Conditions: Trauma Injury Pain Opioid Use
Keywords: Multimodal Pain Therapy Ketamine Trauma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 305
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the effectiveness of Ketamine drip along with usual care and usual care alone on trauma patients and to longitudinally quantify the pain experience of patients during hospitalization.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Ketamine plus usual care intervention 2: Usual Care
Intervention descriptions: intervention 1: Bolus of .35 mg/kg Infusion start @ 0.15 mg/kg/hr; titrate range is 0.1 - 0.25 mg/kg/hr for 24 to 48 hours after admission and each subsequent major surgery plus multi-modal pain therapy considered as standard of care. Standard of care medications include Acetaminophen 1000 mg po q6 hours, Naproxen 500 mg po q12 hours, Gabapentin 300 mg po q8 hours and Lidocaine patch q 12 hours. intervention 2: Standard of care medications include Acetaminophen 1000 mg po q6 hours, Naproxen 500 mg po q12 hours, Gabapentin 300 mg po q8 hours and Lidocaine patch q 12 hours.

Protocol document:
Prot_SAP_000.pdf: 
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Ketamine for Acute Pain after Trauma: KAPT Trial 
 
NCT04129086 
 
Version Date: 08/25/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Title: 
Ketamine for Acute Pain after Trauma: KAPT Trial 
 
Principal Investigator: 
John A. Harvin, MD, MS, FACS 
Associate Professor of Surgery 
Faculty, Center for Translational Injury Research (CeTIR) 
 
Co-Investigators: 
Samuel Prater, MD 
Associate Professor of Emergency Medicine 
 
Paulina Sergot, MD 
Assistant Professor of Emergency Medicine 
 
Christopher Stephens, MD 
Associate Professor of Anesthesiology 
 
Julius G. Balogh, MD, MHA 
Fellow, Anesthesia 
 
Michael Wandling, MD MS 
Fellow, Acute Care Surgery 
 
Thaddeus J. Puzio, MD 
Fellow, Trauma Surgery 
 
Statistician: 
Charles Green, PhD 
Associate Professor, Departments of Pediatrics and Psychiatry 
Center of Clinical Research and Evidence-Based Medicine 
 
Study Coordinator: 
Jeanette Podbielski, R.N. 
Research Project Manager 
 
Kandice Motley 
Research Coordinator 
 
Population: 
Adult trauma patients admitted to the Surgical Intermediate Unit 
(SIMU) and Shock Trauma Intensive Care Unit (STICU) at Memorial 
Hermann Hospital-Texas Medical Center (MHH-TMC) 
 
Number of Sites: 
Single center, MHH-TMC 
 
Study Duration: 
Two years (tentatively) 
 
Subject Duration: 
Time while hospitalized and six month follow up 


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Table of Contents 
 
General Information 
3 
Background 
3 
Hypothesis and Specific Aims 
4 
Study Design 
5 
Setting 
5 
Trial Arms: Treatment Strategies 
5 
Study Population 
5 
Screening 
6 
Randomization 
6 
Consent 
6 
Data Collection 
7 
Data Analysis 
7 
Outcomes 
7 
Sample Size and Feasibility 
8 
General Data Analytic Plan 
8 
Statistical Plan 
10 
Quality Control and Assurance 
10 
References 
11 
Appendix One: Data Elements 
12 
Appendix Two: Euro-QOL EQ-5D-3L 
13 
Appendix Three:  PTSD Screening Tool (PC-PTSD-5) 
15 
Appendix Four:  Opioid Risk Tool (ORT) 
16 


