Clinical trial NCT04284930
Conditions: Pain, Postoperative
Keywords: local anesthetic continuous infusion pump local injection of Exparel
Sponsor: The Cleveland Clinic
Start date: 2016-02-01; Completion date: 2017-11-01
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Effective post surgical pain control in patients undergoing unilateral deep inferior epigastric perforator (DIEP) free flap reconstruction.

Detailed description:
Critical to patient recovery, and can contribute to faster patient mobilization, shorter hospital stays and reduced health care costs. The administration of local anesthetics via wound infiltration is standard of care and an effective practice for post surgical pain management, However this method only provides relatively brief analgesia, usually lasting only 12 hours. Other FDA approved delivery systems using an indwelling fusion pump catheter (On-Q pump) are currently being used in our practice and may be used to extend the duration of action of locally administered analgesia by continuously infusing anesthetic into the wound. Alternatively, a depot form of bupivacaine has been FDA approved and currently used to deliver a single dose administered via wound infiltration for prolonged analgesia by allowing for the diffusion of the drug over an extended period of time. Both of these products are used as a standard practice during DIEP free flap reconstructions. However, no studies compare the efficacy of these two methods patients undergong unilateral DIEP flap reconstructions has been done in a prospective, randomized control manner.

Arms: arm 1: Group 1 will receive an injection of 166mg of Depobupivacaine diluted in 60 ml. arm 2: Group 2 : The OnQ group will receive an infiltration via an OnQ soaker catheter of 0.25% bupivacaine at 4 ml/hour. arm 3: Group 3: The 0.25% bupivacaine patients will receive 2mg/kg of 0.25% bupivacaine.
Interventions: intervention 1: Depobupivacaine intervention 2: OnQ pump intervention 3: 0.25% Bupivacaine
Intervention descriptions: intervention 1: surgeons receive schematic for injection of Depobupivacaine. Subjects receive an injection of 166mg depobupivacaine. Injection on either side of the suture line, injected directly into the fascia. intervention 2: group 2: Surgeons receive instruction sheet with specific placement of catheter. All patients have two OnQ soaker catheters installed into abdominal donor site before donor closure. intervention 3: group 3: given 0.25% bupivacaine without epinephrine between internal oblique and transverse abdominal muscle.

Protocol documents:
Prot_SAP_000.pdf: 
Comparison of Local Anesthetic Infusion Pump Versus Depofoam Bupivacaine for Pain 
Managemen 
 
Date 12/12/2015 
ID: 15-1535 
 
 


 
 
Purpose 
 
We propose a randomized controlled study to compare the effectiveness of a local-
anesthetic continuous infusion pump system versus locally injectable FDA approved 
DepoFoam bupivacaine (Experal) for postsurgical analgesia in patients undergoing 
unilateral DIEP free flap reconstruction.  
 
Specific Aims 
 
1) Compare the amount of postoperative narcotic use in patients with a local-
anesthetic continuous infusion pump system, locally injectable liposomal 
bupivacaine, and a control cohort by recording the type and amount of narcotic 
use from a patient’s medication records. 
2) Examine the incidence of narcotic-related side effects in the experimental groups 
as compared to the control cohort by documenting incidents of nausea and 
vomiting, time to first ambulation, and time to first liquid and solid oral intake.   
3) Survey patient satisfaction with pain management using a visual analog scale 
during their hospital stay. 
 
