Clinical trial NCT02432456
Conditions: Wounds and Injuries Rib Fractures
Sponsor: Medical College of Wisconsin
Start date: 2015-09-01; Completion date: 2018-08-01
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the effectiveness of ketamine infusions in the management of acute pain resulting from broken ribs suffered following a blunt trauma. Half of patients will receive the institutional standard of care and a placebo infusion (no active medication). The other half of patients will receive the institutional standard of care and a ketamine infusion. All subjects and staff will be blinded as to whether they are receiving placebo or ketamine.

Detailed description:
A prospective randomized, double blinded trial of ketamine use in adult and elderly blunt trauma patients with associated rib fractures admitted to the trauma service will be conducted. Examples of blunt mechanisms include assault, falls, motor vehicle collisions, motorcycle crashes, motor vehicle pedestrian collisions, crush injuries, and bicycle accidents. The experimental arm of the trial will receive ketamine infusion therapy while the control arm receives saline placebo infusions at an equivalent rate. All patients will be managed with adjunct therapy including opiates in accordance with the institutional thoracic trauma protocols. Two separate trials based on patient age are included in this study. Elderly rib fracture patients are certainly of interest but will be evaluated as a distinct entity given the discrete differences in the complications of rib fractures and the goals of therapy.

All blunt trauma patients with associated rib fractures will be screened. All patients will be enrolled into the institutional standard thoracic trauma pathway. All individuals will undergo Intercostal Nerve Block (ICNB) in the Emergency Department or on admission to the Intensive Care Unit. In addition to scheduled medications per institutional thoracic trauma protocols, all patients will receive adjunct opiate therapy. Patients will be screened by the clinical and pharmacy staff following the diagnosis of rib fractures for eligibility. Patients enrolled into the trial will be randomized into either the experimental or control arm of the trial. The Investigational Drug Services (IDS) department will randomize all enrollees and handle administration of all trial drugs. The infusate will be mixed by the IDS department and all bags will be labeled "Ketamine / Placebo." The IDS department will have unique bag identifiers, which will allow them to identify which bags have active ketamine and which are placebo in case of emergency.

Patients will be randomized in a 1:1 fashion for experimental and control arms. Those enrolled in the experimental arm will receive early ketamine infusion therapy at a fixed infusion rate. For those enrolled in the adult trial the infusion rate will be 2.5 mcg/kg/min while those in the elderly trial will receive infusions at 2.0 mcg/kg/min. All ketamine infusions will be calculated based on ideal body weight (IBW), unless actual body weight is less than ideal. IBW will be calculated for males as 50kg + 2.3\*(number of inches above 5 feet) and for women as 45.5kg + 2.3\*(number of inches over 5 feet). Patients randomized to the control arm will receive placebo saline solution at an equivalent rate. Time zero will be defined as the time at which the "ketamine / placebo" infusion is begun. For inclusion in the trial, initiation of ketamine / placebo infusions must take place within 6 hours of presentation to Froedtert Memorial Lutheran Hospital (FMLH). Ketamine infusion therapy will be continued for 48 hours. At 6-8 hours post-ICNB all subjects will be assessed for need for repeat ICNB. Need for repeat ICNB will be defined by a thoracic specific numeric pain score greater than seven. Between eight and ten hours post-ketamine infusion initiation, subjects who have thoracic specific pain scores above seven will be evaluated for epidural placement by the Regional Anesthesia and Acute Pain Service.

A subject will be allowed to remove himself/herself from the trial or be un-blinded should he/she, pharmacy, anesthesia, and/or surgical staff deem it medically necessary. Medical necessity would be determined by inability to treat the patient appropriately without knowledge of trial assignment; otherwise the assumption of treating staff will be all patients have received ketamine. All adverse events will be recorded and if necessary subjects will be un-blinded in the event of a serious adverse event. The trauma and anesthesia teams along with the inpatient clinical pharmacists will monitor all trial patients for any adverse event trends. Patients will be followed through the time of discharge.

Arms: arm 1: Subjects in this arm will receive the institutional standard of care for rib fractures along with a placebo (NaCl) infusion.

All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids. arm 2: Subjects in this arm will receive the institutional standard of care for rib fractures along with a ketamine infusion.

All patients will undergo Intercostal Nerve Blockade with administration of scheduled medications including acetaminophen, ibuprofen, pantoprazole, and methocarbamol. All subjects will receive adjunct opioids.
Interventions: intervention 1: Ketamine intervention 2: Placebo intervention 3: Intercostal Nerve Block intervention 4: Acetaminophen intervention 5: Ibuprofen intervention 6: Pantoprazole intervention 7: Methocarbamol intervention 8: Opioid
Intervention descriptions: intervention 1: All individuals randomized to the experimental arm of the trial will receive early ketamine therapy (within 6 hours of admission) at a rate of 0.15 mg/kg/hr dosed based on ideal body weight. Individuals in the control arm will receive our standard of care for thoracic trauma patients, however, they will receive an additional placebo infusion of normal saline. intervention 2: Individuals enrolled into the control arm of the trial will receive a normal saline placebo infusion at a rate equivalent to the dosage of ketamine in the experimental arm. intervention 3: All individuals enrolled into the trial will undergo an Intercostal Nerve Blockade as a part of the institutional standard of care for rib fractures. This procedure will be performed according to current standard protocols in the Emergency Department or on admission. intervention 4: All patients admitted to the hospital will be placed on scheduled acetaminophen 1000mg PO q 6 hours unless signs of liver disease/impairment or creatinine clearance \< 35ml/min at which point dosage would be reduced to 650mg q 8 hours. Individuals unable to take oral medications would be placed on intravenous acetaminophen. intervention 5: All patients will be placed on scheduled Ibuprofen or an equivalent NSAID at dosage of 600mg every 6 hours. Patients must have a Glomerular Filtration Rate \> 60 ml/min with no contraindications to NSAID therapy (e.g. Aspirin use, allergy/sensitivity, concurrent ACE inhibitor use, other nephrotoxins, etc) intervention 6: All individuals on scheduled Non-Steroidal Anti-Inflammatory Drug (NSAID) therapy will receive scheduled pantoprazole at 40mg daily. Individuals unable to take medications orally will be placed on intravenous therapy. Individuals with previous reaction or intolerance to pantoprazole will be placed on an equivalent proton pump inhibitor. intervention 7: All individuals enrolled in the trial will be placed on scheduled methocarbamol 500 mg orally every 6 hours while admitted. Individuals with previous intolerance to methocarbamol will be placed on a pharmacy directed equivalent. intervention 8: All individuals will receive as needed opiate therapy as an adjunct to the scheduled medications and "ketamine/placebo" solution. Choice in opiate therapy will be at the discretion of the attending trauma faculty. Dosage and adjustments will be in accordance with the institutional policy on appropriate opiate dosage adjustment.