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Ketamine for Acute Pain after Trauma: KAPT Trial 
General Information 
Intravenous infusions of ketamine at sub-dissociative doses have gained popularity as the drug 
in low doses is thought to decrease pain and opioid exposure after elective surgery. However, evidence 
supporting ketamine in trauma patients is mixed. With the current opioid epidemic ravaging the United 
States, providers are increasingly searching for effective non-opioid medications to manage acute pain 
after injury. Trauma patients are a particularly vulnerable population. Approximately one-third of 
trauma patients admitted to the Red Duke Trauma Institute (RDTI) at Memorial Hermann Hospital-Texas 
Medical Center (MHH-TMC) are at moderate to high risk for opioid abuse. While regional anesthetic 
techniques are extremely useful in the management of acute pain, trauma patients often have more 
than one body system injured limiting the effectiveness of such techniques. The proposed project is a 
comparative effectiveness study in which acutely injured trauma patients will be randomized to one of 
two acute pain interventions: 1) ketamine drip + usual care or 2) usual care. The primary outcome will 
be opioid exposure during hospitalization. Additionally, we plan to perform an exploratory analysis on 
how best to describe a patient’s pain experience after injury. 
Background 
 
Effective pain relief after trauma is essential to allow for patient mobilization, improve 
functional status, and minimize post-injury emotional stress.(1-4) Opioids continue to be a mainstay in 
acute pain management following injury. Even today, guidelines recommend opioids as first line therapy 
for critically ill patients.(5) However, opioid prescribing practices after traumatic injuries and surgeries 
substantially drive the current opioid epidemic.(6) 
Trauma patients are a particularly vulnerable population. Approximately one-third are at 
moderate to high risk for opioid abuse (Lane S, unpublished data) and 13% progress to persistent opioid 
use after injury (Baker, RC unpublished data). The RDTI has taken great strides to minimize opioid 
exposure in trauma patients, but additional strategies are needed. 
The Red Duke Trauma Institute (RDTI) at Memorial Hermann Hospital-Texas Medical Center 
(MHH-TMC) has a long history of implementing and testing the use of multimodal pain regimens 
(MMPR), whereby non-opioid medications are given in a scheduled fashion with opioids available on an 
as needed basis (https://med.uth.edu/surgery/acute-trauma-pain-multimodal-therapy/). While our 
MMPR has dramatically reduced the in-hospital opioid exposure of injured patients, injury results in 
substantial pain and opioids are often still needed (Wei S, unpublished data). This is especially true in the 
first few days after injury. To further reduce opioid exposure, we need additional treatment strategies in 
addition to the current of an MMPR to further reduce opioid exposure by trauma patients during this 
critical period. 
A promising intervention for acute pain is intravenous ketamine given at a sub-dissociative dose. 
Ketamine is a phencyclidine analog and dissociate anesthetic. The use of sub-dissociative doses of 
ketamine have greatly increased in recent years despite somewhat varying literature supporting its use. 
In one of the most recent clinical trials of ketamine in patients with rib fractures, a sub-dissociative dose 
of ketamine did not significantly reduce opioid exposure in 91 patients, though a significant reduction 
was seen in the more severely injured sub-population.(3) The most recent guidelines published by the 
American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, 


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and the American Society of Anesthesiologists recommend sub-dissociative ketamine infusions for 
patients undergoing painful surgery.(4) 
 
Ketamine has a relatively wide therapeutic window. It is commonly used at higher doses for 
procedural sedation and perioperative anesthesia. Higher doses, however, can precipitate the classically 
associated psychometric properties and induce hypertension and tachycardia. There are few known 
contra-indications for ketamine at sub-dissociative doses, but the following are relative 
contraindications:(4) 
1) Pregnancy 
2) Poorly controlled cardiovascular disease, including unstable coronary artery disease and 
hypertension 
3) Severe hepatic dysfunction (cirrhosis) 
 
For the remainder of this proposal, the sub-dissociative dose of intravenous ketamine (0.25 
mg/kg/hr) will simply be referred to as ketamine. 
 
Lastly, clinical researchers have struggled to fully describe the pain experiences of patients 
across levels of care. For example, pain levels in intubated and non-verbal patients have been assessed 
using visual clues. At the RDTI, the Behavioral Pain Score (BPS) is used in non-verbal patients. The BPS is 
a three domain tool with 4 scores in each domain for a possible score range of 3-12. In contrast, patients 
who can verbalize are asked to report subjective levels of pain. At the RDTI, the Numeric Rating Scale 
(NRS) is used in verbal patients; the NRS is an 11 point scale with a range from 0-11. These scales 
measure the same thing – pain – but with differing values representing different assessments. As the 
two tools are not interchangeable, the longitudinal interpretation of both pain tools over time in the 
same patient is not currently possible. These scoring systems, however, are done universally by nursing 
staff and remain the ubiquitous source of pain data. Other methods of pain testing in clinical research, 
such as sensory testing, are simply not feasible in large, longitudinal, population-based studies. 
 
