Clinical trial NCT03305666
Conditions: Drug Effect Rib Fractures Rib Trauma Surgical Procedure, Unspecified Pain; Catheter (Other) Nerve Pain Local Infiltration Anesthesia, Local Intercostal Rib Opioid Dependence Chest Injury Trauma Pneumonia
Sponsor: Denver Health and Hospital Authority
Start date: 2017-10-05; Completion date: 2021-01-31
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Rib fractures represent a common injury pattern this is highly associated with patient morbidity and mortality, as pain control remains a challenge. Even after surgical stabilization of rib fractures (SSRF), unsuccessful pain control can lead to morbid outcomes such as pneumonia and opioid dependence. Multi-modal anesthesia, with the use of thoracic epidurals and para-vertebral injections/catheters, has shown to lessen these occurrences but are subject to a wide array of limitations. A more directed therapy with liposomal bupivacaine has shown to provide sustained analgesia for up to 72 hours in patients who have undergone other types of thoracic surgery, but not SSRF. The hypothesis of the current clinical trial is that, among patients undergoing SSRF, liposomal bupivacaine delivered via video assisted thoracic surgery (VATS) is an intercostal nerve block that provides comparable analgesia to the pain catheter, as measured by pulmonary function, numeric pain scoring, and postoperative narcotic use.

Detailed description:
Rib fractures represent a common injury pattern with high associated morbidity and mortality. Effective pain control in both the acute and long term periods remains a challenge. Surgical stabilization of rib fractures (SSRF) is now a recommended treatment for patients with severe chest wall injuries. In addition to stabilization of the chest wall, SSRF offers a unique opportunity to deliver directed, loco-regional anesthesia. Loco-regional anesthesia is a recognized, essential component of multi-modal anesthesia for patients with rib fractures in order to both decrease pain and minimize the use of opioids and their associated side effects.

Delivery options for loco-regional anesthesia to patients with rib fractures share in common the intention of anesthetizing the intercostal nerves. Moving from the spinal cord laterally, modalities include thoracic epidural catheters, paravertebral blocks or catheters, and rib/intercostal blocks. Although rib blocks may be accomplished via a variety of techniques, the two most common intra-operative techniques are video-assisted thoracoscopic surgery (VATS) intercostal nerve blocks and indwelling, subscapular catheters In general, neuraxial modalities such as thoracic epidural and para-vertebral injections/catheters are subject to a wide array of limitations, including patient coagulopathy (International Normalized Ratio \> 1.5), co-existing spine fractures, peri-insertion, peri-removal withholding of venous thromboembolism pharmacoprophylaxis, and provider availability. For these reasons, our current practice is to insert a subscapular "pain catheter" at the conclusion of the SSRF operation; this catheter is able to deliver a continuous infusion of 0.25% bupivacaine and may be left in place for several days.

Although favorable results using the pain catheter have been published in patients with rib fractures who have not undergone SSRF, we have noticed several limitations to this treatment modality. First, position is highly variable; and, because the catheter is not truly in the space of the intercostal nerves, drug delivery is likely irregular. This variability may be particularly relevant in obese patients; and the median body mass index of patient who underwent SSRF at Denver Health is 29 kg/m\^2. Beyond catheter placement, we have also experienced issues with leakage of drug from the skin entry site of the catheter. Moreover, catheters frequently become dislodged or inadvertently removed during patient transport. Further, the indwelling foreign body likely introduces some risk of infection. Finally, the presence of the catheter is distressing to many patients.

Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, Inc., Parsippany, NJ, www.pacira.com) has been shown to provide sustained analgesia for up to 72 hours following a single injection of the drug delivery system. The safety and efficacy of liposomal bupivacaine has been evaluated in over 1,300 subjects and 21 clinical trials. Although many of these trials have included thoracic surgery patients, no trial has evaluated the efficacy and safety of liposomal bupivacaine administered to patients with rib fractures undergoing SSRF. Potential benefits as compared to current practice include directed injection immediately adjacent to the intercostal nerve using a VATS approach, as well as obviation of the need for an indwelling catheter. The hypothesis of the current clinical trial is that, among patients undergoing SSRF, liposomal bupivacaine delivered via video assisted thoracic surgery (VATS) is an intercostal nerve block that provides comparable analgesia to the pain catheter, as measured by pulmonary function, numeric pain scoring, and postoperative narcotic use.