Protocol documents:
Prot_SAP_000.pdf: 
PRO00024679 - “Ketamine Infusion Therapy for the Management of Acute Pain Rib Fracture Patients” 
 
Thomas Carver, MD – Principal Investigator 
Page 1 of 17 
 
Version 3 dated 2-1-2018 
 
Background 
 
In the United States alone, more than 3 million individuals suffer non-fatal injuries annually with greater than half of all 
multiply injured patients suffering thoracic injuries.(1) Rib fractures are the most common thoracic injury and represent a 
complicated clinical problem present in nearly 10% of all injured patients.(2, 3) Short-term complications including lung 
consolidation, pneumonia, and empyema are all associated with rib fractures and result in long inpatient hospital stays 
and an increased mortality. Rib fractures often result in the development of chronic pain. Chronic pain development 
among trauma patients at our institution has been documented at rates upwards of 80%, significantly greater than the 
general population.(4) Aside from the addiction and tolerance associated with continued opiate therapy, chronic pain is a 
major public health issue that results in significant health resource utilization, decreased quality of life, and lost work 
productivity.  
 
Prevention of many short-term complications relies on optimal pain control to promote normal respiratory mechanics and 
effort. While opiate medications have long been the therapeutic backbone, they can produce respiratory depression, 
nausea, emesis, pruritus, and/or sedation preventing optimal pain control.(3, 5) To offset such problems, many regional 
adjuncts are utilized with varying degrees of success. Despite many years of research, the optimal analgesic approach 
applicable for all patients remains elusive. Research from our institution recently demonstrated poor acute pain control 
increases the development of chronic pain. The majority of research on optimization of rib fracture pain control has 
focused on regional anesthesia techniques, which provide isolated benefits in the setting of a multiply injured trauma 
patient.  
 
The Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive 
Care Unit by Barr et al. published in January 2013 were adopted as the most recent standard of care for the clinical 
management of pain. The mainstay of acute pain management, albeit postoperative, traumatic, or idiopathic, has been 
opiate based therapy. Utilization of ketamine therapy as an adjunct in the management of acute pain is minimally 
discussed in these guidelines with some previous retrospective and small prospective studies to support its use noted. 
Ketamine infusions are currently part of our standard opiate tolerant pain management pathways. However, its use has 
been reserved for individuals who fail traditional opiate therapy. This trial aims to re-think how we approach acute pain 
management thru early implementation of ketamine infusion therapy. In our model of acute pain management we move 
ketamine from an adjunct therapy to the forefront of therapeutic intervention through which we hope to decrease the 
overall opiate requirements and side effects among trial patients.  
 
As previously stated, chronic pain is a significant contributor to decreased quality of life following injury. Historically, 
clinicians were taught that the pain and disability of rib fractures resolves in 6 to 8 weeks. However, more recent studies 
have demonstrated that a large number of patients report significant chest wall pain and overall disability at or beyond 8 
weeks of injury.(19,20) In one prospective observational study, the most predictive indicator of both prolonged pain and 
disability was the pain intensity within the first several days after injury.(19) With the use of early ketamine infusion 
therapy in the acute injury phase, we also hope to decrease the development of chronic pain and improve quality of life 
after rib fractures. 
 
Hypothesis 
Early utilization of ketamine infusion therapy among adult and elderly patients with rib fractures will improve patient 
reported pain control. 
 
Specific Aims: 
S.A.1: Characterize the efficacy of ketamine infusions in the management of acute thoracic pain associated with 
rib fractures. 
• 
Hypothesis 1A: Utilization of ketamine infusion therapy among rib fracture patients will lead to decreased patient 
reported thoracic numeric pain scores compared to controls. 


PRO00024679 - “Ketamine Infusion Therapy for the Management of Acute Pain Rib Fracture Patients” 
 
Thomas Carver, MD – Principal Investigator 
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• 
Hypothesis 1B: Ketamine infusion therapy will lead to decreased total opiate consumption (standardized to 
morphine equivalent units) in the first 24 and 48 hours compared to controls. 
S.A.2: Characterize the impact of ketamine infusion therapy on the development of chronic pain and quality of life 
in trauma patients who suffer rib fractures. 
Hypothesis 2A: Improved rib fracture and global pain control through early ketamine infusion therapy will decrease the 
rate of chronic pain development and improve quality of life.Methods 
A prospective randomized, double blinded study of adult blunt trauma patients with associated rib fractures admitted to 
the trauma service will be conducted. The experimental arm of the study will receive ketamine infusion therapy while the 
control arm receives saline placebo infusions at an equivalent rate. All patients will be managed with adjunct therapy 
including opiates in accordance with the thoracic trauma protocols (see Appendix I for further details). This study will focus 
on adult blunt trauma patients who have associated rib fractures. The focus on adult rib fracture patients stems from an 
injury pattern in which there is a high incidence of prolonged narcotic utilization and development of chronic pain. Potential 
subjects will be screened according to the previously listed inclusion and exclusion criteria. 
All blunt trauma patients with associated rib fractures will be screened. All patients will be enrolled into our standard 
thoracic trauma pathway (see Appendix I. TPP.0046) with scheduled medications as listed in the protocol. All individuals 
will undergo Intercostal Nerve Block (ICNB) (see Appendix II) in the Emergency Department or on admission to the 
Intensive Care Unit (ICU). In addition to scheduled medications per thoracic trauma protocol, all patients will receive 
adjunct narcotic therapy. Patients will be screened by the clinical and pharmacy staff following the diagnosis of rib 
fractures for eligibility. Patients enrolled into the study will be randomized into either the experimental or control arm of the 
study. The Investigational Drug Services (IDS) department will randomize all enrollees and handle administration of all 
study drugs. Study assignment and blinding will be held by the Investigational Drug Services department. The infusate will 
be mixed by the IDS department and all bags will be labeled “Ketamine / Placebo.” The IDS department will have unique 
bag identifiers, which will allow them to identify which bags have active ketamine and which are placebo in case of 
emergency.  A sign stating “RIB FRACTURE PATIENT” – Please document “Thoracic Pain Scores” will be hung outside 
the subject’s room.  The sign serves as a reminder to those who are providing patient care that they need to record 
thoracic pain scores as part of SoC for treating rib fractures with Ketamine infusion (see Appendix VI). 
 
