Clinical trial NCT04625283
Conditions: Opioid Use Enhanced Recovery After Surgery Anesthesia Ketamine Pain, Postoperative
Keywords: ERAS Enhanced Recovery After Surgery Ketamine Opioid Learning Healthcare System
Sponsor: Vanderbilt University Medical Center
Start date: 2021-04-12; Completion date: 2024-02-01
Enrollment: 1570 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In order to effectively treat surgical pain with the least amount of opioids required, a multi-modal approach must include medications with different mechanisms of actions at alternative receptors. In light of the opioid epidemic, medical providers at Vanderbilt University Medical Center (VUMC) are strategically combining these medications in a bundled pain-regimen after surgery. These regimens have been shown to decrease opioid consumption, improve surgical outcomes, and reduce hospital stays, thus coining the term 'enhanced recovery pathway'. The combination of these medications has an indisputable synergistic effect. However, it is unknown how each medication contributes individually to the overall efficacy of the pathway. This study will examine the effects of ketamine, within the constructs of a multimodal pain regimen, on a) length of stay, b) opioid consumption, and c) surgical outcomes after major abdominal surgery.

Detailed description:
Opioids are powerful analgesic medications that can reduce pain through action at the mu receptor. Unfortunately, activation of the mu receptor also results in undesirable side effects, such as respiratory depression, sedation, bowel ileus, nausea, itching, and tolerance. Therefore, in order to effectively treat pain with the least amount of opioids required, a multi-modal approach must include medications with different mechanisms of actions at alternative receptors. Some examples of non-narcotic pain medications include acetaminophen (Tylenol), anti-inflammatories (NSAIDS), muscle relaxants, local anesthetics, gabapentinoids (Lyrica), and ketamine, to name a few. In light of the opioid epidemic, medical providers at Vanderbilt University Medical Center (VUMC) are strategically combining these medications in a bundled pain-regimen after surgery. These regimens have been shown to decrease opioid consumption, improve surgical outcomes, and reduce hospital stays, thus coining the term 'enhanced recovery pathway' or enhanced recovery after surgery (ERAS). The combination of these medications has an indisputable synergistic effect. However, it is unknown how each medication contributes individually to the overall efficacy of the pathway. Ultimately, the investigators aim to perform a series of randomized controlled trials in which we isolate each component of the pathway to investigate its effects on length of stay, total opioid consumption, and surgical outcomes. The investigators will begin with studying ketamine.

Arms: arm 1: Participants in this arm will receive intraoperative ketamine bolus (0.5mg/kg) followed by continuous infusion 5 mcg/kg/min and also will receive postoperative ketamine infusion (2.5 mcg/kg/min, up to 100kg max) for 48 hours. arm 2: Participants in this arm will receive an equivalent volume of intraoperative saline bolus followed by continuous saline infusion and also will receive postoperative saline infusion for 48 hours.
Interventions: intervention 1: Ketamine intervention 2: Placebo
Intervention descriptions: intervention 1: Participants in the ketamine arm will receive intraoperative and postoperative ketamine. intervention 2: Participants in the placebo arm will receive intraoperative and postoperative saline.

Protocol documents:
ICF_000.pdf: 
Institutional Review Board 
Consent to Participate in Research 
 
Principal Investigator:  Britany Raymond 
 
Version Date: 10/18/2020 
Study Title:  Perioperative Ketamine Infusion and Inpatient Opioid Consumption 
Institution/Hospital:  Vanderbilt University Medical Center 
 
 
1 of 1 
06/01/2017 
 
SHORT FORM WRITTEN INFORMED CONSENT DOCUMENT 
 
This document must be written in a language understandable to the subject and should be 
attached to a written summary of the information that is presented orally. 
  
You are being asked to take part in a research study. 
 
Before you agree, the study doctor must tell you about:  
(i) the reason for doing the study, the things that will be done and how long you will be in the study; 
(ii) any tests or treatments that are experimental;  
(iii) any risks or side effects you can expect, and good effects that might come from the study;  
(iv) other treatments you could get if you decide not to be in the study; and  
 
When any of the following things apply, the study doctor must also tell you about:  
(i) the possibility of other risks that are not known;  
(ii) reasons why the study doctor may take you out of the study;  
(iii) what will happen if you decide to stop being in the study;  
 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  This 
Web site will not include information that can identify you.  At most, the Web site will include a summary 
of the results.  You can search this Web site at any time. 
 
If you have any questions about this research study or if you feel you have been hurt because of this 
study, please feel free to contact Britany L. Raymond, MD at 615-322-8476  
 
You can also contact my Faculty Advisor, Matthew D. McEvoy at 615-936-5194.   
 
If you cannot reach the research staff, please page the study doctor at 615-936-5194. 
 
For additional information about giving consent or your rights as a participant in this study, contact the 
Institutional Review Board Office at (615) 322-2918 or toll free at (866) 224-8273. 
 
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services or other rights.  You can stop being in this study at 
any time. 
 
 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
The research study has been explained to me verbally.  All my questions have been answered, 
and I freely and voluntarily choose to take part in this study. 
 
