Protocol for a Single Center Randomized Controlled Trial of Liposomal Bupivacaine Intercostal Nerve Blockade Versus Continuous Thoracic Epidural for Regional Analgesia in Patients With Multiple Rib Fractures
Phase: PHASE4
Conditions: Trauma, Trauma Injury, Pain, Acute
Sponsor: Chadrick Evans

Protocol for a Single Center Randomized Controlled Trial of Liposomal 
Bupivacaine Intercostal Nerve Blockade versus Continuous Thoracic 
Epidural for Regional Analgesia in Patients with Multiple Rib Fractures 
 
Chadrick Evans, MD, and Melissa Medina, MD, and Victor A. King. 
 
05 June 2017 
 
Address of Corresponding Author: 
Dr. Melissa Medina 
UICOMP Department of Surgery  
North Building, 2nd Floor 
624 NE Glen Oak Avenue 
Peoria, IL 61603 
(224) 659-0349 
Email: mgomedina@gmail.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BACKGROUND 
 
Management of traumatic rib fractures continues to be a challenge for trauma surgeons. The 
prevalence of rib fractures amongst trauma patients ranges between 4-10%.7,9 Associated 
pulmonary complications and mortality range from 16-60% and 3-16% respectively, and 
increases with the number of ribs fractured.1-3,6,7,9 Specifically, the development of pneumonia, 
respiratory distress, and respiratory failure can be devastating, and are risk factors for 
increased mortality amongst this patient population.2-5 It is presumed the development of 
these complications in patients suffering from rib fractures can be secondary to pain alone, 
which limits respiratory excursion and impairs the ability to cough, decreasing the clearance of 
secretions and promotes development of atelectasis.1,4,6,7,9-11,14,16 Therefore, many clinicians 
seek to alleviate this pain, which has been shown to reduce morbidity and mortality associated 
with multiple rib fractures. 
 
Currently, many analgesic options are available to patients suffering from rib fractures. 
Systemic NSAID and opioid analgesics are widely used. These medications significantly improve 
respiratory function and decrease rates of pulmonary complications when the number of rib 
fractures is low and the patient is young with few comorbidities.10 Yet, the use of NSAIDs is 
limited in patients due to concerns for peptic irritation, renal injury, hepatotoxicity, 
hemorrhage, or coagulopathy, while opioids are used judiciously in thoracic trauma due to their 
sedative effects, gastrointestinal symptoms, suppression of cough, and decreased respiratory 
drive.5,7,8,10  
 
More regional and invasive options are also available for older patients with comorbidities, 
individuals with multiple rib fractures, significant pain, or unstable respiratory status.10 These 
include intercostal nerve blockades, catheter delivered continuous intercostal nerve blockades, 
and continuous epidural analgesia (CEA). However, these additional options are not without 
their own drawbacks, risks, contraindications, and their efficacy relative to one another is 
equivocal.10  
 
Formulations currently used for conventional intercostal nerve blocks (CINB) are relatively safe, 
do not require additional equipment or specialized anesthesia personnel, do not require 
catheter repositioning, and provide improved analgesia immediately over the aforementioned 
systemic therapies.10,11,16 However, the analgesic effect is short acting and requires multiple 
administrations, which multiplies the risk of secondary pneumothorax, hemothorax, and 
intravascular injection.10,14 There is also a rare risk of systemic local anesthetic toxicity including 
hypotension, atrioventricular block, arrhythmia, and rash or infection at the needle entry site 
are contraindications.10-12  
 
Catheter delivered continuous intercostal nerve blockade also offers an acceptable safety 
profile. Nevertheless, this modality is invasive, requires advanced training of personnel and 
additional equipment for accurate placement and adequate effect, adds extra cost, can serve as 
a nidus for infection, increases risk of local anesthetic toxicity due to continuous infusion, and is 

contraindicated if rash or infection is present at the insertion site, or if there is a systemic 
infection.5,10,15,16   
 