ADULT PROTOCOL: 
A total of 100 patients aged 18 – 64 years old will be enrolled into the study. The 50 patients randomized to the 
experimental arm will receive early ketamine infusion therapy at a rate of 2.5 mcg/kg/min. All ketamine infusions will be 
calculated based on ideal body weight (IBW), unless actual body weight is less than ideal. IBW will be calculated for 
males as 50kg + 2.3*(number of inches above 5 feet) and for women as 45.5kg + 2.3*(number of inches over 5 feet). The 
50 patients randomized to the control arm will receive placebo saline solution at a rate equivalent. Time zero will be 
defined as the time at which the “ketamine / placebo” infusion is begun. For inclusion in the study, initiation of ketamine / 
placebo infusions must take place within 12 hours of presentation to Froedtert Memorial Lutheran Hospital (FMLH). 
Ketamine infusions will be prepared by the IDS service but will be hung and administered by the inpatient nursing staff. 
Ketamine infusion therapy will be continued for 48 hours. At 6-8 hours post-ICNB all subjects will be assessed for need for 
repeat ICNB. Need for repeat ICNB will be defined by a thoracic specific numeric pain score greater than seven. Between 
8-10 hours post-ketamine infusion initiation, subjects who have thoracic specific pain scores above six will be evaluated 
for epidural placement by the RAAPS service. 
 
 
ELDERLY PROTOCOL: 


PRO00024679 - “Ketamine Infusion Therapy for the Management of Acute Pain Rib Fracture Patients” 
 
Thomas Carver, MD – Principal Investigator 
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An additional seventy-two patients will be enrolled aged 65 and older (see sample size calculation outlined in c.2.3). 
Thirty-six patients randomized to the experimental arm will receive ketamine infusion therapy at 2 mcg/kg/min. Ketamine 
dose is calculated based on ideal body weight (IBW), unless actual body weight is less than ideal. IBW will be calculated 
for males as 50kg + 2.3*(inches over 5 feet) and for women as 45.5kg + 2.3*(inches over 5 feet). Thirty-six patients 
randomized to the control arm will receive placebo solution. Time zero is defined at initiation of the “ketamine / placebo” 
infusion. Ketamine / placebo infusions must begin within 12 hours of presentation to Froedtert Memorial Lutheran Hospital 
(FMLH). Ketamine/placebo therapy will be continued for 48 hours. At 6-8 hours post-ICNB all subjects will be assessed for 
repeat ICNB, defined by a thoracic specific numeric pain score greater than seven. At 8-10 hours post-ketamine/placebo 
initiation, those with thoracic pain scores above seven will be evaluated for epidural placement by the RAAPS service. 
 
All Patient Daily Screening: 
Each individual will undergo daily screening by the trauma and anesthesia rounding teams for complications during the 
infusion. Specific infusion related complications that will be screened daily include: Respiratory Depression, Nausea / 
Emesis, Itching / Hives, presence of disturbing dreams / Hallucinations / Delusions, Blurred vision, Dizziness, and 
Confusion (Utilizing the Confusion Assessment Method currently employed at Froedtert). Additionally, nursing staff 
currently assess sedation and nausea at a per shift minimum. Should any concerns for infusion related complications be 
encountered by nursing staff, a member of the trauma and/or anesthesia care teams will assess the patient. 
Trauma attending’s are available 24/7 should any serious concerns arise. 
 
Elderly Patient Daily Assessment Supplement: 
All subjects will be assessed daily or more frequently for delirium. The institutional CAM and CAM-ICU Delirium screens, 
which have been validated in the literature, will be utilized prior to 7-12-2016  (see appendices IV and V) . and the Nu-
DESC which went into effect at FMLH on 7-12-2016 will be used as well (Appendix V figure 2). Subjects may remove 
oneself from the trial or be un-blinded should he/she, pharmacy, and/or clinical staff deem it medically necessary. Medical 
necessity is determined by inability to treat without knowledge of trial assignment; otherwise treating staff will assume all 
patients have received ketamine. All adverse events will be recorded and if necessary subjects will be un-blinded in the 
event of a serious adverse event. 
 
A subject will be allowed to remove himself/herself from the study or be un-blinded should he/she, pharmacy, anesthesia, 
and/or surgical staff deem it medically necessary. All adverse events will be recorded and if necessary subjects will be un-
blinded in the event of a serious adverse event. The research team will monitor all study patients for any adverse event 
trends. Patients will be followed through the time of discharge. 
Safety Protocol and Protection of the Elderly: Rates of delirium in elderly trauma patients is higher than the average adult 
trauma patient with rates up to 30% quoted in the literature.(6) Interestingly previous work has found thoracic trauma to be 
a protective factor for the development of delirium, speculated due to more frequent nursing care.(6) Additionally, one of 
the concerns with ketamine is the dissociative properties which are beneficial in the treatment of pain but a concern for the 
development of delirium. Studies looking at ketamine in elderly patients have demonstrated the drug side effect profile 
similar among all patients with some increased dissociation in elderly individuals.(7-12) As a result of these concerns, the 
study will have an extensive patient safety monitoring plan in place. 
 