Hypothesis and Specific Aims: 
 
The overall hypothesis of the grant is that intravenous ketamine in addition to usual care (UC) 
will result in a lower opioid exposure than UC alone. 
 
Specific Aims: 
1) To perform a randomized controlled trial of intravenous ketamine/UC to UC alone. The 
infusion will begin as early as possible and continue for a minimum of 24 hours and a maximum 
of 72 hours after admission. Additionally, the infusion will begin again after each subsequent 
major surgery. The primary outcome will be in-hospital opioid exposure (measured as Morphine 
Milligram Equivalents [MME]). Secondary outcomes will be pain scores, complications, and 
patient-centered outcomes. Heterogeneity of treatment effect will be assessed by performing 
both confirmatory and hypothesis-generating subgroup analyses to identify moderators of the 
effect of the different treatment strategies. 
2) To longitudinally quantify the pain experience of a patient during hospitalization by 
incorporating all of the ubiquitous nursing-collected pain scores. This exploratory and novel 
method will require the standardization of the NRS and BPS pain tools and compare the global 


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pain experience quantified by the two to opioid exposure, self-reported health status, and self- 
reported patient experience. 
 
Study Design 
 
Setting: This randomized, clinical trial will occur at the RDTI at MHH-TMC. 
 
Trial Arms: Treatment Strategies 
 
Group 
Ketamine 
Control 
Drug dose 
Bolus: 0.35 mg/kg 
Infusion: start 0.15 mg/kg/hr; titration 
range is 0.1–0.25 mg/kg/hr 
None 
Duration 
24 (minimum) to 72 (maximum) hours after 
admission and each subsequent major 
surgery 
n/a 
Usual Care 
• Acetaminophen 1,000 mg PO q6 hours 
• Naproxen 500 mg PO q12 hours 
• Gabapentin 300 mg PO q8 hours 
• Lidocaine patches 
Opioids as needed for additional pain control 
• Acetaminophen 1,000 mg PO q6 hours 
• Naproxen 500 mg PO q12 hours 
• Gabapentin 300 mg PO q8 hours 
• Lidocaine patches 
Opioids as needed for additional pain control 
Timing 
Ketamine drip to begin as early as possible: 
• Hemodynamically stable patients – start 
immediately (ideally in ED prior to CT scan) 
• Hemodynamically unstable patients – start 
once stabilized 
Notes: 
*At current, ketamine is only possible in the 
SIMU and STICU. One of the clinical tangents of 
the trial is that we will work with nursing to 
allow patients who have been stable on a 
ketamine drip in the SIMU or STICU to be 
transferred to the floor without discontinuing 
the infusion. 
*Patients who fail UC may transition to a 
ketamine drip 
 
Study Population: 
 
Inclusion Criteria 
Exclusion Criteria 
• 
Adult trauma patients (≥16 years) 
• 
Admission to Surgical Intermediate 
Unit (SIMU) and/or Shock Trauma 
Intensive Care Unit (STICU) 
• 
Randomization within 12 hours of 
arrival 
• 
Patient not expected to survive/moribund 
• 
Contraindication to ketamine: 
o Allergy 
o Poorly controlled hypertension 
o Cardiac arrhythmias disorders (including atrial 
fibrillation) 
o Congestive heart failure (diastolic or systolic) 
o Unstable coronary artery disease or recent myocardial 
infarction (<6 months) 
o Cirrhosis 


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Screening: All adult trauma patients (≥ 16 years) arriving to the trauma center and admitted to the 
trauma service will be screened for eligibility by the clinical research staff. The research staff is available 
24/7 and will screen, randomize, and collect data. Once it is determined that the patient is eligible, the 
research staff will randomize the patient into one of the two study treatment groups and will notify the 
clinical physician team of the randomization allocation. 
 
