Clinical trial NCT02749968
Conditions: Blunt Chest Wall Trauma Rib Fracture Sternal Fracture
Sponsor: University of Cincinnati
Start date: 2018-03-09; Completion date: 2021-01-01
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of liposomal bupivacaine for pain control in patients with blunt chest wall trauma.

Detailed description:
The purpose of this study is to evaluate the efficacy of liposomal bupivacaine to provide analgesia via paravertebral intercostal nerve block following significant blunt chest trauma, minimizing adverse outcomes, length of stay and overall narcotic use. The primary outcome of the study is to compare requirements between the bupivacaine group and a standard-of-care group.

Arms: arm 1: 1 mL of liposomal bupivacaine injected with a 25-G needle just below each affected rib by the intercostal neurovascular bundle in a paraspinal position arm 2: 1 mL of 0.9% saline injected with a 25-G needle just below each affected rib by the intercostal neurovascular bundle in a paraspinal position
Interventions: intervention 1: Liposomal bupivacaine intervention 2: 0.9% sodium chloride
Intervention descriptions: intervention 1: 1 mL of liposomal bupivacaine injected with a 25-G needle just below each affected rib by the intercostal neurovascular bundle in a paraspinal position intervention 2: 1 mL of 0.9% saline injected with a 25-G needle just below each affected rib by the intercostal neurovascular bundle in a paraspinal position

Protocol documents:
Prot_SAP_000.pdf: 
 
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Page 1 of 27 
 
Study Title: 
Intercostal Liposomal Bupivacaine for the Management of Blunt Chest Wall Trauma 
 
Research Team: 
 
Principal Investigator: 
Michael Goodman, MD 
 
Co-Principal Investigator: 
Christopher Droege, PharmD 
 
 
 
 
 


 
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1. Length of time for research 
a. Subject enrollment, data collection, and regulatory reporting: 18 months 
b. Statistical analysis of data: 2 months 
c. Manuscript and poster preparation, writing, and publication: 4 months 
 
2. Research Location(s): University of Cincinnati Medical Center (UCMC) and UC 
Medical Science Building 
 
3. Abstract/Brief Overview:  
Polytrauma patients with rib fractures are at risk for poor pain control resulting in 
adverse pulmonary outcomes, including the development of pneumonia or 
respiratory failure. Liposomal bupivacaine provides a novel medication and 
administration route that may prevent the need for rescue intubation and 
development of pneumonia, avoid epidural use, and improve overall patient 
satisfaction and pain control.  This study plans to enroll adult, polytrauma 
patients with blunt chest wall trauma resulting in rib and/or sternal fractures to 
receive either liposomal bupivacaine or normal saline intercostal nerve injections 
in addition to current standard of care (including intravenous, oral, or epidural 
narcotics).  Patients will be excluded if they have a known allergy to bupivacaine, 
respiratory failure requiring intubation within 24 hours of enrollment, have a 
known atrioventricular nodal blockade process, hemodynamic instability, active 
myocardial infarction, greater than 20 rib fractures, or if they are pregnant or 
actively incarcerated.  The purpose of this study is to evaluate the efficacy of 
liposomal bupivacaine to provide analgesia via posterior intercostal nerve block 
following significant blunt chest trauma, minimizing adverse outcomes and length 
of stay and overall narcotic use. The primary outcome of this study is to compare 
opioid requirements between groups.  Secondary outcomes include comparison 
of clinical outcomes and treatment failures (e.g., development of pneumonia; 
median patient analgesic score by verbal numerical rating scale [NRS]; median 
time to first breakthrough opioid dose; incentive spirometer [IS] ability; intensive 
care unit [ICU] length of stay [LOS]; hospital LOS; use of additional analgesia 
adjuncts) and to perform a cost effective analysis.    
 
4. Purpose of Study:  
The primary purpose of this pilot study is to compare opioid requirements 
between groups receiving intercostal liposomal bupivacaine to standard of care 
for acute traumatic pain related to blunt chest wall trauma with resultant rib 
and/or sternal fractures.  Pain scores will be evaluated using the NRS 
(Appendix). Uncontrolled analgesia following rib fractures can result in intubation, 
pneumonia, prolonged length of stay, and death. Achieving adequate pain control 
in native airway patients prevents clinical challenges. Multimodal analgesia 
regimens are necessary to optimize patient outcomes and prevent untoward 


 
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effects of opioid analgesia. Liposomal bupivacaine offers a novel therapy that 
may revolutionize pain management in patients with rib fractures. Pain control 
with one injection may provide analgesia for up to 96 hours through a unique 
mechanism of action and site of application. Overall, the combination of a 
nonopioid analgesic, liposomal bupivacaine, with standard of care may lead to 
improved analgesia with fewer adverse effects.  Specific aims include to 1) 
compare opioid requirements (in morphine equivalents) between patients with 
blunt chest wall trauma and rib and/or sternal fractures receiving liposomal 
bupivacaine versus standard of care; 2) compare clinical outcomes and 
treatment failures including development of pneumonia, median patient analgesia 
score using verbal NRS, median time to first breakthrough opioid dose, IS ability, 
ICU LOS, hospital LOS, and use of additional analgesic adjuncts; 4) and to 
perform a cost-effectiveness analysis 
 