All individuals enrolled into the study prior to 7/12/2016 will be screened prior to therapy utilizing the confusion 
assessment method (CAM) which has been previously validated in the literature and is an institutional practice currently 
utilized in both the ICU and on the general wards.(13-18) There are two different versions of the CAM currently utilized in 
Froedtert Memorial Lutheran Hospital specific to location. The general ward CAM is outlined in Appendix IV while a 
separate CAM-ICU is designated for utilization in all intensive care units and is outlined in Appendix V. Both the CAM and 
CAM-ICU tools are simple easy to utilize tools that can be administered by nursing staff, aids, residents, or clinical faculty. 
Currently in the ICU the CAM tool is administered by the nursing staff to all patients as a screening method for delirium. 
The CAM-ICU will be administered in the ICU per current nursing protocol. Additionally, both the trauma and anesthesia 


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Thomas Carver, MD – Principal Investigator 
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RAAPS teams in charge of patient care will administer the CAM-ICU for all ICU patients during daily rounds to screen for 
the presence of delirium. As a result of this, all patients in the ICU will undergo at least three CAM-ICU screens daily to 
help address delirium concerns. All patients admitted to the floor prior to 7/12/2016 will undergo CAM screening by both 
the trauma and anesthesia RAAPS teams during daily rounds to screen for the presence of delirium. Additionally, should 
any nurse or house staff have concerns for the possibility of delirium, the CAM tool will be available for their utilization. 
 
All individuals enrolled into the study after 7/12/2016 will be screened using the Nursing Delirium Screening Scale (Nu-
DESC) per hospital change.  
 
Any patient that screens positive on a CAM or Nu-DESC assessment by nursing staff or other non-physician staff would 
mandate a clinical evaluation by the anesthesia and trauma clinical teams. Should a patient screen positive for delirium 
utilizing the appropriate CAM or Nu-DESC assessment by a clinical team (i.e. anesthesia or trauma), the patient will be 
assessed by other rounding clinical team (i.e. anesthesia or trauma). Should both CAM or Nu-DESC screens be positive 
for the presence of delirium, the patient will be withdrawn from the study with cessation of the ketamine/placebo solution 
immediately. Additionally, the traditional delirium workup for the presence of infection or other underlying cause will 
happen in parallel with cessation of the ketamine/placebo solution. Given the short half-life of ketamine, approximately 15 
minutes, if the ketamine/placebo solution is the cause of the altered mental status, patient should improve shortly. If the 
patient does not improve, continued delirium workup will continue in congruence with the current standard of care. 
 
In the event that the two clinical CAM or Nu-DESC assessments are in disagreement with the presence of delirium, a 
clinical workup for delirium in congruence with the current standard of care will be initiated. However, the 
ketamine/placebo infusion will continue with repeat assessment in one hour by the clinical teams. If both team CAM or 
Nu-DESC assessments screen positive or disagreement remains as to the delirium status of the patient, the patient will be 
withdrawn from the trial with cessation of the ketamine/placebo solution. In the event both teams agree no delirium is 
present, the patient’s therapy will be continued according to study protocol. For the duration of the trial, should any 
questions as to the presence of delirium or whether the ketamine/placebo infusion should be stopped arise, there will 
always be an available clinical research staff (i.e. research resident, trauma staff, or anesthesia staff) that is heavily 
involved in the trial available for questions 24/7.  
 
All individuals who require withdrawal from the study with cessation of the ketamine/placebo solution will be reported to 
the Investigational Drug Services department for monitoring of drug safety. Should the IDS department have concern for 
the safety of ketamine utilization in this elderly patient population, a formal IRB report will be filed with no further 
enrollment of patients until final IRB consensus is reached. 
 
All aspects of the safety protocol for the protection of elderly patients in general along with study specific protections will 
be incorporated as a part of resident, staff, and nursing education efforts prior to enrollment of patients into the trial.  
 
Unblinding Protocol: Breaking of blinding for any subject should only be performed for medical emergency conditions in 
which the identification of the subject's treatment assignment is critical for proper medical care. In all cases, it should be 
assumed the subject received active drug. In such rare and special circumstances where the selection of a treatment 
approach for the medical emergency would differ based on whether the subject was on active or placebo, the investigator 
should contact the Medical Affairs Associate at the CRO acting as the designated medical contact for the permission to 
unblind. The representative or back-up will be available 24 hours a day. If a decision is made to unblind a subject's 
assignment, the investigator will utilize the IVRS to request the subject's treatment group. Only the investigator will be 
unblended to the subject's treatment group and he/she will be responsible for documenting the time, date, and reason for 
code break. Under these circumstances, study treatment would be discontinued, but all efforts would be made to ensure 
the remaining per protocol safety and efficacy evaluations were conducted. The investigator will ensure that only study 
staff involved in the immediate medical treatment of the subject are aware of the unblinding and will ensure, whenever 
possible, that all other study staff involved in the remaining assessments remain blinded. If applicable, the investigator will 


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Thomas Carver, MD – Principal Investigator 
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document the date and time other study staff were unblended. In the situation where a non-study physician requires 
emergency unblinding in order to provide urgent care to the subject, the Medical Monitor or back-up will be contacted to 
discuss and then, if needed, the treatment code will be provided. The Medical Monitor or backup is available 24 hours a 
day, 7 days a week. 
 