______________________________________________  
_____________________ 
Signature of Participant  
 
 
 
 
Date 
 
 
______________________________________________ 
______________________ 
Signature of Translator (if applicable) 
 
 
 
Date 
Date of IRB Approval: 08/16/2023
Date of Expiration: 08/15/2024

SAP_002.pdf: 
Statistical Analysis Plan for the Effect and Contribution of a Perioperative Ketamine Infusion in an 
Established Enhanced Recovery Pathway 
Leena Choi, Yue Gao, and Christopher J. Lindsell 
 
Version 1.0 
September 6, 2023 
NCT04625283 
IRB #200210 
 
 
Principal Investigator: Britany Lynn Raymond, MD 
 
 
Key Study Personnel: 
 
Mary Lynn Dear, PhD 
 
Brian Allen, MD 
 
Pamela Butler, BS 
 
Leena Choi, PhD 
 
Robert E. Freundlich, MD, MS 
 
Yue Gao, MS 
 
Cheryl Gatto, PhD 
 
Wu Gong, MS 
 
Sydney Lagalante, MPH 
 
Christopher J. Lindsell, PhD 
 
Lodhi Zameeruddin, MS 
 
Matthew McEvoy, MD 
 
Miles Merrick, MD 
 
Crystal Parrish, NP 
 
Todd W. Rice, MD, MSc 
 
Teresa Turnbo, BS, CCRP 
 
Grace Van Winkle, BA 
 
 
 


Introduction 
This document describes the statistical analysis plan (SAP) for a cluster randomized, pragmatic clinical 
trial studying the effect of ketamine within a pre-established enhanced recovery program on patients 
presenting for elective major abdominal surgery. Each week is considered a cluster with each cluster 
being randomly assigned to either the control or intervention condition.  
Opioid consumption during the perioperative period is associated with adverse outcomes. In efforts to 
decrease opioid exposure after surgery, medical providers at Vanderbilt University Medical Center 
(VUMC) employ a multi-modal approach to pain control, which includes strategic combinations of non-
narcotic pain medications and regional nerve blocks. Evidence is clear that combinations of  non-narcotic 
pain medications with different mechanisms of actions are synergistically effective. What is not known, 
however, is the individual contribution of each medication to the overall efficacy of the regimen. This 
trial intends to explore the contribution of ketamine and hypothesizes patients randomized to receive 
ketamine will have a significant reduction in length of stay (LOS), following anesthesia start, compared to 
those receiving placebo.  
 
 
 
Study Population 
Adult patients presenting on a weekday for an elective major inpatient abdominal surgery at VUMC will 
be screened for eligibility. Indications for exclusion will be noted if they meet criteria specified in the 
study protocol. Two post-randomization exclusions have been prespecified for this study. First, a patient 
directly transferred from the operating room to the Intensive Care Unit (ICU) with an endotracheal tube 
placed will not be included. The rationale is that these patients are exposed to both a sedative and narcotic 
infusion for the duration of their intubation, which would confound the ability to determine analgesic 
efficacy and/or side effects from the study drug. Furthermore, Enhanced Recovery After Surgery (ERAS) 
protocols are not followed in the ICU, and therefore there would be significant deviations from study 
protocol. Importantly, we aim to study ketamine’s effects within ERAS principles for specifically elective 
surgeries. A transfer to the ICU while intubated reflects the occurrence of a major, unintended, and 
unanticipated intraoperative event for these elective procedures. The focus for that patient is no longer 
expedited recovery, but rather life-sustaining measures. Second, abortion of planned surgical procedure 
will qualify as a post-randomization exclusion. These patients do not undergo the intended surgical 
experience, will have different care pathways and goals, and are often discharged prior to 48 hours (length 
of time for the intervention). This exclusion will be defined as the patient being discharged home within 
23 hours of anesthesia stop time, consistent with an ‘observation’ status rather than ‘inpatient admission’ 
to the hospital. Manual chart review will be performed to ensure appropriate exclusion. The occurrence of 
these exclusions will be tracked between study arms. Eligible patients will be consented for inclusion in 
the trial usually on the day of their surgery; patients returning for a follow up procedure that meets 
inclusion criteria will be reapproached for consent and rerandomized as appropriate. 
 
Cohort Definition for Data Analysis 
Intent-to-Treat Cohort 
Intent-to-treat cohort includes all participants who are eligible and did not meet exclusion criteria 
specified in the study protocol. 


Per-Protocol Cohort 
To better understand the potential efficacy of ketamine, a per protocol cohort will be analyzed which will 
include patients in both arms who did not have the study infusion stopped for adverse effects. The per-
protocol cohort includes participants who finished the 48-hour post-operative infusion (either ketamine or 
placebo), as well as participants for whom the study infusion was intentionally discontinued early because 
the patient met appropriate recovery milestones and was preparing for discharge. However, this per-
protocol cohort will exclude any patients in whom the study infusion was stopped for intolerance or side 
effects, including those patients who were discharged prior to 48 hours but had the post-operative study 
infusion stopped prior to 48 hours due to intolerances or side effects. 
 
Treatment Arms 
Randomization of treatment arms will occur in clusters of one week so that all patients in the same week 
will receive the same therapy (i.e., ketamine or placebo).  
A. Intervention: Patients will receive a weight-based (up to 100 kg max) intraoperative ketamine 
bolus (0.5 mg/kg) followed by continuous infusion (5 mcg/kg/min), and an additional 
postoperative ketamine infusion (2.5 mcg/kg/min, up to 100 kg max) for 48 hours.  
B. Placebo: Patients will receive an intraoperative saline bolus followed by continuous infusion of 
equivalent volume to study drug dosed for 5 mcg/kg/min, and an additional postoperative saline 
infusion for 48 hours at an equivalent volume of infusion as the intervention arm.  
 