Randomization: Randomization will be blocked and stratified by unit of admission. An independent 
statistician will determine the randomization sequence. REDCap will be utilized for the randomization. 
 
Consent: 
Effective pain control should begin as early as possible. Often, in the Emergency Department, 
opioids are the first line of acute pain control because they are ubiquitous and well known. Ketamine is 
commonly used in the Emergency Department as well, but at higher doses for moderate sedation during 
procedures (fracture reduction and splinting, tube thoracostomy, etc…). The fundamental change this 
trial addresses is the provision of lower doses of ketamine earlier in the patient’s emergency care. 
We request a waiver of consent to randomize patients as: 
• 
The intervention is minimal risk; the ketamine dosing proposed is already being used by 
prehospital personnel, emergency room physicians, and trauma surgeons at similar or 
higher doses. It is widely considered a safe drug with a wide therapeutic window. 
• 
The research could not be practicably carried out without the waiver; due to the acute 
clinical status of the trauma patient population (intubation, intoxication, severe pain, 
emotional stress), truly informed consent cannot be obtained in the vast majority of patients 
(or their legally authorized representative [LAR]) before the ketamine would be given. 
• 
The waiver would not adversely affect the rights and welfare of the subjects; patients often 
receive opioids and/or ketamine in the Emergency Department acutely without their 
knowledge or written consent, they simply want pain control. We will be providing pain 
control and rescue opioids would not be withheld from the intervention group. 
 
Once the patient is randomized, a member of the trauma research team will make attempts to contact 
either the patient or LAR to obtain consent for using Protected Health Information (PHI), to return to 
perform discharge surveys, and to contact after discharge for post-discharge surveys. Consents will be 
obtained by trained research personnel. Once appropriate to approach the patient for consent, a study 
team member will explain the study, its implications for the patient, and give the patient written study 
o Seizure disorder 
o In patients with an unknown past medical history, 
patients will be excluded if: 
▪ 
They have a median sternotomy scar 
▪ 
Mechanism of injury is fall from standing 
▪ 
Age >65 years 
▪ 
Any arrhythmia on EKG 
• 
Pregnancy 
• 
Prisoners (defined as those arriving from a correctional 
facility) 
• 
History of dementia or movement disorder (e.g. 
Parkinson’s) 


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information. If, after 5 days, the patient remains unable to self-consent and no LAR is available to 
consent, the consent will be waived and data included. Additionally, if the subject does not survive 
following the traumatic injury or is discharged from the hospital before the study team is able to obtain 
consent, their information will be included in the data analysis. 
Additionally, an educational pamphlet on safe opioid use will be given to the patient. 
If the subject consents to participation, they will sign the consent document. If the subject 
refuses, data collection will stop at time of refusal. 
In a previous acute pain trial (Multi-modal Analgesic Strategies for Trauma [MAST] Trial) of 1,616 
patients using a similar methodology for consent, 1,207 (75%) patients signed consent, 35 (2%) were 
waived due to death prior to consent, 178 (11%) were waived as the patient was discharged prior to 
consent, 141 (9%) were waived due to 5 days of attempts elapsing, and 55 (3%) patients declined 
participation. 
 
Data Collection 
Data collection will occur by one of two methods: manual entry or automatic capture of data. 
Data points to be collected are detailed in Appendix 1. Appendix 1 also indicates the manner by which 
data points will be collected – manually, from National Trauma Data Base registry, or automatic capture 
from the electronic medical record. A RedCap database will be utilized to securely store all data. 
 
In addition to the in-hospital data collection, the research staff will contact the subject 6 months 
following hospital admission to complete the Euro-QOL EQ-5D-3L and PTSD Screening Tool assessments 
and collect information regarding pain level and opioid use. 
 
Data Analysis 
 
Outcomes: 
Primary outcome: average MME per day. 
 
