoring) and data 
capture during operative 
procedure 
X 
Medical History and 
Demographics 
X 
STOP-Bang Questionnaire 
X 
Mini-Cog 
X 
X 
Mini-Mental Status Exam 
(MMSE) 
X 
X 
Cognitive Failure Questionnaire 
(CFQ) 
X 
X 
Pain Assessment using Visual 
Analog Scale (VAS) 
X 
X 
X2 
X3 
X3 
X3 
X 
Follow provider guidelines 
X 
Confusion Assessment Method 
fo Intensive Care Unit (CAM- 
ICU) delirium score 
X 
X7 
X4 
X4 
X4 
X4 
Richmond Agitation Score 
(RASS) 
X7 
Pain assessment (Observer 
based Behavior Pain Scale or 
Behavior Pain Scale) 
X 
X2 
X3 
X3 
X3 
Use and amount of narcotics 
daily 
X 
X 
X 
X 
X 
EEG Analysis 
X 
Adverse Events6 
X 
X 
X 
X 
X 
X 
Surgery Characteristics 
X 
Length of ICU and Hospital Stay 
X 
 
1 Just after anesthesia induction time 
APPENDIX A- Study Flowchart and Schedule of Assessments 
2 Assessment to occur in afternoon or evening, obtain VAS if possible 
3 Pain assessments recorded for SOC, as available 
4 CAM-ICU scores as recorded per SOC, during ICU stay, as available 
5 Post op visit may occur at ~ 2 weeks and/or ~6 weeks 
6 Adverse Events to be collected only after treatment with study product/placebo 
7 30 minutes after PACU arrival and at PACU discharge 


October 8, 2019 
Page 17 of 27 
 
 
 
 
 


October 8, 2019 
Page 18 of 27 
 
 
 
 
The Cognitive Failures Questionnaire (Broadbent, Cooper, FitzGerald & Parkes, 1982) 
 
The following questions are about minor mistakes which everyone makes from time to time, but 
some of which happen more often than others. We want to know how often these things have 
happened to you in the past 6 months. Please circle the appropriate number. 
 
Very 
often 
Quite 
often 
Occasion- 
ally 
Very 
rarely 
Never 
1. 
Do you read something and find you 
haven’t been thinking about it and 
must read it again? 
4 
3 
2 
1 
0 
2. 
Do you find you forget why you went 
from one part of the house to the 
other? 
4 
3 
2 
1 
0 
3. 
Do you fail to notice signposts on the 
road? 
4 
3 
2 
1 
0 
4. 
Do you find you confuse right and left 
when giving directions? 
4 
3 
2 
1 
0 
5. 
Do you bump into people? 
4 
3 
2 
1 
0 
6. 
Do you find you forget whether 
you’ve turned off a light or a fire or 
locked the door? 
4 
3 
2 
1 
0 
7. 
Do you fail to listen to people’s names 
when you are meeting them? 
4 
3 
2 
1 
0 
8. 
Do you say something and realize 
afterwards that it might be taken as 
insulting? 
4 
3 
2 
1 
0 
9. 
Do you fail to hear people speaking to 
you when you are doing something 
else? 
4 
3 
2 
1 
0 
10. 
Do you lose your temper and regret 
it? 
4 
3 
2 
1 
0 
11. 
Do you leave important letters 
unanswered for days? 
4 
3 
2 
1 
0 
12. 
Do you find you forget which way to 
turn on a road you know well but 
rarely use? 
4 
3 
2 
1 
0 
13. 
Do you fail to see what you want in a 
supermarket (although it’s there)? 
4 
3 
2 
1 
0 


October 8, 2019 
Page 19 of 27 
 
 
 