Rationale for the Project 
 
Effective post-surgical pain control in patients undergoing unilateral deep inferior 
epigastric perforator (DIEP) free flap reconstruction. is critical to patient recovery, and 
can contribute to faster patient mobilization, shorter hosital stays and reduced health 
care costs.  The admisitration of local anesthetics via wound infiltration is standard of 
care and an effective practice for postsurgical pain management.  However, this method 
only provides relatively brief analgesia, usually lasting only 12 hours.  Other FDA 
approved delivery systems using an indwelling fusion pump catherter (On–Q pump)  are 
currently being used in our practice and may be used to extend the duration of action of 
locally adminisisted analgesia by continously infusing anesthetic into the wound.  
Alternativley, a depot form of bupivicaine has been FDA approved and currently used to 
deliver a single-dose admistered via wound infiltration for prolonged analgesia by 
allowing for the diffusion of the drug over an extended period of time.  Both of these 
products are used as standard practice during DIEP free flap reconstructions.  However, 
no studies compare the efficacy of these two methods patients undergoing unilateral 
DIEP flap reconstructions has been done in a prospective, randomized control manner.    
 
 
Significance 
 
We would like to compare Clevleland Clinic Foundation’s experience with unilateral DIEP 
flap breast reconstruction to determine if postoperive pain management is improved 


with either Depobupivicaine, a local infusion anesthetic pump as comapred to patients 
given standaad analgesic. We would like to conduct this study to better serve DIEP 
surgery patients 
 
In a IRB approved pilot study performed by Dr Amir Ghaznavi, at Henry Ford Medical 
Center in Detroit,MI in 2014 ,  depoFoam Bupivicaine was compared to Bupivicane alone 
in patient undergoing breast reconstrcution with transverse rectus abdonius muscle 
(TRAM) or abdominoplasty procedures.   
 
The primary endpoints were postoperative pain as measured by total postoperative 
morphine or hydromorphone utilization in a patient controlled analgesia (PCA) and pain 
scores on visual analog scale (VAS). The VAS was measured while the patients were at 
rest (VAS-R) and after the patient was asked to cough (VAS-C). Morphine usage was 
tracked by amount dispensed by the PCA pump. Using the medication chart any rescue 
medications beyond the PCA usage was also recorded. Patients were also interviewed 
and asked to rate their postoperative pain on a 10-point scale with 0 being no pain and 
10 being the most pain. Other variables recorded were incidents of nausea or vomiting, 
time to first ambulation, and time to first liquid and solid oral intake. All variable 
measurements were obtained at 30 minutes, 6 hours, 12 hours, 24 hours, 48 hours, and 
72 hours postoperatively 
 
A total of twenty patients were randomized into Depofoam bupivacaine group (Exparel, 
n=15), and continuous infusion pump system (On-Q, n=5) after undergoing 
abdominoplasty or TRAM flaps. The Exparel group demonstrated higher morphine usage 
at the 30 minute time point compared to the On-Q group (5.2 mg vs 1.2mg), but a 
significantly lower volume at all other time points when compared to the On-Q group 
(6.2 mg vs 16.42 mg at 6 hrs; 5.5 mg vs 14.8 mg at 12 hrs; 5.98 mg vs 14.9 mg at 24 hrs; 
5.23 mg vs 11.63 mg at 48 hrs; 2.7 mg vs 12.65 mg at 72 hrs). The VAS scores for the On-
Q group were higher at the earlier time points (up to 6 hours) when compared to 
Exparel group and relatively the same during the remainder of the study (Figure 1 and 
Figure 2). The remaining variables that were examined revealed that the Exparel group 
had more nausea and vomiting at earlier time points but that the same group was 
ambulating, drinking and eating solid food at earlier time points than the On-Q group.  
 
From this pilot study we concluded that with the use of a depot form of bupivicaine 
(Exparel), more effective postsurgical pain control was achieved in patients undergoing 
abdominoplasty or TRAM flap reconstruction than those that used an indwelling fusion 
pump catherters (On–Q pump). Further studies are necessary to enroll more 
participants undergoing these specific procedures in which this type of post surgical pain 
control may be most effective. 
 
Our goal in this study is to expand the finding based from our pilot study by observing 
only those that undergo breast reconstruction with a DIEP flap.   
 