Outcomes 
Primary Outcome  
The primary outcome is the LOS in days for the placebo arm and the intervention (ketamine) arm. LOS is 
defined as the time between anesthesia start and the patient being discharged (patient physically leaving 
the hospital).  
Secondary Outcomes 
1. Total consumption of post-enrollment inpatient opioids in morphine milligram equivalents during 
the perioperative period to hospital discharge 
2. The incidence of following surgical outcomes: 
a. rapid response team calls  
b. transfer to ICU (not including direct transfer from OR to ICU as these patients are 
excluded from the study) after patient has been sent to the PACU or floor 
3. The incidence of the following indications or side effects requiring early cessation of the study 
medication, as documented by the provider at the time of discontinuing the order (from Best 
Practice Advisory, BPA)  
a. Meeting milestones/preop for discharge 
b. Mild side effects, but prefers discontinuation 
c. Debilitating hallucinations 
d. Debilitating dizziness 
e. Hemodynamic instability 
f. Other severe side effect 


4. The incidence of ileus requiring gastric decompression as defined by orogastric or nasogastric 
tube placement in the postoperative period 
Exploratory Outcomes 
1. Instances of reoperation within the index encounter 
2. VUMC hospital readmissions within 30 days post-discharge (not including ED visits) 
 
Design Considerations 
Randomization 
Randomization will occur in clusters of one week. All patients in the same week will receive the same 
therapy (ketamine or placebo), with the selection being determined by a pre-generated random sequence. 
Power and Sample Size 
We anticipate the use of ketamine will reduce LOS following surgery start. To determine how long this 
trial will need to run to have sufficient power to detect a meaningful difference, we assumed 85% power, 
a type I error rate of 5%, and a 10% reduction in LOS. We estimated the within period correlation from 
preliminary data concerning the length of stay for major abdominal surgeries to be about 0.014. Given 
these assumptions, about 1514 patients would need to be included overall. An increase in sample size is 
necessary to accommodate for the two post-randomization exclusions that are pre-specified. We expect 
approximately 30 participants to be impacted by these post-randomization exclusions and will therefore 
increase the sample size by 30 to account for this exclusion (n=1544). Given surgical volumes, we expect 
20 patients to be enrolled each week, and for the trial to last approximately 18 months. 
 
Statistical Approach 
Descriptive Analysis 
We will describe the study cohort both overall and by treatment arm. To characterize the study sample, 
demographic and clinical data will be described. Categorical variables will be described using frequencies 
and proportions; continuous variables will be described using means and standard deviations as well as 
medians and interquartile ranges (IQR). Missingness will be recorded for each variable. To further assess 
the distribution of variables, graphical summaries will be displayed using graphs such as boxplots, 
dotplots, and/or histograms. No statistical testing will be performed to compare characteristics between 
groups. At a minimum, the following baseline variables will be described: 
• 
Age (years) 
• 
Sex assigned at birth (male, female, unknown)  
• 
Race 
o Caucasian 
o African American 
o American Indian 
o Asian 
o Decline to answer 
o White 


o Hispanic/Latino/a 
o None of these 
o Other 
o Unknown 
• 
Ethnicity (Hispanic/Latino, Non-Hispanic/Not Latino, Unknown) 
• 
Weight (kg) and height (m2), and BMI (kg/m2) will be calculated with weight and height 
• 
Van Walraven modified Elixhauser score 
• 
History of Smoking 
• 
Type of Surgical Procedure (colorectal, ventral hernia, or surgical oncology – mutually exclusive 
categories) 
• 
Epidural vs. truncal nerve block 
• 
Intraoperative time, as defined by anesthesia start time to anesthesia stop time 
• 
The last American Society of Anesthesiologists (ASA) Physical Status classification associated 
with the surgery (anesthesia encounter) 
• 
Opioid exposed or naïve, as defined by the perioperative medicine initial consult note 
• 
Known history of anxiety, as defined as any code present in the patient’s chart prior to, and 
including the date of enrollment 
• 
Known history of depression, as defined as any code present in the patient’s chart prior to, and 
including the date of enrollment 
• 
Known history of PTSD, as defined as any code present in the patient’s chart prior to, and 
including the date of enrollment 
 
Main Analysis 
The main statistical analyses will be performed with the intent-to-treat cohort. As a part of sensitivity 
analyses, the per-protocol analysis will be performed with the primary outcome and the first secondary 
outcome defined in Secondary Outcomes section (i.e., total consumption of post-enrollment inpatient 
opioids in morphine milligram equivalents). 
Primary analysis: A mixed-effect proportional odds model will be used to compare the primary outcome 
(i.e., LOS) between the intervention and placebo arms with cluster as a random effect. The model will 
include baseline characteristics such as age, body mass index (BMI), Van Walraven modified Elixhauser 
score, history of smoking, epidural vs. truncal nerve block, intraoperative time, the last ASA Physical 
Status classification associated with the surgery, opioid naïve status, known history of anxiety, known 
history of depression, and known history of PTSD. Continuous variables will be modeled using cubic 
splines to examine non-linear relationship. For missing covariates, if the proportion of missingness is very 
small, single imputation will be used as appropriate; otherwise, multiple imputation will be used. 
Secondary analyses: The secondary outcomes will be analyzed with the same covariates. A mixed-effect 
proportional odds model will be used to evaluate difference in opioid use in the hospital between the 
intervention and placebo arms. For each of the binary outcomes, a mixed-effect logistic regression will be 
used to compare the odds of events between the two arms.  
Exploratory analyses: The exploratory outcomes will be presented in tables comparing the incidences of 
reoperation and hospital readmission within 30 days post-discharge between two arms.  
 


Differential Treatment Effects 
Differential treatment effects will be explored by examining the interaction between the treatment 
indicator and each variable that potentially interacts with treatment, one variable at a time, but subgroup 
analysis will not be performed. The variables we consider include sex, opioid naïve status, type of 
surgical procedure (colorectal, ventral hernia, or surgical oncology), epidural vs. truncal nerve block, 
known history of depression, and known history of PTSD. 
 