5. Background:  
Background and Significance 
Blunt chest wall trauma remains the second most common injury observed in 
non-intentional injury-related death in the U.S.A. and accounts for 10% of 
trauma-related emergency department visits worldwide.1-3  Current literature has 
identified high morbidity and mortality rates for patients suffering from blunt chest 
wall trauma, with mortality ranging from 4 to 20%.2,4 The prevalence of rib 
fractures among blunt chest wall trauma patients requiring hospital admission is 
4 to 10%.5 One of the most prominent contributing factors to blunt chest wall 
trauma morbidity is pain.6-8 The management of resultant pain serves as a core 
intervention in managing these patients.8   
 
The standard of care for analgesia in trauma patients with rib fractures is the use 
of multimodal pharmacotherapy, which includes opioids administered via 
continuous infusion epidural routes,  intermittent intravenous push, or oral dosing 
or provided as patient-controlled analgesia.9,10 Although opioid agents can 
provide effective analgesia, they exhibit untoward effects that may be dose 
limiting. These adverse effects include hypotension, bradycardia, central nervous 
system depression, and respiratory depression.9 Patients may not achieve 
adequate pain relief when doses are limited because of the risk of these 
effects.11 Consequences of uncontrolled pain from rib fractures in trauma patients 
include exhaustion due to lack of sleep, disorientation, agitation, stress response, 
post-traumatic stress disorder, pneumonia, and death.9,12 Multimodal therapeutic 
strategies may be used in an effort to limit the need for opioids in this population, 
and newer analgesic agents may be incorporated into these strategies to achieve 
optimal analgesia.13 
 


 
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Bupivacaine liposomal injectable suspension is a novel formulation of the amide-
type anesthetic, bupivacaine, approved by the Food and Drug Administration for 
local infiltration into surgical sites to produce postsurgical analgesia.13 This 
formulation allows for the prolonged release of bupivacaine from multivesicular 
liposomes, providing anesthetic effects that can be observed for up to 96 hours. 
Side effects of liposomal bupivacaine infiltrated locally are generally mild and 
include nausea, constipation, and vomiting. Pyrexia, dizziness, peripheral 
edema, anemia, hypotension, pruritis, and procedural pain occurred in clinical 
trials at lower rates.14 
 
Bupivacaine liposomal injectable suspension has been shown to improve 
analgesia scores and decrease opioid use when infiltrated locally at the surgical 
site in a variety of procedure types, including hemorrhoidectomy and 
bunionectomy.15-17 Similar results of lower pain scores and decreased opioid use 
with liposomal bupivacaine compared to standards of care have been shown for 
patients undergoing mammoplasty, ileostomy reversal, and open colectomy.18-21 
Conventional bupivacaine, when administered as a single nerve block, has a 
duration of activity of 8 to 24 hours.22 Liposomal bupivacaine, given its prolonged 
release, has the potential to provide anesthetic activity at the nerve site beyond 
24 hours. Animal studies and phase 1 trials in healthy volunteers have shown 
safety with use of liposomal bupivacaine as a peripheral nerve block.23  
 
Further investigation is needed to fully evaluate this route of administration. This 
study aims to assess the efficacy of liposomal bupivacaine when used as a 
regional block compared to standard of care for analgesia in trauma patients with 
rib fractures. This has only been done in case reports and preliminary studies to 
date.24-26 
 
Study Justification 
The potential utility of liposomal bupivacaine in trauma patients suffering from 
multiple rib or sternal fractures is unknown. Recent evidence has shown 
pharmacodynamic benefits of liposomal bupivacaine through prolonged pain 
relief and subsequent opioid reduction. The sustained analgesia may also reduce 
the likelihood of respiratory failure, development of pneumonia, increased length 
of stay, and patient mortality.  The purpose of this study is to evaluate the 
efficacy of liposomal bupivacaine to provide analgesia via posterior intercostal 
nerve block following significant blunt chest trauma, minimizing adverse 
outcomes and length of stay and overall narcotic usage. 
 
Intercostal nerve blockade has been chosen over paravertebral block, as the 
intent of the study is to identify a therapeutic strategy that can be employed 
based on standard training for emergency medicine or surgery practitioners. Both 


 
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emergency medicine and surgery practitioners are familiar with intercostal blocks 
for placement of tube thoracostomy. Intercostal blocks do not require additional 
training, as would be done in the setting of a pain medicine fellowship, and do not 
incur the risks of hypotension associated with epidural catheters. Additionally, 
intercostal and paravertebral blocks carry similar risks of pneumothorax or 
intercostal neurovascular bundle injury.  
 
 
Study design:  
This is an investigator-initiated, single-center, prospective, double-blinded, 
placebo-controlled trial funded by the United States Air Force.  Multi-system, 
adult trauma patients greater than or equal to 18 years of age admitted to the 
University of Cincinnati Medical Center (UCMC), an urban American College of 
Surgeons-verified Level 1 trauma center with more than 3500 annual trauma 
admissions annually will be identified by the research team. Patients will be 
screened and those who meet all inclusion/exclusion criteria will be approached 
for informed consent by study personnel in their rooms.    Informed consent will 
be obtained prior to enrollment and any study procedures are done. Patients will 
then receive either receive 1 mL of liposomal bupivacaine just below each 
affected rib or 0.9% sodium chloride peri-intercostal subcutaneous injection (as 
placebo control) via a 25-G needle.  Goal enrollment is 200 patients with 100 
patients in each group.  Patients included in the study will be followed during 
inpatient hospitalization through discharge. 
 