Figure 1 
 
 
Figure 2 
 
 
 
 
 


Subjects in the project 
Study participants will include non-pregnant women aged 18 years or older scheduled 
to have unilateral DIEP flap breast reconstruction.  Patients will be required to have an 
ASA physical status classification of 1, 2, or 3. Patients will be excluded if they have a 
concurrent or recent medical condition that could interfere with study participation, 
including history of hepatitis, alcohol/substance abuse, uncontrolled psychiatric 
disorders, known allergy, or contraindication to amide-type local anesthetics, opioids, or 
propofol. Patients will also be excluded if they have a body weight of less than 50 kg, 
have participated in another study involving an investigational medication within the 
prior 30 days, or are taking analgesics (ie, nonsteroidal anti-inflammatory drugs, 
acetaminophen, or opioids), antidepressants, or glucocorticoids within the 3 days before 
surgery.  
 
Describe the control population 
Group 3 of our study will compromise the control group for our study.  Patients in this 
arm will receive .25% bupivacaine without epinephrine injected using ultrasound 
guidance in between the internal oblique and transversus abdominis muscles as well as 
along incisional lines.  This form of local wound infiltration  is the current standard of 
care for post-operative pain management for DIEP reconstructions of the breast.   
 
Support the likelihood of recruiting the number of subjects required 
Evidence from our Breast Reconstrcution database using  data transferred from 
Epic/Clarity, in 2014 show fifty four unilateral DIEP breast reconstructions were 
performed and in 2013 sixty six unilateral DIEP breast reconstructions were performed.   
 
Project Design and Protocol 
 
All patients meeting the inclusion criteria will be randomized using a blocked 
randomization technique, stratifying patients by the timing of the procedure, and it will 
be employed to allocate patients in equal numbers to each group.  The randomization 
will be created using the plan procedure within SAS software (version 9.3 or higher; 
Cary, NC)..  Patients will be assigned to one of three groups: Group 1 -DepoBupivicaine 
Injection; Group 2- OnQ catheter placement, and the control Group 3- 0.25 % 
Bupivicaine injection. 
 
Bupivacaine is a commonly utilized medicaiton for post-operative pain control with a 
favorable side-effect profile.  The dosages of medications given in the study are within 
safe limits.    
 
The maximum safety dosage of bupivicaine is 2mg/kg with a half life of 3.5 hours.  This 
means a 70kg adult could receive 150mg (.15g).  This calculation does not account for 
the slow release profile of DepoBupivicaine which would increase the maximum safe 
dose.  
 


The DepoBupivicaine patients (Group 1) will receive an injection of 166mg of 
DepoBupivicaine diluted in 60mL, the On Q patients (Group 2) will receive an infiltration 
via an OnQ soaker catheter of 0.25% bupivicaine at 4mL/hour (ie. .01 gram/hour) and 
0.25 % Bupivicaine patients (Group 3) will receive 2mg/kg of 0.25% of bupivicaine.  
 
 Consent 
All patients will sign an informed consent that will be presented to them during a pre-
operative visit with their attending surgeon.   
 
Pre-operative Protocol 
No preemptive morphine was given to patients.  Patients at high risk for post-operative 
nausea and vomiting will be given Dexamethasone 4mg and Reglan 10 mg.  Anesthesia 
will be given according to Table 1. 
 
 
Table 1: 
 
 
Induction 
Propofol 
Intubation (muscle relaxation) 
Succinylcholine 
Maintenacnce 
Sevoflourane 
Muscle relaxation 
Rocuronium 
Analgesia 
Fentanyl 2-7 mcg/Kg 
Prophylactic Analgesia  
Toradol 30- 60 mg 
Reversal 
Glycopirolate + Neostigmine 
Anti-emetic 
Zofran 4 mg 
 
Operative Technique  
Surgeons for patients randomized to Group 1( DepoBupivicaine ) will be given a 
schematic for injection of DepoBupivicaine. One 20 cc vial of EXPERAL (266 mg) will be 
diluted with 60 cc preservative-free normal sterile saline for a total volume of 80 cc. The 
infiltration technique for the DepoBupivicaine (See Baxter et al, and Hivelin et al) will be 
20 cc of injected with a 25-gauge needle on either side of the suture line, (Figure 2 and 
Figure 3) injected directly into the fascia.  The injections will be done in between the 
internal oblique and transversus abdominus  muscles as determined via ultrasound. 