References 
1.  Pergolizzi JV, Rosenblatt M, LeQuang JA. Three YearsDown the Road: The Aftermath of the CDC Gu
ideline fo Prescribing Opioids for Chronic Pain. Adv Ther. 2019;36(6):1235-1240. doi:10.1007/s12325-
019-00954-1. 
2.  Kent ML, Hurley RW, Oderda GM, et al. American Societyfor Enhanced Recovery and Perioperative 
Quality Initiative-4 Joint Consensus Statement on Persistent Postoperative 
Opioid Use:  Definition, Incidence, Risk Factors,  
and Health Care System Initiatives. Anesth Analg. 2019;129(2):543-
552. doi:10.1213/ANE.0000000000003941. 
3.  Brummett CM, Waljee JF, Goesling J, et al. NewPersistent Opioid Use After Minor and Major Surg
ical Procedures in US Adults. JAMA Surg. 2017;152(6):e170504. doi:10.1001/jamasurg.2017.0504. 
4.  Kurokawa Y, Kurokawa T, Tanimoto T. Opioid Prescription After Surgery. JAMA Surg. 
2019;154(7):675-675. doi:10.1001/jamasurg.2019.0573. 
5.  Mercadante S. Opioid Analgesics Adverse Effects: The Other Side Of The Coin. Curr Pharm 
Des. 2019;25:1-6. doi:10.2174/1381612825666190717152226. 
6.  McEvoy MD, Wanderer JP, King AB, et al. A perioperativeconsult service results in reduction in cost
 and length of stay for colorectal surgical patients: evidence from a healthcare redesign project. 
Perioper Med (Lond). 2016;5(1):3. doi:10.1186/s13741-016-0028-1. 
7.  Hawkins AT, Geiger TM, King AB, et al. An enhanced recovery program in colorectal surgery is 
associated with decreased organ level rates of complications: a difference-in-differences analysis.  
Surg Endosc. 2019;33(7):2222-2230. doi:10.1007/s00464-018-6508-2. 
8.  King AB, Spann MD, Jablonski P, Wanderer JP, Sandberg WS, McEvoy MD. An enhanced 
recovery program for bariatric surgical patients significantly reduces 
perioperative opioid consumption and postoperative nausea. Surg Obes Relat Dis. 2018;14(6):849-
856.doi:10.1016/j.soard.2018.02.010. 
9.  Li Z, Zhao Q, Bai B, Ji G, Liu Y. Enhanced Recovery 
After Surgery Programs for Laparoscopic Abdominal Surgery: A Systematic Review and Meta-
analysis. World J Surg. 2018;42(11):3463-3473. doi:10.1007/s00268-018-4656-0. 
10.  Ni X, Jia D, Chen Y, Wang L, Suo J. Is the Enhanced 
Recovery After Surgery (ERAS) Program Effective and Safe in Laparoscopic Colorectal Cancer 
Surgery? A Meta-Analysis of Randomized Controlled Trials. J Gastrointest Surg. 2019;23(7):1502-
1512. doi:10.1007/s11605-019-04170-8. 
11.  Doan LV, Wang J. An Update on the Basic and Clinical Science of Ketamine 
Analgesia. Clin  J Pain. 2018;34(11):1077-
1088.doi:10.1097/AJP.0000000000000635. 
12.  Brinck EC, Tiippana E, Heesen M, et al. Perioperative 
intravenous ketamine for acute postoperative pain in adults. 
Cochrane Database Syst Rev.2018;12:CD012033.doi:10.1002/14651858.CD012033.pub4. 


13.  Peyton PJ, Wu C, Jacobson T, Hogg M, Zia F,Leslie K. The effect of a perioperative ketami
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2017;45(4):459-465. doi:10.1177/0310057X1704500408. 
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16.  Plyler SS, Muckler VC, Titch JF, Gupta DK, RiceAN. Low 
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Perianesth Nurs. February 2019. doi:10.1016/j.jopan.2018.11.009. 
 

Prot_001.pdf: 
Version 9/05/2023 
1. Title of project:  The Effect and Contribution of a Perioperative Ketamine Infusion in 
an Established Enhanced Recovery Pathway. 
 
2. Investigators:   Raymond, B1; Allen, B1; Freundlich, R1; Lindsell, C2; Rice, T3; 
Chang, Y2; Dear, M3; Furman, K1; Hayhurst, C1; Miles, M1; Mueller, D1; Smith, R1; 
Weaver, S1; McEvoy, M1 
1Department of Anesthesiology 
2Department of Biostatistics 
3Learning Health System, Vanderbilt Institute for Clinical and Translational Research 
 
3. Background and significance:   
Over the last 20 years, opioid use disorder and related deaths have risen to epidemic 
proportions in the United States. Unfortunately, data suggests that long-term opioid 
use often begins from a discharge prescription intended to treat acute surgical pain. 
Additionally, opioid consumption during hospitalization is associated with adverse 
outcomes, including respiratory arrest, delirium, bowel ileus, nausea, and prolonged 
length of stay. 
 
In efforts to decrease opioid exposure after surgery, medical providers at Vanderbilt 
University Medical Center (VUMC) employ a multi-modal approach to pain control, 
which includes strategic combinations of non-narcotic pain medications and regional 
nerve blocks. This intentional practice, termed 'enhanced recovery pathway', has been 
extremely successful over the last few years, with internal data showing significant 
reductions in opioid consumption, improved surgical outcomes, and earlier 
discharges from the hospital. Our results are consistent with experiences from other 
enhanced recovery programs. 
 
Evidence is clear that combinations of non-narcotic pain medications with different 
mechanisms of actions are synergistically effective. What is not known, however, is 
the individual contribution of each medication to the overall efficacy of the regimen. 
Thus, we aim to perform a series of randomized, controlled trials in which we 
systematically isolate each component of our bundled pathway. 
 