Secondary outcomes: 
• 
In-hospital: 
o Pain scores 
o Morbidity: 
▪ 
Delirium 
▪ 
Unplanned intubation 
▪ 
Unplanned admission to an intensive care unit 
o Ketamine: 
▪ 
Time to ketamine drip starting 
▪ 
Time on ketamine drip 
▪ 
Patient request to discontinue for any complaint 
o Use of other pain control adjuncts: regional anesthesia, lidocaine drip 
o Lengths of stay: ventilator-/hospital-/ICU-free days 
• 
Discharge: 
o Discharge from the hospital with an opioid prescription (type and number) 
o Discharge Euro-QOL EQ-5D-3L (Appendix 2) 
o Discharge PTSD Screening Tool (PC-PTSD-5) (Appendix 3) 
o Discharge Opioid Risk Tool (ORT) (Appendix 4) (may be obtained from medical records) 


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• 
6 month follow up: 
o Euro-QOL EQ-5D-3L (Appendix 2) 
o Presence of continued post-traumatic pain (Yes/No) 
o Persistent opioid use (Yes/No) 
o PTSD Screening Tool (PC-PTSD-5) (Appendix 3) 
 
Sample Size and Feasibility: 
Given the uncertainty of an exact treatment effect of ketamine in our patient population and 
the potential for contamination of the control group if the trial is continued for a prolonged length of 
time, we recommend performing the largest feasible study over 18 months with a Bayesian analysis of 
the primary and secondary outcomes. 
Treatment effect: Though not exactly generalizable to our population, the previous ketamine 
trial in trauma patients reported a 20% reduction in MME over the first two days after admission. 
Feasibility: Over the last 6 months (November 2018 – April 2019), manual review of admission to 
the trauma service revealed 302 potentially eligible patients. This is equivalent to 906 patients 
potentially eligible patients over the 18-month trial period. Given the emergent nature of the 
intervention and general difficulties enrolling severely injured patients, we conservatively estimate 
enrolling 40% of potentially eligible patients. 
Sample size and power: We therefore anticipate recruiting approximately N = 395 into the 
current trial. Based on its skewed distribution we posit that MME’s per day will be Gamma distributed 
(MME’s need not be integer values). Using the 50th and 75th percentiles, MME = 45 and 67 respectively, 
from our previous data we estimate the control condition as following the distribution ~Gamma(shape = 
2.7784923, scale = 18.343307). Further, assuming that the ketamine condition results in a 20% decrease 
in MME’s (50th and 75th percentiles MME = 36 and 53.6 respectively) we assume the observed data for 
this condition is distributed ~Gamma (shape = 2.7784923, scale = 14.674646). We assume that 
clustering within unit induces a substantial ICC = 0.2. Finally, we stipulated that a 75% chance that the 
ketamine treatment reduces MME’s by at least 15% relative to treatment as usual would constitute 
sufficient evidence to warrant a larger clinical trial. Assuming the previously stated sample size, effect, 
ICC and decision rule, K = 1000 Monte Carlo simulations suggest there is a > 99% chance of observing 
this effect. 
 
General Data Analytic Plan: 
The data analytic strategy will use Bayesian inference, applying generalized linear multilevel 
modeling with level-two random effects or fixed effects (depending on model convergence) to account 
for clustering of participants within department and, where applicable, observations within participants. 
Modeling will use R v. 3.4 and Stan v. 1.10.(9, 10) Initial analyses will examine group differences for 
baseline variables and examination of correlations between baseline variables and specified outcomes. 
For the purposes of evaluating the comparability of groups, a posterior probability that a 
difference/correlation exists of > 95% will constitute evidence for statistically reliable differences. 
Potential confounders, so identified, will result in two sets of analyses: one in which the relevant 
variable is included as a covariate and one in which it is not.(11, 12) This will permit determination of 
the degree to which any group differences might confound conclusions regarding treatment. All 
analyses will use intention-to-treat principles. Bayesian approaches will implement joint modeling of 
observed outcomes and the missing data which is robust to ignorable missingness (i.e., MCAR and 
MAR).(13) Sensitivity analyses will evaluate robustness of analytic conclusions to missing data. Non- 
ignorable missing data patterns will be addressed through pattern-mixture modeling methods.(14) 