Lastly, CEA is noted by numerous authors, including the Eastern Association for the Surgery of 
Trauma, to be the standard of care in the setting of multiple or bilateral rib fractures.1,7,8,10,19 
Yet, CEA is invasive and its initial placement requires an anesthesiologist. Once placed, 
hospitalization is mandated and the associated pumps and catheter require close monitoring, 
often on a unit with telemetric support. These factors can delay treatment and significantly 
increase cost. CEA also carries risk of complications including failed catheter placement, 
inadequate analgesia, urinary retention, pruritis, hypotension, bradycardia, motor block, 
epidural hematoma, epidural abscess, dural puncture, spinal cord injury, meningitis, and 
respiratory failure.1,5,7,10,15 It also has many significant contraindications common to trauma 
patients including hypotension, hypovolemia, heavy sedation, significant head injury, vertebral 
or spinal cord injury, spinal deformity, coagulopathy, prophylactic or therapeutic 
anticoagulation, and mechanical ventilation.7,10,15,16 Finally, recent studies assessing CEA’s 
superiority compared to other regional techniques have been equivocal.2,7,9,10 
 
Therefore, it is the goal of these authors to introduce an additional safe option for extended 
local analgesia in the setting of multiple rib fractures given the inconclusive evidence 
supporting or refuting the current standard of care. The advent of liposomal bupivacaine makes 
an extended local intercostal nerve blockade of up to 72 hours a possibility.13,15,16 With it comes 
a safety profile that is at least as favorable as the currently available local anesthetic 
drugs.11,13,14 Theoretically, the liposomal bupivacaine formulation is designed to reduce the risk 
of systemic local anesthetic toxicity by providing a lipid bilayer that entraps the bupivacaine. 
This liposome then acts as a vehicle for delivery of the bupivacaine to the target area, which is 
hypothesized to limit diffusion away from the site of infiltration.13 Thus, the utilization of 
liposomal bupivacaine as the local anesthetic nerve blocking agent is not expected to add any 
additional risk beyond that of conventional intercostal nerve blocks with bupivacaine HCl.  
 
Nonetheless, the most common adverse events associated with liposomal bupivacaine nerve 
blockades in previous phase I-III studies include nausea, pyrexia, constipation, vomiting, and 
pruritis. Other less commonly associated adverse events included hypesthesia, dizziness, 
bradycardia, and sinus tachycardia. Retrospective pooling of 6 prospective trials that utilized 
liposomal bupivacaine in peripheral nerve blocks suggested the liposomal formulation has a 
similar safety and side effect profile to bupivacaine HCl and normal saline.13  
 
To our knowledge, the quality and duration of analgesia provided by liposomal bupivacaine has 
yet to be evaluated in a prospective controlled trial for rib fractures. However, it has been 
studied as an intercostal nerve blocking agent post-thoracotomy. First, in 2015, Rice et al 
compared patients receiving liposomal bupivacaine intercostal nerve blockades (LBINB) to case 
matched CEA controls post-thoracotomy. The authors found no significant difference in 
postoperative pain scores and complications, but do report significant reduction in the mean 
length of stay in the LBINB cohort.18 Similar findings are also reported by Khalil and colleagues 
post-thoracotomy, with the exceptions of lower postoperative pain scores at day 1 and day 3. 

Khalil et al also reports significant reductions in pulmonary complications and length of stay.15 
Limitations of the two previously mentioned studies include their retrospective methodology 
and potentially under powered patient cohorts.  
 
Extrapolating from this retrospective data, we feel it is appropriate to assess LBINB against CEA 
prospectively to evaluate its efficacy in providing sustained analgesia during recovery from 
multiple rib fractures. Our Trauma Service has extensive experience with CEA, and how its many 
contraindications mentioned above limit our ability to provide safe, quality regional analgesia in 
a trauma patient. Consequently, we often find ourselves prescribing systemic opioids or 
applying CINBs with short acting local anesthetics. Both analgesic modalities decline in analgesic 
efficacy in minutes to hours and must be scheduled or readministered.12 As a result, many 
patients with rib fractures endure significant pain and are under treated due to the lack of 
available evidence based therapies. Therefore, please consider our protocol that follows. It is 
our presumption based on the evidence above LBINB will providing equally efficacious, 
sustained analgesia, with a safety profile similar to CINB, and with fewer contraindications than 
CEA.  
 