 
6. Research data collection/study procedures:  
Intervention 
Patients will be identified on admission and will be screened by 
inclusion/exclusion criteria.  After informed consent is obtained they will be 
randomized into one of two possible groups: 
a. Liposomal bupivacaine intercostal (group 1; interventional) 
b. 0.9% sodium chloride peri-intercostal subcutaneous (group 2; placebo-
control)   
Patients will be placed on continuous monitoring of heart rate, EKG, and pulse 
oximetry. Blood pressure and respiratory rate will be measured every 5 to 10 
minutes during the procedure and every at least 15 minutes for the first hour after 
the procedure. All patients undergoing injection will remain on heart rate, EKG, 
and pulse oximetry monitoring by telemetry for 96 hours following injection.  
 
In addition, while in the ICU all study subjects will monitored with a non-invasive 
respiratory monitor (Expiron) to determine respiratory rate, tidal volume, minute 
volume and breathing pattern for up to 96 hours.  This monitoring will aid in 


 
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detection of respiratory depression and add additional safety to the trial.  This 
device measures chest expansion by thoracic impedance and is FDA approved. 
 
Supplemental oxygen will be provided to maintain a peripheral oxygen saturation 
of 90% or greater. 
 
Injections will be performed by trained trauma / critical care physicians. Training 
prior to initiating the study will include familiarization with the standardized 
procedure as described below, which will be documented in study records. 
Patients will be monitored by bedside nurses before, during, and after the block 
procedure. Standard inpatient cardiac arrest carts will be immediately available 
before, during, and after the block procedure.  
 
A 20-mL vial will be obtained from IDS Pharmacy that either contains liposomal 
bupivacaine (266 mg in 20-mL) or 0.9% sodium chloride.  Patients will be 
positioned either sitting up or in logroll/decubitus position. Rib fractures will be 
noted from previously obtained CT scan of the chest from initial trauma 
evaluation. The thoracic posterolateral area will be prepped and draped in sterile 
fashion. After aspiration to prevent intravascular injection, 1 mL of liposomal 
bupivacaine will be injected with a 25-G needle just below each affected rib by 
the intercostal neurovascular bundle in a posterior but not paravertebral position 
or 0.9% saline (as placebo control) will be injected with a 25-G needle in the 
subcutaneous space just superficial to each affected rib to minimize risk of 
placebo-injection complications. Optimal regional blockade will include the rib 
immediately above the most superior and the rib immediately below the most 
inferior fractured rib.  
 
Regional blockade will only be performed once per patient enrolled in the study 
and at one injection site per fractured rib. Patients will only be enrolled once per 
acute traumatic event and admission. 
 
If a patient enrolled in the study should have an adverse event during the course 
of intercostal rib block administration and the reaction is severe or life-
threatening, then the patient will be withdrawn from the study and no further 
injections will be administered, regardless of how many injections were originally 
planned.   
 
A chest xray will be obtained as clinically indicated following the procedure if 
there is concern for the development of pneumothorax. 
 
Self-reported pain will be measured using the verbal NRS, a 0-10 ordinal scale 
(e.g., 0 = “no pain”; 10 = “worst pain imaginable”).27 Breakthrough opioid dosing 


 
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will be guided by a formal inpatient analgesia protocol.  Pain assessments will 
occur every 6 hours or per standard of care for the appropriate setting (e.g., 
intensive care unit, trauma ward) for the first 96 hours. All opioid dosing will be 
converted to oral morphine equivalents for comparison purposes. Time to first 
breakthrough opioid dose will be recorded.  Incentive spirometry will be used and 
assessed and recorded by respiratory therapist, with adjunct inspiratory 
assistance (e.g., EzPAP) applied per our institutional volume expansion protocol.  
 
Follow-up will occur daily by study coordinators and trauma service physicians 
for the first 96 hours after block procedure, then daily by the trauma service 
physicians for 14 days or until discharge from the hospital if it occurs earlier.   
 
Standard of care analgesia regimen on the trauma service will be provided to all 
patients enrolled in the study, regardless of liposomal bupivacaine or placebo 
injection. This regimen will be per the Trauma acute multimodality pain 
management protocol (Appendix).  
Typical escalation of analgesics provided for these patients, as deemed 
medically appropriate based on age and comorbid medical conditions, includes 
(in order of addition to regimen): 
• Acetaminophen, oral or enteral 
• NSAIDs, ibuprofen or ketorolac 
• Lidocaine 5% transdermal patch 
• Oral or enteral tramadol 
• Oral or enteral hydrocodone or oxycodone 
• IV morphine or hydromorphone, intermittent dosing 
• Patient controlled analgesia morphine or hydromorphone 
• Long-acting narcotics, including methadone, oxycodone ER, or morphine 
ER 
• Neuromodulating adjuncts, including gabapentin or pregabalin 
• Epidural analgesia catheter placement 
 
During this time all adverse events will be recorded.  Subjects who experience 
serious adverse events will be followed until the event resolves.  If necessary 
these patients will be followed up by weekly phone calls as well as at the 
standard of care clinic visit two weeks post-discharge.   
 
Randomization 
Following informed consent, patients will undergo 2x1 block randomization to 
ensure equal allocation to each intervention group.  Randomization will be 
performed by study personnel and will be blinded as there will be placebo 
injections for patients randomized into group two and the same number of 
injections would be used regardless of intervention arm. 


 
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Data Collection:  
Verbal NRS, pain assessment data, opioid use, and time to first opioid 
breakthrough dose will be collected as previously described. Portable spirometry 
will be used daily to objectively and serially assess lung function. Additional data 
collection points include patient sex, age, weight, body mass index, body surface 
area, injury severity score, chest abbreviated injury score, and ICU and hospital 
length of stay.  Safety will be evaluated by the occurrence of a priori serious 
adverse events. Costs will be evaluated utilizing hospital and pharmacy 
databases. 
 