We propose to conduct a randomized controlled trial to investigate the weight of 
ketamine, within a the construct of a pre-established enhanced recovery program, on 
a) length of stay, b) total inpatient opioid consumption, and c) surgical outcomes after 
major abdominal surgery. Eligible patients in our enhanced recovery program will be 
randomized to receive either ketamine or saline during the perioperative period, with 


Version 9/05/2023 
the remainder of the multimodal analgesic regimen consistent between the groups. 
Breakthrough pain will be addressed pragmatically, in accordance with suggested 
pathway guidelines and routine practice of our physicians. 
 
4. Rationale, specific aim(s), and hypotheses: 
AIMS: Examine the effects of ketamine, within the constructs of a multimodal pain 
regimen, on a) length of stay, b) opioid consumption, and c) surgical outcomes after major 
abdominal surgery. 
4.1  Primary Outcome:   total length of hospital stay (days). LOS is defined as 
the time between anesthesia beginning and the patient being discharged. 
 
     4.2  Secondary Outcomes:   
a) total consumption of inpatient opioids in morphine milligram equivalents 
b)  surgical outcomes including rapid response, transfer to icu, and ileus 
c) the incidence of side effects, including hallucinations, sedation, adverse 
reactions requiring early cessation 
4.3 Exploratory Outcomes 
a) Instances of reoperation within the index encounter 
b) Hospital readmissions to VUMC within 30 days post-discharge 
 
4.4  Primary Hypothesis:  Utilization of ketamine as part of a perioperative 
multimodal pain regimen will result in a significant reduction in length of stay as 
defined as the time between anesthesia beginning and the patient being 
discharged. 
 
 
5. Preliminary results including animal studies and previous human studies (if 
applicable): 
Ketamine has been used as a core intraoperative component of several VUMC enhanced 
recovery pathways since we adopted the practice. As evidence of its safety and utility 
became more available, we expanded its use to include the postoperative period as well 
(2016 consensus guidelines). 
 
To date, no study has looked at the contribution of ketamine within an established 
enhanced recovery pathway.  However, studies looking at perioperative ketamine 
infusions individually are summarized below: 
PMID:  30113350:  129 patients either “opioid tolerant” or “naiive.” Were randomized to Ketamine 0.12 
mg/kg/h x 24 hours or a saline placebo.  The primary outcome was opioid consumption during the first 24 
h postoperatively. The secondary outcome was numerical pain scores during the first 24 h and central 


Version 9/05/2023 
nervous system side effects. Postoperative hydromorphone consumption was significantly reduced in the 
opioid-tolerant ketamine group, compared with the opioid-tolerant placebo group [0.007 (95% CI 0.006 to 
0.008) versus 0.011 (95% CI 0.010 to 0.011) mg kg−1 h−1, Bonferroni corrected P < 0.001]. Postoperative 
low-dose ketamine infusion reduces opioid requirements for the first 24 h following spinal fusion surgery 
in opioid-tolerant, but not in opioid-naïve patients. 
 
 
 
PMID: 26283834:  Zakine et al. [49] performed a double-blinded study comparing the effectiveness of 
ketamine administration in two different settings with one control group which received placebo. The first 
ketamine group received a 0.5 mg/kg bolus perioperatively and a 2 μg/kg/min infusion thereafter for 48 
hours; the second ketamine group received a 0.5 mg/kg bolus perioperatively and a 2 μg/kg/min infusion 
only for the duration of the surgical procedure. All of the patients were given morphine PCA. The authors 
found that cumulative morphine consumption was significantly lower in the group receiving the 48-hour 
infusion when compared to the shorter infusion and control groups. VAS scores were measured 
postoperatively and were significantly lower in the ketamine groups when compared to the control group. 
As an added effect, while all patients in the study received hydroxyzine preoperatively, the 48-hour 
infusion group experienced significantly less nausea than the control group (4% versus 27%, ). It is worth 
nothing that there were no side effects of the ketamine, psychotomimetic, or otherwise. 
 
PMID:  23814653:  Hadi et al. [40] used low-dose IV ketamine as an adjunct to therapy during and after 
lumbar microdiscectomy surgery. Patients were divided into a control group, a group receiving 
1 μg/kg/min perioperatively and a group receiving both 1 μg/kg/min perioperatively and 1 μg/kg/min 
postoperatively. The patients in the control group required first analgesic demand dose earlier than the 
ketamine groups. Total morphine consumption, visual analog scale (VAS) pain scores, and rates of 
nausea and vomiting were significantly lower in the group receiving both peri- and postoperative ketamine 
versus the control group. 
 
PMID:  22374377:  Suppa et al. [48] performed a similar study in women undergoing elective Cesarean 
sections, using a 0.5 mg/kg ketamine bolus 10 minutes after birth in addition to a 2 μg/kg/min IV ketamine 
infusion for 12 hours thereafter. Usage of ketamine reduced morphine requirements at the 4–8, 8–12, and 
12–24-hour time points. The patients in the ketamine group showed reduced pain sensitivity at the T-10 
dermatome, suggesting an antihyperalgesic effect. At three years after surgery, patients reported no 
differences in residual pain or dysesthetic symptoms. 
 
