Clinical trial NCT06236113
Conditions: Blunt Injury of Thorax Multiple Rib Fractures, Involving Three Ribs
Keywords: Blunt Thoracic Trauma
Sponsor: North Memorial Health Care
Start date: 2021-10-01; Completion date: 2023-06-26
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this Randomized controlled double-blinded trial is to compare the addition of a ketamine infusion to placebo, when added to standard care in adult blunt trauma patients with multiple rib fractures. The main question it aims to answer are: • addition of low dose ketamine infusion (LDKI) decreases narcotic use • does LDKI impact pulmonary complications, readmission, or hospital length of stay Participants will receive usual standard of care with up to 48 hours of LDKI or placebo. If there is a comparison group: Researchers will compare infusion of a saline infusion to LDKI to see if LDKI decreases need for narcotic analgesics use.

Detailed description:
Study Design: Randomized controlled double-blinded trial: Patients will then be randomized into one of two study groups. Both groups will receive a normal saline infusion for 48 hours of therapy. The treatment group will have ketamine added to their saline infusion via blinded pharmacy protocol to receive continuous infusion of ketamine at 0.1mg/kg/hour. The control group will receive only normal saline. Administration will occur via piggyback infusion in accordance with nursing policy.

Setting/Participants:

* North Memorial Health Hospital: patients on 5-South - Trauma Neuro Intensive Care Unit (TNICU) and 6-West - Trauma Floor
* 50 people will take part in this study. 25 study subjects will receive an infusion of ketamine and 25 will receive a saline infusion.
* Patients 18 years of age or older with 3 or more rib fractures admitted to North Memorial Health Hospital will be considered for the study.

Study Interventions and Measures:

* Ketamine low-dose infusion administered at 0.1 mg/kg/hr for 48 hours as an adjunct to standardized rib fracture management interventions as outlined in facility-approved Guidelines for Rib Fracture Management.
* The primary study outcome will be amount of narcotic used over the 48-hour study period (expressed as morphine mg equivalents).
* Secondary outcome measures will include: need for endotracheal intubation or non-invasive positive pressure ventilation, oxygen requirements, daily incentive spirometer values, daily forced vital capacity measurements, and subjective patient pain ratings.
* Other outcomes measured will be Intensive Care Unit stay, total hospital length of stay, and adverse medication effects.

Arms: arm 1: Pharmacist will check randomization schedule. For placebo/control subject they will prepare an infusion bag of saline with no added medication. The Study Drug Bag will be released with a label that includes: Name of Study, Study Subject #, Patient (Pt) Name, Pt Medical record number (MR#), Pt Date of birth (DOB), and INFUSION RATE. arm 2: Infusion Bag will receive 100 mg of ketamine (Ketamine Infusion Subject). The Study Drug Bag will be released with a label that includes: Name of Study, Study Subject #, Patient Name, Pt MR#, Pt DOB, and INFUSION RATE. (Note: infusion rate is 0.1 mg/kg/hr and concentration of standard ketamine infusion bag is 1 mg/mL. That is, 100 mg of ketamine added to 100 mL saline).
Interventions: intervention 1: Ketamine 1 Mg/mL-NaCl 0.9% Intravenous Solution
Intervention descriptions: intervention 1: administered at rate of 0.1 mg/kg/hr

Protocol documents:
ICF_002.pdf: 
Ketamine for Rib Fracture Study Consent Form 
12 November 2020 
PAGE 1 OF 5 
 
NORTH MEMORIAL HEALTH 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Study Title: Low Dose Ketamine for Blunt Thoracic Trauma 
 
 
 
 
 
What you should know about this study: 
 
This is a clinical research study. Your study doctor or a trained provider from the North 
Memorial Acute Care Surgery Department will explain the study to you. 
 
Research studies include only people who volunteer, or choose, to take part. Please take your 
time to make your decision about participating. You may discuss your decision with your family 
and friends and with your health care team. If you have any questions, you may ask your study 
doctor. 
 
You are being asked to take part in this study because you have 3 or more broken ribs. 
 
Why is this study being done? 
 
The purpose of this study is to see if adding the drug ketamine to usual therapy treats the pain 
from broken ribs better than standard medications. In this study, you will get an intravenous (IV) 
infusion that includes either ketamine or saline. You will not get both. Adding ketamine to the 
usual treatments for broken ribs may decrease pain and improve lung function. 
 
Intravenous (IV) infusion is when liquid medicine given through your vein using a needle 
attached to a tube. Saline is a commonly used fluid given through an IV for hydration and 
to help administer medication. 
 
How long will I be in the study? 
 
You will receive either the study medication or a placebo by a continuous infusion through an 
intravenous (IV) catheter for 48 hours (2 days). Before, during, and after the study you will 
receive the standard care for broken ribs at North Memorial. 
 
How many people will take part in this study? 
 
About 50 people will take part in this study.  25 study subjects will receive an infusion of 
ketamine and 25 will get saline infusion. 
Study Coordinator: 
Alondra Dial, Phone: 763.581.3741 
e-mail: Alondra.Dial@NorthMemorial.com 
Research Project 
Director: 
Michaela West, M.D., North Memorial Acute Care Surgery 
Department. 
3300 Oakdale Blvd, Robbinsdale, MN 55422. 
Phone: 415.686.5554; 
e-mail: Michaela.West@NorthMemorial.com 


Ketamine for Rib Fracture Study Consent Form 
12 November 2020 
PAGE 2 OF 5 
 
What will happen if I take part in this research study? 
 
You will be "randomized" into one of the study groups described below.  Randomization means 
that you are put into a group by chance.  A computer program will place you in one of the 
groups.  Neither you nor your doctor can choose the group you will be in. You will have an 
equal chance of being placed in any group. 
 