Schedule of subject identification and data collection 
Subjects will be identified based on inclusion criteria at the time of admission to 
the trauma service following evaluation in the emergency department. Subjects 
meeting inclusion criteria will be enrolled within 6 hours of admission. Vitals 
monitoring will occur during the intercostal nerve block procedure and continue 
by telemetry for the next 96 hours or until hospital discharge, whichever occurs 
first.  
 
7. Specimen collection:  
No serum assays are necessary for this study and will not be collected. 
 
8. Potential Benefits:  
Blunt chest wall trauma remains a common injury seen in non-intentional injury-
related deaths.  It accounts for nearly 10% of trauma-related emergency 
department visits worldwide and is associated with high morbidity and mortality.  
This morbidity and mortality are influenced by the pain experienced by these 
events which can involve rib or sternal fractures as instigating stimuli.  
Uncontrolled analgesia following rib fractures can result in intubation, pneumonia, 
prolonged length of stay, and death. Achieving adequate pain control in native 
airway patients prevents clinical challenges. Multimodal analgesia regimens are 
necessary to optimize patient outcomes and prevent untoward effects of opioid 
analgesia (e.g., hypotension; bradycardia; central nervous system depression; 
respiratory depression). 
 
Liposomal bupivacaine offers formulation that provides prolonged yield of the 
anesthetic properties up to 96 hours.  It has been shown to improve analgesia 
scores and decrease opioid requirements when used locally at surgical sites 
such as bunionectomies and hemorrhoidectomies (Figure 1a).  It has also been 
shown to reduce the time to first opioid dose needed (Figure 1b).  Reductions in 
opioid requirements have also been appreciated.   
 


 
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Figure 1. Cumulative postsurgical pain score in hemorrhoidectomy patients15  
 
Figure 2. Cumulative portion of patients requiring opioid therapy post-
hemorrhoidectomy15 
 
Patients randomized into the standard analgesia plus placebo intercostal 
injection group will benefit from increased nursing attention to pain score 
assessment and treatment as well as increased respiratory therapist attention to 
pulmonary toilet and objective assessments of spirometry volume capacities. 
Patients randomized into the standard analgesia plus liposomal bupivacaine 
group will additionally receive the anticipated benefit of intercostal nerve blocks 
for improved analgesia. 
 


 
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In addition, all subjects will be monitored with a non-invasive respiratory monitor 
(Expiron) to determine respiratory rate, tidal volume, minute volume and 
breathing pattern.  This monitoring is in addition to standard care and will aid in 
detection of respiratory depression and add additional safety to the trial.   
 
 
Future patients can benefit from the cultivation of this knowledge to have both 
potential patient benefit (e.g., decreased morbidity and mortality; improved pain 
scores; decreased risk of pneumonia) and cost-savings (e.g., decreased 
medication requirement; less time in the ICU or hospital). Overall, optimal use of 
liposomal bupivacaine may help improve patient pain scores, pulmonary toilet 
and ability to use IS, and decrease the need for opioid therapy.  Improved patient 
outcomes, expansion of scientific knowledge, and development of new blunt 
chest wall trauma pain protocols may result.  
 
9. Potential Risks, Discomforts, and inconveniences:  
Level of Risk 
Consequences of poorly controlled pain associated with rib and/or sternal 
fractures as well as opioid use have been previously outlined above. Risks of 
liposomal bupivacaine include major and minor adverse events (Tables 1 and 2). 
Risks will be mitigated by appropriate exclusion of patients with low and high 
body weights as well as known cardiac history as previously described to 
minimize pharmacodynamic failure or excess.   
 
Table 9.1. Adverse events occurring in >2% of patients in any treatment group15,17,31 
 


 
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Table 9.2. Incidence of serious adverse events occurring in >1 patient in any 
treatment group30 
Cardiac and neurotoxicity that are generally seen with increased serum 
bupivacaine concentrations (i.e. >2000 ng/mL) should serve minimal risk as 
concentrations seen in previous studies using the maximum FDA-approved dose 
of 266 mg of liposomal bupivacaine measured maximum concentrations of 867 
and <300 ng/mL each.15, 28-29 Patients will require and be monitored by a central 
cardiac monitoring unit to assess for any changes in heart rate or rhythm for the 
first 96 hours at minimum. 
 
There may be temporary pain or local discomfort associated with repeated 
intercostal injections. Additionally, there will be a small risk of a pneumothorax if 
the intercostal injection needle violates the parietal pleura. 
 
Additionally, the trauma team will have discretion to hold or stop enoxaparin 
doses if patient is deemed to have bleeding.  Patients may also have doses held 
due to perioperative plans.  This will also allow for appropriate, safe patient care.  
 
If a patient enrolled in the study should have an adverse event during the course 
of the intercostal rib block administration and the reaction is severe or life 
threatening, then the patient will be withdrawn from the study and no further 
injections will be administered, regardless of how many injections were originally 
planned. In addition, an adverse event based on physiologic response will 
include a sustained (greater than five minute) change in heart rate by > 40% from 
baseline or absolute heart rate greater than 160 or less than 50, change in 
systolic blood pressure by 40% or absolute systolic blood pressure less than 80 
mmHg or greater than 180 mmHg, change in respiratory rate by 50% or absolute 
respiratory rate greater than 30 or less than 6, or decreasing oxygen saturation 


 
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by 10% SpO2 or less than absolute SpO2 < 85%.Any non-sinus rhythm or ST 
segment changes seen on the EKG monitoring strip will lead to immediate 
subject discontinuation. 
 