PMID:  19923527:  Remérand studied the effects of a 24-hour ketamine infusion in patients undergoing 
primary elective total hip arthroplasty in France. In a prospective, randomized, placebo-controlled, double-
blind study of 154 patients, the group received an IV bolus of 0.5 mg/kg of study drug (either ketamine or 
placebo/saline) followed by an IV infusion for 24 hours at a dose of 2 mcg/kg/minute.  ll patients received 
general anesthesia, acetaminophen, ketoprofen (NSAID), and a morphine/droperidol mixture via IV PCA. 
The primary outcome of interest was 24-hour morphine consumption.  The ketamine treatment group had 
a mean 24-hour morphine consumption of 14 mg versus 19 mg in the placebo group (P = 0.004). 
Although statistically significant, the clinical relevance of a 5 mg decrease in IV morphine is unclear. 
However, on secondary analysis, the ketamine treatment group had statistically significant decreases in 
(1) the need for two crutches or a walking frame at Postoperative Day 30 (31% vs 56%; P = 0.0035); (2) 
pain at rest from Postoperative Days 30 to 180 (P = 0.008); and (3) persistent pain in the operative hip at 
rest at Postoperative Day 180 (8% vs 21%; P = 0.036; relative risk reduction, 67%). 
 
6.  Inclusion/exclusion criteria: 
6.1  Inclusion criteria: 


Version 9/05/2023 
• 18 years old or greater 
• presenting for major, elective, abdominal surgery on the colorectal, ventral 
hernia, or surgical oncology services on a weekday 
 
 
6.2  Exclusion criteria: 
• allergy or contraindication to ketamine 
• unable or refused to receive a neuraxial or regional nerve block 
• patient refusal 
• direct transfer from operating room to ICU with endotracheal tube placed 
• treating team elects to exclude the patient prior to study drug administration 
• abortion of surgical procedure 
 
 
7.  Enrollment/randomization: 
Patients presenting for elective major abdominal surgery at VUMC are automatically 
screened to receive care within our enhanced recovery program. Patients are 
approached on the day of their surgery by a physician member of our Perioperative 
Medicine team, who describes our goals, multimodal pathways, and obtains consent 
to perform a regional nerve block. Eligible patients will be consented for inclusion in 
the trial during this initial encounter; patients returning for a follow up procedure that 
meets inclusion criteria will be reapproached for consent and rerandomized as 
appropriate. Consent for the trial will be included as an adaptation to our current 
consent form for neuraxial or regional nerve block procedures, with the addition of 
the following language: 
 
“Vanderbilt University Medical Center (VUMC) is a learning healthcare system 
where we evaluate how well our routine treatments and interventions for pain 
control work after surgery and possible side effects they may produce. As part of 
your perioperative care, you will receive a bundled approach of different pain 
regimens that have been shown to work both alone and together to relieve pain. At 
VUMC, we are studying different aspects of our routine bundled pain regimen to 
determine the most effective parts and combinations.  
 
If you are eligible for enrollment in a study about treatment of your pain, you may be 
assigned to one of multiple routinely used regimens to help control your pain. Upon 
enrollment, you will be randomized to receive either a ketamine or saline infusion. We 
are doing this study to understand which regimens have better pain control and fewer 
side effects in different patients. You will have pain medicine available as you need it 
regardless of the regimen used. Potential side effects of those pain medicines include 
confusion, sleepiness, agitation, slowing of your breathing, and changes in blood 
pressure. Data will be collected from your medical record to evaluate how well your pain 


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is controlled and whether or not you have any side effects. The risk of the study is that 
your data could be seen by people not part of the study. To help prevent this, data will 
be stored in a secure database to minimize the risk of anybody seeing your information. 
You can choose not to have your data be part of the study. Ultimately, the health care 
providers involved in your care will determine the best treatment plan for your pain, 
regardless of your taking part in the study or not. You do not have to take part in the 
study. If you decide not to take part in the study, none of your care will be changed 
because you opted not to take part. You can also choose to stop taking part in the study 
at any time. Patients can choose to opt out of taking part in the study by initialing the 
following statement:  
I would like to opt-out of any studies evaluating how well my surgical pain regimen 
works. I understand that the physicians caring for me will determine the best treatment 
plan for my pain, and that this plan may still include the bundled pain regimen being 
studied. However, data from my medical record will not be used to evaluate how well 
the pain treatment regimen works or its side effects. 
 
Randomization will be in cluster format, scheduled and tracked by the OR 
pharmacy.  Patients and their medical providers will be blinded to their randomization 
arm. Provisions for breaking the blind include medical emergencies, adverse 
medication reactions, and participant or medical provider request. 
 
A subset of patients may be readmitted for an additional surgery during the study 
period. In these instances, if the planned surgery meets inclusion criteria, the 
patient will be re-randomized and the readmission will be considered a new 
instance/encounter. For patients undergoing re-operation within the same 
encounter/admission, we will not re-randomize these patients. Instead, providers 
will order ketamine or not as appropriate per their clinical judgement. 
 
8.  Study procedures: 
Procedure/Activity 
Frequency 
Patient randomization 
 Randomization will occur in clusters of one week. All 
patients in the same week will receive the same therapy 
(ketamine or placebo), with the choice being determined 
by a pre-generated random sequence. 
intraoperative ketamine bolus (0.5mg/kg) vs placebo 
followed by continuous infusion 5 mcg/kg/min 
once 
postoperative ketamine infusion (2.5 mcg/kg/min, up 
to 100kg max) vs placebo for 48 hours 
once 
electronic medical record chart review 
for data capture and statistical review 
 