• 
If you are in group 1 you will receive an intravenous fluid infusion that contains ketamine 
dissolved in saline. 
• 
If you are in group 2 you will receive an intravenous fluid infusion that contains only 
saline (placebo). 
• 
You will receive all of the standard therapies and medications for treatment of broken 
ribs regardless of whether you are assigned to group 1 or group 2. 
 
Before you begin the main part of the study... 
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
main part of the study. These exams, tests or procedures are part of regular care. 
 
• 
Physical examination by Emergency Medicine and Trauma doctors 
• 
X-ray studies to determine if you have broken ribs and how many broken ribs you have. 
 
During the main part of the study... 
 
If the exams, tests and procedures show that you have more than 3 broken ribs and you choose 
to take part, then you will need the following tests and procedures. They are part of regular 
clinical care. 
 
 
X-ray studies to examine your lungs 
 
Tests to see how well your lungs are functioning 
 
Monitoring the amount of oxygen in your blood stream 
 
Questions about how much pain you are having 
 
Other tests or procedures that your doctors feel are needed for evaluation or treatment 
of other injuries or conditions. 
 
When you are finished receiving 48 hours of infusion of the study drug solution... 
 
The continuous intravenous drug (ketamine) or saline infusion will be stopped and 
disconnected. Your doctor will determine whether or not to continue intravenous fluids and/or 
medications (saline, pain medications, antibiotics, etc). You will continue to receive all 
standard care for multiple broken ribs. Your doctors and nurses will decide when you can be 
discharged from the hospital. 
 
Where will the study take place? 
 
All study procedures will be done in the Trauma Surgical ICU (5SW) and the inpatient trauma 
unit (6W) at North Memorial Health Hospital in Robbinsdale, MN. 


Ketamine for Rib Fracture Study Consent Form 
12 November 2020 
PAGE 3 OF 5 
 
Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 
 
What side effects or risks can I expect from being in the study? 
 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen. 
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. In some cases, side effects can be serious, long lasting, or may never go 
away. 
 
You should talk to your study doctor about any side affects you experience while taking part in 
the study. 
 
Risks and side effects related to use of ketamine include those which are: 
 
Common (~90%) 
 
 
Most patients do not have side effects from ketamine 
 
Less Common (≥ 10%) 
 
 
Neurologic symptoms seen with recovery from anesthesia, including confusion, dream- 
like states, excitement, irrational behavior, hallucinations, and vivid imagery. 
 
Rare (<10%) 
 
 
serious, potentially life-threatening allergic reaction 
 
elevated pressure around the brain 
 
elevated pressure within the eye 
 
elevated blood pressure 
 
rapid or irregular heart rate 
 
Unknown Risks: The experimental treatments may have side effects that no one knows about 
yet.  The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study. 
 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better. While doctors hope adding 
ketamine to the standard medications used to treat rib fractures will improve pain control and 
decrease the need for narcotics (narcotics are strong pain relievers such as oxycodone, 
morphine, or fentanyl, which can be addictive and are intended for short-term use). 


Ketamine for Rib Fracture Study Consent Form 
12 November 2020 
PAGE 4 OF 5 
 
If pain is better controlled there may also be improved lung function and faster recovery. There 
is no proof that this will occur. We do know that the information from this study will help doctors 
learn more about ketamine as a treatment for pain associated with multiple broken ribs. This 
information could help future trauma patients. 
 
What other choices do I have if I do not take part in this study? 
 
If you decide not to participate in this study you will receive the standard treatment for multiple 
broken ribs at North Memorial Health Hospital. 
 
How will information about me be kept confidential? 
 
We will do our best to make sure that information about you is kept confidential, but we cannot 
guarantee total privacy. Study subjects will get a study number when they are enrolled in the 
study. Once the study is over your medical information will only be identified by your study 
number. Your medical information may be used in future research studies, but this would not 
include any private health information. 
 
Some information from your medical records will be collected and used for this study.  Your 
signed consent form and some of your research tests will be added to your North Memorial 
Health medical record. Therefore, people who can see your health records may find out that 
you were in this study.  Your personal information may be given out if required by law. Your 
name and personal information will not be used if this study is published or presented at 
scientific meetings. 
 
Authorized representatives from the following organizations may review your research data for 
the purpose of monitoring or managing the conduct of this study: 
 
 
Representatives of North Memorial Health 
 
Will any research-related procedures be billed to me? 
 
Two types of procedures will be done during this study.  You or your insurer will be billed for the 
standard medical care. You will be responsible for your co-pays, deductibles, and any other 
charges that your insurer will not pay. There is a possibility that your insurer may not cover all 
standard medical care costs if you are receiving medical services out of network. Any 
medications or procedures done only for research will not be charged to you or your insurer. 
 
Will I be paid for taking part in this study? 
 
You will not be paid for taking part in this study. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, Michaela West, MD if you feel that you have been 
injured because of taking part in this study. You can tell the doctor in person or call them at 763- 
581-3717. If you are injured as a result of being in this study, North Memorial Health will provide 
necessary medical treatment. The costs of the treatment may be billed to you or your insurer 
just like any other medical costs, or covered by North Memorial Health depending on a number 
of factors.  North Memorial Health and the study sponsor do not normally provide any other form 


Ketamine for Rib Fracture Study Consent Form 
12 November 2020 
PAGE 5 OF 5 
 
of compensation for injury.  For further information about this, you may call the office of the 
Institutional Review Board at 763-520-5353. The IRB is a group of individuals designated by the 
hospital under federal law to approve research studies. The North Memorial IRB monitors 
research related rights and safety of study subjects at North Memorial Medical Center 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor(s) Michaela West, MD at 763-581-3717. 
 
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have 
about the study, please call the office of the Institutional Review Board at 763-520-5353. 
 
A description of this clinical trial will be available on http://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. 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits. Leaving the study will not affect your medical care. You can still get your 
medical care from our institution. 
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
CONSENT 
 
You have been given copies of this consent form and the Experimental Subject's Bill of Rights 
to keep. 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to participate 
or to withdraw at any point in this study without penalty or loss of benefits to which you are 
otherwise entitled. 
 