Another 20 cc of will be injected on the outside edge of the surgical site where the 
sensory nerves branch up from the fascia to the skin flap. () The final 20 cc will be 
injected along the length of the incision where the skin will be anchored down with care 
to inject the product near the ileoinguinal nerve to ensure appropriate analgesic 
coverage . Once again, the DepoBupivicaine will be injected directly into the fascia 
above the muscle layer. All patients will have two closed-suction drains placed at the 
inferior aspect of the donor site, oriented horizontally and remote from the any infusion 
catheter.. 
 
For patients assigned to the Group 2 (OnQ) the surgeons will be given an instruction 
sheet with specific placement of catheter (See Bulter et al).  All patients in the group will 
have two ON-Q soaker catheters installed into the abdominal donor site before donor-
site closure. The catheters will be inserted through 3-mm stab incisions in the 
suprapubic area and 3 cm caudal to the donor-site incision. One catheter will be placed 
directly in the plane between the internal oblique and the transversus abdominus (see 
Hebbard et al) , and the second catheter will be placed subcutaneously, superficial to 
the anterior rectus sheath along the superior aspect of the donor site (Figure 1).  At the 
conclusion of surgery, a 4-ml/hour infusion 0.25% Bupivicaine % solution will be 
delivered continuously by the continuous infusion 
pump system (2 ml/hour through each catheter). All patients will have two closed-
suction drains placed at the inferior aspect of the donor site, oriented horizontally and 
remote from the any infusion catheters. 
 
Patients assigned to the control Group 3 (0.25 % Bupivicaine) will be given 0.25% 
bupivacaine without epinephrine.  A dose of 2mg/kg will be given. Thus, a 80 kg patient 
will be given 80 cc of 0.25% Bupivacaine .   The infiltration technique for the Maracine 
will be identical to the EXPERAL injection whereby 20 cc of will injected with a 25-gauge 
needle on either side of the suture line (Figure 2 and Figure 3) directly into the fascia 
above the muscle layer. The injections will be done in between internal oblique and 
transversus abdominus muscles as determined via ultrasound. Another 20 cc of will be 
injected on the outside edge of the surgical site where the sensory nerves branch up 
from the fascia to the skin flap (Figure 3). The final 20 cc will be injected along the length 
of the incision where skin will be anchored down; care will be taken to inject the 
product near the ileoinguinal nerve to ensure appropriate analgesic coverage (Figure 4). 
Once again, the 0.25% Bupivacaine will be injected directly into the fascia above the 
muscle layer.  All patients will have two closed-suction drains placed at the inferior 
aspect of the donor site remote from the any infusion catheters and oriented 
horizontally. 
 
 
 


 
 
Figure 1.  A. OnQ catheter in vivo prior to closure of open abdomen (See Haller et al) B. 
Schematic of OnQ catheter place in a plane above the Tranversus Abdominus (TA) (see 
Hebbard et al) 
 
 
A. 
 
 
 
  B. 
 
 
 
C. 
Figure  2.  Injecting bupivacaine into fascia and along incisional lines (C) prior to 
closure(Baxter et al).   
 
 
 
 
Caudal 
Cephalad 
Umbilicus 
OnQ 
catheter 
Injecting fascia 
Injecting abdominal incisional line 
Injecting fascia 


 
 
 
 
Figure 3 A. Open abdomen prior to closure marking site of injection of either 
DepoBupivicaine or 0.25 % Bupivicaine (White Arrow) B. Using ultrasound probe in vivo 
C. Schematic of plane between the Internal Oblique and Transversus Abdominus  
 
