Conditions: Pain, Postoperative Major Abdominal Surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 514
Healthy volunteers: no

Brief summary:
Comparison of Bilateral Transversus Abdominis Plane Block with Exparel versus Continuous Epidural Analgesia With Bupivacaine

Detailed description:
The investigator goal is to compare the analgesic efficacy of TAP blocks with liposomal bupivacaine (Exparel) and continuous epidural blocks in patients who are scheduled for major lower abdominal surgery. To assess whether TAP block with Exparel is noninferior to continuous epidural analgesia on pain management, defined as noninferior for both pain control and total opioid consumption for 72 hours, in patients who had major lower abdominal surgery.

Arms:
arm 1: Bilateral Transversus Abdominis Plane (TAP) block procedure following injection of liposomal bupivacaine (Exparel) arm 2: Epidural catheters with an infusion of Bupivacaine standard solution without additives

Interventions: intervention 1: TAP block intervention 2: Epidural analgesia intervention 3: EXPAREL intervention 4: Bupivacaine
Intervention descriptions: intervention 1: Transversus Abdominis Plane (TAP) blocks will be performed preoperatively. An in-plane ultrasound will be used in TAP block procedure. intervention 2: Epidural catheters will be inserted preoperatively. intervention 3: Once the target area is positioned, plain bupivacaine 0.25%, 20ml will be given to open the space and then single dose (10ml) of liposomal bupivacaine (Exparel) mixed with saline (10 ml) will be injected in each side. Total dose of Exparel will be 20 mL. intervention 4: Once an epidural catheter is successfully positioned, an infusion will be initiated intraoperatively. Bupivacaine standard solution without additives will be prepared for each patient in epidural group.

Protocol document:
Prot_SAP_000.pdf: 
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Comparison of Bilateral Transversus Abdominis 
Plane Block with Exparel versus Continuous 
Epidural Analgesia With Bupivacaine: 
A Randomized, Controlled Trial 
 
 
 
 
Alparslan Turan, MD and Colleagues 
 
 
 
 
 
Department of OUTCOMES RESEARCH 
Cleveland Clinic 


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Table of Contents 
 
Specific Aims 
 
1 BACKGROUND 
 
A. Postoperative pain 
 
B. Postoperative pain management and regional analgesia 
 
C. Epidural Analgesia and side effects 
 
D. Transverses Abdominis Plane (TAP) Blocks 
 
E. Exparel 
 
F. Rationale of the study 
 
2 STUDY OBJECTIVES 
 
3 METHODS and STUDY DESIGN 
 
A. Study Overview 
 
B. Setting and Population 
Inclusion Criteria 
Exclusion Criteria 
C. Withdrawal Criteria 
 
D. Administration of Acetaminophen 
 
E. Protocol 
 
F. Measurements 
 
G. Data Analysis 
 
H. Sample Size Considerations 
 
I. References 


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Specific Aims 
Pain management after major abdominal surgery remains challenging. The best- 
accepted analgesic approach is continuous epidural analgesia, however, epidural 
analgesia can cause hemodynamic instability, along with motor weakness and 
consequent restriction of ambulation. Furthermore, epidural catheter placement can be 
time consuming and challenging, and is contraindicated in anti-coagulated patients. 
The Transversus Abdominis Plane infiltration is an alternative approach to 
providing postoperative analgesia to the anterior abdominal wall. TAP infiltration are 
relatively easy to perform, generally safe, and can be performed in patients who are anti- 
coagulated. TAP infiltration can be performed as a single injection, or a catheter can be 
inserted for continuous local anesthetic infusion. Single-shot TAP infiltration with 
conventional local anesthetics do not last sufficiently long to provide effective 
postoperative analgesia. However, recently developed liposomal bupivacaine provides 
much longer-lasting analgesia than plain bupivacaine. 
Therefore we proposed to compare single-shot TAP infiltration with liposomal 
bupivacaine were as effective as continuous epidural analgesia. The proposed research 
will have the following specific aims, all of which will be assessed over 72 hours, or the 
duration of hospitalization if shorter: 
Primary Aim: Bilateral TAP blocks with single‐shot liposomal bupivacaine are noninferior 
to continuous epidural analgesia with conventional bupivacaine for both pain control and 
opioid consumption. 
Secondary Aim 1: To compare the effect of TAP block with Exparel and epidural 
analgesia on activity after surgery. 
 
Secondary Aim 2: To compare TAP block with Exparel and epidural analgesia on opioid 
related side effect. 
Secondary Aim 3: To assess hemodynamic changes with TAP block with Exparel and 
epidural analgesia. 


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Secondary Aim 4: To compare quality of recovery after anesthesia with TAP block 
Exparel and epidural analgesia. 
Secondary Aim 5. To compare length of stay in TAP block with Exparel and epidural 
analgesia patients after surgery. 
 
Secondary Aim 6. To evaluate cost-effectiveness of TAP block with Exparel. 


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1. Background 
 
 
 
A. Postoperative pain 
 
Pain is a psychological sensory experience that is provoked by surgical tissue 
injury. Postoperative pain results from a of combination of nociceptive and inflammatory 
components.1 The nociceptive component results from activation of peripheral sensory 
neurons damaged by surgical incision and fades gradually as tissues heal. The 
inflammatory component enhances pain sensitivity via release of mediators from the 
surgically injured tissue. Central neuronal sensitization also seems to contribute to 
postoperative pain and hyperalgesia.1,2 Both mechanisms contribute to resting pain is in 
and around surgical incisions. Movement of wounds or touching them, breathing, 
coughing, and gastrointestinal motility can all evoke pain. 
 
Unrelieved postoperative pain leads to multiple physiological and psychological 
consequences, which potentially worsen outcomes. For example, inadequate 
perioperative analgesia is associated with myocardial ischemia, impaired wound healing, 
delayed 
gastrointestinal 
motility, 
atelectasis, 
and 
postoperative 
pneumonia.3-5 
Furthermore, poorly controlled acute pain is strongly associated with development of 
persistent incisional pain, which can be devastating for patients.6,7 
B. Postoperative pain management and Regional Analgesia 
 
Postoperative pain management has improved, but remains problematic. Thirty 
percent of patients still report severe postoperative pain, and 47% report moderate pain.8 
Researchers estimate that only one in four surgical patients in the USA receive adequate 
relief of acute pain. Consequently, postoperative pain remains the major preoperative 
concern for patients having surgery.9 
Pain involves multiple mechanisms and is thus ideally treated with a variety of 
analgesic techniques with additive, or better, synergistic effects.1 In theory, at least, 


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combining techniques improves overall analgesia while reducing side effects. Consistent 
with this theory, studies indicate that multimodal analgesia shortens hospitalization times, 
improves recovery and function, and decreases health care costs.1,10 
Multimodal analgesia can be achieved by combining various classes of drugs.1,10,11 
But the most common approaches are a combination of an opioid and non-opioid, with or 
without regional anesthesia-analgesia.11 While opioids remain the mainstay for treatment 
of postoperative pain, sole reliance on opioids is often inadequate and lead to substantial 
side effects including ileus, sedation, respiration depression, and hyperalgesia.12 There 
is also evidence opioids impair cellular and humoral immune function in humans, thereby 
potentially enhancing infection risk.13-16 An important clinical goal is thus to decrease 
opioid use and, consequently, reduce opioid-related side effects. 
 