Unblinding: Breaking of blinding for any subject should only be performed for medical emergency conditions in which the 
identification of the subject's treatment assignment is critical for proper medical care. In all cases, it should be assumed 
the subject received active drug. In such rare and special circumstances where the selection of a treatment approach for 
the medical emergency would differ based on whether the subject was on active or placebo, the investigator should 
contact the medical representative or back-up. The representative or back-up will be available 24 hours a day. If a 
decision is made to unblind a subject's assignment, the investigator will contact the Investigational Drug Services 
Department to request the subject's treatment group. Only the investigator will be unblinded to the subject's treatment 
group and he/she will be responsible for documenting the time, date, and reason for code break. Under these 
circumstances, study treatment would be discontinued, but all efforts would be made to ensure the remaining per protocol 
safety and efficacy evaluations were conducted. The investigator will ensure that only study staff involved in the 
immediate medical treatment of the subject are aware of the unblinding and will ensure, whenever possible, that all other 
study staff involved in the remaining assessments remain blinded. If applicable, the investigator will document the date 
and time other study staff were unblinded. In the situation where a non-study physician requires emergency unblinding in 
order to provide urgent care to the subject, the Medical Monitor or back-up will be contacted to discuss and then, if 
needed, the treatment code will be provided. The Medical Monitor or backup is available 24 hours a day, 7 days a week. 
Pain Assessments: The study design is based on the utilization of IV narcotics on an hourly basis for adjunctive pain 
management in accordance with the current trauma protocols and study overview. The utilization for IV narcotics on all 
patients out thru 24 hours’ post-infusion ensures the proper nursing interaction with patients. While IV narcotics are not 
required to be administered each hour, a nursing assessment hourly is necessary in order to determine need for IV 
narcotic administration. Should the patient request narcotics or it is deemed necessary by the nursing staff this would be 
recorded in the electronic medical record. All pain assessments by the nursing staff would be recorded into the EMR for 
patient care purposes and for research team recording. It is unreasonable to except hourly nursing pain assessments for 
the duration of the hospitalization which is why the primary endpoint of the study is the assessment of the 12-24 hour 
period. Additionally, the design accounts for the possibility that some time points might not have pain assessments. The 
utilization of the AUC pain analysis as detailed in the data analysis section describes how this accounts for missing data 
points. Extensive nursing education on the importance of ensuring hourly assessments by either the nurse or aid will be 
stressed. 
Side Effect Assessments: Side effects will be screened for daily by the rounding services. The particular side effects of 
interest include: nausea (0 = absent, 1 = present, no therapy, 2 = present, therapy effective, 3 = present, therapy 
ineffective), respiratory depression (defined as RR <8 or SpO2 < 90%), sedation (0= no sedation noted, 1= sedation 
causing documentation by RN in patient chart, 3=sedation causing increased monitoring in an intensive care unit 
4=sedation causing the need for intubation), pruritus (0 = absent, 1 = present, no therapy, 2 = present, therapy effective, 3 
= present, therapy ineffective), and the presence of hallucinations and/or disturbing dreams (0=no 1=yes). 
Quality of Life Assessment: Following hospitalization, we will follow up with participants at three, six, twelve months, 
and/or 24 months after enrolling in the study. This follow up interview will occur via telephone call, or in person if the 
participant is still in the hospital. At each follow up interview, an assessment of quality of life, post-traumatic stress 
disorder (PTSD), depression, anxiety, and stress will be conducted via the following measures: 
1. Depression Anxiety Stress Scales 21 (DASS-21): Assess severity of symptoms of depression, anxiety, or stress. 
2. PTSD Checklist for DSM-5 (PCL-5): Assess the 20 symptoms of PTSD listed in the Diagnostic and Statistical 
Manual of Mental Disorders (DSM-5). 


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Thomas Carver, MD – Principal Investigator 
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3. Short Form 36 Health Survey version 2 (SF-36v2): Assess health status including physical functioning, vitality, 
bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role 
functioning, and mental health. 
4. Trauma Quality of Life measure: Assess domains unique to trauma populations, including emotional well-being, 
functional engagement, recovery / resilience, peritraumatic experience, and physical well-being. 
3, 6, 12 and 24 Month Study Procedure: A follow-up assessment will occur via a telephone call or in person. During the 
interview, subjects will complete the following measures: DASS-21, PCL-5, SF-36v2, and Trauma Quality of Life measure. 
This will take approximately 15-20 minutes to complete. 
 
For those subjects currently active in the study or who have already completed their participation in the study, 
we will perform a new verbal telephone consent in order to obtain the quality of life surveys. This document can 
be found in section 3, titled: "AME #17808 Verbal Consent Telephone Script 2.1.2018" 
 
Inclusion Criteria: 
1) Age 18 years or greater– Adult arm = 18 to 64 years of age, Elderly arm = 65 years of age or older 
2) Trauma patients admitted to Froedtert Hospital with 3 or more rib fractures documented on plain film or cross-
sectional imaging. 
 
Exclusion Criteria: 
1) history of adverse reaction to ketamine therapy 
2) chronic opioid therapy defined as > 3 weeks of >30mg oral morphine equivalents per day 
3) current substance abuse with opiates including prescription and/or heroin 
4) intubation on arrival or need for urgent intubation on arrival 
5) significant traumatic brain injury or suspicion of elevated intracranial pressure resulting in an inability to 
communicate with staff 
6) history of psychosis 
7) active delirium 
8) glaucoma 
9) ischemic heart disease defined as active acute coronary syndrome 
10) severe, poorly controlled hypertension 
11) concurrent use of monoamine oxidase inhibitors (MAOIs) 
12) pregnancy 
13) prisoners 
 
Statistical Analysis 
Sample Size Analysis: 
Adult Study: The primary outcome for this study is a clinically significant difference in pain scores. A clinically significant 
decrease in acute pain scores is defined as a 2-point interval on the 11-point numeric pain scale. A total enrollment of 52 
patients (26 control patients, 26 experimental patients) was calculated utilizing previous institutional data on acute pain 
scores. A sample size of 52 patients provides an 80% power for the detection of a clinically significant difference in 
postoperative pain scores. Given confounding factors such as epidural placement and possibility patients may decide to 
withdraw from the study, a planned sample size of 60 patients will provide a 15% buffer in patient enrollment. 
Elderly Study: A planned enrollment of 60 patients provides a 15% buffer. Rates of delirium among all elderly trauma 
patients are quoted around 30%(35); therefore, a budget is outlined for a total of 72 patients providing a 38% buffer for 
any perceived patient attrition. 