Arms: arm 1: Bupivacaine indwelling OnQ pain pump catheter will be placed in the subscapular space at the time of surgery, at infusion of 12 ml/hr of 0.25% bupivacaine, and left in place for a maximum of 120 hours arm 2: A single injection of liposomal bupivacaine: mixture of 20 mL liposomal bupivacaine, 20 mL 0.25% bupivacaine, and 10 mL sterile saline (50 mL total), will be delivered in the intercostal space during VATS (with a 178 mm, 22 gauge needle, at ribs 3-8).
Interventions: intervention 1: Liposomal bupivacaine injection intervention 2: Bupivacaine indwelling catheter
Intervention descriptions: intervention 1: A single injection of liposomal bupivacaine is administered at the time of SSRF, directly to the fracture site via VATS intervention 2: Bupivacaine indwelling OnQ pain pump catheter is placed in the subscapular space at the time of SSRF for continuous bupivacaine infusion post op

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Template 
Page 1 
CF-146, Effective 7/10/11 
 
Document Cover Page 
 
 
Official Title of the Study: A randomized clinical trial of single dose liposomal bupivacaine 
delivered via VATS intercostal nerve block vs continuous bupivacaine infusion delivered via 
indwelling subscapular analgesic catheter in patients undergoing surgical stabilization of rib 
fractures 
 
 
 
NCT Number:  NCT03305666 
 
 
Date of Document:  April 27, 2017 
 


Protocol Template 
Page 2 
CF-146, Effective 7/10/11 
 
 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 17-0685 
Project Title: 
A randomized clinical trial of single dose liposomal bupivacaine delivered 
via VATS intercostal nerve block vs continuous bupivacaine infusion 
delivered via indwelling subscapular analgesic catheter in patients 
undergoing surgical stabilization of rib fractures 
 
 
 
Principal Investigator:  Pieracci, Fredric MD 
Version Date: V1 4/27/2017 
 
 
 
 
 
  
 
I. Hypotheses and Specific Aims:   
    
The hypothesis of this clinical trial is that among patients undergoing surgical stabilization 
of rib fractures (SSRF), liposomal bupivacaine delivered via VATS intercostal nerve block 
provides comparable analgesia to the pain catheter, as measured by both pulmonary function 
and narcotic use.  
 
II. Background and Significance:  
Rib fractures represent a common injury pattern with high associated morbidity and 
mortality (1). Effective pain control in both the acute and long term periods remains a challenge 
(2). Surgical stabilization of rib fractures (SSRF) is now a recommended treatment for patients 
with severe chest wall injuries (3-5). In addition to stabilization of the chest wall, SSRF offers a 
unique opportunity to deliver directed, loco-regional anesthesia. Loco-regional anesthesia is a 
recognized, essential component of multi-modal anesthesia for patients with rib fractures in 
order to both decrease pain and minimize the use of opioids and their associated side effects (6, 
7). 
Delivery options for loco-regional anesthesia to patients with rib fractures share in 
common the intention of anesthetizing the intercostal nerves. Moving from the spinal cord 
distally, modalities include thoracic epidural catheters, paravertebral blocks or catheters, and rib 
blocks. Although rib blocks may be accomplished via a variety of techniques, the two most 
common intra-operative techniques are video-assisted thoracoscopic surgery (VATS) intercostal 
nerve blocks [Figure 1] and indwelling, subscapular catheters (Figure 2).   
In general, neuraxial modalities such as thoracic epidural and para-vertebral 
injections/catheters are subject to a wide array of limitations, including patient coagulopathy 
(Internal Normalized Ratio > 1.5), co-existing spine fractures, peri-insertion and removal holding 
of venous thromboembolism pharmacoprophylaxis, and provider availability. For these reasons, 
our current practice is to insert a subscapular “pain catheter” at the conclusion of the SSRF 
operation (Figure 2); this catheter provides a continuous infusion of 0.25% bupivacaine and may 
be left in place for several days.  
Although favorable results using the pain catheter have been published in patients with rib 
fractures who have not undergone SSRF (8), we have noticed several limitations to this 
treatment modality. First, position is highly variable; and, because the catheter is not truly in the 
space of the intercostal nerves (Figure 3), drug delivery is likely irregular. This variability may be 
particularly relevant in obese patients; and the median body mass index of patient who 
underwent SSRF at Denver Health is 29 kg/m2. Beyond catheter placement, we have also 
experienced issues with leakage of drug from the skin entry site of the catheter. Moreover, 
catheters frequently become dislodged or inadvertently removed during patient transport. 
Further, the indwelling foreign body likely introduces some risk of infection. Finally, the presence 
of the catheter is distressing to many patients.  
 
Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals, Inc., Parsippany, NJ, 
www.pacira.com) provides sustained analgesia for up to 72 hours following a single injection of 
the drug delivery system. The safety and efficacy of liposomal bupivacaine has been evaluated 


Protocol Template 
Page 3 
CF-146, Effective 7/10/11 
 
in over 1,300 subjects and 21 clinical trials (refs from pamphlet). Although many of these trials 
have included thoracic surgery patients (9-11), no trial has evaluated the efficacy and safety of 
liposomal bupivacaine administered to patients with rib fractures undergoing SSRF. Potential 
benefits as compared to current practice include directed injection into the intercostal nerve 
space using a VATS approach, as well as obviation of the need for an indwelling catheter. The 
hypothesis of the current clinical trial is that, among patients undergoing SSRF, liposomal 
bupivacaine delivered via VATS intercostal nerve block provides comparable analgesia to the 
pain catheter, as measured by both pulmonary function and narcotic use.   
 
III. Preliminary Studies/Progress Report:   
 
Although SSRF is now a recognized treatment for patients with severe chest wall injuries, 
the method of loco-regional anesthesia is less standardized.  Currently thoracic epidural and para-
vertebral catheters are a both common methods for delivering loco-regional anesthesia.  Thoracic 
epidural catheters offer the benefit of bilateral analgesia and have been shown to reduce the 
length of mechanical ventilation (3).  Unfortunately they are contra-indicated in the setting of spine 
fractures and mild coagulopathy, and may require the addition of a consultative service to manage.  
Paravertebral pain catheters have equivalent pain control to epidural catheters, but can be used in 
patients with spine fractures and can be placed surgically or by emergency teams using anatomic 
landmarks or ultrasound guidance (3).  Denver health has found that these catheters are not 
without issues for our patients.  Some issues that we have personally experienced include drug 
leakage, dislodgement, and irregular drug delivery.  Other pain loco-regional analgesic modalities 
such as intrapleural pain catheters, transcutaneous patches, transcutaneous electrical nerve 
stimulation, and acupuncture have limited evidence to support their use (3).   While still a relatively 
new technique for loco-regional anesthesia, liposomal bupivacaine has shown favorable results in 
patients undergoing thoracoscopies and thoracotomies, resulting in shorter hospital length of stay 
(11) and statistically significant additional analgesics (10).  The ease of delivery of liposomal 
bupivacaine and the ability to avoid bothersome catheters may make it the optimal method for 
loco-regional anesthesia in patients undergoing SSRF.   
 
IV. Research Methods 
 
A.  Outcome Measure(s):   
 
Individuals undergoing SSRF will be randomized to two treatment arms.  Primary 
outcomes will be pulmonary function and narcotic requirement by each subject.   
 
 
Pulmonary function will be measured using the Standardized Assessment of Respiratory 
Function (SCARF) score, measured at 10 am daily.   This scale has 4 components, and one point 
award for each of the following: 
1) Numeric Pain score >4 (on the 10 point pain scale) 
2) Incentive spirometry <50% predicted  
3) Poor cough 
4) Respiratory rate ≥ 20 
 
Daily Narcotic use will be measured using equi-analgesic doses as shown in the table below.   
 
 
Narcotic 
Dose 
Unit 
Route 
Hydromorphone 
1.5 
Mg 
IV 
Hydromorphone 
7.5 
Mg 
PO 
Fentanyl 
100 
Mcg 
IV 
Morphine 
10 
Mg 
IV 
Morphine 
30 
Mg 
PO 
Oxycodone (Percocet) 
20 
Mg 
PO 
Hydrocodone (Vicodin) 
30 
Mg 
PO 
 


Protocol Template 
Page 4 
CF-146, Effective 7/10/11 
 
 
B. Description of Population to be Enrolled:   
Adults undergoing surgical stabilization for rib fractures are eligible for this clinical trial.  
Any individuals that are pregnant, incarcerated, less than 18 years old, or have a known allergy 
or hypersensitivity to bupivacaine will not be eligible for enrollment.   
 