Regional anesthesia (RA) is a promising approach to reducing the need for high- 
dose opioids. Regional techniques can be categorized as neuraxial blocks (spinals, 
epidural) that involve local anesthetics injected around the spinal cord or as peripheral 
nerve blocks that involve local anesthetic administration near peripheral nerves. The 
basis of regional analgesia is local anesthetics or/and opioids which locally block voltage- 
gated sodium channels, thus interrupting nerve conductions and rendering enervated 
regions insensitive to pain.17 Peripheral nerve blocks, especially, have become popular 
in recent decades largely because improvements in ultrasound technology make blocks 
faster and safer — and because blocks speed recovery and improved patient 
satisfaction.18 
Surgery is associated with hormonal and metabolic derangements, the "stress 
response," which results from activation of the hypothalamic-pituitary-adrenal axis and 
the sympathetic system. It is characterized by systemic release of catecholamines, 
cortisol, and cytokines.19 The stress response is associated with increased catabolism, 
immunosuppression, poor postoperative outcomes, and prolonged recovery.20,21 RA 
surpasses general anesthesia in ability to minimize the stress response.19,22 RA blocks 
the afferent neural transmission from reaching the central nervous system and activating 
the stress response, and by blocking descending efferent activation of the sympathetic 


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nervous system.22-24 In clinical practice, RA has been shown to be superior to systemic 
opioids alone in thoracic, abdominal, gynecological, and orthopedic surgeries.25-28 
Studies have consistently shown RA to reduce postoperative pulmonary, gastrointestinal, 
and cardiac morbidities. Furthermore, there is evidence that RA decreases postoperative 
morbidity and mortality, and shortens postoperative hospitalization.29-32 
Regional approaches including epidural and TAP blocks are considered key 
elements in “fast-track” protocols for patients recovering from colorectal surgeries 
because they facilitate recovery and shorten hospitalization.33 Thoracic epidural 
analgesia reduces sympathetic outflow from T6-L12, speeds return of gastrointestinal 
motility by as much as 3 days.34,35 RA also reduces consumption of opioids, a major risk 
factor for postoperative nausea and vomiting, which delays resumption of oral diet. 
Improved intestinal blood flow may also improve anastomotic healing.36,37 
Pulmonary complications are common side effect of thoracic and major abdominal 
surgery, in fact occurring more often than cardiac complications.38 Important 
complications include atelectasis, pneumonia, and respiratory failure — and are 
associated with morbidity, prolonged hospital stay, and increased cost of care.39 
Inadequate analgesia also leads to ineffective breathing ("splinting"), characterized by 
rapid and shallow breathes which itself contribute to atelectasis, impaired gas exchange, 
and inability to clear secretions. The use of RA reduces pulmonary complications in 
patients recovering from thoracic and abdominal surgeries by providing excellent 
analgesia, preventing “splinting,” and thus improved respiratory mechanics.40-43 
The most serious opioid-induced complication is respiratory depression. 
Respiratory depression is the main fatal hazard of opioid use and has been identified as 
a safety target by the Joint Commission on Hospital Accreditation.57 Supporting this 
concern, a study conducted in United Kingdom ranked opioids as the second most 
common cause of adverse events in hospitalized patients.58 The current national goal of 
better controlling postoperative pain by making it a quality indicator is likely to increase 
opioid use — and almost surely also increase associated complications. 


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Both hypdrophilic (i.e., morphine) and lipophilic (i.e., fentanyl) opioids promote 
respiratory depression by: 1) systemic uptake via epidural venous plexus; and 
2) arachnoid penetration and cephalad spread. The result is a dose-dependent reduction 
in responsiveness of brainstem respiratory centers to carbon dioxide partial pressure 
(PCO2) with opioids. This is clinically manifested as an increase in resting PCO2 and a 
shift in the CO2 response curve.59,60 We will also evaluate hypoxic events in this patients 
and compare the effect of opioid sparing on these events. 
Postoperative nausea and vomiting (PONV) is a common complication which 
causes considerable patient discomfort and lowers patient satisfaction.61 In patients given 
epidural opioids, it is caused by upward migration of opioids in CSF which then stimulate 
the chemoreceptor trigger zone of the medulla.62 Consequently, PONV remains common 
during epidural analgesia, with a reported incidence of up to 70%. 
Opioids also enhance sphincter tone and reduce peristaltic contraction. Delayed 
gastric emptying is caused by decreased motility, increased antral tone, and increased 
tone in the first part of the duodenum. Delay in passage of intestinal contents leads to 
greater absorption of water, increased viscosity, and desiccation of bowel contents — 
which in turn causes constipation and contributes to postoperative ileus. 63 Postoperative 
ileus, with an incidence of 4.5%, prolongs hospital stay and increases hospital costs.64 
Opioids also inhibit urinary bladder function, thus increasing the risk of urinary retention. 
 
 
C. Epidural Analgesia and side effects 
 
Epidural analgesia (EA) is an indispensible part of modern perioperative pain 
management because it provides better postoperative analgesia after abdominal surgery 
than systemic opioids.26 Commonly, a small dose of local anesthetic-opioid combination 
is injected through a catheter into the epidural space, then the mixture diffuses across the 
dura, reaching spinal nerve roots, dorsal root ganglion, or the spinal cord to block afferent 
pain signals to attenuate the surgical stress response and provide excellent analgesia.44 
Meta-analysis shows that epidural analgesia reduces mortality by a third compared with 
systemic opioids; it also decreases cardiovascular and pulmonary morbidities in high-risk 


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patients, speeds return of bowel function, and decreases the risk of venous 
thromboembolism. EA also enhances patient satisfaction compared with parental 
opioids.45 
Despite its widespread use, EA is has several limitations. First, locating the 
epidural space (ES) by loss-of-resistance is a blind procedure and is operator 
dependent.46 Anatomical variations from age-related vertebral changes, spine 
pathologies (i.e. scoliosis), previous back surgeries, body habitus, and normal variations 
in skin-to-epidural space all contribute to difficult epidural catheter insertion. The ES is a 
potential space consisting of a labyrinth of epidural fat, lymphatics, venous plexus, spinal 
nerves, and compartments separated by tissue band which make location of catheter tip 
hard to control; a consequence can be nonuniform spread of anesthetics and subsequent 
unilateral or failed block.47,48 
A further problem is that epidural catheter migration is common, with incidence of 
36%, and is due to body movement and oscillations of CSF.49,50 The tip can migrate out 
of the epidural space via intervertebral foramen (resulting in epidural failure), laterally 
(result in unilateral block), into subarchnoid space (resulting high or total spinal), or into 
epidural vein (result in systemic anesthetic toxicity).49,51,52 All of these factors contribute 
to a high failure rate, reported to be 23-30%50,53 
There are also situations in which patients are unable to receive epidural 
anesthesia, or epidural blocks are especially prone to failure. Anticoagulated patients, for 
example, are not ideal candidates for neural anesthesia due to risk of epidural hematoma. 
Patients with history of chronic back low back pain, spine pathologies (scoliosis, spina 
bifida), or history of back surgery are also at increased risk of failed epidural blocks. In 
patients with previous spine surgeries, epidural scarring or altered anatomy may make 
the ES nearly impossible to locate; and even when an epidural catheter can be inserted, 
scarring of ligamentum flavum often reduces the size of the epidural space leading to 
patchy blocks.51 
Serious complications from EA are fortunately rare. Nonetheless, epidural 
analgesia can cause side effects either from administered medications or from injury from 