 
OBJECTIVES 
 
The objective of this study is to quantify and draw inferences on the efficacy of a multiple level 
liposomal bupivacaine intercostal nerve blockade (LBINB) in patients with multiple traumatic rib 
fractures by comparing it to the current standard of care, continuous epidural analgesia (CEA). 
 
The primary objective is to assess the quality and duration of analgesia provided by LBINB over 
a 96 hour period by numeric grading pain scale and/or critical-care pain observation tool when 
compared to CEA. 
 
The secondary objective of this study is to assess and compare the following between the two 
treatment arms:  
 Cumulative breakthrough analgesia in morphine equivalents 
 Incentive spirometry measurements 
 Reduction in pulmonary complication including atelectasis, pneumonia, respiratory 
failure, and ventilator days 
 Length of stay 
 Duration of intensive care unit (ICU) days (if applicable) 
 Cost associated with the administration of CEA versus LBINB  
 Overall rate of complications associated with CEA versus LBINB 
 
METHODS AND ANALYSIS 
 
The trial will be conducted in accordance with the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46). The Principal Investigator will assure that no 

deviation from, or changes to, the protocol will take place without prior approval from the 
University of Illinois College of Medicine at Peoria IRB 1, Peoria, IL, except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct 
of this study have completed Human Subjects Protection Training. 
 
A single center, two arm, parallel group trial will be completed. All patients 18 years of age or 
older suffering 3 or more rib fractures treated by University of Illinois College of Medicine at 
Peoria (UICOMP) attending or resident physicians at OSF St. Francis Medical Center (OSFMC) 
are potentially eligible for enrollment in the trial. However, patients with any of the following 
will not be eligible since they are contraindications to CEA, LBINB, or both: 
 
1. Intracranial hemorrhage  
2. Fever >101 degrees Fahrenheit for ≥ 1 hour(s) 
3. Rash at site of catheter insertion or administration of nerve block 
4. Hemodynamic instability 
5. Spinal cord injury 
6. Vertebral fractures 
7. Allergy to bupivacaine  
8. Systemic therapeutic anticoagulation required for duration of hospital admission20 
9. Altered mental status without medical decision maker to provide consent 
10. Patients without the capacity to consent or the lack of a medical decision maker to 
consent 
11. Patients that are pregnant 
12. Legally confined patients.  
 
Additional criteria for exclusion of patients on antithrombotic therapies can be found in the 
attached supplement developed by the University of Washington based on American Society of 
Regional Anesthesia and Pain Medicine guidelines for anticoagulation in patients receiving 
regional anesthesia.20, 21 These guidelines will not supersede clinical judgement, or the 
judgement and recommendations of the Anesthesia department at OSF St. Francis Medical 
Center. Lastly, intubated and mechanically ventilated patients will not be enrolled. However, 
should a patient require intubation and mechanical ventilation after enrollment, the patient will 
remain in the trial. 
 
Patients fulfilling the eligibility criteria will be identified by the UICOMP Trauma Surgery staff 
during the initial trauma evaluation. Patients will be recruited by the senior trauma surgery 
resident or attending. The trial and interventions will be described in a consistent and unbiased 
manner. Patients will be given 48 hours to consider their participation to ensure informed 
consent to participate in the trial. Signed and dated informed consent will be obtained by 
medically trained personnel. In the event any further information becomes available which may 
influence the patient’s willingness to continue in the trial, the trial team will contact the 
participant. A participant may refuse enrollment or withdrawal their trial involvement at any 
time. Prerandomization eligibility checks will be carried out to ensure that a patient fits the 

eligibility criteria and is not randomized in error. Inclusion of a patient in the trial will be flagged 
in their EMR, clinical notes by means of a trial sticker, and a trial flyer on the door to their room. 
 