Safety Assessments 
 
Every adverse event, whether or not thought to be related to study drug, will be 
recorded and entered into the RAVE Case Report Form database.   
 
Any medical condition present prior to study enrollment should not be reported as an 
adverse event, unless the medical condition worsens in severity or seriousness during 
the study.  In this case it may be reported as an adverse event at the discretion of the 
Investigator. 
 
The Investigator will review each event and assess its severity and relationship to the 
study treatment.   
 
Adverse event Definitions: 
 
Adverse Event  
Adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality. An adverse event can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 
 
Suspected Adverse Reaction  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
 
Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are 
a subset of all suspected adverse reactions where there is reason to conclude that the 
drug caused the event. 
 


 
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Unexpected  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended.  
 
Serious  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: Death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 
Life-Threatening  
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
 
 
 
Table 9.3. Causality Definitions: 
Causality term 
Assessment criteria* 
Certain 
• Event or laboratory test abnormality, with 
plausible time relationship to drug intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible 
(pharmacologically, pathologically) 
• Event definitive pharmacologically or phenomenologically 
(i.e. an objective and specific medical disorder or a 
recognised 
pharmacological phenomenon) 
• Rechallenge satisfactory, if necessary 


 
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Probable/ Likely 
• Event or laboratory test abnormality, with 
reasonable time relationship to drug intake 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Rechallenge not required 
Possible 
• Event or laboratory test abnormality, with 
reasonable time relationship to drug intake 
• Could also be explained by disease or other drugs 
• Information on drug withdrawal may be lacking or unclear 
Unlikely 
• Event or laboratory test abnormality, with a time to drug 
intake that makes a relationship improbable (but not 
impossible) 
• Disease or other drugs provide plausible explanations 
Conditional/ 
Unclassified 
• Event or laboratory test abnormality 
• More data for proper assessment needed, or 
• Additional data under examination 
Unassessable/ 
Unclassifiable 
• Report suggesting an adverse reaction 
• Cannot be judged because information is 
insufficient or contradictory 
• Data cannot be supplemented or verified 
 
 
 


 
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Table 9.4. Toxicity Grading Scale: 
  
Local 
Reaction to 
Injectable 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of non- 
narcotic pain reliever 
> 24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness*  
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling**  2.5 – 5 cm and 
does not 
interfere with 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
*In addition to grading the measured local reaction at the greatest single diameter, the 
measurement should be recorded as a continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the 
actual measurement. 
Vital Signs * 
Mild (Grade 1) 
Moderate(Grade 2) Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
 (°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats per 
minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats per 
minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) - 
mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension (diastolic) 
- 
mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension (systolic) – 
mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – 
breaths 
17 – 20 
21 – 25 
> 25 
Intubation 
* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 - 100 beats per minute. Use clinical judgment when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes. 
 
 


 
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Systemic (General) 
Mild (Grade 1) 
Moderate(Grade 2) Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity or 1 – 
2 episodes/24 
hours 
Some interference 
with activity or > 
2 episodes/24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 – 3 loose stools 
or 
< 400 gms/24 
hours 
4 – 5 stools or 
400 – 800 
gms/24 hours 
6 or more watery 
stools or 
> 800gms/24 hours 
or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with 
activity 
Repeated use of 
non- 
narcotic pain 
reliever > 24 hours 
or some 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
 
Table 9.4 extracted from: Guidance for Industry, Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials, 
U.S. Department of Health and Human Services, Food and Drug Administration, 
Center for Biologics Evaluation and Research, August 2016 
 
Treatment of cardiovascular and neurologic adverse events 
• Local anesthetic systemic toxicity  
o Treatment will be initiated as recommended as the American Society of 
Regional Anesthesia and Pain Medicine, according to the society’s 
checklist (Appendix) 
• Treatment will include: transfer to intensive care unit setting if not already in 
intensive care unit, continuous hemodynamic monitoring for at least 24 hours, 
appropriate airway management with assistance from respiratory therapy and a 
critical care consultant as needed, cardiovascular stabilization and assistance 
from a critical care consultant as needed, administration of Lipid Emulsion 
therapy, as per ASRA checklist in Appendix, Neurology consult for any observed 
systemic neurologic toxicity (including change in vision, mental status change, 
persistent headache, seizure), Cardiology consult for any arrhythmias that persist 
greater than 30 minutes, beyond initial appropriate medical treatment, or result in 
hypotension with systolic blood pressure < 80mmHg. 
 


 
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10. Data Safety monitoring plan and/or DSMB:  
Patients will be screened for the adverse events described above.   
 
Adverse events will be continuously assessed on an ongoing basis by Dr. 
Jason Schrager, medical monitor.  Study will be stopped if: 
  
• 
Adverse events probably/likely or certainly related to study drug, 
regardless of severity, occur in > 10% of enrolled patients, or  
• 
Serious/life-threatening adverse events, regardless of causality, 
occur in > 2% of enrolled patients. 
 
11. Data Analysis:  
Primary Endpoint  
1) Compare opioid requirements (in morphine equivalents) between trauma 
patients with rib and/or sternal fractures receiving liposomal bupivacaine 
versus standard of care. 
 