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epidural vessels and neurological structures. Epidural analgesia also causes hypotension 
in about 3-7% of patients54 consequent to blocking sympathetic outflow which promotes 
venous and arterial vasolidation and a “functional” hypovolemia. Although hypotension is 
usually transient, strokes have been reported in patients with low reserve.55 More 
commonly, hypotension prompts clinicians to at lease temporarily cease local anesthetic 
administration and to give fluids or vasopressors.56 Typically, opioids are substituted 
during hypotensive periods, at least transiently exposing patients to opioid-related 
complications. 
Although rare, neurologic complication consequent to neuraxial blocks can be 
devastating. Examples include epidural hematoma, epidural abscess, and postdural 
puncture headache.65 With widespread use of anticoagulants, patients are at increased 
risk of developing epidural hematoma from initial needle insertion to catheter 
manipulation. If unrecognized, epidural hematoma can cause cord compression and 
permanent paraplegia. Postdural puncture headache, although rare (~1%), cause 
significant morbidity, require additional treatments (i.e., bed rest, blood patch), prolong 
hospital stays, and may persist for months.66 
Including opioids to epidural local anesthetics has become the standard for 
providing epidural analgesia. Beneficial therapeutic effects of epidural opioids as a result 
of improved analgesia include improvement in pulmonary function, modification of the 
endocrine-metabolic stress response, improvement in time to ambulation, decreased 
morbidity, and shorter hospital stay. The epidural administration of opioids is associated 
with potential side effects and complications, the most serious potential side effect being 
that of respiratory depression. This, as well as most of the other potential opioid-related 
side effects is associated with epidural opioid analgesia. A consequence of these toxicities 
and side effects is that epidural sometimes needs to be stopped at least temporarily, thus 
reducing the analgesic benefits of RA. 
In summary, epidural analgesia provoke numerous limitations and severe 
complications that cause substantial patient morbidity. Nonetheless, epidural analgesia 
provides superior pain control and causes fewer side effects than systemic opioids. 


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Epidural analgesia also delays discharge from hospital, increases the cost of care, and 
reduces patient satisfaction. 
 
 
D. Transverses Abdominis Block 
 
 
The Transversus Abdominis Plane (TAP) block, first described by Rafi in 2001, is 
an alternative approach to providing post-operative analgesia to the anterior abdominal 
wall (Figure 1).67 For a TAP block, local anesthetic is injected into the plane between the 
transversus abdominis and internal oblique muscles to interrupt the innervation of afferent 
nerves (T6-L1) of the anterior abdominal wall including the parietal peritoneum, muscles, 
and skin. 
 
 
Complications related to TAP blocks are rare. Early reports of liver laceration from 
the block were likely from a combination of landmark technique and improper use of 
ultrasound.68 The TAP block is easier to perform than epidural anesthesia (especially with 
ultrasound guidance), safer, relatively inexpensive, and can be used safely in patients 
who are anti-coagulated. Local anesthesia to the TAP can be given as a “single shot” or 
via continuous local anesthetic infusion. Widespread clinical TAP catheter use is limited 
because of easy dislodgment of catheter and close vicinity to surgical site. 


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TAP appear to be safe and effective as part of multimodal analgesia for various 
abdominal surgeries including open appendectomy, hysterectomy, caesarean delivery, 
abdominoplasty, prostectomy, renal transplant, and laparoscopic surgeries.69-76 It is even 
possible to use TAP as sole anesthetic technique in open abdominal procedures.77,78 TAP 
blocks in colorectal surgery requiring a midline incision reduce postoperative opioid 
consumption, PONV, and sedation.79 
TAP blocks only provide somatic pain relief whereas epidural anesthesia also 
provides visceral and somatic relief. TAP blocks nonetheless provide effective analgesia 
and reduce opioid requirements. Furthermore, retention of sensory and motor function 
lower extremities facilitates early ambulation and presumably reduces the risk of falls. 
E. Exparel 
 
Use of local anesthetics in postsurgical pain is limited because the duration-of- 
action of current local anesthetics is short. Effective postoperative analgesia thus usually 
requires insertion of a catheter and continuous or repeated anesthetic administration. 
Exparel (Exparel®, bupivacaine liposome injectable suspension, Pacira 
Pharmaceuticals Inc., Parsippany, NJ, USA) is a sterile, non-pyrogenic white to off-white 
preservative-free aqueous suspension of multivesicular liposomes (DepoFoam® drug 
delivery system) containing bupivacaine. Exparel is a liposome injection of bupivacaine, 
an amide-type local anesthetic, indicated for administration into the surgical site to 
produce postsurgical analgesia and intended for single-dose administration. Depofoam 
technology is based on multiple microscopic spherical particles with many aqueous 
chambers separated by lipid membranes. When refrigerated, the particles are stable; but 
after injection of Exparel into soft tissue, bupivacaine is released from the multivesicular 
liposomes over a period of time. The components of Depofoam particles are non-toxic 
and clinical trials have demonstrated no adverse events. Furthermore this technology 
previously has been safely used in different settings and provided sustained release in 
other target areas. 
Various doses of Exparel were compared with plain bupivacaine in patients having 
inguinal hernia repairs. Evaluations revealed that Exparel administration produces dose- 
dependent increases in plasma bupivacaine concentrations, and that the half-life of 


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Exparel was almost twice that of plain bupivacaine. However, maximum plasma 
concentrations were similar with plain bupivacaine and Exparel. Studies in other surgical 
models demonstrated similar results, and analgesia lasting up to 72 hours. Bupivacaine 
is metabolized through hepatic pathways, hepatic insufficiency thus increases the risk of 
toxicity. 
The clinical efficacy of Exparel has been studied in number of clinical trials. In 
wound infiltration for hemorrhoidectomy, 189 patients were randomized to Exparel or 
placebo. Significant reductions in pain scores were seen at each measurement time 
points for 72 hours. Patients given Exparel required 45% less opioid, and the first opioid 
dose was almost 12 hours later in Exparel group. In a different study performed in patients 
having bunionectomies, cumulative pain scores were lower, and the time to first opioid 
use was significantly prolonged by Exparel. Furthermore, Exparel has also been 
investigated and demonstrated significant analgesic effect in patients having knee 
arthroplasty, breast augmentation, and hernia repair. Surgical wound infiltration was also 
studied in 10 clinical trials, which showed that cumulative pain scores were improved with 
Exparel through 24-72 hours. However, TAP studies with Exparel in abdominal surgeries 
are mainly retrospective, with limited number of patients. None of these studies directly 
compare TAP and epidural analgesia. 
F. Pharmaco-economics 
 
Exparel costs about $300 per vial, which is substantial, and some institutions 
consequently regulate its use. However, in retrospective study demonstrated significant 
cost effectiveness with Exparel when compared with epidural. There is potential economic 
benefit of using EXPAREL in TAP blocks. Even after agreeing with the efficacy of 
EXPAREL, one reason for its slow adaptation into mainstream acute pain practice is the 
drug would drive up cost of heath care. In addition, it has been documented that 
EXPAREL-based multimodal analgesia was associated with lower cost and length of 
hospital stay ($8766, 2 days) versus opioid-based analgesia ($11850, 4.9 days) in 
patients after open colectomies.80 


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Due to the long history on epidurals, there might be a underestimation of the overall 
cost associated with epidurals. Schuster et al. conducted a retrospective cost analysis on 
the cost drivers of total expense of managing a patient-controlled epidural in a variety of 
surgeries and discovered that 51% of the cost was staff related and 15% was related to 
PCA pumps and pump materials.81 In many hospitals, patients with epidurals are 
continuously monitored by both ward nurses and acute pain service residents for opioid 
and epidural related side effects. These costs can potentially be reduced or eliminated by 
the opioid-free Exparel. More time and resources can thus be freed to care for more 
patients in need. 
F. Rationale of the study 
 