If you wish to participate in this study, you should sign below. 
 
 
 
 
 
Date 
Participant's Signature for Consent 
 
 
 
 
 
Date 
Person Obtaining Consent 

Prot_SAP_000.pdf: 
 
Ketamine for Rib Fractures Study 
 
Protocol Version Date: 8 March 2018 
 
Title: 
Low Dose Ketamine for Blunt Thoracic Trauma: A 
Prospective Randomized Trial 
Short Title 
Ketamine for Rib Fracture Study 
Study Type: 
Randomized, double-blinded study of low dose Ketamine infusion 
(off-label pain control) in patients with 3 or more rib fractures 
Protocol Date: 
1/13/21 
Joseph Farhat, MD 
NORTH MEMORIAL HEALTH HOSPITAL 
Trauma Services 
3300 Oakdale Ave N 
Robbinsdale, MN 55422 
Phone: 763-581-3700 
email: joseph.farhat@northmemorial.com 
 
 
 
 


 
 
 
 
Ketamine for Rib Fractures Study 
 
Protocol Version Date: 13 January 2021 
ii 
 
TABLE OF CONTENTS 
 
ABSTRACT ....................................................................................................................................................... III 
2 
BACKGROUND INFORMATION AND RATIONALE ..................................................................... IV 
3 
STUDY OBJECTIVES ............................................................................................................................. V 
3.1 
PRIMARY OBJECTIVE 
V 
3.2 
SECONDARY OBJECTIVES 
V 
4 
INVESTIGATIONAL PLAN .................................................................................................................. VI 
4.1 
STUDY DESIGN 
VI 
4.2 
STUDY PHASES 
VI 
4.2.1 
Screening Phase 
vi 
4.2.2 
Treatment Phase 
vi 
4.3 
ALLOCATION TO TREATMENT GROUPS AND BLINDING 
VI 
4.4 
STUDY DURATION, ENROLLMENT 
VII 
4.4.1 
Duration of Study Participation 
vii 
4.5 
STUDY POPULATION 
VII 
4.5.1 
Inclusion Criteria 
vii 
4.5.2 
Exclusion Criteria 
vii 
4.6 
SUBJECT COMPLETION/WITHDRAWAL 
VIII 
4.7 
SAFETY EVALUATION 
VIII 
5 
STATISTICAL CONSIDERATIONS ................................................................................................. VIII 
5.1 
EFFICACY ANALYSIS 
IX 
5.2 
SAFETY ANALYSIS 
IX 
5.3 
INTERIM ANALYSIS 
IX 
6 
SAFETY MANAGEMENT ...................................................................................................................... X 
6.1 
CLINICAL ADVERSE EVENTS 
X 
6.2 
ADVERSE EVENT REPORTING 
X 
6.3 
TREATMENT ASSIGNMENT METHODS 
X 
6.3.1 
Randomization 
x 
6.3.2 
Blinding 
xi 
6.3.3 
Unblinding 
xi 
6.4 
DATA COLLECTION AND MANAGEMENT 
XI 
6.5 
CONFIDENTIALITY 
XI 
6.5.1 
Risk Assessment 
xi 
6.5.2 
Potential Benefits of Trial Participation 
xi 
6.5.3 
Risk-Benefit Assessment 
xi 
7 
REFERENCES ...................................................................................................................................... XIII 
 
 
 
 


 
 
 
 
Ketamine for Rib Fractures Study 
 
Protocol Version Date: 13 January 2021 
iii 
ABSTRACT 
Introduction:  
Thoracic trauma creates a significant burden of morbidity and mortality in those suffering from blunt 
traumatic injuries. Optimal contemporary management of blunt thoracic injury includes intravenous 
narcotics, epidural analgesia, and both noninvasive and invasive positive pressure ventilation for 
those patients that progress to respiratory failure. In 2019, the Medical College of Wisconsin 
published the first randomized controlled trial evaluating the effects of a low-dose ketamine infusion 
on pain scores (primary outcome), opioid analgesic use, epidural rates, and pulmonary complications 
in adult and elderly patient with 3 or more rib fractures. Their results demonstrated decreased oral 
morphine equivalents (OME) utilization, but only in severely injured patients (ISS>15). Their results 
were otherwise equivocal and additional study was recommended. Low dose ketamine therapy has 
been examined in multiple studies as a therapeutic adjunct for postoperative analgesia (FDA off-
label use). In this capacity it has been shown to significantly lower pain scores and reduce narcotic 
requirements. We hypothesize that low-dose ketamine infusion will decrease narcotic use (OME), 
improve pain control, and improve pulmonary morbidity in patients who suffer blunt chest trauma.   
Objectives:  
Primary: Determine if addition of a low-dose ketamine infusion decreases narcotic analgesic 
use (OME) in trauma patients with ≥ 3 rib fractures. 
Secondary: Determine if adjunctive low-dose ketamine infusion in trauma patients with ≥ 3 
rib fractures results in: improved pain control, fewer pulmonary complications, and 
decreased hospital (or Intensive Care Unit, if applicable) length-of-stay. 
Study Design:  
• Randomized controlled double-blinded trial: Patients will then be randomized into 
one of two study groups.  Both groups will receive a normal saline infusion for 48 
hours of therapy. The treatment group will have ketamine added to their saline 
infusion via blinded pharmacy protocol to receive continuous infusion of ketamine at 
0.1mg/kg/hour. The control group will receive only normal saline. Administration 
will occur via piggyback infusion in accordance with nursing policy. 
Setting/Participants: 
• North Memorial Health Hospital: patients on 5S – TNICU and 6W – Trauma Floor 
• 50 people will take part in this study.  25 study subjects will receive an infusion of 
ketamine and 25 will receive a saline infusion.  
 