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Data will be abstracted from the EMR. Some data will be obtained through the 
Research Derivative. The Research Derivative is a database of clinical and related data 
derived from the Medical Center’s clinical systems and restructured for research. Data 
is repurposed from VU’s enterprise data warehouse, which includes data from 
StarPanel, VPIMS, and ORMIS (Operating Room Management Information System), 
EPIC, Medipac, and HEO among others. The medical record number and other person 
identifiers are preserved within the database. Data types include reimbursement codes, 
clinical notes and documentation, nursing records, medication data, laboratory data, 
encounter and visit data, among others. Output may include structured data points, 
such as ICD 9 codes or encounter dates, semi-structured data such as laboratory tests 
and results, or unstructured data such as physician progress reports. The database is 
maintained by the Office of Research Informatics under the direction of Paul Harris, 
Ph.D.  
Due to a national shortage of ketamine, study enrollment was paused on April 3rd, 
2023 and then resumed on September 18th, 2023.    
9.  Risks: 
Ketamine is an analgesic that has been proven to reduce opioid consumption after 
surgery. It also has a role in reducing the development of chronic pain. Compared to 
opioids, ketamine has a favorable side-effect profile, including the maintenance of 
respiratory and cardiovascular stability. Ketamine does not act at the mu opioid 
receptor, and therefore is not associated with nausea, itching, constipation, and 
tolerance. 
We have been safely utilizing perioperative ketamine VUMC for several years as part of 
our enhanced recovery pathways. 
 
Ketamine is a controlled substance and is highly regulated, recorded, and tracked. 
Patients are evaluated daily at the bedside by our Preoperative Medicine Service, 
and patients are screened for side effects of ketamine on daily rounds. Nurses are 
trained to immediately report any suspicion of an adverse ketamine reaction to a 
member of our team, who is in-house 24/7. 
Adverse reactions to ketamine: Adverse reactions and allergies to ketamine are 
routinely reviewed by both medical providers and pharmacy personnel prior to ordering 
and administering the drug. Ketamine is a controlled substance and is highly regulated, 
recorded, and tracked. Patients are evaluated daily at the bedside by our Preoperative 
Medicine Service, and patients are screened for side effects of ketamine on daily 
rounds. Nurses are trained to immediately report any suspicion of an adverse ketamine 
reaction to a member of our team, who is in-house 24/7. 
 
Selection of patients: Only patients receiving care through our enhanced recovery 
pathway (which includes the standard administration of ketamine) will be eligible for 
participation. 
 


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Ineffective pain control: Patients with breakthrough pain will receive routine 
treatment guided by our preoperative protocols and discretion of medical 
providers. 
 
Breach of confidentiality: The investigators have access to the medical data as 
part of their job standing. All database work will be performed on VUMC approved 
and password protected servers that are physically located in the VUMC computing 
environment and maintained by VUMC security standards. Only the PI and KSP will 
have access to study specific data. 
 
 
10.  Reporting of adverse events or unanticipated problems involving risk to 
participants or others: 
Quality controls will include regular data verification and protocol compliance checks. 
Protocol adherence will be monitored by the PI throughout the study. Events determined 
by the PI to be unanticipated problems involving risks to subjects will be reported by the 
PI to the IRB as per VHRPP Policies and Procedures 
If any breach of confidential patient material were to occur, the Institutional Review 
Board at Vanderbilt University Medical Center would be immediately contacted. 
 
11.  Study withdrawal/discontinuation: 
Patients and their medical providers will be blinded to their randomization arm. 
Provisions for breaking the blind include medical emergencies, adverse medication 
reactions, and participant or medical provider request.  Patients can request to be 
withdrawn from the study at any time. Should a patient choose to withdraw from 
continued study drug administration, outcomes will continue to be collected from 
the EMR unless the patient indicates they do not want their data collected.  
 
 
12.  Statistical considerations including sample size justification (power analysis) 
and statistical analysis plan (optional at this stage for investigators not versed in 
statistical methodology): 
This study is a cluster randomized, pragmatic clinical trial. Initial analysis will use 
descriptive statistics and data visualizations to both identify and address spurious 
values, and to characterize the study cohort. Characteristics will be grouped by study 
arm, but we do not plan to compare the study arms with statistical tests. 
The primary outcome is length of stay, measured in days. It is expected that length of 
stay is a skewed distribution, and so non-parametric methods are preferred. However, it 


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is not possible to consider the clustering or baseline covariates using a Wilcoxon test. 
Therefore, a proportional odds regression model will be used. Clustering will be taken 
into account using a mixed-effects model. If there are patients included twice because 
they underwent two elective major abdominal surgeries, patient will also be included as 
a random effect. The model will include baseline characteristics such as age, BMI, 
history of substance use (smoking status and opioid status if available), and type of 
surgical procedure. The common odds ratio from the model will be estimated; this 
quantity can be interpreted similar to the concordance probability and is robust to the 
proportional odds assumption. We will also report the model-assisted estimands of 
mean and median length of stay. Bootstrapping will be used to generate appropriate 
confidence intervals. 
We will use an intention to treat analysis and all participants who are randomized will be 
included in the statistical analysis and analyzed according to group assignment. 
Participants will be removed from the analysis if their provider deems the patient 
ineligible prior to study drug administration. If a participant or provider withdraws the 
participant from the study following study drug administration, the participant will receive 
care at the provider’s discretion, but will remain in the statistical analysis.   
The secondary outcomes will be explored in a similar way. The proportional odds model 
will be used to evaluate differences in opioid use in the hospital. Occurrence of events 
will be reported as rates with confidence intervals. Logistic regression will be used to 
compare the odds of events between groups. 
In all statistical modeling, emphasis will be placed on effect sizes over p-values. In 
addition, continuous variables will be modelled flexibly using cubic splines. Differential 
treatment effects will be explored by examining the interaction between the treatment 
indicator and the putative subgrouping variable. We will explicitly test for effects of 
treatment by sex. As before, continuous variables will not be categorized, and the 
interaction will be with the continuous variable. Subgroup analyses will not occur in 
reporting the main results of this trial unless there is evidence of a differential treatment 
effect.   
To determine how long this trial will need to run to have sufficient power to detect a 
meaningful difference, we assumed 85% power, a type I error rate of 5%, and a 10%, 
reduction in LOS. We estimated the within period correlation from preliminary data 
concerning the length of stay for major abdominal surgeries to be about 0.014. Given 
these assumptions, about 1514 patients would need to be included overall. If the effect 
size were bigger, say 20%, then 370 patients would be required. An increase in sample 
size is necessary to accommodate for the two post-randomization exclusions that are 
pre-specified. We expect ~30 participants to be impacted by these post-randomization 
exclusions and will therefore increase the sample size by 30 to account for this 
(n=1544). Given surgical volumes, we expect 20 patients to be enrolled each week, and 
for the trial to last approximately 18 months. The current accrual rate has been more 
aligned with ~15 patients enrolled each week. Accordingly, the trial is anticipated to last 
approximately 26 months.   
 