Secondary Endpoints  
1) Compare clinical outcomes and treatment failures including: 
a. Development of pneumonia, defined as >100,000 cfu/mL bacteria on 
bronchoalvelolar lavage, or clinically with leukocytosis, pulmonary 
infiltrate and fever 
b. Median patient analgesic score by verbal NRS 
c. Median time to first breakthrough opioid rescue dose 
d. Incentive spirometry serial volume capacity 
e. ICU LOS 
f. Hospital LOS 
g. Use of additional analgesia adjuncts 
i. Epidural catheter 
ii. Non-opioid analgesics (e.g., non-steroidal anti-inflammatory 
drugs; gabapentin; pregabalin; carbamazepine; ketamine; 
acetaminophen) 
2) Perform a cost-effectiveness analysis 
3) Calculate dose and exposure of lidocaine or bupivacaine over time from 
Lidoderm patches, intercostal nerve blocks, or epidural catheters 
 
Statistical analyses will be performed using SAS.  An intention-to-treat model will 
be used for data analysis.  Patients randomized into the treatment arm will be 
included in the primary outcome analysis.  Patients withdrawn from the study will 
have data included up to the point of withdrawal.  Nominal data will be reported 
using frequencies of occurrence and proportions as appropriate. Continuous data 
will be reported using means and standard deviations or medians and 


 
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interquartile ranges as appropriate per distribution. Hypothesis testing for 
nominal data will be performed using the Fisher’s exact test or chi square test as 
required based on sample size. Continuous data will be compared using 
student’s t-test/ANOVA or rank sum/Kruskal-Wallis ANOVA for normally 
distributed and non-normally distributed data, respectively as appropriate. A p-
value < 0.05 will designate statistical significance.  Costs associated with the 
cost-effectiveness analysis will be pulled from hospital and pharmacy databases. 
 
Given the pilot nature of the study, a total of 200 patients will be enrolled. 
Assuming a 96-hour requirement of 250-mg oral morphine equivalents 
(approximately 12.5-mg IV hydromorphone), we anticipate a 20% reduction to 
200-mg oral morphine equivalents (approximately 10-mg IV hydromorphone) 
resulting in an expected difference in means of 50 mg and an anticipated 
standard deviation of 50 mg. To achieve an 80% power with an alpha of 0.05 for 
this primary outcome, the goal enrollment is 200 patients. 
 
12. Data storage and confidentiality (include sample storage if applicable)  
This project will use Medidata Rave® as its Electronic Data Capture (EDC) 
software, which is a robust EDC platform for capturing, managing and reporting 
clinical research data. This system includes a robust query management system 
based on the Data Quality Plan, which will identify data quality checks to be 
programmed into the database design. Frequent monitoring of the database 
throughout the study will allow for corrective action to be taken quickly if 
problems are identified with the data collection process.  The database will be 
password protected and appropriately secured such that only authorized study 
personnel will have access to the data.  Data will be maintained in a confidential 
manner with regular reminders of the need for confidentiality provided from the 
senior investigator. A single subject log will be kept by the principal investigators 
for matching patient study number, initials, medical record number, and 
admission date (attached). Once assigned to the log, patients will only be 
evaluated using their de-identified, study number.  Data entered into the 
electronic database will be de-identified. 
 
Once the study has been completed, the subject log will be destroyed and only 
the de-identified electronic database will be kept.  Only study personnel will have 
access to the data.  
 
13. Study Population  
UCMC is an urban, academic American College of Surgeons-verified Level 1 
trauma center that treats over 3500 trauma patients each year.  Patients 
admitted to the UCMC trauma service are eligible for enrollment. Patients will be 
screened on admission or identified per the daily trauma census. Trauma team 


 
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physicians may also contact study personnel daily once a patient is identified as 
a potential candidate. Study personnel will screen subjects for inclusion and 
exclusion. If patient meets inclusion criteria, then consent will be administered by 
study personnel (see section 14). 
 
Inclusion Criteria 
a. Patients with an anticipated length of stay of at least 72 hours 
b. Trauma patients with two or more rib or sternal fractures 
c. Patients demonstrating the inability to achieve greater than 50% predicted 
inspiratory capacity based on ideal body weight using IS within the first 24 
hours of admission (Appendix) 
d. Adults age 18 and older 
 
Exclusion Criteria  
a. Patients with a known allergy to bupivacaine 
b. Respiratory failure requiring intubation within 24 hours prior to enrollment 
c. Patients with known or suspected atrioventricular nodal blockade process 
requiring cardiology evaluation and/or pacemaker placement 
d. Hemodynamic instability (defined as a new intravenous vasopressor or 
inotrope requirement [e.g., norepinephrine; epinephrine; phenylephrine; 
dobutamine; milrinone] or a mean arterial pressure < 55 mmHg) 
e. Signs of active myocardial ischemia or non-ST elevation MI  
f. Patients with greater than 20 rib fractures (20-mL vial [266-mg dose]; 1-mL 
[13.3 mg] per rib) 
g. Weight < 50 kg or > 150 kg 
h. Pregnancy as defined by urine pregnancy test in all females of child-bearing 
potential 
i. Incarceration  
j. Inability to obtain informed consent 
k. Severe traumatic brain injury, GCS <8 
 
Patients will be followed for outcome assessment during hospitalization through 
discharge. 
 