• Patients 18 years of age or older with 3 or more rib fractures admitted to North 
Memorial Health Hospital will be considered for the study. 
Study Interventions and Measures:  


 
 
 
 
Ketamine for Rib Fractures Study 
 
Protocol Version Date: 13 January 2021 
iv 
• Ketamine low-dose infusion administered at 0.1 mg/kg/hr for 48 hours as an adjunct 
to standardized rib fracture management interventions as outlined in facility-
approved Guidelines for Rib Fracture Management (see Appendix A) 
• The primary study outcome will be amount of narcotic used over the 48 hour 
study period (expressed as morphine equivalents).   
• Secondary outcome measures will include: need for endotracheal intubation or 
non-invasive positive pressure ventilation, oxygen requirements, daily 
incentive spirometer values, daily forced vital capacity measurements, and 
subjective patient pain ratings.   
• Other outcomes measured will be Intensive Care Unit stay, total hospital 
length of stay, and adverse medication effects. 
1 
BACKGROUND INFORMATION AND RATIONALE 
Thoracic trauma creates a significant burden of morbidity and mortality in those suffering 
blunt traumatic injuries.  Thoracic injuries are found in approximately 60% of multiply 
injured patients1.  In all demographics with blunt chest trauma, pulmonary complications 
occur in over a third of cases with a pneumonia rate up to 30%2.  Thoracic injury is 
responsible for 25% of blunt trauma mortalities1,3.  In patients over 65 years old, morbidity 
and mortality rates are much higher2.  Optimal contemporary management of blunt thoracic 
injury includes IV narcotics, epidural analgesia, and both noninvasive and invasive positive 
pressure ventilation for those patients that progress to respiratory failure2,3.  Multi-modal 
pain control therapies are considered standard of care for these patients4.  However, certain 
modalities such as use of opioids are well known to have unwanted side effects. Use of 
epidural catheters, although conditionally recommended as a beneficial treatment, is not 
always available and may be contraindicated in certain patients4. 
A single randomized controlled study has been published, in 2019 by the Division of 
Trauma and Acute Care Surgery at the Medical College of Wisconsin, evaluating the effects 
of low-dose ketamine infusion on pain, opioid use, pulmonary complications, and epidural 
use in adult and elderly patients with 3 or more rib fractures. Their results demonstrated a 
statistically significant reduction in oral morphine equivalent (OME) use in patients with 
injury severity scores of greater than 158,9. These findings were encouraging but warrant 
additional study. 
Low dose ketamine infusion has additionally been examined in multiple studies as a 
therapeutic adjunct for postoperative analgesia5-7.  In a recent meta-analysis, low dose 
ketamine infusion for up to 48 hours postoperatively significantly reduced pain scores and 
decreased opioid consumption by 40% with no major complications6.  In patients 
undergoing thoracotomy or sternotomy, a randomized study demonstrated 50% lower 


 
 
 
 
Ketamine for Rib Fractures Study 
 
Protocol Version Date: 13 January 2021 
v 
morphine consumption with no major side-effects in those started on a low dose ketamine 
infusion in addition to a morphine PCA7.   
Adequate pain control remains a crucial element in management of blunt thoracic trauma.  
By providing effective analgesia, the provider may successfully limit the increased 
morbidity and mortality inherent in the progression to respiratory failure2.  The 
postoperative literature, including a study specific to chest surgery, demonstrates a clear 
effect in improving analgesia and decreasing narcotic usage with no major complications5-7.  
We hypothesize that low dose ketamine infusion will improve pain control, decrease 
narcotic use, and improve pulmonary morbidity in patients who suffer blunt chest trauma.   
This study will be conducted in full accordance with all applicable North Memorial Medical 
Center Research Policies and Procedures and all applicable Federal and state laws and 
regulations. All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with North Memorial Health Hospital IRB Policies and Procedures and 
all federal requirements. Collection, recording, and reporting of data will be accurate and 
will ensure the privacy, health, and welfare of research subjects during and after the study.  
2 
STUDY OBJECTIVES 
The purpose of the study is to determine if adjunctive low-dose ketamine infusion enhances 
pain control and decreases respiratory complications in adult patients with 3 or more rib 
fractures. 
2.1 Primary Objective 
Primary: Determine if adjunctive low-dose ketamine infusion results in decreased narcotic 
usage. 
2.2 Secondary Objectives  
The secondary objectives are to: 
• Determine if low-dose ketamine infusion as an analgesic adjunct leads to improved pain 
control as measured by subjective patient pain ratings  
• Determine if low-dose ketamine infusion as an analgesic adjunct leads to decreased 
pulmonary complications as evidenced by decreased rates of respiratory infections, 
decreased rates of intubation or use of non-invasive positive pressure ventilation, and/or 
stable to improving pulmonary function testing 
• Determine if low-dose ketamine infusion as an analgesic adjunct leads to decreased 
Intensive Care Unit (as applicable) and/or hospital length of stay 
 


 
 
 
 