C. Study Design and Research Methods   
This is a non-inferiority, randomized clinical trial that compares two different delivery 
options for loco-regional anesthesia for patients undergoing surgical stabilization of rib 
fractures.  Randomization will be accomplished using a standard function in Microsoft Excel 
that randomly chooses either the number 0 or 1.   
Prior to patient’s SSRF procedure they will be localized to one of two study arms: 
1) Pain Catheter: placed in the subscapular space at the time of surgery and 
results in a continuous infusion of 12ml/hr of 0.25 bupivacaine and is left in 
place for a maximum of 120 hours.   
2) Single injection liposomal bupivacaine: a mixture of 20mL liposomal 
bupivacaine, 20 mL 0.25% bupivacaine, and 10mL sterile saline (50mL total) 
that is delivered into the intercostal space during VATS using a 22 gauge 
needle directed at ribs 3 through 8.  (178mm????) 
The SSRF procedure will be standardized for all patients to include: 1) flexible 
bronchoscopy, 2) E-Z Blocker bronchial blocker (figure 5), and 3) VATS evacuation/irrigation of 
the pleural space.  
Postoperatively, standard multimodal analgesia will be used in all patients (barring any 
contra-indications) to include:  1) Acetominophen 650 mg PO q6H,  2) Ibuprophen 800 mg PO 
q6h, and 3) Gabapentin 300 mg PO TID 
Subjects will be followed for 28 days or until discharged from the hospital, whichever 
comes first.  Crossover from one study arm to the other will not be permitted.  Patients in whom 
pain is not well controlled postoperatively will be given additional analgesics other than 
bupivacaine.   
Occasionally patients with rib fractures receive a pain catheter placed prior to surgery 
using anatomic landmarks.  For these patients the presence of a pre-existing pain catheter will 
be noted in the data collection sheet.  Patient’s with a pre-existing pain catheter will have it 
removed at the time of SSRF.  Depending on randomization status, the patient will receive 
either a new pain catheter placed intra-operatively and under direct vision, or liposomal 
bupivacaine administered via VATS intercostal nerve block.   
 
 
D.   Description, Risks and Justification of Procedures and Data Collection Tools: 
On October 28th 2011, the Food and Drug Administration approved liposomal 
bupivacaine for the following indication: “administration into the surgical site to produce 
postsurgical analgesia”.   
This study will be conducted and reported in accordance with the recommendations of 
the Consolidated Standards of Reporting Trials Statement (14) and registered with the U.S. 
National Institutes of Health (clinicaltrials.gov).  An independent study monitor (Catherine 
Dionne, Pharm D) will submit written reports to COMIRB every six months.  Adverse 
events will be recorded and reported to both the data safety monitor and COMIRB.  
 
  
    
E.   Potential Scientific Problems:   
 
This is a randomized, clinical trial, however, due to the nature of the two treatment arms 
this study is not blinded.  Clinical providers, patients, and the research coordinator collecting data 
will know which treatment arm the patient is assigned to.  This study is subject to the Hawthorne 
Effect in which the patients may modify their behavior while being observed.  Specifically, patients 
may exaggerate or downplay their pain level while being enrolled.   Reported pain, especially on 
the 10-point pain scale is also highly subjective and will be a limitation in this study.  The SCARF 


Protocol Template 
Page 5 
CF-146, Effective 7/10/11 
 
score also incorporates other variables, such as respiratory rate and incentive spirometry volumes 
which are less subject measures.  These will help mitigate the subjectivity of self-reported pain 
scores.   
 
F.   Data Analysis Plan:   
Inferiority of liposomal bupivacaine as compared to pain catheter will be defined as 
median daily SCARF score one point higher.  Standard deviation of the SCARF score among 
patients with rib fractures in Denver Health surgical intensive care unit is 1.1.  Using beta = 
0.80 and alpha = .05, this returns a total sample size of 34 subjects.  Twenty-four SSRF 
procedures are performed annually at Denver Health, thus we conclude that the trail is 
feasible and may be completed in 1.5 years.   
A standard data collection tool will be used (see Data Collection Tool).  All statistical 
analysis will be conducted using SAS version 9.4 (SAS Inc., Carey, NC).  Statistical 
significance will be defined as p < .05.  The distribution of continuous variable will be accessed 
for normality using the Kolmogorov-Smirnov test.  Normally distributed continuous variables 
will be compared using the student’s t-test.  Non-normally distributed variables will be 
compared using the Wilcoxon Rank test.  Categorical variables will be compared using chi-
squared test, unless expected cell counts were <10, in which case Fischer’s exact test will be 
used.   
 