The recent enhancement of conventional bupivacaine with encapsulated 
bupivacaine much prolongs the duration-of-action and resulting pain control with a single 
application. TAP blocks appear to be easier to perform than epidurals (especially with 
ultrasound guidance), safer, relatively inexpensive, and can be used safely in patients 
who are anti-coagulated. 
Only three studies have compared the analgesic effects of TAP blocks and 
epidural catheters.82-84 Niraj et al. compared the analgesic effects of bilateral subcostal 
TAP catheters and epidural catheters and reported a success rate of 78% for epidural 
versus 63% for TAP, although the results were not statistically significant.82 Another study 
in 2013 did not show any significant difference in analgesic effects of bilateral TAP 
catheters and epidural catheters.83 And finally, in a recent study, single-injection TAP was 
compared with IV opioid and epidural analgesia. The authors found that single-injection 
subcostal TAP blocks were more effective than IV opioid analgesia, while continuous 
thoracic epidural analgesia was more effective than the single-injection subcostal TAP 
block. Existing studies suffer from small sample size and inconsistent conclusions. 
Experts in regional anesthesia have emphasized the need for well-powered studies 
comparing the different methods.85-88 
In our institution we retrospectively investigated patients who received TAP with 
Exparel for abdominal surgery and compared it with patients who received epidural. 318 


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patients were propensity matched on 18 potential factors among three groups (106 per 
group): 1) TAP infiltration with bupivacaine liposome; 2) continuous Epidural analgesia 
with plain bupivacaine; and; 3) intravenous patient-controlled analgesia (IV PCA). TAP 
infiltration were non-inferior to Epidural on both primary outcomes (p<0.001). TAP 
infiltration were non-inferior to IV PCA on pain scores (p=0.001) but not superior on opioid 
consumption (p=0.37) (Figure 1). TAP infiltration with liposomal bupivacaine and 
continuous epidural analgesia were similar in terms of pain and opioid consumption, and 
not worse in pain compared with IV PCA. Which demonstrated that TAP infiltrations with 
exparel are a reasonable alternative to epidural analgesia in abdominal surgical patients. 
 
 
Figure 1 Results for comparison TAP infiltration and Epidural patients on postoperative 
time-weighted average pain score in the 0-10 VRS pain scale and 
intravenous morphine equivalent dose of opioid within 72 hours of the 
surgery. 
 
 
Furthermore, preferable because they are easier to perform and thought to be 
safer. 


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2. Study Objectives 
 
We will prospectively compare the analgesic efficacy of TAP blocks with liposomal 
bupivacaine (Exparel) and continuous epidural blocks in patients who are scheduled for 
major lower abdominal surgery. Specifically, we will test the primary hypothesis that TAP 
blocks with single‐shot liposomal bupivacaine are noninferior to continuous epidural 
analgesia for pain control and opioid consumption in patients recovering from major lower 
abdominal surgery. 
The proposed research will have the following aims, all of which will be assessed 
over 72 hours or the duration of hospitalization if shorter: 
Primary Aim. 
 
To assess whether TAP block with Exparel is noninferior to continuous epidural 
analgesia on pain management, defined as noninferior for both pain control and total 
opioid consumption for 72 hours, in patients who had major lower abdominal surgery. We 
define noninferiority as no worse than 25% greater opioid consumption and no worse than 
1 point higher in pain score. We choose a 1 point delta for VRS pain score since that is 
approximately half as large as a delta we would use to assess superiority, and it is also 
about half of the expected standard deviation in the VRS pain score, both standard 
methods for choosing a noninferiority delta. 
Hypothesis. Bilateral TAP blocks with single‐shot liposomal bupivacaine are noninferior 
to continuous epidural analgesia for both pain control and opioid consumption in patients 
recovering from major lower abdominal surgery. 
Total opioid consumption, in morphine equivalents, will be the major measure of 
opioid use. However, we will also record the number of times analgesic given for 
breakthrough pain. Our major outcome for pain will be time-weighted pain scores from 
discharge from the PACU until 72 hours after the end of surgery. PACU pain scores will 
also be compared separately. Sedation will be determined and recorded at roughly 4- 
hour by ward nurses per clinical routine. 
Secondary Aims. 


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Secondary Aim 1: To assess the effect of TAP block with Exparel and epidural analgesia 
on activity after surgery. 
Hypothesis. TAP block with Exparel will have increased amount of time spend sitting or 
lying with epidural patients. 
ViSi mobile (Sotera Wireless) patient monitoring system a platform for 
comprehensive vital sign monitoring will be used to quantify patient activity over the initial 
72 postoperative hours. This system continuously measures position (lying versus sitting) 
and activity. 
Secondary Aim 2: To evaluate TAP block with Exparel and epidural analgesia on opioid 
related side effect. 
Hypothesis. Patients in TAP group have fewer opioid-related side effects than epidural 
group. 
We will use a validated composite outcome, Opioid–Related Symptom Distress 
Scale (ORSDS), to evaluate opioid-related side effect.89 ORSDS is 4-point scale that 
evaluates 3 symptom distress dimensions (frequency, severity, bothersome 4-point scale 
that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 
12 opioid related side effects. ORSDS questionnaire will be administered by a trained 
research fellow on first, second, and third postoperative mornings while patients remain 
hospitalized. 
Secondary Aim 3: To assess hemodynamic instability TAP block with Exparel and 
epidural analgesia. 
Hypothesis. Patients in TAP group will have higher blood pressure and less hemodynamic 
instability compared to epidural patients. Hypotension will be defined as MAP hypotension 
MAP < 55 mmHg and SBP hypotension defined as SBP < 80 mmHg. 
ViSi mobile (Sotera Wireless) patient monitoring system will be used to obtain vital 
signs including beat-to beat noninvasive blood pressure of the patient for 72 hours. 
Secondary Aim 4: To assess Quality of recovery after anesthesia with TAP block Exparel 
and epidural analgesia. 


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Hypothesis. Patients in TAP group will have higher quality of recovery score than epidural 
patients. 
Quality of recovery after anesthesia and surgery is an important measure of the 
early postoperative health status of patients, and the Quality of Recovery scale is highly 
validated.90 Patients will be questioned on morning of POD 1 and 3. 
 
Secondary Aim 5. To assess length of stay in TAP block with Exparel and epidural 
analgesia patients after surgery. 
Hypothesis. Patients in Epidural group will have prolonged length of hospital stay 
compared to epidural patients. 
 
Secondary Aim 6. To assess the cost-effectiveness of TAP block with Exparel after 
surgery. 
Hypothesis TAP block with Exparel reduces the cost of care by decreasing opioid-related 
side effects and better maintaining hemodynamic stability. 
 
 
Exploratory 
 
Exploratory Aim 1. To compare TAP block with Exparel and epidural analgesia on 
postoperative opioid-related hypoxic events. 
Hypothesis. TAP block with Exparel reduces hypoxic events compared to epidural 
analgesia patients. 
Patients will have continuous pulse-oximeter monitoring and recording. Nurses 
and the study personal will be blinded to data on the monitor and standard of care will be 
provided. Data from the monitor will be downloaded daily for 72 hours postoperatively, 
incidence of hypoxia and the time spend hypoxic will be determined. We will be using ViSi 
mobile (Sotera Wireless) patient monitoring system a platform for comprehensive vital 
sign monitoring. This system will measure 3 lead ECG, SpO2 and number of respirations 
continuously. The outcome will be area-under-the-curve for saturation over time with the 
threshold set at 90%. 