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Protocol Version Date: 13 January 2021 
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3 
INVESTIGATIONAL PLAN 
3.1 Study Design 
The study will be conducted as a prospective, randomized, double-blinded, placebo-
controlled study comparing saline infusion with low-dose ketamine, versus saline infusion 
alone. 
3.2 Study Phases 
3.2.1 Screening Phase 
Patients will be identified based on initial Emergency Room documentation, initial imaging 
studies, and/or admission History and Physical, or initial Consultation by the Trauma 
Services Provider. Prospective study participants will be selected based on the inclusion/ 
exclusion criteria below. They will be approached after admission regarding study 
participation via a face to face contact. Final screening and consent will be conducted by 
trained personnel from the Trauma Services department. 
Informed consent will be obtained prior to conducting any study-related activities beyond 
the typical medical care for the patient’s condition.   
3.2.2 Treatment Phase 
The treatment phase will be initiated as soon as the subject has been identified as meeting 
inclusion criteria and consented to participate. Pharmacy will be notified of inclusion in the 
study and the infusion bag prepared based on a pre-determined randomization protocol (see 
Appendix B, Sample Randomization Schedule). The medication, either normal saline or 
normal saline with low-dose ketamine, will be administered by the Registered Nurse (RN) 
following nursing medication administration policy. Nursing staff will reorder infusion bags 
from the Pharmacy per medication policy as needed. The infusion will be discontinued at the 
end of the 48 hour period. 
3.3 Allocation to Treatment Groups and Blinding 
Study drug will be ordered within EPIC by selecting “Rib Fracture Study Drug”. The 
research pharmacist will obtain information about the patient (Name, MR#, and weight) and 
will then consult the Randomization Schedule to determine whether the 100 mL Saline 
Infusion Bag will receive 100 mg of ketamine (Ketamine Infusion Subject) or no added 
medication (Saline Infusion Subject). The Study Drug Bag will be released with a label that 
includes: Name of Study, Study Subject #, Patient Name, Pt MR#, Pt DOB, and INFUSION 
RATE. (Note: infusion rate is 0.1 mg/kg/hr and concentration of standard ketamine infusion 
bag is 1 mg/mL. That is, 100 mg of ketamine added to 100 mL saline). 
Bags will be labeled as Study Drug (using consecutive numbers, between 1-50, that 
correspond to the randomization envelope), but the patient, nurses, physicians, and all others 
caring for the patient will be blind with respect to the contents of the infusion bag. Pharmacy 
personnel would be the only individuals with knowledge of the infusion bags and would not 


 
 
 
 
Ketamine for Rib Fractures Study 
 
Protocol Version Date: 13 January 2021 
vii 
communicate with caregivers once the medications leave the pharmacy. See unblinding 
section below for further detail. 
3.4 Study Duration, Enrollment 
3.4.1 Duration of Study Participation 
Study subjects will receive the ketamine versus normal saline infusion for 48 hours after 
identification and enrollment. Information from their entire hospital course will be evaluated 
as related to the objectives as discussed above. 
Recruitment will stop when 50 subjects are successfully enrolled.  
 
3.5 Study Population 
3.5.1 Inclusion Criteria 
1) Males or females 18 years of age or older 
2) Diagnosis of 3 or more acute rib fractures related to blunt traumatic chest injury. 
3) Able to undergo consent procedure and give valid consent, or availability of family 
member to provide consent for the study 
3.5.2 Exclusion Criteria 
1) Age <18 years 
2) Cognitively impaired 
3) Pregnant or lactating females.  
4) Glasgow Coma Score (GCS) of ≤ 14 at time of admission 
5) Evidence of increased intraocular pressure 
6) Presence of acute coronary syndrome 
7) Diagnosed moderate to severe traumatic brain injury   
8) Evidence of uncontrolled intracranial hypertension 
9) History of seizures or stroke 
10) History of severe psychiatric disorders 
11) Allergy to ketamine 
12) Currently being treated, prior to admission, with opiate agonist/antagonist therapy 


 
 
 
 
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viii 
13) Presence of poorly controlled hypertension, cardiac arrhythmias, and/or tachycardia on 
admission 
14) Subjects who, in the opinion of the Investigator, may be inappropriate for study 
participation. 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  
3.6 Subject Completion/Withdrawal 
Study participation is considered completed when they have received the 48 hours of 
medication infusion. 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the investigator and/or attending 
provider for lack of adherence to study treatment, adverse events, or due to other 
circumstances in which patient treatment may be impeded by continuation of the study 
treatment. 
The providers caring for patients enrolled in the study may withdraw subjects from the study 
if they have concerns about possible administration of ketamine. Caregivers should make 
clinical decisions based on the idea that patients are receiving ketamine, since the 
randomization code will not be broken.    
3.7 Safety Evaluation 
Subject safety will be monitored for adverse events as outlined by the Ketamine, Low Dose 
for Analgesia, Adult Order Set. This includes monitoring heart rate, blood pressure, and 
respiratory rate 15 minutes after starting infusion and every 4 hours thereafter while 
receiving infusion. The ordering provider will be notified if systolic blood pressure is less 
than 90 or greater than 180, if heart rate is less than 60 or greater than 120, or if the 
respiratory rate is less than 10 during infusion. Mental status will also be monitored during 
normal nurse rounding and the ordering provider notified if sedation, hallucinations, 
cognitive changes, dysphonia, anxiousness, and/or restlessness are observed. 
4 
STATISTICAL CONSIDERATIONS 
A power analysis was used to inform the investigators about appropriate sample size. 
Numerous studies of ketamine infusion for post-op analgesia suggest that the morphine 
equivalent opiate use is decreased from 17% to 46% (average decrease 34.1%, Pain 
Medicine 2014;383-403). Assuming a mean baseline narcotic use of 32+10 mg statistical 
power (alpha = 0.05, 2-tailed test) to detect a 15% decrease in narcotic use is 92.4%. 
Assuming a similar baseline opioid use there would be an 80.7% chance of observing a 
12.5% in morphine equivalents with a 1-tailed analysis. Therefore, the investigators feel 
confident that the likelihood of a Type II error would be minimal with the proposed sample 
size of 50.  