 
G.  Summarize Knowledge to be Gained:   
 
Rib fractures are common and associated with both acute and chronic pain.  This trial will 
compare two loco-regional treatment modalities currently in use at Denver health to determine the 
optimal method to decrease post-operative pain and minimize opioid use.  Denver Health is a 
leader in trauma care, including rib fractures.  Our team has been produced multiple peer reviewed 
studies detailing current recommendations for treatment of rib fractures.  We will continue to 
explore novel approaches for trauma patients suffering from rib fracture pain control to further 
improve patient outcomes and patient satisfaction.    
 
H. References: 
 
1. 
Bulger EM, Arneson MA, Mock CN, Jurkovich GJ. Rib fractures in the elderly. The Journal 
of trauma. 2000 Jun;48(6):1040-6; discussion 6-7. PubMed PMID: 10866248. 
2. 
Mayberry JC, Kroeker AD, Ham LB, Mullins RJ, Trunkey DD. Long-term morbidity, pain, 
and disability after repair of severe chest wall injuries. The American surgeon. 2009 May;75(5):389-
94. PubMed PMID: 19445289. Epub 2009/05/19. eng. 
3. 
Pieracci FM, Majercik S, Ali-Osman F, Ang D, Doben A, Edwards JG, et al. Consensus 
statement: Surgical stabilization of rib fractures rib fracture colloquium clinical practice guidelines. 
Injury. 2017 Feb;48(2):307-21. PubMed PMID: 27912931. 
4. 
Kasotakis G, Hasenboehler EA, Streib EW, Patel N, Patel MB, Alarcon L, et al. Operative 
fixation of rib fractures after blunt trauma: A practice management guideline from the Eastern 
Association for the Surgery of Trauma. The journal of trauma and acute care surgery. 2017 
Mar;82(3):618-26. PubMed PMID: 28030502. 
5. 
Pieracci FM, Rodil M, Stovall RT, Johnson JL, Biffl WL, Mauffrey C, et al. Surgical 
stabilization of severe rib fractures. The journal of trauma and acute care surgery. 2015 
Apr;78(4):883-7. PubMed PMID: 25742255. 
6. 
Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a 
national survey suggest postoperative pain continues to be undermanaged. Anesthesia and 
analgesia. 2003 Aug;97(2):534-40, table of contents. PubMed PMID: 12873949. 
7. 
American Society of Anesthesiologists Task Force on Acute Pain M. Practice guidelines for 
acute pain management in the perioperative setting: an updated report by the American Society of 
Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012 Feb;116(2):248-
73. PubMed PMID: 22227789. 


Protocol Template 
Page 6 
CF-146, Effective 7/10/11 
 
8. 
Truitt MS, Murry J, Amos J, Lorenzo M, Mangram A, Dunn E, et al. Continuous intercostal 
nerve blockade for rib fractures: ready for primetime? The Journal of trauma. 2011 Dec;71(6):1548-
52; discussion 52. PubMed PMID: 22182865. 
9. 
Yin C, Matchett G. Intercostal administration of liposomal bupivacaine as a prognostic 
nerve block prior to phenol neurolysis for intractable chest wall pain. Journal of pain & palliative 
care pharmacotherapy. 2014 Mar;28(1):33-6. PubMed PMID: 24476569. 
10. 
Parascandola SA, Ibanez J, Keir G, Anderson J, Plankey M, Flynn D, et al. Liposomal 
bupivacaine versus bupivacaine/epinephrine after video-assisted thoracoscopic wedge 
resectiondagger. Interactive cardiovascular and thoracic surgery. 2017 Mar 01. PubMed PMID: 
28329326. 
11. 
Jackson SM, Whitlark JD. Pain Control With Liposomal Bupivacaine After 
Thoracoscopies/Thoracotomies. The Annals of thoracic surgery. 2015 Dec;100(6):2414-5. PubMed 
PMID: 26652554. 
12. 
Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C, Dasta JF, et al. Clinical practice 
guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care 
unit. Critical care medicine. 2013 Jan;41(1):263-306. PubMed PMID: 23269131. 
13. 
Majercik S, Vijayakumar S, Olsen G, Wilson E, Gardner S, Granger SR, et al. Surgical 
stabilization of severe rib fractures decreases incidence of retained hemothorax and empyema. 
American journal of surgery. 2015 Dec;210(6):1112-6; discussion 6-7. PubMed PMID: 26454653. 
14. 
Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for 
improving the quality of reports of parallel-group randomized trials. Jama. 2001 Apr 
18;285(15):1987-91. PubMed PMID: 11308435. eng.