14. Consenting process and plan  
Patients will be identified as previously described and permission to consent per 
the trauma team attending will be obtained prior to administration of consent. 
Study personnel will administer consent in the patient’s room. Patients who meet 
inclusion and exclusion criteria will be eligible for consent.  Informed consent will 
be obtained prior to randomization into treatment arms.  Patients unable to give 
consent will have LAR or next of kin consented. LAR must show proof of health 
care POA or court document. A copy of the documents will be kept with the 


 
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consent form. Next of kin is a person who may act as LAR without a document 
granted by court. Next of kin will be determined by team social workers’ note. 
The order in which the next of kin may act as LAR is: spouse, parent, adult son 
or daughter, adult brother or sister. If next of kin available at the time of consent 
cannot agree, the person cannot participate in the research.  Investigators will be 
available seven days a week and will continue correspondence with subjects 
throughout the study for up to 7 days or until hospital discharge, whichever 
comes first.   
 
Subjects can withdraw from the study at any time per their desire or may be 
withdrawn at the discretion of the trauma team. Subjects will be withdrawn as 
appropriate based on any adverse event that may occur as described above in 
Section 9. Any subject who withdraws will be placed on standard of care.  
 
15. Compensation:  
Patients will not receive any compensation for research involvement.  
 
16. Subject costs:  
There are no additional costs to subjects.  
 
In case of injury or illness related to the study, the University of Cincinnati 
Medical Center will provide emergency medical care at no cost to the subject.  
The University of Cincinnati will review each case and determine on a case by 
case basis whether to reimburse any out of pocket expenses. 
 
 
18. Literature cited  
1. Gage A, Rivara F, Wang J, et al. The effect of epidural placement in patients 
after blunt thoracic trauma. J Trauma Acute Care Surg 2014 Jan;76(1):39-45. 
2. Ziegler DW, Agarwal NN. The morbidity and mortality of rib fractures. J 
Trauma 1994 Dec;37(6):975-9. 
3. Quaday KA. Morbidity and mortality of rib fractures. J Trauma 1995;39:617. 
4. Battle CE, Hutchings H, Evans PA. Risk factors that predict mortality in patients 
with blunt chest wall trauma: a systematic review and meta-analysis. Injury 2012 
Jan;43(1):8-17. 
5. Lee RB, Bass SM, Morris JA Jr, MacKenzie EJ. Three or more rib fractures as an 
indicator for transfer to a Level I trauma center: a population-based study. J 
Trauma 1990 Jun;30(6):689-94. 
6. Kerr-Valentic MA, Arthur M, Mullins RJ, et al. Rib fracture pain and disability: can 
we do better? J Trauma 2003 Jun;54(6):1058-63. 
7. Flagel BT, Luchette FA, Reed RL, et al. Half-a-dozen ribs: the breakpoint for 
mortality. Surgery 2005 Oct;138(4):717-23. 


 
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8. Sirmali M, Turut H, Topcu S, et al. A comprehensive analysis of trauma rib 
fractures: morbidity, mortality, and management. Eur J Cardiothorac Surg 2003 
Jul;24(1):133-8. 
9. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the 
management of pain, agitation, and delirium in adult patients in the intensive care 
unit. Crit Care Med 2013;41:263-306. 
10. Smythe M. Patient-controlled analgesia: a review. Pharmacother 1992;12:132-
43. 
11. Pergolizzi J, Boger RH, Budd K, et al. Opioids and the management of chronic 
severe pain in the elderly: consensus statement of an International Expert Panel 
with focus on the six clinically most often used World Health Organization Step III 
opioids. Pain Pract 2008;8(4):287-313. 
12. Bulger EM, Arneson MA, Mock CN, Jurkovich GJ. Rib fractures in the elderly. J 
Trauma 2000; 48(6): 1040-7. 
13. Tong YCI, Kaye AD, Urman RD. Liposomal bupivacaine and clinical outcomes. 
Best Pract Res Clin Anesthesiol 2014; 28(1): 15-27. 
14. Candiotti K. Liposomal bupivacaine: an innovative nonopioid local analgesic for 
the management of postsurgical pain. Pharmacotherapy 2012; 32(9 Suppl): 19S-
26S. 
15. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release 
liposome injection for prolonged postsurgical analgesia in patients undergoing 
hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled 
trial. Dis Colon Retum 2011; 54: 1552-9. 
16. Haas E, Onel E, Miller H, et al. A double-blind, randomized, active-controlled 
study for post-hemorrhoidectomy pain management with liposome bupivacaine, a 
novel local analgesic formulation. The American Surgeon 2012; 78(5): 574-81. 
17. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of 
DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in 
bunionectomy. Adv Ther 2011; 28(9): 776-88. 
18. Marcet JE, Nfonsam VM, Larach S. An extended pain relief trial utilizing the 
infiltration of a long-acting multivesicular liposome formulation of bupivacaine, 
Exparel (IMPROVE): a phase IV health economic trial in adult patients 
undergoing ileostomy reversal. J Pain Res 2013; 6: 549-55.  
19. Cohen SM. Extended pain relief trial utilizing infiltration of Exparel®, a long-acting 
multivesicular liposome formulation of bupivacaine: a phase IV health economic 
trial in adult patients undergoing open colectomy. J Pain Res 2013; 6: 567-72. 
20. Vogel JD. Liposome bupivacaine (Exparel®) for extended pain relief in patients 
undergoing ileostomy reversal at a single institution with a fast-track discharge 
protocol: an IMPROVE phase IV health economics trial. J Pain Res 2013; 6: 605-
10. 
21. Smoot JD, Bergese SD, Onel E, et al. The efficacy and safety of DepoFoam 
bupivacaine in patients undergoing bilateral, cosmetic, submuscular 