 
 
 
 
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Total narcotic analgesics administered during the 48 hour study period will be abstracted 
from the electronic medical record and converted to morphine equivalents (with aid of 
pharmacy or morphine equivalent calculator, for example: 
http://www.agencymeddirectors.wa.gov/calculator/dosecalculator.htm). Mean + standard 
deviation morphine equivalents for ketamine and placebo groups will be compared. 
Descriptive categorical and continuous characteristics of each cohort will be tabulated and 
compared. Categorical variables (including, gender, age > 55, use of epidural catheter, 
operative fracture stabilization, and disposition) will be analyzed using Chi-square tests. 
Continuous variables will be compared using ANOVA, multiple linear regression, or t-tests 
as appropriate. Continuous variables to be abstracted, tabulated, and compared including: 
age, ICU length of stay, hospital length of stay, number of fractured ribs, Injury Severity 
Score (ISS), negative inspiratory force (NIF), and vital capacity (VC). 
4.1 Efficacy Analysis 
The primary analysis will be based on an intention to treat basis (i.e., randomization to study 
arm and at least 1 hour of study drug infusion) and will include all subjects enrolled into the 
study. The primary endpoint will be the total dose of all narcotic analgesics (converted to 
morphine equivalents) received during the 48 hour period after the patient begins study drug 
infusion. (Note, for the purposes of the study initiation of study drug infusion starts the 48 
hour window for narcotic use monitoring).  
Secondary endpoints will include examination of hospital, and/or ICU, length of stay, 
pulmonary function studies (NIF and VC), subjective pain scores (visual analog pain scores 
from electronic medical record), and the incidence/number of adverse events (e.g., ICU 
readmission, pneumonia, bronchoscopy, etc.).   
4.2 Safety Analysis 
No specific safety analysis is planned, because ketamine is an approved medication for 
adjunctive treatment of post-operative and other types of surgical pain. All subjects will be 
monitored for any adverse events per the usual care parameters. Such events are noted by 
caregivers, care adapted appropriately if concern related to study drug, and findings and 
interventions documented in the electronic health record.  
4.3 Interim Analysis 
No interim analysis is planned for this study. All subjects will receive care based on the 
existing standard of care, as outlined in the Rib Fracture Management Guideline (Appendix 
A). While it is conceivable that as few as 20 randomized subjects might be sufficient to 
show statistically significantly decreased opioid analgesic use (Primary Endpoint), it is 
anticipated that the full cohort of 50 randomized subjects would be desirable to examine the 
important secondary endpoints relating to resource utilization (hospital and ICU LOS), as 
well as to better understand the how ketamine improved care. Discontinuation of the study 
would be considered if greater than 33% of participants suffer adverse events felt to be 
related to the study drug. 


 
 
 
 
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5 
SAFETY MANAGEMENT 
5.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study and recorded as a 
secondary study outcome. If concern for adverse events related to study medication 
administration, providers will manage as if receiving low-dose ketamine infusion. 
Discontinuation of study drug will be at provider discretion. 
5.2 Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen 
during the course of this study (including SAEs) they will be reported to the IRB in 
accordance with NMHH guidelines. AEs that are not serious but that are notable and could 
involve risks to subjects will be summarized in narrative or other format and submitted to 
the IRB at the time of continuing review.  
Jouguelet-Lacoste et al. (2015) reviewed five meta-analyses and 39 clinical trials from 1996 
to 2013 in which over 1400 patients received low-dose IV ketamine for pain control. No 
major complications, related to ketamine administration, were reported in this analysis6.  
STUDY ADMINISTRATION 
5.3 Treatment Assignment Methods 
5.3.1 Randomization 
A randomization schedule (see Appendix B for sample) will be created using Microsoft 
Excel. The sample randomization schedule includes fictitious names and MR#s. Note: once 
the schedule is created. In a final document Column C would be hidden and probably 
Columns A-D would be “locked” (Protected), so that they could not be modified (values in 
Column D would change, but the formula to create those values could not be changed in a 
Protected document).  
The randomization schedule will be generated (with appropriate instructions) in the 
pharmacy, who will also be responsible for maintaining and protecting the list, as subjects 
are enrolled. Neither the PI, Co-investigators, physicians, nurses, or others caring for the 
patient will be aware of whether or not a given patient is receiving ketamine or placebo 
infusion.  
Once a patient agrees to participate in the study, a licensed physician, nurse practitioner, or 
physician assistant will enter an order for Rib Fracture Study Drug in the EPIC electronic 
record. That caregiver is responsible for insuring that the subject has consented to participate 
in the study and that a signed consent form resides in the subject’s medical record. Prior to 
commencing infusion of the any study drug, the nursing staff will also confirm that a signed 
consent for the subject is present in the patient’s medical record.  


 
 
 
 
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5.3.2 Blinding 
During the duration of the study, the pharmacy personnel will be the only individuals who 
will have knowledge of study drug assignment. At the completion of the study (enrollment 
of 50 subjects) this information will be turned over to the study investigators. Under no 
circumstances should be drug allocation be released to any individuals prior to completion 
of the study.  
5.3.3 Unblinding 
Since ketamine is an approved medication, this is no specific reason for any caregiver to 
reasonably request that an individual’s study drug allocation be unblinded. However, it is 
entirely reasonable that any and all caregivers should consider that all patients enrolled in 
the study are receiving ketamine and to use that information to make clinical decisions. If a 
caregiver is concerned that any aspect of a patient’s condition, responses to treatment, etc. 
might be adversely impacted by possible administration of ketamine, then that clinician may 
discontinue the study drug at any time.  
5.4 Data Collection and Management 
Data will be extracted from patient records as contained in EPIC electronic health record.  
5.5 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy. The Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study.  
5.5.1 Risk Assessment 
Risks are not greater than minimal as discussed above in Section 5.2. Patients will be 
monitored as previously discussed in Section 3.7 according to Ketamine, Low Dose for 
Analgesia, Adult Order Set which is an approved NMHH Hospital Order Set. 
The medication being studied is already approved for use as a pain medication adjunct at 
NMHH. 
5.5.2 Potential Benefits of Trial Participation 
Potential benefits of trial participation include the benefit to society as related to potentially 
convincing study results which may sway clinical practice in a manner that brings clinical 
benefit to those suffering from multiple rib fractures. Additionally, trial participants included 
in the experimental group may benefit from improved pain control related to the drug 
therapy. 
5.5.3 Risk-Benefit Assessment 
The risk of participation is related to the possible lack of ketamine infusion, in those that 
could benefit from its use, in the control group. There is also a very low risk of adverse 


 
 
 
 
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reaction to those receiving the medication in the experimental group. The benefit is 
enhanced pain relief those receiving the medication. 
 