 
Very 
often 
Quite 
often 
Occasion- 
ally 
Very 
rarely 
Never 
14. 
Do you find yourself suddenly 
wondering whether you’ve used a 
word correctly? 
4 
3 
2 
1 
0 
15. 
Do you have trouble making up your 
mind? 
4 
3 
2 
1 
0 
16. 
Do you find you forget appointments? 
4 
3 
2 
1 
0 
17. 
Do you forget where you put 
something like a newspaper or a 
book? 
4 
3 
2 
1 
0 
18. 
Do you find you accidentally throw 
away the thing you want and keep 
what you meant to throw away – as in 
the example of throwing away the 
matchbox and putting the used match 
in your pocket? 
4 
3 
2 
1 
0 
19. 
Do you daydream when you ought to 
be listening to something? 
4 
3 
2 
1 
0 
20. 
Do you find you forget people’s 
names? 
4 
3 
2 
1 
0 
21. 
Do you start doing one thing at home 
and get distracted into doing 
something else (unintentionally)? 
4 
3 
2 
1 
0 
22. 
Do you find you can’t quite remember 
something although it’s “on the tip of 
your tongue”? 
4 
3 
2 
1 
0 
23. 
Do you find you forget what you came 
to the shops to buy? 
4 
3 
2 
1 
0 
24. 
Do you drop things? 
4 
3 
2 
1 
0 
25. 
Do you find you can’t think of 
anything to say? 
4 
3 
2 
1 
0 
 
 
Reproduced by permission from the British Journal of Clinical Psychology. 
References 
Broadbent, D.E., Cooper, P.F., FitzGerald, P., & Parkes, K.R. (1982). The Cognitive Failures 
Questionnaire (CFQ) and its correlates. British Journal of Clinical Psychology, 21, 1-16 


October 8, 2019 
Page 20 of 27 
 
 
 
Mini-Mental State Examination (MMSE) 
Patient’s Name: 
Date: 
 
Instructions: Score one point for each correct response within each question 
or activity. 
Maximum 
Score 
Patient’s 
Score 
Questions 
5 
“What is the year? Season?  Date? Day?  Month?” 
5 
“Where are we now?  State? County? Town/city?  Hospital? Floor?” 
3 
The examiner names three unrelated objects clearly and slowly, then 
the instructor asks the patient to name all three of them. The patient’s 
response is used for scoring. The examiner repeats them until patient 
learns all of them, if possible. 
5 
“I would like you to count backward from 100 by sevens.” (93, 86, 79, 
72, 65, …) 
Alternative: “Spell WORLD backwards.” (D-L-R-O-W) 
3 
“Earlier I told you the names of three things.  Can you tell me what 
those were?” 
2 
Show the patient two simple objects, such as a wristwatch and a pencil, 
and ask the patient to name them. 
1 
“Repeat the phrase: ‘No ifs, ands, or buts.’” 
3 
“Take the paper in your right hand, fold it in half, and put it on the floor.” 
(The examiner gives the patient a piece of blank paper.) 
1 
“Please read this and do what it says.” (Written instruction is “Close 
your eyes.”) 
1 
“Make up and write a sentence about anything.” (This sentence must 
contain a noun and a verb.) 
1 
“Please copy this picture.” (The examiner gives the patient a blank 
piece of paper and asks him/her to draw the symbol below.  All 10 
angles must be present and two must intersect.) 
30 
TOTAL 


October 8, 2019 
Page 21 of 27 
 
 
 
Interpretation of the MMSE: 
Method 
Score 
Interpretation 
Single Cutoff 
<24 
Abnormal 
Range 
<21 
>25 
Increased odds of dementia 
Decreased odds of dementia 
Education 
21 
<23 
<24 
Abnormal for 8th grade education 
Abnormal for high school education 
Abnormal for college education 
Severity 
24-30 
18-23 
0-17 
No cognitive impairment 
Mild cognitive impairment 
Severe cognitive impairment 
 