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Thomas Carver, MD – Principal Investigator 
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Interim Sample Size Recalculation: The expected variability of the primary outcome was estimated in a slightly different 
population, thus there is a concern that the actual variability will be different, affecting the overall power of the trial. Thus, 
an internal pilot will be incorporated into the trial [Friede T, Kieser M (2006) Sample Size Recalculation in Internal Pilot 
Study Designs: A Review Biometrical Journal, 48(4), 537-555]. When half the patients have been randomized, the primary 
outcome will be evaluated for them, and a blinded sample size recalculation will be performed using the original target 
effect size of 2 point difference and the observed standard deviation of the pooled data adjusted for the expected 
treatment difference using Zucker’s formula: 
S2adj = S2 - (n1*d2)/[4*(n1-1)], 
where d=2 is the expected treatment difference. The recruitment will not stop during the recalculation phase, as the 
originally planned sample size of 26 patients per group will always be recruited. If the recalculation indicates the need for 
a higher sample size, it will be increased to its calculated value, but not exceeding 39 patients per group (a 50% increase 
in sample size). This approach maintains the overall type I error rate but protects against moderate underestimation of the 
between-patient variability. 
Analysis: The primary outcome will be the area under curve for the pain trajectory (AUC pain) 12 – 24 hours after initiation 
of treatment. AUC pain is calculated using the trapezoid rule; linear interpolation will be used between the last pain score 
before start of the period and first pain score after start of the period to obtain the 12-hour pain score, with a similar 
calculation for the 24-hour score. This measure can be interpreted as a time-weighted average of pain scores. 
Demographic and other baseline data as well as outcome measures will be presented overall and by treatment group. 
Categorical data, such as gender, race, etc., will be presented by frequencies and percentages. Descriptive summary 
statistics (e.g. frequency, mean, median, range and standard deviation) will be used to present numeric data. The primary 
outcome will be compared between the two groups using Student’s two-sample t-test. 
 
Quality of Life Analysis: Independent samples t-tests with multiple correction will be conducted to evaluate whether those 
who received early ketamine infusion therapy experience significant differences in quality of life, PTSD, depression, 
anxiety, and stress. 
 
References: 
1. 
Manlulu AV, Lee TW, Thung KH, Wong R, Yim AP. Current indications and results of VATS in the 
evaluation and management of hemodynamically stable thoracic injuries. European journal of cardio-
thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 
2004;25(6):1048-53. 
2. 
Sharma OP, Oswanski MF, Jolly S, Lauer SK, Dressel R, Stombaugh HA. Perils of rib fractures. The 
American surgeon. 2008;74(4):310-4. 
3. 
Flagel BT, Luchette FA, Reed RL, Esposito TJ, Davis KA, Santaniello JM, et al. Half-a-dozen ribs: the 
breakpoint for mortality. Surgery. 2005;138(4):717-23; discussion 23-5. 
4. 
Trevino CM, Essig B, deRoon-Cassini T, Brasel K. Chronic pain at 4 months in hospitalized trauma 
patients: incidence and life interference. Journal of trauma nursing : the official journal of the Society of 
Trauma Nurses. 2012;19(3):154-9. 
5. 
Brown SD, Walters MR. Patients with rib fractures: use of incentive spirometry volumes to guide 
care. Journal of trauma nursing : the official journal of the Society of Trauma Nurses. 2012;19(2):89-91; 
quiz 2-3. 
6. 
Bryczkowski SB, Lopreiato MC, Yonclas PP, Sacca JJ, Mosenthal AC. Risk factors for delirium in 
older trauma patients admitted to the surgical intensive care unit. The journal of trauma and acute care 
surgery. 2014;77(6):944-51. 


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7. 
Ketamine for Adult Patients who Have Suffered Painful and Traumatic Injuries: A Review of 
Clinical Effectiveness, Cost-Effectiveness, Safety and Guidelines. Ottawa ON: 2014 Canadian Agency for 
Drugs and Technologies in Health.; 2014 Mar 06. 
8. 
Edwards ND, Fletcher A, Cole JR, Peacock JE. Combined infusions of morphine and ketamine for 
postoperative pain in elderly patients. Anaesthesia. 1993;48(2):124-7. 
9. 
Liang SW, Chen YM, Lin CS. [Low-dose ketamine combined with fentanyl for intravenous 
postoperative analgesia in elderly patients]. Nan Fang Yi Ke Da Xue Xue Bao. 2006;26(11):1663-4. 
10. 
Maneglia R, Cousin MT. A comparison between propofol and ketamine for anaesthesia in the 
elderly. Haemodynamic effects during induction and maintenance. Anaesthesia. 1988;43 Suppl:109-11. 
11. 
Miner JR, Gray RO, Bahr J, Patel R, McGill JW. Randomized clinical trial of propofol versus ketamine 
for procedural sedation in the emergency department. Acad Emerg Med. 2010;17(6):604-11. 
12. 
Vardy JM, Dignon N, Mukherjee N, Sami DM, Balachandran G, Taylor S. Audit of the safety and 
effectiveness of ketamine for procedural sedation in the emergency department. Emerg Med J. 
2008;25(9):579-82. 
13. 
Friedman Z, Qin J, Berkenstadt H, Katznelson R. The confusion assessment method--a tool for 
delirium detection by the acute pain service. Pain practice : the official journal of World Institute of Pain. 
2008;8(6):413-6. 
14. 
Grossmann FF, Hasemann W, Graber A, Bingisser R, Kressig RW, Nickel CH. Screening, detection 
and management of delirium in the emergency department - a pilot study on the feasibility of a new 
algorithm for use in older emergency department patients: the modified Confusion Assessment Method 
for the Emergency Department (mCAM-ED). Scand J Trauma Resusc Emerg Med. 2014;22:19. 
15. 
Han JH, Wilson A, Graves AJ, Shintani A, Schnelle JF, Dittus RS, et al. Validation of the Confusion 
Assessment Method for the Intensive Care Unit in older emergency department patients. Acad Emerg 
Med. 2014;21(2):180-7. 
16. 
Shi Q, Warren L, Saposnik G, Macdermid JC. Confusion assessment method: a systematic review 
and meta-analysis of diagnostic accuracy. Neuropsychiatr Dis Treat. 2013;9:1359-70. 
17. 
Soja SL, Pandharipande PP, Fleming SB, Cotton BA, Miller LR, Weaver SG, et al. Implementation, 
reliability testing, and compliance monitoring of the Confusion Assessment Method for the Intensive Care 
Unit in trauma patients. Intensive Care Med. 2008;34(7):1263-8. 
18. 
Waszynski CM. Confusion Assessment Method (CAM). Medsurg Nurs. 2004;13(4):269-70. 
 