 
 
 
 
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6 
REFERENCES 
1.  Mowery, NT, et al.  Practice management guidelines for management of hemothorax and 
occult pneumothorax.  J Trauma.  2011;70:510-518. 
2.  Simon, BJ, et al.  Pain management guidelines for blunt thoracic trauma.  J Trauma.  
2005;59:1256-1267. 
3.  Simon B, et al.  Management of pulmonary contusions and flail chest:  an eastern 
association for the surgery of trauma practice management guideline.  J Trauma Acute Care 
Surg.  2012;73:S351-S361. 
4.  Galvagno SM, et al.  Pain management for blunt thoracic trauma: A joint practice 
management guideline from the Eastern Association for the Surgery of Trauma and Trauma 
Anesthesiology Society.  Journal of Trauma and Acute Care Surgery.  2016;81(5):936-951. 
5.  Zakine, J, et al.  Postoperative ketamine administration decreases morphine consumption 
in major abdominal surgery:  a prospective, randomized, double-blind, controlled study.  
Anesthesia and Analgesia.  2008;106: 1856-1861 
6.  Jouguelte-Lacost, J, et al.  The use of intravenous infusion or single dose of low-dose 
ketamine for postoperative analgesia:  a review of the current literature.  Pain Medicine.  
2015;16:383-403. 
7.  Nesher, N, et al.  Ketamine spares morphine consumption after transthoracic lung and 
heart surgery without adverse hemodynamic effects.  Pharmocological Research.  
2008;58:38-44. 
8. Kugler, N, et al. Ketamine infusion for pain control in elderly patients with multiple rib 
fractures: Results of a randomized control trial. Journal of Trauma and Acute Care Surgery. 
2019; 87(5): 1181-1188. 
9. Carver, T, et al. Ketamine infusion for pain control in adult patients with multiple rib 
fractures: Results of a randomized control trial. Journal of Trauma and Acute Care Surgery. 
2019; 86(2): 181-188. 
 
 
 


 
 
 
 
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Appendix A      Rib Fracture Management Guideline 
Purpose 
The following guideline is intended to address and optimize pain management while 
monitoring pulmonary function in patients with multiple traumatic rib fractures with the 
goal of minimizing morbidity and mortality associated with blunt thoracic injury.  A 
multidisciplinary clinical pathway in managing rib fractures has been shown to decrease 
associated infectious morbidity and mortality (Todd et al., 2006). 
Definitions 
Vital Capacity (VC): Maximum volume of air that a person can exhale after maximum 
inhalation.  
Indication 
In patients with multiple rib fractures, the following procedures will be implemented to 
minimize associated complications and optimize outcomes. 
Procedures 
1) The following patients should be considered for TNICU admission, related to 
diagnosis of rib fractures: 
a. Patients 65 years of age or older, with multiple rib fractures 
b. Patients with 4 or more rib fractures and/or flail segment 
c. At provider discretion. 
2) Multimodal Analgesic Strategy 
a. Scheduled Acetaminophen  - 1000 mg PO every 6 hours unless 
contraindicated 
i. GERIATRIC DOSING: Age ≥ 65 y/o -  1000 mg PO every 8 hrs 
unless contraindicated 
ii. For intubated patients or inability to safely take PO: 
1. 650mg suppository every 6 hrs, or 
2. 1000 mg IV every 6 hours unless contraindicated 
a. GERIATRIC DOSING: Age ≥ 65 y/o -  1000 mg IV 
every 8 hrs unless contraindicated 
b. Scheduled NSAID – Ibuprofen 600mg PO every 6 hours, or Ketorolac 15-
30mg IV every 6 hours, unless contraindicated and for duration specified by 
attending provider 
i. GERIATRIC DOSING: Age ≥ 65 y/o – 400mg po every 6 hrs, or 
Ketorolac – 7.5-15mg IV every 6 hours, unless contraindicated and 
for duration specified by attending provider 
c. Lidoderm 5% patches (1-3) over and/or medial to fracture site(s) 
d. Narcotic analgesics  


 
 
 
 
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i. Initial treatment to include oxycodone – 5mg to 10mg po every 4hrs 
PRN mild to moderate pain; and hydromorphone – 0.4mg to 0.8mg 
IV every 2 hrs prn moderate to severe pain, with dosing adjusted for 
patient age and weight, unless contraindicated 
ii. Age ≥ 65 y/o, opioid-naïve, and low body mass - oxycodone – 2.5mg 
to 5mg po every 4hrs prn mild to moderate pain; and hydromorphone 
– 0.2mg to 0.4mg IV every 2-4 hrs prn moderate to severe pain, 
unless contraindicated 
iii. If pain inadequately controlled, based on patient report and provider 
assessment, with above analgesics, Patient Controlled Analgesia 
pump to be considered with appropriate dosing (per Adult Opioid 
Naïve or Tolerant PCA Orderset) and likely discontinuation of other 
narcotic analgesics based on provider assessment 
e. Muscle relaxants – methocarbamol 500-1000mg PO every 6 hrs as needed or 
500-1000mg IV every 8 hrs (not to exceed 3 day course), unless 
contraindicated and based on provider discretion 
i. GERIATRIC DOSING: methocarbamol 500mg PO every 6 hrs as 
needed 
f. Ketamine infusion (per Ketamine, Low Dose for Analgesia orderset)– 
0.1mg/kg/hr (5-20mg/hr) to be used as analgesic adjunct for poorly controlled 
pain or at provider discretion 
g. Consider as needed: other pharmacologic modalities such as gabapentin 
and/or Vistaril (hydroxyzine) (Vistaril not recommended in geriatric 
population) 
h. Anesthesiology consult for placement of epidural catheter is recommended 
for the following patients (contact at x13982, intubated patients may not be 
candidates, INR must be less than 1.3): 
i. patients ≥65 y/o with multiple rib fractures, and/or flail segment 
ii. patients ≥45 y/o with 4 or more rib fractures, and/or flail segment 
iii. at provider discretion 
i. Non-pharmacologic treatments 
i. Splinting education/implementation per Nursing  
ii. Ice (cold pack) therapy 
iii. Positioning/activity (see below) 
3) Multidisciplinary Orders 
a. Respiratory Therapy  
i. EZ-PAP- three times daily if failing to meet IS goal, if increasing 
oxygen demands from baseline, or at provider discretion. 
Contraindicated if untreated pneumothorax is present. Chest XR may 
need to be ordered prior to initiation of therapy. 