Interpretation of MMSE Scores: 
Score 
Degree of 
Impairment 
Formal Psychometric 
Assessment 
Day-to-Day Functioning 
25-30 
Questionably 
significant 
If clinical signs of cognitive impairment 
are present, formal assessment of 
cognition may be valuable. 
May have clinically significant but mild 
deficits. Likely to affect only most 
demanding activities of daily living. 
20-25 
Mild 
Formal assessment may be helpful to 
better determine pattern and extent of 
deficits. 
Significant effect. May require some 
supervision, support and assistance. 
10-20 
Moderate 
Formal assessment may be helpful if 
there are specific clinical indications. 
Clear impairment. May require 24- 
hour supervision. 
0-10 
Severe 
Patient not likely to be testable. 
Marked impairment. Likely to require 
24-hour supervision and assistance 
with ADL. 
 
Source: 
• 
Folstein MF, Folstein SE, McHugh PR: “Mini-mental state: A practical method for grading 
the cognitive state of patients for the clinician.” J Psychiatr Res 1975;12:189-198. 


October 8, 2019 
Page 22 of 27 
 
 
 
 
 


October 8, 2019 
Page 23 of 27 
 
 
 
 
A Randomized Placebo-controlled Pilot Study of Single-dose Intraoperative Ketamine for the 
Prevention of Delirium in Otolaryngeal Cancer Surgery Patients 
 


October 8, 2019 
Page 24 of 27 
 
 
 
 
 
 
 
 
 
 
ADMINISTRATION 
SPECIAL INSTRUCTIONS 
1.Getpatient’sattentionandaskhimor 
her to remember three unrelated words. 
Ask patient to repeat the words to 
ensure the learning was correct. 
• Allow patient three tries, then go to next item. 
• The following word lists have been validated in a clinical study:1–3 
Version 1 
Version 3 
Version 5 
• Banana 
• Village 
• Captain 
• Sunrise 
• Kitchen 
• Garden 
• Chair 
• Baby 
• Picture 
Version 2 
Version 4 
Version 6 
• Daughter 
• River 
• Leader 
• Heaven 
• Nation 
• Season 
• Mountain 
• Finger 
• Table 
2. Ask patient to draw the face of a clock. 
After numbers are on the face, ask patient 
to draw hands to read 10 minutes after 
11:00 (or 20 minutes after 8:00). 
• Either a blank piece of paper or a preprinted circle (other side) may be used. 
• A correct response is all numbers placed in approximately the correct positions 
AND the hands pointing to the 11 and 2 (or the 4 and 8). 
• These two specific times are more sensitive than others. 
• A clock should not be visible to the patient during this task. 
• Refusal to draw a clock is scored abnormal. 
• Move to next step if clock not complete within three minutes. 
3.  Askthepatienttorecallthethree 
words from Step 1. 
Askthepatienttorecallthethreewordsyoustatedin  Step  1. 
 
 
 
3 recalled words 
Negative for cognitive impairment 
1-2 recalled words + normal CDT 
Negative for cognitive impairment 
1-2 recalled words + abnormal CDT 
Positive for cognitive impairment 
0 recalled words 
Positive for cognitive impairment 
 
 
1. Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. The mini-cog: a cognitive “vital signs” measure for dementia screening in 
multi-lingual elderly. Int J Geriatr Psychiatry. 2000;15(11):1021-1027. 
2. Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog as a screen for dementia: validation in a population-based sample. J Am 
Geriatr Soc. 2003;51(10):1451-1454. 
3. McCarten JR, Anderson P Kuskowski MA et al. Finding dementia in primary care: the results of a clinical demonstration project. J 
Am Geritr Soc. 2012;60(2):210-217. 
References 
Scoring 
Instructions 


October 8, 2019 
Page 25 of 27 
 
 
 
 
Mini-CogTM Copyright S Borson. Reprinted with permission of the author (soob@uw.edu). All rights reserved. 
 
 
 
 
 
 
 
 
Patient Name: 
_ 
Date:
  
CLOCK  
 


October 8, 2019 
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October 8, 2019 
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