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Exploratory Aim 2. To compare TAP block with Exparel and epidural analgesia on 
persistent postoperative pain. 
Hypothesis. TAP block with Exparel reduces persistent postoperative pain (defined by 
pain at incision at three month follow up) similar to epidural analgesia patients. 
Patients were also contacted by one of the investigators at 3 and 6 months after 
discharge to evaluate whether persistent surgical pain. Presence and VAS score for 
persistent surgical pain and effect on MBPI will be asked to rate. DN4 Test will be used 
to evaluate postoperatively at 3 months for defining the type of pain.91 


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3. Method and Study Design 
 
 
A. Study Overview 
 
We propose a randomized trial comparing TAP blocks with Exparel to continuous 
epidural blocks in patients having elective lower-abdominal surgery. The study will be 
performed at multiple sites including various Cleveland Clinic hospitals. 
B. Setting and Population 
Inclusion criteria: 
(1) Written informed consent; 
 
(2) 18-85 years old; 
 
(3) ASA Physical Status 1-3; 
 
(4) Scheduled for elective open or laparoscopic abdominal surgery, including 
colorectal and hysterectomy surgeries; 
 
(5) Anticipated hospitalization of three nights; 
 
(6) Expected requirement for parenteral opioids for at least 72 hours for 
postoperative pain; 
 
(7) Able to use IV PCA systems. 
 
 
Exclusion criteria: 
(1) Hepatic disease, e.g. twice the normal levels of liver enzymes; 
(2) Kidney disease, e.g. twice the normal level of serum creatinine; 
(3) Bupivacaine sensitivity or known allergy; 
(4) Women who are pregnant or breastfeeding; 
(5) Anticoagulants considered to be a contraindication for epidural or TAP blocks. 
(6) Surgeries with high port sites will be excluded 
 
 
C. Withdrawal Criteria 
Patients will be free to withdraw from study at any time. Patients will also be 


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removed from study at any time for adverse events, or deemed necessary for patient 
safety. 
Protocol 
 
After eligibility is confirmed, patients will receive complete information about the 
study both verbally and in writing. Informed consent must be obtained from the patients 
prior to randomization and study-specific procedures. Research fellow will also apply an 
8-item STOP-BANG questionnaire. Randomization will be web-based and independent 
to investigators interference. 
Randomization (1:1) will be web-based and initiated at induction of anesthesia; 
allocation will thus be concealed from investigators. Randomization will be stratified 
based on chronic opioid use, defined by opioid use for more than 30 consecutive days 
within three preoperative months, at a daily dose of 15 mg or more of morphine or 
equivalent. 
All blocks will be performed preoperatively by attending anesthesiologists or 
regional anesthesia fellows who are experienced in epidural blocks and TAP blocks. 
Premedication will be administered at the discretion of the attending anesthesiologist and 
standard monitors will be used. All the patients will receive 1000 mg oral acetaminophen 
one hour before surgery and they will receive 500 mg every 6 hours for 72 hours after 
surgery starting with oral intake. 
Patients will be randomly assigned to: 1) Epidural catheter, 2) Bilateral TAP block 
with Exparel. Randomization will be stratified by open and laparoscopic procedures in 
addition to chronic opioid use. An in-plane ultrasound will be used in TAP block procedure. 
Once the target area is positioned, plain bupivacaine 0.25 %, 20 ml will be given to open 
the space and then single dose (10 ml) of EXPAREL mixed with (10 ml) saline will be 
injected in each side. Total dose of Exparel will be 20 ml. Epidural catheters will be 
inserted preoperatively. Once an epidural catheter is successfully positioned, an infusion 
will be initiated intraoperatively. Bupivacaine standard solution without additives will be 
prepared for each patient in epidural group. 


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Standard general anesthesia will be given using propofol or etomidate, fentanyl, 
rocuronium for induction and sevoflurane or isoflurane. Intraoperative analgesic use will 
be limited to short acting opioids. Postoperatively, patients will be given intravenous 
patient-controlled analgesia. Hydromorphone will be the default drug, but fentanyl will be 
substituted if necessary. Clinicians will adjust analgesic management as necessary in an 
effort to keep verbal response pain scores (details below) <4. If patients would not use 
the PCA for more than 2 hours, PCA will be deceased and it will be changed to PRN 
hydromorphone or fentanyl. Nurses will adjust analgesic management as necessary in 
an effort to keep verbal response pain scores <4. Blinded clinicians to the study will adjust 
epidural infusion rates. 
Other anti-inflammatory drugs will not be used intraoperatively or for the initial 72 
postoperative hours. A single dose of dexamethasone (4-8 mg) will be permitted for 
PONV prophylaxis for patients with Apfel risk score of 2 or more, and inhaled steroids will 
be permitted as necessary to treat reactive airway disease. Other opioid sparing 
medications like gabapentin, pregabalin, ketamine or lidocaine patch will also not be 
permitted through the initial 72 postoperative hours. 
Clinical evaluators for the outcomes will be blinded to study aim and Pharmacy 
personnel not involved in evaluations will prepare the study drugs. Patients will be 
continuously monitored and recorded with a wireless monitor starting after extubation in 
the operating room. Clinicians including nurses will be blinded to monitoring and will be 
required to perform their standard of care management after surgery. 
Patients will be allowed to receive prophylactic anti-emetic (first choice 
ondansetron) intraoperatively based on the risk assessment for nausea and vomiting. 
Postoperative anti-emetics for symptomatic treatment will also be allowed; again 
ondansetron will be the first choice. 
Measurements 
 
Demographic and Background Information: 


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Demographic data to be obtained includes height (cm), weight (kg), age (yr), 
gender, (ASA) physical status, self-declared ethnicity, and the specific type of procedure 
will be recorded. Patients will be questioned for social history (tobacco) and medical 
history (pulmonary disease, kidney disease, diabetes mellitus, neurological disease, 
chronic pain conditions, illegal drug usage, alcohol abuse, myocardial infarction, previous 
surgery or stent placement and medications usage). Available preoperative laboratory 
tests and medication list will be recorded. Individual risk for nausea and vomiting will be 
determined using the Apfel score. Patients excluded for any reason including technical or 
contraindication will be recorded for both groups. 
ViSi mobile (Sotera Wireless) patient monitoring system will be used to 
continuously record noninvasive blood pressure, patient activity, posture, 3-lead ECG, 
SpO2, and respiratory rate. Data will be recorded at one-minute intervals and downloaded 
daily to a laptop. 
Opioid requirements will be measured as the total amount of opioids (converted to 
morphine sulfate equivalents) used intraoperatively and during the first 72 postoperative 
hours. Use of PCA and discontinuation will be recorded. Pain Scores after surgery with 
be measured using a Verbal Response Scale (VRS). VRS is a scale from 0 to 10 where 
0 signifies no pain and 10 signifies worst pain ever experienced. The VRS will be recorded 
every 30 minutes in the recovery area for the first 2 hours, then every ≈4 hours thereafter 
while awake for 72 hours. Extra boluses of local anesthetics or block failure will be notified 
to acute pain service and will be documented in EPIC. 
Patient satisfaction with their pain treatment will be questioned after 72 
hours/discharges using 0-100 scales and we will also use Myles QoR scale to formally 
evaluate quality of recovery. Myles QoR scale is a validated scoring system allows 
quantification of patient’s early postoperative health status, which is also a description of 
quality of recovery. We will record the hospitalization period. 
 