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Convergence of Bayesian analyses on the posterior distributions via Monte-Carlo Markov chain (MCMC) 
will be assessed via graphical (Gelman-Rubin Plots) and quantitative (Gelman-Rubin Diagnostics and 
Effective Sample Size) evidence. Evaluation of posterior distributions will permit statements regarding 
the probability that effects of varying magnitudes exist, given the data. Diffuse, neutral priors will reflect 
the initial uncertainty regarding effect sizes. For all generalized linear multilevel models, priors for 
regression coefficients will be specified as ~Normal (µ=0, σ2=1000) on the identity or log-scale 
depending upon the model, level one error variances will be specified as ~Half-T (df = 3, mean = 0, 
standard deviation = 100). Prior distribution for level two variances will use ~Half-T (df = 3, mean = 0, 
standard deviation = 1000). Priors for the comparison of proportions will be specified as ~Beta (α=0.5, 
β=0.5). For all subgroup analyses using multilevel models the approach will follow that used in Tyson, et 
al.(15) 
 
One of the major limitations in the conduct of clinical trials on acute pain is the difficulty 
interpreting patients’ pain experience in the hospital. While the NRS pain scores are ubiquitous, easy to 
use, and compliance is high, the scores are subjective and relative to a patient’s expectations, pain 
tolerance, and immediate context. The BPS is a validated tool for measuring pain in non-verbal patients 
and is more objective. However, it has not been scaled to allow for use in conjunction with the NRS to 
fully describe a patient’s pain experience. 
In addition to the above limitations, both the NRS and BPS are measurements of a patient’s pain 
at one time point. Pain is dynamic. The amount of time a patient spends at a given pain level is likely 
more reflective of their global pain experience than single measures. 
To attempt to address the pain score limitation noted in the Background section, we plan an 
exploratory analysis whereby we will: 
1) Create a scale to standardize the two measurements (See Table 1) 
2) Use the date and time of each measure to model the trajectory of pain assessments and the 
time for which a patient stays at those pain levels 
3) Use the area under the curve to quantify the global pain experience of the patient 
4) Compare varying levels of this area under the curve to different outcomes, including: 
• 
Euro-QOL EQ-5D-3L at discharge (Appendix 2) 
• 
Euro-QOL EQ-5D-3L at 6 months (Appendix 2) 
• 
Presence of continued post-traumatic pain (Yes/No) 
• 
Persistent opioid use (Yes/No) 
• 
PTSD Screening Tool (PC-PTSD-5) (Appendix 3) at discharge 
• 
PTSD Screening Tool (PC-PTSD-F) (Appendix 3) at discharge 
• 
ORT Screening Tool (Appendix 4) at discharge 
 
Example: 
Table 3. Recorded Pain Scores 
Date/Time 
Pain Score 
Standardized 
Score 
Patient admitted to STICU intubated 
HD 1 @ 0730 
BPS = 8 (3/3/2) 
0.67 
HD 1 @ 1200 
BPS = 6 (2/2/2) 
0.50 
HD1 @ 1700 
BPS = 4 (1/2/1) 
0.33 
Patient extubated 
HD1 @ 2100 
NRS = 8 
0.80 


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1 
2 
3 
4 
5 
6 
7 
8 
 
 
 
Traditionally reported pain scores are listed as 
to the left (Table 3). This, however, neglects 
the amount of time spent at said pain levels. To 
try and address this limitation, we will model pain and 
time, as below (Figure Two). In this model, the area under 
the curve would quantify both the level and duration of 
acute pain, representing a global assessment of a 
patient’s pain experience. 
 