Post-operative Protocol 
 
No short-acting analgesics, such as Fentanyl, will be given post-operatively.  All patients 
will receive a narcotic intravenously through a patient-controlled analgesia pump 
programmed for demand-only mode (no basal rate). The patient-controlled anesthesia 
will be filled with morphine or hydromorphone (if patient sensitivity to morphine). Oral 
narcotics will be offered when the patient’s diet is advanced as tolerated, typically post-
operative day 1. Patients will be encouraged to ambulate on post-operative day 1. The 
continuous infusion pump catheters will be removed by the surgeon when the pump is 
empty.  Drains will be removed when output is less than 30mL in a consecutive 24 hour 
period.   
 
Our primary endpoints will be postoperative pain as measured by total postoperative 
morphine or hydromorphone utilization from a patient controlled anesthesia pump 
(PCA) and pain scores on visual analog scale (VAS).  The VAS will be measured while the 
patient is at rest (VAS-R) and after the patient is asked to cough (VAS-C).  For each 
patient, the area  under the curve (AUC) of the VAS-R will be calculated.  Morphine 
usage will be tracked by patient controlled analgesia (PCA) dispensed.  Using the 
medication chart, any rescue medications beyond the PCA will also be recorded.  
Patients will be interviewed and asked to rate their postoperative pain on a 10-point 
scale with 0 being no pain and 10 being the most pain. Another variables recorded will 
include incidents of nausea or vomiting, time to first ambulation, and time to first liquid 
and solid oral intake.   All measurements for variables were obtained at 6 hrs, 12 hrs, 24 
hrs, 48 hrs, 72 hrs.  Nursing staff on our designated breast reconstruction floor  will be 
instructed on how to interview patients and collect data for the 6 and 12 hour 
timepoints.   This information will be stored on Epic EMR in a stardard note and nurses 
will be given a smart text to use in order to appropriately ascertain all information.  The 
24, 48, and 72 hour time points will be collected by the co-investigators.  Any pain 
medications given by PCA, IV or PO will recorded and converted to morphine as 
diagramed below: 


 
 
Discuss limitations and difficulties 
 
The limitations of our study include potential confounding pain from the mastectomy 
site, the subjectivity in patient perception of pain, and differences in patient threshold 
to request patient- controlled anesthesia and oral narcotics 
 
Provide the tentative schedule for completion 
 
Our schedule for the study will be 6 months continuous enrollment and 
experimentation from September to February, or until our groups are filled.    .   
 
Data collection 
The data fields will be: Birth date, sex, type of surgery, utilization of mesh, number of 
mg on PCA, VAS at rest and VAS with cough, number of rescue pain medications given, 
number of incidents of nausea/vomiting, time to first ambulation, time to first liquid and 
solid intake post surgery.   
 
Planned Data Analysis 
 
 
The data will be examined with an analysis of variance (ANOVA) procedure with 
repeated measures.  The design will have one between factor, (group (3), and one 
within factor, time (6).  The analysis will test for a group effect, a time effect and a group 
by time interaction.  We anticipate that the three groups will be comparable at the start.  
This implies the likelihood of a significant interaction term.  If this happens, our primary 
analysis will focus on the ANOVA for the 72-hour time point.  This will show us if a 
differential effect has occurred.  All assumptions of the test will be examined and data 
transformations or nonparametric methods used if indicated. 
 
We will not be utilizing QHS, rather, one of the plastic surgery residents, Steven Rueda, 
will serve as our statistician. 


 
Sample Size Justification 
 
 
We propose to randomly assign individuals recruited during the recruitment 
period into 3 equal groups.  With three groups this translates to a difference between 
groups of 5 for total morphine used on day 3 and 0.7 for the VAS.  This assumes 
standard deviations of 4.9 for morphine and 0.7 for VAS.  Effects of these sizes represent 
clinically important differences in the range that we believe will happen.   
 
 
 


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