The Effect and Contribution of a Perioperative Ketamine Infusion in an Established Enhanced Recovery Pathway
Phase: PHASE4
Conditions: Opioid Use, Enhanced Recovery After Surgery, Anesthesia, Ketamine, Pain, Postoperative
Sponsor: Vanderbilt University Medical Center

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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 

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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 

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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: 

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• 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. 
 
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