 
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augmentation mammoplasty: a randomized, double-blind, active-control study. 
Aesthetic Surg J 2012; 32(1): 69-76. 
22. Mulroy MF, Larkin KL, Batra MS, et al. Femoral nerve block with 0.25% or 0.5% 
bupivacaine improves postoperative analgesia following outpatient arthroscopic 
anterior cruciate ligament repair. Reg Anesth Pain Med 2001; 26: 24-9. 
23. Richard BM, Newton P, Ott LR, et al. Safety evaluation of EXPAREL 
(bupivacaine liposomal injectable suspension) administered by peripheral nerve 
block in rabbits and dogs. J Drug Deliv 2012; 2012: 962101. 
24. Ilfeld BM, Malhotra N, Furnish TJ, et al. Liposomal bupivacaine as a single-
injection peripheral nerve block: a dose-response study. Anesth Anagl 2013; 
117(5): 1248-56. 
25. Draper E, Pearce-Smith BA, Chelly JE. Liposomal bupivacaine for analgesia 
following multiple rib fractures: a case report. Reg Anesth Pain Med 2013. 
Abstract A182. 38th Annual Regional Anesthesiology and Acute Pain Medicine 
Meeting, Boston, Massachusetts, May 2013. 
26. Yin C, Matchett G. Intercostal administration of liposomal bupivacaine as a 
prognostic nerve block prior to phenol neurolysis for intractable chest wall pain. J 
Pain Palliat Care Pharmacother 2014; 28(1): 33-6. 
27. Jennings PA, Cameron P, Bernard S. Measuring acute pain in the prehospital 
setting. Emerg Med J 2009;26:552-5. 
28. Knudsen K, Beckman SM, Blomberg S, et al. Central nervous and cardiovascular 
effects of IV infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J 
Anaesth 1997;78:507-514. 
29. White PF, Ardeleanu M, Schooley G, Burch RM. Pharmacokinetic sof 
depobupivacaine following infiltration in patients undergoing two types of surgery 
in normal volunteers. International Anesthesia Research Society Annual Meeting, 
San Diego, CA, March 14-17, 2009. 
30. Viscusi ER, Sinatra R, Onel E, Ramamoorthy SL. The safety of liposome 
bupivacaine, a novel local analgesic formulation. Clin J Pain 2014 Feb;30(2):102-
10. 
31. Pacira Pharmaceuticals Inc. EXPAREL (bupivacaine liposome injectable 
suspension) prescribing information. Parsippany, NJ; 2011. Accessed January 
23, 2016. 
32.  Safety Reporting Requirements for INDs and BA/BE Studies 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation
/Guidances/UCM227351.pdf 
33. The use of the WHO-UMC system for standardized case causality assessment 
http://who-umc.org/Graphics/24734.pdf 
34. Toxicity Grading Scale for Health Adult and Adolescent Volunteers Enrolled in 
Preventative Vaccine Clinical Trials. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceReg
ulatoryInformation/Guidances/Vaccines/ucm091977.pdf 


 
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APPDENDIX 
 
Numeric rating scale 
 
 
 
 


 
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 TRAUMA ACUTE MULTIMODAL PAIN MANAGEMENT PROTOCOL 
(Originated 07/14; revised 11/14; reviewed 06/15) 


 
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OBJECTIVE 
 Provide a multidisciplinary trauma service protocol for acute pain management in non-
intubated, alert and oriented patients (GCS 15) with transition through inpatient and outpatient 
settings. 
  
Medication and Injury-Specific Guidelines  
Rib fractures (≥ 2 ribs): 
1. Lidocaine 5% transdermal patch 
a. Apply 1-2 patches to affected area 
b. Apply for 12 hours and remove for 12 hours 
c. Do not apply to open cuts or abrasions 
d. Use caution if applied for > 7 days 
2. Epidural 
a. Consider AIPS consult 
3. IV Acetaminophen 
a. Restricted to patients who are NPO with no feeding access 
b. Patients must be ≥ 65 years old with ≥ 2 rib fractures 
c. Patients can only receive IV acetaminophen for 24 hours or until PO/FT status 
confirmed, whichever comes first 
d. All other IV acetaminophen use is subject to a non-formulary request per current 
UC Health policies and procedures 
 
Non-steroidal anti-inflammatory drug (NSAIDs) 
4. Allowable in orthopedic fractures EXCEPT: 
a. Tibia shaft fracture 
b. Humerus shaft fracture 
c. Spine fractures/surgeries 
d. Any non-union or fusion surgeries 
 
Nerve Injury / Burn Injury / Neuropathic Pain 
5. Gabapentin 
a. Start at 300 mg q8h 
i. Elderly (age ≥ 65 years), low-weight (≤ 50 kg), or renal dysfunction (CrCl 
≤ 30 mL/min) will require dose reduction to daily administration 
b. Up titrate q72h as needed based on patient response  
c. Caution in patients with altered mental status 
 
  
 
History of Narcotic / Heroin Abuse / High Pain Scores or Tolerance 
6. Initiate patient home medications as able 
a. If on formulary, initiate home dose 


 
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b. If non-formulary, consult pharmacy for appropriate conversion 
7. Early Methadone initiation should be initiated for early pain control in patients with high 
pain scores or opioid tolerance 
a. Initiate the lowest effective dose and up/down titrate as able 
b. Up titrate q48-72h as needed based on patient response 
c. Contraindicated in patients with history of QTc prolongation > 500 seconds, 
elderly patients, or those on concomitant NMDA receptor antagonists