19. 
Fabricant, L., et al., Prolonged pain and disability are common after rib fractures. The American 
Journal of Surgery, 2013. 205(5): p. 511-516. 
20. 
Gordy, S., et al., The contribution of rib fractures to chronic pain and disability. The American 
Journal of Surgery, 2014. 207(5): p. 659-663. 
 
 


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Appendix I. TPP.0043 Geriatric Rib Fracture Management 
 
Pain Management for Elderly Patient (≥65y) with Rib Fractures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix I. TPP.0043 Geriatric Rib Fracture Management cont. 
Rib Block 
(consider in Trauma Room) 
Pain Plan 
RT/PT therapy 
Epidural, 
RT protocol, 
PT 
≥65yo with rib fractures determined by CXR &/or exam 
≤3 rib fx’s 
&/or requires 
admission 
4+rib fx’s or severe pain 
(≥7/10 pain scale) 
Candidate for Epidural? 
No
Yes 


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Pain Plan 
 
 
 
Appendix I. TPP.0043 Geriatric Rib Fracture Management cont. 


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Thomas Carver, MD – Principal Investigator 
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DETAILS  
Rib Blocks  
Location: Performed in Emergency Dept at tender, fractured rib including one level above and below. Medication: 5 ml of 
0.25% Bupivicaine with Epinephrine 1:200,000 utilize 25ga needle, inject just below the rib in the intercostal groove. May 
repeat every 6-8 hours as needed.  
 
RT/PT  
• Order respiratory care consult  
• Incentive spirometry every hour independent of RT  
• Early mobilization with Physical Therapy  
 
Antihistamines  
Use Loratadine (Claritin) or Cetirizine (Zyrtec) Diphenhydramine (Benadryl) is contraindicated  
 
Topicals  
If skin intact, may use:  
• Methylsalicylate(Ben-Gay/Icy Hot) applied to painful area 3-4 times daily or  
• Capsaicin cream/lotion/gel applied to painful area 3-4 times daily  
 
IV Opiods  
If needed, start with low does (morphine 1mg or hydromorphone 0.1mg) Hydromorphone is preferred in patients with 
renal dysfunction Opiod equivalency: oxycodone 20mg orally = morphine10mg IV= hydromorphone 1.5mg IV  
 
Benzodiazepines and muscle relaxants including benzodiazepines, methocarbamol(Robaxin), metaxolone(Skelaxin), 
cyclobenzaprine(Flexeril) are all contraindicated  
 
Other Considerations  
If significant rib displacement and/or flail chest with significant volume loss, rib stabilization should be considered.  


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Appendix II. Intercostal Nerve Block Protocol 
What you will need: 
- 
0.25% Bupivacaine with 1 : 200,000 epinephrine  
 
-     10 or 20 mL syringe 
- 
22 gauge needle (1.5” or spinal per patient size)  
 
-     Chloraprep or Betadine prep 
- 
Ultrasound (Optional –utilize high frequency linear probe) 
 
-     Sterile Gloves 
 
Procedure Outline: 
1. Patient should be consented and all questions answered. 
2. Pre-Block measurements to be obtained: 
• 
Global and Thoracic specific numeric pain score 
• 
Vital Capacity and Incentive Spirometry 
3. Identify the location and number of ribs fractured. 
4. Calculate the maximum volume of bupivacaine for the patient. 
• 
Max bupivacaine dose = 3 mg / kg (Volume of 0.25% = 1.2 ml / kg) 
5. Patients should be placed into lateral decubitus position with arm above the head to improve access. 
• 
Placement of the block proximal to the site of fracture is optimal in all patients. 
6. If using: 
• 
Landmark à Palpate all ribs you plan to block. 
• 
US à Visualize each of the ribs that you plan to block. 
7. Prep the posterior axillary line for all ribs you plan to block. 
• 
If plan to block posterior, prep the back in a paravertebral fashion. 
8. Approach: 
• 
Landmark Based: 
o Advance needle down onto the rib of interest 
o Withdraw needle slightly. Re-directing the needle caudal, advance down the rib until you feel the 
need advance just underneath the rib. 
o Advance needle 1-2 mm under the rib and aspirate the syringe. 
o After negative aspiration (i.e. no bubbles or blood), inject 5 mL of solution into rib space.  
• 
Ultrasound Guided: 
o Visualize the rib and intercostal space of interest with the high frequency ultrasound probe.  
o Note the presence or absence of pneumothorax on ultrasound examination. 
ü Pneumothorax defined by absence of lung sliding on exam. 
o Under direct visualization, advance needle down onto the rib of interest.  
ü Note: Keep tip of needle in view at all times to ensure correct depth. 
o Reposition needle just caudal the rib of interest.  
o Inject 5mL of local anesthetic with needle tip placed just superficial the pleural surface. 
o Withdraw needle and check for pneumothorax at the end of the procedure. 
  
 
 
9. Repeat procedure as outlined in step 7 for each fracture including one level above and below known fractures. 
10. Post-Block measurements to be obtained. (Note: should be ~15-60 minutes after completion) 
• 
Global numeric pain score and Thoracic specific numeric pain score. 
• 
Vital Capacity and Incentive Spirometry. 


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Thomas Carver, MD – Principal Investigator 
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Appendix III. Acute Pain Management Protocol 
 
Scheduled Medications to start on Admission  
- 
Acetaminophen 1000mg PO q 6 hours 
o 
If liver disease/impairment or CrCl < 35ml/min è Acetaminophen 650mg q 8 hours 
- 
Ibuprofen 600mg PO q 6 hours OR Ketorolac 15mg IV q 6 hours 
o 
Patients must have GFR > 60 
o 
Must have no contra-indication to NSAID therapy (i.e. ASA use, allergy/sensitivity, concurrent ACE 
inhibitor use, other nephrotoxins, etc.) 
o 
Ulcer prophylaxis àIf on NSAID then Pantoprazole 40mg IV or PO Daily 
- 
Methocarbamol 500mg PO q 6 hours 
 
Intercostal Nerve Block (ICNB) Performed in the Emergency Department or on Admission. 
- 
Please see ICNB protocol for details on how to properly perform an ICNB. 
- 
Pre and Post ICNB: Global and Thoracic Pain scores, Vital Capacity, and Incentive Spirometry measurements. 
 