 
 
Figure Two 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Plan: 
Multilevel generalized linear or generalized additive models will fit functional forms to pain 
scores. Random effects will permit each participant to have individualized functional forms. Comparison 
of different functional forms will use the AIC or AICc. Having estimated the functional form for each 
participant’s pain-score curve we will estimate the area under each curve using appropriate methods of 
integration. The resulting AUC’s will serve as summary measures of each participant’s pain experience. 
Multilevel generalized linear models will then evaluate the Euro-QOL EQ-5D-3L at discharge, patient 
satisfaction with pain management at discharge, Euro-QOL EQ-5D-3L at 6 month, presence of continued 
post-traumatic pain (Yes/No), persistent opioid use (Yes/No), PTSD Screening Tool (PC-PTSD-5) each as a 
function of pain AUC. 
 
Quality Control and Assurance 
Each item on the web forms will have validity checks performed to ensure that the data 
entered are accurate and that items are not skipped during entry by mistake. Bi-weekly audits of 
data will be performed by both clinical investigators and research assistants. 
Date and Time of Pain Assessment 
HD1@1700 
HD1@2100 
HD2@0700 
HD2@1300 
HD2@1900 
HD3@0700 
HD1@0730 
HD1@1200 
0.00 
Patient’s Pain Experience 
0.20 
0.33 
0.40 
0.40 
0.50 
0.50 
0.60 
0.60 
0.70 
0.67 
0.80 
0.80 
1.00 
Stnadardized Pain Value 
HD2 @ 0700 
NRS = 6 
0.60 
HD2 @ 1300 
NRS = 7 
0.70 
HD2 @ 1900 
NRS = 5 
0.50 
HD3 @ 0700 
NRS = 4 
0.40 
Patient discharged 


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References: 
 
1. 
Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, et al. Clinical Practice Guidelines for 
the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption 
in Adult Patients in the ICU. Crit Care Med 2018:46:e825-e873. 
2. 
Cicero TJ, Ellis MS, Surratt HL, Kurtz SP The changing face of heroin use in the United States: a 
retrospective analysis of the past 50 years. JAMA psychiatry 2014:71:821-826. 
3. 
Carver TW, Kugler NW, Juul J, Peppard WJ, Drescher KM, et al. Ketamine infusion for pain 
control in adult patients with multiple rib fractures: Results of a randomized control trial. The journal of 
trauma and acute care surgery 2019:86:181-188. 
4. 
Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, et al. Consensus Guidelines on 
the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of 
Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American 
Society of Anesthesiologists. Regional anesthesia and pain medicine 2018:43:456-466. 
5. 
Team RC R: A Language and Environment for Statistical Computing. Vienna, Austria: R 
Foundation for Statistical Computing, 2017. 
6. 
Team. SD RStan: the R interface to Stan: Stan Development Team. Available from: http://mc- 
stan.org . 2017. 
7. 
Assmann SF, Pocock SJ, Enos LE, Kasten LE Subgroup analysis and other (mis)uses of baseline 
data in clinical trials. Lancet 2000:355:1064-1069. 
8. 
Pocock SJ, Assmann SF, Enos LE, Kasten LE Subgroup analysis, covariate adjustment and baseline 
comparisions in clinical trial reporting: Current practice and problems. Statistics in Medicine 
2002:21:2917-2930. 
9. 
Best N, Thomas AEp- Bayeisan Graphical Models and Software for GLMs. In: D. Dey, Ghosh SK, 
Mallick BK eds., Generalized Linear Models: A Bayesian Perspective. New York: Marcel Dekker, Inc., 
2000. 
10. 
Fitzmaurice GM, Laird NM Generalized linear mixture models for handling nonignorable 
dropouts in longitudinal studies. Biostatistics 2000:1:141-156. 
11. 
Tyson JE, Pedroza C, Langer J, Green C, Morris B, et al. Does aggressive phototherapy increase 
mortality while decreasing profound impairment among the smallest and sickest newborns? J Perinatol 
2012:32:677-684. 