RANDOMIZATION 
 
The UICOMP Department of Surgery will perform randomization. Randomization will be 
performed in 10 patient blocks utilizing a 1:1 allocation based on a computer-generated 
randomization schedule. Once generated, this schedule will be used by the UICOMP Trauma 
Surgery service and research team to enroll patients. Concealment of allocation will be 
maintained by sequential sealed envelopes. Upon enrollment in the study, the next envelope in 
sequence will be opened to reveal which treatment arm the patient is assigned. The rest of the 
trauma team will be notified, and the appropriate intervention will be initiated. 
 
SAMPLE SIZE 
 
We estimated the sample size based on our primary hypothesis. The primary outcome is 
numeric grading pain scale. We hypothesize that there is no significant difference between 
LBINB and CEA patients in terms of the numeric grading pain scale.  
 
If we assume the true difference in means of pain score does not exceed 0.1, with a standard 
deviation of 1.0, then we need totally 38 subjects (19 per group) with 80% power and 0.05 
significance level. In anticipation of a probable 15% drop-in/out and missing data in the two 
treatment groups, we inflate the sample size by a factor of 1.15. Therefore, the final sample size 
for this trial would be 44 subjects (22 per group). 
 
If we assume the true difference in means of pain score does not exceed 0.1, with a standard 
deviation of 2.5, then we need totally 224 subjects (112 per group) with 80% power and 0.05 
significance level. In anticipation of a probable 15% drop-in/out and missing data in the two 
treatment groups, we inflate the sample size by a factor of 1.15. Therefore, the final sample size 
for this trial is 258 subjects (129 per group).  
 
Considering the potential for a large sample size requirement for rejection of the null 
hypothesis, it is our intent to enroll a minimum of 44 patients. This will allow us to roughly 
estimate the true difference in means of pain scores and standard deviation to predict a more 
accurate sample size requirement, without unnecessary utilization OSF and UICOMP resources. 
 
BLINDING 
 
Owing to the nature of the interventions, the patient and the UICOMP Trauma Surgery faculty 
will not be blinded once the patient is assigned to their respective treatment arms. This is to 
ensure the patient is appropriately managed in case of an adverse event or complication. Data 
collection also will not be blinded since the UICOMP Trauma Surgery team will be responsible 
for recording data during the patient’s treatment. However, the trial statistician will be blinded 
to the treatment allocations during data analysis. 

 
INTERVENTIONS 
 
Patients will receive one of the following methods of analgesia for their rib fractures: 
 
1. Liposomal bupivacaine intercostal nerve blockade (LBINB) 
 
Under aseptic conditions the insertion sites will be marked 3-4 cm lateral to the midline at 
the level of each fractured rib, and 1-2 ribs levels above and below if possible. The fingers of the 
non-dominant palpating hand will straddle the first insertion site at the inferior border of each 
rib and fix the skin to avoid unwanted skin movement. 3-5 ml of a 1.3% (13.3 mg/mL) of 
liposomal bupivacaine will be drawn into a syringe with a 1.5-in, 22-gauge needle. The needle 
will then be advanced at an angle of approximately 20° cephalad to the skin at the marked 
injection site.  Contact with the rib will be made. While maintaining the same angle of insertion, 
the needle will be walked off the inferior border of the rib and the skin allowed to return to its 
initial position. The needle will be advanced 3 mm below the inferior margin of the rib, placing 
the tip in the space containing the neurovascular bundle.  Following negative aspiration for 
blood or air, 3-5 mL of local anesthetic will be infused and the needle withdrawn. This process 
will be repeated to provide nerve blockade at the remaining marked levels. No more than 266 
mg, or 20 ml, of the 1.3% (13.3 mg/mL) liposomal bupivacaine solution will be injected in total 
per the manufacturer recommended maximum dosage. 
 
2. Continuous analgesia by epidural catheter (CEA) 
 
If the patient is assigned to the CEA group, anesthesia will be consulted. The following is a 
general description of the procedure required to insert an epidural catheter. Management of 
CEA will be conducted in accordance with OSF St. Francis Medical Center standards, with 
oversight provided by the anesthesia department.  
 