Failure to meet four criteria was determined as the factors delaying discharge: (1) 
adequate analgesia (defined as NRS <4); (2) independence from intravenous opioids for 
at least 12 h; (3) ability to independently stand and sit down (evaluated with the Timed 


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Up and Go test); and (4) unassisted ambulation of at least 30 m (evaluated with the 6- 
min walk test). Blinded investigator will evaluate patients for discharge readiness and 
patients having all four factors will be accepted as discharge ready. 
Data obtained from electronic medical records will include: operation time, surgery 
type, intraoperative opioid consumption, postoperative opioid consumption in PACU and 
in ward, breakthrough pain medication requirements, pain scores in PACU and ward, 
requirement of oxygen in PACU and ward, pruritus, requirement of antihistaminic 
medications, requirement of naloxone, itching, ambulation time, flatus, ileus, bowel 
movements (first time, all bowel sounds at all quadrants), constipation, length of stay and 
any side effects or complications. Patient functionality will also be recorded including, 
bathing, toileting, walking and moving. 
We will also record any interruptions with comments in epidural group 
administration because of hemodynamic instability and lower extremity weakness. Blood 
pressure will be continuously monitored with VISI monitor system. 
Brief Pain Inventory and the Short Form 12 health survey (SF 12) will be completed 
before surgery, and at the 90-day follow up. Brief Pain Inventory is a practical method of 
evaluating pain severity and impact on patient function. BPI includes four rating pain 
intensity, and seven covering the impact of pain. Intensity is recorded on an ordinal scale 
from zero (no pain) to ten (worst imaginable pain). Impact of the pain section these ratings 
are made on zero-to ten numeric scales running from no interference to complete 
interference. The Short Form 12 health survey is an abbreviated version of the SF-36 
health survey, a well-established instrument to assess psychological and physical 
aspects of health related quality of life. 
G. Data Analysis 
 
Randomized groups will be compared for baseline balance using standard descriptive 
statistics and the standardized difference (difference in means or proportions divided by 
the pooled standard deviation). 


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Primary Aim. TAP with Exparel will be considerable noninferior to continuous epidural 
analgesia (and vice versa) on pain management if found noninferior on each of total opioid 
consumption and mean pain score in the first 72 hours post-op. Noninferiority deltas are 
defined a priori as no worse than 25% higher in opioid consumption and no worse than 1 
point in pain score. Overall alpha will be 0.05, and thus 0.025 in each direction of testing. 
No correction to the significance criterion will be made for assessing 2 primary outcomes 
since both are required to be noninferior in order to reject the null hypothesis and claim 
one intervention noninferior on pain management. 
We will assess noninferiority for opioid consumption by first estimating the treatment 
effect (TAP with Exparel minus continuous epidural analgesia, and vice versa) on log- 
transformed opioid consumption in a linear regression model and then conducting 1-tailed 
tests to assess whether the exponentiated difference, i.e., ratio of geometric mean, is less 
than the noninferiority delta of 1.25. 
We will assess noninferiority for mean pain score over time by first estimating the 
treatment effect (TAP with Exparel minus continuous epidural analgesia, and vice versa) 
on VRS pain score in a repeated measures linear model adjusting for within-subject 
correlation (R matrix autoregressive (1) structure) across the times. We will then use the 
estimated treatment effect (collapsed over time) and its standard error to conduct 1-tailed 
tests to assess whether the difference in means is less than the noninferiority delta of 1. 
Secondary aims. Standard statistical analyses will be used. 
 
Interim analyses for efficacy and futility will be conducted at each 25% of the planned 
enrollment (N=160, 320, 480 and 640) using a group sequential design with a gamma 
spending function (gamma = - 4 for efficacy and -2 for futility). The probability of crossing 
a boundary at the 1st, 2nd, 3rd and last analyses will be 8%, 29%, 38% and 25%, 
respectively, if the alternative hypothesis is true. Thus, there is a 75% chance of crossing a 
boundary (efficacy or futility) by the third look (N=480). We chose a design with 3 interim 
analyses and a final as opposed to fewer or more interim looks based on both practical 
and statistical grounds (allowing the chance to stop early, middle or late if warranted, but 
not too many looks as not much is gained by a larger number). The study 


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has been designed with non-binding statistical boundaries, such that the monitoring 
committee is not required to stop the study after crossing an efficacy or futility boundary 
(i.e., it will not affect the stated type I or type II errors to continue the study after a boundary 
has been crossed). 
H. Sample Size Considerations 
 
Sample size is based on being able to detect noninferiority on both total opioid 
consumption and pain score in the first 72 hours with about 90% overall power (90% for 
opioid consumption and 99.5% for pain score; overall power = 0.90 x 0.995 assuming 
independence) at the overall 0.025 significance level. In our retrospective data we 
observed a coefficient of variation (CV=SD/mean) of about 1.10 for opioid consumption 
in similar patients. For a single-analysis study we would need a total of 588 patients to 
have 90% power to detect noninferiority for opioid consumption at the 0.025 significance 
level assuming a CV of 1.0 and noninferiority delta of 1.25 in ratio of geometric means. A 
single-analysis total of 588 patients would give over 99.5% power to detect noninferiority 
in pain score with a delta of 1 point assuming (conservatively) a standard deviation of 2.5 
(from prior studies we expect the SD to be closer to 2.0; a total of N= 296 patients would 
be required for 99% power assuming a SD of 2.0 for pain score). We therefore plan the 
study to be able to detect noninferiority on both primary outcomes, which is largely driven 
by opioid consumption. 
Planning for a maximum of 3 interim analyses and a final analysis would require a 
maximum of 640 total patients. 
Economic Analysis 
 
A cost-effectiveness analysis will be conducted to determine the optimal strategy for 
economic outcomes related to pain control and surgery. In a cost-effectiveness analysis, 
costs are measured in monetary terms and benefits are measured in a unit of effect. For 
this study, the costs will be considered from the perspective of the hospital. The benefits 
will be evaluated on the cost to decrease the pain scores by 1 point using the visual 
analogue scale. For this cost-effectiveness analysis, the incremental difference in costs 
and effects between interventions being evaluated will determine the optimal strategy of 


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choice. 
 
To undertake this form of analysis, a decision analytic model using Treeage Pro® will be 
developed. A decision analytic model is a systematic, quantitative approach to decision 
making and can aid in health-care resource allocation. The decision analytic model will 
compare two possible intervention arms: A- Exparel, andB-Epidural analgesia. All 
possible outcomes will be incorporated into the model. Successful epidural placement 
and all adverse events, including PONV and ileus, will be incorporated as arms within the 
models. LOS, labor and 30 day adverse events will be incorporated at the terminal nodes. 
A simplified decision tree is presented in Figure 1. A hospital/payer perspective will be 
adopted and include all relevant costs and outcomes. Only costs and benefits relevant to 
the interventions in question will be included. All outcome probabilities used in the model 
will be determined from the clinical trial. 