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Appendix One: Data 
 
Variable 
Manual extraction 
From Registry/NTDB 
Electronic Data 
Withdrawal 
In-hospital 
Demographics 
• Age 
• Sex 
• Race 
• Prior opioid use 
Injury Characteristics 
• AIS values 
• ISS 
Complications 
• Cardiac arrest 
• Unplanned 
admission to ICU 
• Unplanned 
intubation 
Outcomes 
• Hospital length of 
stay 
• ICU length of stay 
• Ventilator days 
• Mortality 
• Daily morphine 
milligram equivalents 
• Pain scores 
• Costs 
Injury characteristics 
• Mechanism of injury 
• Specific injuries: 
- Total number ribs with a 
fracture (0-24) (two or more 
fractures in a single rib counts as 
1) 
- Flail chest 
- Long bone fracture (radius, ulna, 
humerus, femur, tibia, fibula) 
- Vertebral body fracture 
- Laparotomy 
- Thoracotomy 
- Amputation 
- Any pelvis/acetabular fracture 
Complications 
• Ketamine specific complications 
Discharge 
• Discharge opioid status 
• Regional anesthetic used 
• Euro-QOL EQ-5D-3L 
Follow up 
• Euro-QOL EQ-5D-3L 
• Presence of continued post- 
traumatic pain (Yes/No) 
• Persistent opioid use (Yes/No) 
• PTSD Screening Tool (PC-PTSD-5) 


KAPT 
Version 1.3 
20AUG2020 
IRB NUMBER: HSC-MS-19-0726 
IRB APPROVAL DATE: 08/25/2020 
14 
 
 
 
Appendix Two: Euro-QOL EQ-5D-3L 
 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking 
❑ 
I have slight problems walking 
❑ 
I have moderate problems walking 
❑ 
I have severe problems walking 
❑ 
I am unable to walk 
❑ 
SELF-CARE 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself 
❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 
PAIN / DISCOMFORT 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am severely anxious or depressed 
❑ 


IRB NUMBER: HSC-MS-19-0726 
IRB APPROVAL DATE: 08/25/2020 
14 
 
 
KAPT 
Version 1.3 
20AUG2020 
 
I am extremely anxious or depressed 
❑ 
 
 
• We would like to know how good or bad your health is TODAY. 
 
• This scale is numbered from 0 to 100. 
 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
• Mark an X on the scale to indicate how your health is TODAY. 
The best health you 
can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
 
60 
 
55 
YOUR HEALTH TODAY = 
50 
• Now, please write the number you marked on the scale in the box 
below. 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
The worst health 
you can imagine 


KAPT 
Version 1.3 
20AUG2020 
IRB NUMBER: HSC-MS-19-0726 
IRB APPROVAL DATE: 08/25/2020 
15 
 
 
Appendix Three: PTSD Screening Tool (PC-PTSD-5) 
 
 


KAPT 
Version 1.3 
20AUG2020 
IRB NUMBER: HSC-MS-19-0726 
IRB APPROVAL DATE: 08/25/2020 
16 
 
 
 
Appendix Four: Opioid Risk Tool (ORT) 
1. Do you have a family history of substance abuse? 
(Substance abuse means having problems from using a substance too much or too often) 
 
Yes 
No 
Did not respond 
Alcohol 
 
 
 
Illegal Drugs 
 
 
 
(e.g., marijuana, cocaine, methamphetamine, heroin) 
 
Prescription Drugs 
 
 
 
(e.g., Xanax, hydrocodone, Vicodin) 
 
 
2. Have you had a personal history of substance abuse? 
(Substance abuse means having problems from using a substance too much or too often) 
Yes 
No 
Did not respond 
 
Alcohol 
Illegal Drugs 
 
 
 
 
 
 
(e.g., marijuana, cocaine, methamphetamine, heroin) 
Prescription Drugs 
 
 
 
(e.g., Xanax, hydrocodone, Vicodin) 
3. Age 
□  
 
(Mark box if 16 – 45 years old) 
4. Do you have a history of preadolescent 
sexual abuse? 
 
(This means unwanted sexual contact 
by an adult before you were age 13) 
 
 
5. Do you have any psychological 
disorders or diseases? 
ADD (Attention Deficit Disorder) 
 
 
 
OCD (Obsessive Compulsive Disorder) 
Bipolar Disorder 
Schizophrenia 
Depression