If possible, the patient will be in the sitting position. The skin will be prepped with 
chlorhexidine and sterilely draped.  With strict aseptic technique including mask, cap, and 
gloves, the closest interspace to the rib fractures between T4 -T12 will be identified.  3 mL of 
lidocaine 1% will be infiltrated with a 25 gauge 1-1/2 inch needle.  Next, a 17 gauge Touhy 
needle will be inserted, and the epidural space identified by loss of resistance technique. A 
Braun epidural catheter will then be inserted to a depth of 12cm, measured from the skin, into 
the epidural space. 
Next, 3 mL of test solution containing lidocaine 1.5% with epinephrine, 1:200,000 will be 
injected with continuous EKG and SpO2 monitoring. Upon confirmation of a negative response, 
the catheter will be secured with a transparent dressing and tape and the returned to a supine 
position. Delivery of a 0.125% bupivacaine solution will then be continuously infused and 
titrated based on the patient’s clinical status.  
An alternative solution or procedure may be used for CEA if indicated based on 
information gathered during the patient’s history and physical. This decision will be made by 

the representative from anesthesiology that places the catheter. The variation will be recorded 
for analysis in the study. 
 
Both study arms will receive a standardized formulary of 325mg acetaminophen PO q6h, 5mg 
PO TID cyclobenzaprine, and 400mg ibuprofen PO q6h will be scheduled barring any patient 
specific contraindications. Both arms will also receive systemic NSAID and opioid analgesia for 
breakthrough pain as needed. The amount and type of breakthrough analgesia provided to the 
patient will be based on what is safe to prescribe, indicated, and will provide the most pain 
relief. The amount of systemic analgesia administered will be reviewed in total and recorded in 
morphine equivalents. 
 
OUTCOME ASSESSMENTS AND TIME POINTS 
 
The primary outcome of interest is the quality of analgesia provided measured by numeric 
grading pain scale assessment every 24 hours. 
 
The secondary outcomes of interest include:  
 Amount of breakthrough analgesia required in morphine equivalents 
 The duration of analgesia provided measure by numeric grading pain scale assessment 
every 24 hours 
 Pulmonary function measured by incentive spirometry every 24 hours 
 Supplemental oxygen requirements 
 SpO2 
 Development of pulmonary complications including: 
a. Atelectasis 
b. Pneumonia 
c. Respiratory failure 
 Ventilator days 
 Length of stay 
 Duration of intensive care unit (ICU) days 
 Cost associated with the administration of CEA versus LBINB  
 Overall rate of complications associated with CEA versus LBINB 
 
If a patient agrees to enroll in the trial, all primary and secondary outcome measures available 
from the time of admission will be recorded after obtaining the informed consent.  
 
 
DATA MANAGEMENT  
 
Information will be obtained via admission history and physical, pre-intervention history and 
physical immediately after obtaining informed consent, daily examinations during morning 
rounds every 24 hours, discussions with the nursing staff, review of the electronic medical 
record per this protocol, and as clinically indicated while the patient is admitted to the hospital. 

Relevant patient charts will then be reviewed by the investigative team to collect outcome 
variables of interest. This information will be entered into a secure spreadsheet for analysis at 
the end of the enrollment period. 
 
All electronic patient-identifiable information will be held on a secure, password protected 
database accessible only to essential personnel. Paper forms with patient identifiable 
information will be held in secure, locked filing cabinets within the Department of Surgery at 
OSF Saint Francis Hospital in Peoria, IL. Participants will be identified by name and medical 
record number throughout the data collection process. All personal identifying information will 
then be stripped from the raw data upon transition to the data analysis phase. No personal 
identifying information will be published. Direct access to source data/documents will be 
required for trial-related monitoring. All paper and electronic data will be retained upon 
completion of the study in accordance with the law and the University of Illinois College of 
Medicine at Peoria IRB 1, Peoria, IL, or otherwise destroyed to ensure no risk to patient privacy.   
 
STATISTICAL ANALYSIS 
 
The ITT principle will be applied our analysis. We will use different methods to compute the 
missing data, such as last observation carried forward, mean replacement, and maximum 
likelihood estimation. 
  
For the primary outcome, we will use two-sample equivalence test for the univariate analysis. 
We will also use general linear model adjusting for appropriate covariates for multivariate 
analysis. 
  