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Figure 1 – Skeleton Decision Tree – Exparel vs Epidural Analgesia 
 
Costs to be included will be the costs of the intervention drugs, cost of consumables, the 
cost of adverse events, cost of any labor including nursing and physician time in the OR, 
PACU and on the floor, and the cost of any healthcare resources required in the 30 days 
post-surgery. These resources may include ER visits, physician visits or hospitalizations 
attributable to the procedure. Drug costs will be valued using the average wholesale 
acquisition cost as reported from the Elselvier Rx Verify database. Consumable costs will 
be sourced from supply management and verified from the published literature. The value 
of LOS will be valued based on Medicare/Medicaid reimbursement schedules. Adverse 
event costs will be sourced from the clinical trial where available and verified using 
published literature. Labor prices will be sourced from the Bureau of Labor and 


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Statistics using US averages. All costs will be adjusted to the same base year using the 
Medical Component of the Consumer Price Index. As costs and effects are being 
calculated for only a short time frame, no future discounting will be used. 
The determined costs and effects for each arm of the decision tree will be incorporated. 
The analysis of the model will use the costs, effects and probabilities of each arm of the 
decision tree. The analysis outcome will be a cost-effectiveness ratio for each arm. The 
incremental cost-effectiveness ratio will be calculated for the interventions. Depending on 
the results, one intervention may be dominated in terms of cost and effect or the optimal 
strategy may be dependent on willingness to pay for additional units of effect. 
The initial analysis would use direct clinical trial data. One criticism of clinical trial data, 
especially when it is used in an economic evaluation is that its outcomes can’t always be 
generalized to other settings. Through the use of economic modeling, clinical trial 
outcomes can be modeled to real world conditions. Models can also extrapolate data 
beyond the clinical trial, link intermediate clinical endpoints to final outcomes, and simulate 
head to head comparisons of interventions where a trial does not exist. For this study, 
complex sensitivity analysis will be conducted to test the robustness of the results to 
variability and uncertainty in the models values and its effect on the choice of optimal 
strategy. The model will be populated with not just point estimates, but with the range of 
data values and their associated distributions. 
Variability and uncertainty in the model will be analyzed from 3 aspects; variability in the 
population, uncertainty in the structure of the model, and uncertainty of the variables used 
within the model. Variability of the population will be tested using a Monte Carlo 
Microsimulation. This analysis involves running one patient at a time through the model 
with the events based on the underlying probabilities and a random number generator 
within the model. This analysis simulates differences in populations and the distribution 
of potential outcomes including optimal intervention choice can be plotted. Uncertainty 
within the model will be analyzed using one-way sensitivity analysis. This analysis 
involves varying the value of one variable at a time within the predetermined range. From 
this analysis will be conducted where one value will be varied at a time. From this analysis, 
the variables who are the biggest drivers of changes in the model will be identified and 


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summarized with a tornado diagram. These drivers will be compared to the drivers 
identified from the retrospective analysis to ensure uncertainty surrounding the values of 
these variables is adequately addressed. 
To test the uncertainty of the variables used in the model, probabilistic sensitivity analysis 
will be conducted. This form of analysis allows the uncertainty of all the variables in the 
model to be assessed at the same time. The values of variables are sampled from the 
distributions within the model. Using these results, the incremental cost benefit ratios will 
be determined with confidence intervals. Incremental net benefits will also be determined 
by determining a cost-effectiveness acceptability curve. This curve summarizes what 
proportion of time the optimal strategy will indeed be the optimal strategy as it depends 
on willingness to pay. To further validate the results and support the identification of the 
optimal strategy, a cost-effectiveness acceptability frontier will be produced along with an 
expected value of perfect information analysis. 
From all the analyses presented above, a transparent, easy to follow cost-effectiveness 
summary will be produced to aid persons in decision making positions. The summary will 
include the costs and effects of each intervention, the incremental costs and effects 
between the interventions, the cost-effectiveness ratio of the interventions, and the 
incremental cost-effectiveness ratio between the interventions. The uncertainty around 
the results will also be summarized to show that the optimal strategy is the choice strategy 
in ‘what’ percentage of time and for ‘what’ variable values and the value of any additional 
research. 


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M: Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient- 
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patients willing to pay to avoid postoperative nausea and vomiting? Anesth Analg 2001; 
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Senagore AJ: Postoperative ileus: it costs more than you expect. J Am Coll Surg 2010; 
210: 228-31 
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central neuraxial blockades in Sweden 1990-1999. Anesthesiology 2004; 101: 950-9 
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Turnbull DK, Shepherd DB: Post-dural puncture headache: pathogenesis, 
prevention and treatment. Br J Anaesth 2003; 91: 718-29 
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ICF_001.pdf: 
 
July 26, 2018 
Page 1 of 6 
 
 
 
Cleveland Clinic 
Consent to Participate in a Research Study 
 
 
Study Title: Comparison of Bilateral Transversus Abdominis Plane Block with Exparel versus 
Continuous Epidural Analgesia With Bupivacaine: A Randomized, Controlled Trial 
 
Principal Investigator: Alparslan Turan, MD  
9500 Euclid Avenue, P7 
Cleveland, Ohio 44195 
During office hours:   216 445-9857 
After office hours:      216-312-9526 
 
Fairview General Hospital 
Co- Investigator:  Azfar Niazi, MD 
18101 Lorain Avenue 
Cleveland, Ohio 44111 
During Office hours:  216-476-2275 
After office hours:  216-476-7052 
 
Hillcrest Hospital:   
Co-Investigator:  Manal Hassan, MD   
6780 Mayfield Road 
Cleveland, Ohio 44124 
Office and after office hours:  440-312-5259 
 
Carefully review this consent document. The purpose of a consent document is to provide you with 
information to help you decide whether you wish to participate in research.  Your decision is completely 
voluntary and will not affect your medical care if you choose not to participate.  It is important for you to 
ask questions and understand the research risks, benefits and alternatives.   
 
Please note: 
• You are being asked to participate in a research study 
• Carefully consider the risks, benefits and alternatives of the research 
• Your decision to participate is completely voluntary and will have no effect on the quality of 
your medical care if you choose not to participate. You can also withdraw from the study at 
any time. 
 
This research was approved by the Institutional Review Board (IRB). The IRB is a committee that 
reviews human research studies to ensure the safety and welfare of research volunteers are protected in 
accordance with federal human subject regulations and ethical principles.  
 
************************************************************************************* 


 
July 26, 2018 
Page 2 of 6 
 
1. CONFLICT OF INTEREST DISCLOSURE 
 
One or more of the Investigators conducting this study serve as paid speakers, consultants or advisory 
committee members for the company that is paying for this research or a company that makes 
products used in this study.  These financial interests are within permissible limits established by the 
Cleveland Clinic Conflict of Interest Policy.  If you have any questions, please ask your study doctor 
or call the Institutional Review Board at 216-444-2924. 
 
2. INFORMATION ON THE RESEARCH 
 
Why Are You Being Asked To Take Part In This Research?  
 
You are being invited to participate in this study because you are scheduled for elective abdominal 
surgery.  
 
     Why Is This Study Being Done? 
 
Many patients have pain after abdominal surgery. Nerve blocks can reduce the pain. One type is called 
an epidural block and involves a continuous infusion of local anesthetic near the spinal cord. Another is 
called a transversus abdominis plane (TAP) block which involves injecting a long-acting local 
anesthetic between abdominal muscles in 2 points on each side. The long-acting local anesthetic is 
Exparel, an FDA-approved drug. The main purpose of the study is to compare pain relief with 
continuous epidural blocks and TAP blocks with a long-acting local anesthetic. 
 
How Many People Will Take Part In The Study? 
 
A total of 640 people will take part in this study at the Cleveland Clinic and other medical centers. 
 
What Is Involved In The Study? 
 