 
 
 
 
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ii. Consider Pulmonary function testing, via RT consultation, 
specifically Forced Vital Capacity (FVC), if evidence of failure to 
progress or worsening IS volumes 
1. FVC values < 1L should be communicated by RT staff to 
Trauma Service Provider for consideration of escalation of 
respiratory interventions and/or TNICU admission  
b. Physical Therapy consult – evaluate and treat with emphasis on early 
mobilization 
c. Nursing 
i. Daily ambulation (as allowed by weight-bearing status, activity 
orders, and/or clinical status) 
ii. Up in chair multiple times daily and for meals (as allowed by weight-
bearing status, activity orders, and/or clinical status) 
iii. Incentive Spirometry (IS) – Ten or more times every hour while 
awake with ongoing monitoring and coaching by RN. Goal of 
>15mL/kg volumes written on communication board. If patient failing 
to meet IS goal, Trauma Provider to be notified. Incentive Spirometry 
volumes obtained and frequency to be recorded in System Assessment 
Pulmonary flowsheet 
4) Repeat imaging 
a. Repeat chest x-ray and/or CT chest should be completed if concern for 
worsening pulmonary function and/or at provider discretion 
5) Surgical intervention 
a. Rib fixation should be considered in the following patients: 
i. 3 or more displaced rib fractures 
ii. Flail chest 
iii. Failure of medical management 
iv. Severe chest wall deformity  
 
 


 
 
 
 
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Appendix B      Sample Randomization Schedule 
Subject 
# 
Drug 
Rand# 
Subject 
Infusion 
Rate 
(mL/hr) 
Subject 
Weight (Kg) 
Subject Name 
(Last, First)  
Subject MR# 
1 
Ketamine 
0.0075 
7 
70 
Smith, John 
1234567 
2 
Ketamine 
0.01395 
6.5 
65 
Nelson, Sophia 
2345678 
3 
Saline 
0.03597 
8.1 
81 
North, Katrina 
9876542 
4 
Saline 
0.05186 
7.85 
78.5 
Campbell, 
Robert 
56789123 
5 
Ketamine 
0.06602 
6.73 
67.3 
Mueller, 
Thomas 
432189 
6 
Saline 
0.06938 
0 
  
  
  
7 
Ketamine 
0.10318 
0 
  
  
  
8 
Ketamine 
0.11022 
0 
  
  
  
9 
Ketamine 
0.13401 
0 
  
  
  
10 
Saline 
0.13672 
0 
  
  
  
11 
Ketamine 
0.1671 
0 
  
  
  
12 
Saline 
0.18297 
0 
  
  
  
13 
Ketamine 
0.25649 
0 
  
  
  
14 
Ketamine 
0.25992 
0 
  
  
  
15 
Ketamine 
0.26027 
0 
  
  
  
16 
Saline 
0.31793 
0 
  
  
  
17 
Ketamine 
0.3418 
0 
  
  
  
18 
Saline 
0.35012 
0 
  
  
  
19 
Saline 
0.3554 
0 
  
  
  
20 
Ketamine 
0.40807 
0 
  
  
  
21 
Saline 
0.40814 
0 
  
  
  
22 
Saline 
0.41905 
0 
  
  
  
23 
Saline 
0.4319 
0 
  
  
  
24 
Saline 
0.44334 
0 
  
  
  
25 
Saline 
0.45316 
0 
  
  
  
26 
Ketamine 
0.48629 
0 
  
  
  
27 
Saline 
0.53763 
0 
  
  
  
28 
Saline 
0.54659 
0 
  
  
  
29 
Ketamine 
0.55659 
0 
  
  
  
30 
Ketamine 
0.5639 
0 
  
  
  
31 
Ketamine 
0.5734 
0 
  
  
  
32 
Ketamine 
0.57587 
0 
  
  
  
33 
Saline 
0.58346 
0 
  
  
  
34 
Ketamine 
0.60677 
0 
  
  
  


 
 
 
 
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Subject 
# 
Drug 
Rand# 
Subject 
Infusion 
Rate 
(mL/hr) 
Subject 
Weight (Kg) 
Subject Name 
(Last, First)  
Subject MR# 
35 
Ketamine 
0.61165 
0 
  
  
  
36 
Saline 
0.61363 
0 
  
  
  
37 
Ketamine 
0.66886 
0 
  
  
  
38 
Saline 
0.67536 
0 
  
  
  
39 
Ketamine 
0.7464 
0 
  
  
  
40 
Saline 
0.75254 
0 
  
  
  
41 
Saline 
0.8133 
0 
  
  
  
42 
Saline 
0.81479 
0 
  
  
  
43 
Saline 
0.8249 
0 
  
  
  
44 
Ketamine 
0.83454 
0 
  
  
  
45 
Saline 
0.85056 
0 
  
  
  
46 
Ketamine 
0.88193 
0 
  
  
  
47 
Ketamine 
0.90319 
0 
  
  
  
48 
Ketamine 
0.93575 
0 
  
  
  
49 
Saline 
0.93703 
0 
  
  
  
50 
Saline 
0.98351 
0