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13.  Privacy/confidentiality issues: 
Study team members will access the EMR in order to collect data for our primary and 
secondary outcomes. All team members have been trained in proper care of PHI. After 
enrollment with PHI, participants will be assigned a corresponding number to de-
identification purposes, and they key will be secured in a database separate from the 
study data collected.  All database work will be performed on VUMC approved and 
password protected servers that are physically located in the VUMC computing 
environment and maintained by VUMC security standards. Only the PI and KSP will 
have access to study specific data.   
 
 
14.  Follow-up and record retention details: 
Identifiers will be maintained only through the duration of the study and subsequent 
publication, after which the information will be destroyed. 
 
15.  References: 
 
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2.  Kent ML, Hurley RW, Oderda GM, et al. American Societyfor Enhanced Recovery and Perioperative Quality I
nitiative-4 Joint Consensus Statement on Persistent Postoperative 
Opioid Use:  Definition, Incidence, Risk Factors,  
and Health Care System Initiatives. Anesth Analg. 2019;129(2):543-
552. doi:10.1213/ANE.0000000000003941. 
3.  Brummett CM, Waljee JF, Goesling J, et al. NewPersistent Opioid Use After Minor and Major Surgical 
Procedures in US Adults. JAMA Surg. 2017;152(6):e170504. doi:10.1001/jamasurg.2017.0504. 
4.  Kurokawa Y, Kurokawa T, Tanimoto T. Opioid Prescription After Surgery. JAMA Surg. 
2019;154(7):675-675. doi:10.1001/jamasurg.2019.0573. 
5.  Mercadante S. Opioid Analgesics Adverse Effects: The Other Side Of The Coin. Curr Pharm 
Des. 2019;25:1-6. doi:10.2174/1381612825666190717152226. 
6.  McEvoy MD, Wanderer JP, King AB, et al. A perioperativeconsult service results in reduction in cost and le
ngth of stay for colorectal surgical patients: evidence from a healthcare redesign project. Perioper Med 
(Lond). 2016;5(1):3. doi:10.1186/s13741-016-0028-1. 
7.  Hawkins AT, Geiger TM, King AB, et al. An enhanced recovery program in colorectal surgery is 
associated with decreased organ level rates of complications: a difference-in-differences analysis.  
Surg Endosc. 2019;33(7):2222-2230. doi:10.1007/s00464-018-6508-2. 
8.  King AB, Spann MD, Jablonski P, Wanderer JP, Sandberg WS, McEvoy MD. An enhanced recovery 
program for bariatric surgical patients significantly reduces 
perioperative opioid consumption and postoperative nausea. Surg Obes Relat Dis. 2018;14(6):849-
856.doi:10.1016/j.soard.2018.02.010. 
9.  Li Z, Zhao Q, Bai B, Ji G, Liu Y. Enhanced Recovery After Surgery Programs for Laparoscopic Abdominal 
Surgery: A Systematic Review and Meta-analysis. World J Surg. 2018;42(11):3463-
3473. doi:10.1007/s00268-018-4656-0. 


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10.  Ni X, Jia D, Chen Y, Wang L, Suo J. Is the Enhanced Recovery After Surgery (ERAS) Program Effective and 
Safe in Laparoscopic Colorectal Cancer Surgery? A Meta-Analysis of Randomized Controlled Trials. J 
Gastrointest Surg. 2019;23(7):1502-1512. doi:10.1007/s11605-019-04170-8. 
11.  Doan LV, Wang J. An Update on the Basic and Clinical Science of Ketamine 
Analgesia. Clin  J Pain. 2018;34(11):1077-1088.doi:10.1097/AJP.0000000000000635. 
12.  Brinck EC, Tiippana E, Heesen M, et al. Perioperative 
intravenous ketamine for acute postoperative pain in adults. 
Cochrane Database Syst Rev.2018;12:CD012033.doi:10.1002/14651858.CD012033.pub4. 
13.  Peyton PJ, Wu C, Jacobson T, Hogg M, Zia F,Leslie K. The effect of a perioperative ketamine 
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Medicine, the American Academy of Pain Medicine, and the American 
Society of Anesthesiologists. Reg Anesth Pain Med. 
2018;43(5):456-466. doi:10.1097/AAP.0000000000000806. 
15.  Allen CA, Ivester JR. Low Dose Ketamine for Postoperative Pain Management.  
J Perianesth Nurs. 2018;33(4):389-398.doi:10.1016/j.jopan.2016.12.009. 
16.  Plyler SS, Muckler VC, Titch JF, Gupta DK, RiceAN. Low Dose Ketamine Infusion to Decrease 
Postoperative Delirium for Spinal Fusion Patients. J Perianesth Nurs. February 2019. 
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