Ketamine / Placebo Protocol 
- 
Order placed in the Emergency Department upon patient enrollment. 
- 
“Ketamine/Placebo” solution to run at 1.5 mcg/kg/min with NO dosage adjustments. 
 
Opiate Therapy Protocol 
- 
All patients will be placed on IV opiate therapy for at least 24 hours following admission. 
- 
Initial Assessment of Pain on Admission through Numeric Pain Score (NPS) 
o 
All patients should have both a Global Score and a Thoracic Score. 
o 
Initial IV opiate medication choice per the discretion of the admitting physician. 
o 
Initial IV Opiate dosage per the discretion of the admitting physician. 
- 
Reassessment of NPS at 1 hours: 
o 
If NPS > 7 à Dosage of IV opiate should be doubled and administered as 2nd dose. 
o 
If NPS < 7 à Continue current IV opiate dosing. 
- 
Reassessment of NPS at 2 hours: 
o 
If NPS > 7 à Dosage of IV opiate should be doubled and administered as 3rd dose. 
o 
If NPS < 7 à Continue current IV opiate dosing. 
- 
Reassessment of NPS hourly / q2 hours: 
o 
If NPS > 7 à Dosage of IV opiate should be adjusted based on clinical scenario. 
o 
If NPS < 7 à Continue current IV opiate dosing.  
 
- 
Reassessment at 6 hours: 
o 
If Thoracic NPS > 7 à Patient should have a repeat ICNB performed. 
o 
If Thoracic NPS < 7 à Continue current opiate therapy. 
 
- 
IF patient receives a repeat ICNB: 
o 
Reassessment at 4 hours post-ICNB and Thoracic NPS > 7 à RAAPS to consider Epidural placement 
o 
Reassessment at 4 hours post-ICNB and Thoracic NPS < 7 à Continue current therapy. 
- 
IF patient DOES NOT receive repeat ICNB: 
- 
Continue reassessments and if Thoracic NPS > 7 à Repeat ICNB at time of that assessment. 


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Appendix IV. Froedtert Confusion Assessment Method (CAM) 
Figure 1. Froedtert Memorial Lutheran Hospital General Confusion Assessment Method Assessment. 
 
Feature 1 = Acute onset 
1. 
Is there evidence of an acute change in mental status from the patient's baseline? 
 
Feature 2 = Inattention 
1. 
Did the patient have difficulty focusing attention, for example, being easily distractible, or having difficulty keeping 
track of what was being said? 
a. 
Not present at any time during interview. 
b. 
Present at some time during interview, but in mild form. 
c. 
Present at some time during interview, in marked form. 
d. 
Uncertain. 
2. 
(If present or abnormal) Did this behavior fluctuate during the interview, that is, tend to come and go or increase 
and decrease in severity? 
a. 
Yes. 
b. 
No. 
c. 
Not applicable. 
3. 
(If present or abnormal) Please describe this behavior: 
 
Feature 3 = Disorganized thinking 
1. 
Was the patient's thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or 
illogical flow of ideas, or unpredictable switching from subject to subject? 
 
Feature 4 = Altered level of consciousness 
1. 
Overall, how would you rate this patient's level of consciousness? 
a. 
Alert (normal). 
b. 
Vigilant (hyperalert, overly sensitive to environmental stimuli, startled very easily). 
c. 
Lethargic (drowsy, easily aroused). 
d. 
Stupor (difficult to arouse). 
e. 
Coma (unarousable). 
 
Note: The diagnosis of delirium by CAM requires the presence of features 1 and 2 and either 3 or 4. 
 
Figure 1. Froedtert Memorial Lutheran Hospital General Confusion Assessment Method Assessment. 


PRO00024679 - “Ketamine Infusion Therapy for the Management of Acute Pain Rib Fracture Patients” 
 
Thomas Carver, MD – Principal Investigator 
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Appendix V. Froedtert Confusion Assessment Method Intensive Care Unit (CAM-ICU)  
 
Figure 1. Froedtert Memorial Lutheran Hospital Intensive Care Unit Confusion Assessment Method Assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Thomas Carver, MD – Principal Investigator 
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Figure 2. Nursing Delirium Screening Scale (Nu-DESC) 
 
Nursing Delirium Screening Scale (Nu-DESC) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gaudreau JD, et al. Gen Hosp Psychiatry. 2005;27(3):194-9. 
 
 
 
 
 
 
 
 
 
 
Gaudreau JD, et al. Gen Hosp Psychiatry. 2005;27(3):194-9 
 
Appendix VI: Rib Fracture Sign 
NU-DESC >2 
Sensitivity=85.7% 
Specificity=86.8% 
NU-DESC >2 
Sensitivity=85.7% 
Specificity=86.8% 
Disorientation 
0 - Alert, orientated to person, place and time 
1 - Disoriented but easily reoriented 
2 - Disoriented x2 or x3, not easily oriented 
Inappropriate behavior 
0 – Calm and Cooperative 
1 – Restless but cooperative 
2 - Agitated, pulling at devices, climbing over side rails 
Inappropriate communication 
0 - Appropriate 
1 - Unclear thinking or rambling speech 
2 - Incoherence, nonsensical or unintelligible speech 
Illusions/Hallucinations 
0 - None Noted 
1 - Paranoia, fears 
2 - Hallucinations, distortions of visual objects 
Psychomotor 
0 - None 
1 - Delayed or slow responsiveness 
2 - Excessive sleeping, somnolent, lethargic 


PRO00024679 - “Ketamine Infusion Therapy for the Management of Acute Pain Rib Fracture Patients” 
 
Thomas Carver, MD – Principal Investigator 
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RI B FRACTURE 
PATI ENT 
 
Please document 
''Thoracic Pain Scores''