For other variables, we will conduct univariate analysis using Pearson’s chi-square or Fisher’s 
exact tests on categorical variables, and t test or equivalent non-parametric methods on 
continuous variables depending on the distributions. In addition, we will use general linear 
model or generalized linear model for multivariate analysis, adjusting for appropriate 
covariates. 
  
Since we collect data at different time points, we will use generalized estimating equation(GEE) 
models to assess the correlated outcome variables when comparing the group differences over 
time. 
  
The two-tailed p values will be calculated for all tests, and p< 0.05 is considered the statistical 
significant test. SAS 9.4 (SAS Institute Inc., Cary, NC) will be used for all data management and 
analysis. 
 
TRIAL ORGANIZATION, REGULATION, AND OVERSIGHT 
 
The trial will be coordinated by the Principal Investigator and Director of Trauma/Critical Care, 
Dr. Chadrick Evans, and the Trial Manager, Dr. Melisa Medina. All issues pertaining to the 
management of the trial will be continuously monitored by these individuals, including 

unanticipated problems in research involving research subjects or others (UPIRSOs) and 
unanticipated adverse events (AEs). 
 
These trial leaders are also responsible for data safety monitoring. Statistical analysis will be 
performed every 6 months. The trial leaders will present this analysis, which will include both 
outcomes and safety data, to the Trauma Morbidity and Mortality Boards conducted by the  
UICOMP Department of Surgery and the OSF St. Francis Medical Center Drug Analysis Work 
Group (OSF SFMC DAWG). The statistical model for data analysis developed with the UICOMP 
Division of Research Services in the section titled “Statistical Analysis” will be applied to the 
presented data if applicable. Research will be immediately suspended if sufficient data has 
been collected to determine a clear and significant benefit or risk to the patient from either the 
CEA or LBINB pain protocols. In the absence of significant data displaying risk/benefit, and 
mean differences in pain scores and standard deviations outside of the parameters required to 
accept or reject the null hypothesis based on our power analysis, the trial leaders will request 
continuation of the study through the Department of Surgery and the OSF SFMC DAWG. Yearly 
status reports will be submitted to Peoria IRB 1 as required by section 6 of the University of 
Illinois College of Medicine at Peoria IRB 1, Peoria, IL “Policies and Procedures,” or more 
frequently as determined by Peoria IRB 1. 
 
At no time will participation in this trial compromise the quality of care provided to the patient, 
elevate the patient to a level of care beyond that required based on the patient’s clinical 
condition, or extend a patient’s hospital stay beyond what is clinically required. Patients 
suffering multiple injuries will be assessed, and their injuries addressed, in the appropriate 
order based on severity. The enrollment and consent process for this trial will never interfere 
with this evaluation and management. Also, once enrolled, ALL patients will have the option to 
receive CEA (the current standard of care) for their rib fractures, barring contraindications, 
regardless of randomization. Patients will also receive systemic analgesia for severe, 
breakthrough pain. Participating patients may withdrawal from participation in the study at any 
time. However, data collected up to the time of their withdrawal will be included in analysis, 
and the patient will be informed of this during the consent process.  
 
ETHICS AND DISSEMINATION 
 
All UPIRSOs and AEs will be reported in accordance with section 9 of the University of Illinois 
College of Medicine at Peoria IRB 1, Peoria, IL “Policies and Procedures.” 
 
Participants in the study are not covered by indemnity for negligent and non-negligent harm 
through UICOMP. UICOMP does not have, or provide, insurance to cover for non-negligent 
harm associated with the protocol. The liability of the manufacturer of medicinal products 
being administered is strictly limited to those claims arising from faulty manufacturing of the 
product.  
 
The results of the trial will be disseminated via scholarly article in peer reviewed academic 
journals, presentation at local, regional, national, and international conference, and on 

http://www.ClinicalTrials.gov, as required by U.S. Law. All published results will be stripped of 
personal identifying information to ensure privacy rights of the participants are fully protected. 
 
 
FUNDING AND SPONSORSHIP 
 
This study will not be funded. 
 
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