If you agree to take part in this study, you will be randomized (like flipping a coin) to either TAP 
blocks on each side of your abdomen or an epidural catheter inserted at your mid-back The assigned 
block will be performed before surgery by an experienced anesthesiologist. You will be given local 
anesthesia and, if necessary, mild sedation. After surgery, if your anesthesia provider finds it 
appropriate, you will be given control of a pump that will give you intravenous pain medications as 
needed. 
 
We will collect information about your recovery from your medical record. A member of the study 
team will approach you on each of the first 3 days after surgery and ask about pain, anxiety, quality of 
your recovery, and overall satisfaction. Your blood pressure, heart rate, electrocardiogram, posture, 
activity and blood oxygen saturation will be continuously monitored using a wireless device which is 
external to your body and causes no pain (see figure). Three months after surgery, you will be called 
and asked questions about pain and your recovery over the phone. This conversation will take less than 
five minutes.  
 


 
July 26, 2018 
Page 3 of 6 
 
 
      
2.  RISKS AND DISCOMFORTS 
 
Both epidural and TAP blocks are routine and commonly used. They have different potential benefits 
and risks, but one is not obviously better or safer than the other.  
 
Potential side-effects of epidural blocks: 
- 
Low blood pressure 
- 
Temporarily decreased strength and sensation of the legs which can cause a fall 
- 
Headache 
- 
Intravenous injection of local anesthetic, that can lead to ringing in the ears, anxiety, dizziness or 
very rarely to seizures or heart rate problems 
- 
Infection of the epidural space or spinal cord 
- 
Bleeding around the spinal cord which may require surgery 
- 
Damage to nerves 
 
Potential side-effects / complications of TAP blocks: 
- 
Intravenous injection of local anesthetic, that can lead to ringing in the ears, anxiety, dizziness or 
very rarely to seizures or heart rate problems 
- 
Bleeding around the site of injection 
- 
Puncture of intra-abdominal organs, that might cause infection or bleeding 
 
 
3.  BENEFITS 
Are There Benefits To Taking Part In The Study? 
 
There is no direct benefit to you for your participation in this study. Knowledge gained from this 
research may help determine the efficacy of different pain control approaches after abdominal 
surgeries. 
    
 
4.  ALTERNATIVES 
What Other Options Are There? 
 
The alternative is to not participate in the study.  If you do not participate, you will receive standard 
anesthesia and post-operative pain management which may include either epidural or TAP blocks. You 
can also stop being in the study at any point.  


 
July 26, 2018 
Page 4 of 6 
 
5. PRIVACY AND CONFIDENTIALITY 
 
The medical and research information recorded about you will be used within the Cleveland Clinic 
and/or disclosed outside the Cleveland Clinic as part of this research.  Tests and procedures done 
solely for this research study may be placed in your medical record to indicate your participation in 
this study.  Upon completion of the study, you may have access to the research information if 
contained in the medical record. 
 
Your access to research information about you will be limited while the study is in progress.  
Preventing this access during the study keeps the knowledge of study results from affecting the 
reliability of the study.  This information will be available should an emergency arise that would 
require your treating physician to know this information to treat you best. 
 
Your research information may be shared with the Cleveland Clinic research staff, the U.S. Food and 
Drug Administration and the Department of Health and Human Services. The Cleveland Clinic also 
may use and disclose this information for treatment and payment reasons.  The Cleveland Clinic must 
comply with legal requirements that mandate disclosure in unusual situations.  Otherwise, the 
information recorded about you as part of this research will be maintained in a confidential manner.  It 
is possible that information disclosed about you outside the Cleveland Clinic could be re-disclosed 
and no longer protected by federal privacy laws.  
 
Your research information may be used and disclosed indefinitely, but you may stop these uses and 
disclosures at any time by writing to Dr. Alparslan Turan, at The Cleveland Clinic Foundation, 9500 
Euclid Avenue, Mail Code P-77, Cleveland, Ohio 44195.   At Fairview General Hospital write to 
Azfar Niazi, MD 18101 Lorain Avenue Cleveland Ohio 44111.  At Hillcrest Hospital write to Manal 
Hassan, MD 6780 Mayfield Road, Cleveland Ohio 44124. 
 
If you do so, any information previously disclosed cannot be withdrawn.  The Cleveland Clinic will 
not use or disclose the information collected in this study for another research purpose without your 
written permission unless the Cleveland Clinic Institutional Review Board gives permission after 
ensuring that appropriate privacy safeguards are in place.  The Institutional Review Board is a 
committee whose job is to protect the safety and privacy of research subjects.   
 
If you choose not to sign this consent form, you will not be permitted to participate in this research 
study. 
 
6.   RESEARCH RELATED INJURIES 
      What Happens If An Injury Occurs? 
 
In the event you are injured as a result of participation in this research, medical care is available to 
you.  The costs of such medical care will be billed to you or your insurance company.  There are no 
plans to provide compensation for lost wages, direct or indirect losses.  The Cleveland Clinic will not 
voluntarily provide compensation for research related injury.  You are not waiving any legal rights by 
signing this form.   
 


 
July 26, 2018 
Page 5 of 6 
Further information about research related injury is available by contacting the Institutional Review 
Board at 216-444-2924.   
 
7.  COSTS 
What Are The Costs?  
 
There are no additional costs to you for participation in this research study.  The cost for routine tests 
and services that would normally be performed even if you don’t participate in the study will be billed 
to you or your insurance provider.   
 
 
 
8. VOLUNTARY PARTICIPATION 
What Are Your Rights As A Participant? 
 
Taking part in this study is voluntary.  You will be told of any new, relevant information from the 
research that may affect your health, welfare, or willingness to continue in this study.  You may choose 
not to take part or may leave the study at any time.  Withdrawing from the study will not result in any 
penalty or loss of benefits to which you are entitled.  If you decide to withdraw from the study you 
should discuss with your study doctor your decision to ensure a safe withdrawal. 
 
9.  QUESTIONS 
     Whom Do You Call With Questions Or Problems? 
 
If you have any questions, concerns or complaints about the research, or develop a research-related 
problem, contact Dr. Alparslan Turan at 216 445-9857 or the Department of Outcomes Research at 
216-445-6500 and after hours at 216-312-9526.  For patients being seen at Fairview General Hospital 
contact Azfar Niazi, MD at 216-476-2275 and after hours at 216-476-7056.  For patients being seen 
at Hillcrest Hospital contact Dr. Manal Hassan at 440-312-5259.  If you have questions about your 
rights as a research subject, you should contact the Institutional Review Board at (216) 444-2924.   


 
July 26, 2018 
Page 6 of 6 
 
 
 10.  SIGNATURE   
 
Statement of Participant 
 
I have read and have had verbally explained to me the above information and have had all my 
questions answered to my satisfaction.  I understand that my participation is voluntary and that I may 
stop my participation in the study at any time. Signing this form does not waive any of my legal 
rights. I understand that a copy of this consent will be provided to me. By signing below, I agree to 
take part in this research study.   
 
_____________________________ 
Printed name of Participant 
 
 
_____________________________ 
 
___________  
 
Participant Signature 
 
 
 
 
Date 
 
 
 
 
Statement of Person Conducting Informed Consent Discussion 
 
I have discussed the information contained in this document with the participant and it is my opinion 
that the participant understands the risks, benefits, alternatives and procedures involved with this 
research study. 
 
 
_____________________________ 
Printed name of person obtaining consent 
 
_____________________________ 
 
___________  
 
Signature of person obtaining consent  
Date