Randomized Controlled Trial of Postoperative Thoracic Epidural Analgesia Versus Intravenous Patient Controlled Analgesia (3:1) in Patients Undergoing Liver and/or Pancreatic Resection
Phase: PHASE3
Conditions: Liver Cancer, Pancreatic Cancer
Sponsor: M.D. Anderson Cancer Center

Protocol 2011-0146 
November 12, 2015 
Page 1 
 
Randomized Controlled Trial of Postoperative Thoracic Epidural Analgesia 
Versus Intravenous Patient Controlled Analgesia (3:1) in Patients 
Undergoing Liver and/or Pancreatic Resection 
 
 
Table of Contents 
 
 
 
 
 
 
 
1 
 
Study Personnel 
 
 
 
 
 
 
 
2 
 
List of Abbreviations 
 
 
 
 
 
 
3 
1.0 
Objectives 
 
 
 
 
 
 
 
 
4 
2.0 
Background and Rationale  
 
 
 
 
 
4 
3.0 
Patent Eligibility 
 
 
 
 
 
 
 
10 
4.0 
Treatment Plan: Analgesic Regimens 
 
 
 
 
11 
5.0 
Treatment Plan: Perioperative Monitoring 
 
 
 
12 
6.0 
Postoperative Assessments 
 
 
 
 
 
13 
7.0 
Measure Outcomes  
 
 
 
 
 
 
14 
8.0 
Statistical Considerations  
 
 
 
 
 
16 
9.0 
Data and Protocol Management 
 
 
 
 
 
18 
10.0 
Data Safety and Monitoring Board  
 
 
 
 
18 
11.0 
Confidentiality 
 
 
 
 
 
 
 
16 
 
References 
 
 
 
 
 
 
 
 
20 
 
Appendix A – Inpatient IVPCA Orders 
 
 
 
 
25 
 
Appendix B – Inpatient Thoracic Epidural Orders 
 
 
26 
 
Appendix C – Motor Block Scale  
 
 
 
 
27 
 
Appendix D – Dermatome Sensory Block Map 
 
 
 
28 
 
Appendix E – Richmond Agitation Symptom Scale 
 
 
29 
 
Appendix F – Numeric/Visual Analog Pain Scale  
 
 
30 
 
 

Protocol 2011-0146 
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STUDY PERSONNEL 
 
Study Chairs:   
Jean-Nicolas Vauthey, MD 
 
 
 
Department of Surgical Oncology 
 
 
 
 
Vijaya Gottumukkala, MD 
 
 
 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
 
Study Co-Chairs:  
Keyuri U. Popat, MD  
 
 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
 
 
 
 
Debra L. Kennamer, MD 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
 
 
 
 
Juan P. Cata, MD 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
 
Study Collaborators: Mark J. Truty, MD 
 
 
 
 Mayo Clinic, College of Medicine 
 
 
 
 
Allen A. Holmes, MD 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
 
 
 
 
Jose Soliz, MD 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
 
 
 
 
Jeffrey Morris, PhD 
 
 
 
Department of Biostatistics 
 
 
 
 
Lianchun Xiao, MS 
 
 
 
Department of Biostatistics 
 
 
 
 
Yun Shin Chun, MD 
 
 
 
Department of Surgical Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 2011-0146 
November 12, 2015 
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LIST OF ABBREVIATIONS 
 
APS 
Acute Pain Service 
aPTT 
Activated Partial Thromboplastin Time 
CBC 
Complete blood count 
cc 
Cubic Centimeter 
DSMB 
Data Safety and Monitoring Board 
DVT 
Deep Vein Thrombosis 
GI 
Gastrointestinal 
HORQ 
Health Outcomes Recovery Questionnaire 
Hr 
Hour 
HR 
Heart Rate 
ICU 
Intensive Care Unit 
ICU 
Intensive Care Unit 
INR 
International Normalized Ratio 
IV 
Intravenous 
IVPCA 
Intravenous Patient Controlled Analgesia 
MAP 
Mean Arterial Pressure 
MCS 
Mental Health Component Summary 
MDACC 
MD Anderson Cancer Center 
mg 
Milligram 
MH 
Mental Health 
ml 
Milliliter 
NK 
Natural Killer 
NO 
Nitric Oxide 
OR 
Operating Room 
PACU 
Post Anesthesia Care Unit 
PCA 
Patient Controlled Analgesia 
PCS 
Physical Component Summary 
PPS 
Postoperative Pain Survey 
PPV 
Pulse Pressure Variation 
prn 
As Needed 
PT 
Prothrombin Time 
Q/q 
Every 
QOL 
Quality of Life 
QOR 
Quality of Recovery 
RASS 
Richmond Agitation Symptoms Scale 
SBP 
Systolic Blood Pressure 
SDS 
Symptom Distress Scale 
SICU 
Surgical Intensive Care Unit 
SV 
Stroke Volume 
SVV 
Stroke Volume Variation 
TEA 
Thoracic Epidural Analgesia 
Th1 
T-Helper Lymphocyte 
VAS 
Visual Analog Scale 
VEGF 
Vascular Endothelial Growth Factor 
 
 
 

Protocol 2011-0146 
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1.0 
Objectives 
 
1.1 
Primary Objective: 
 
1.1.1 - To compare postoperative pain control and quality of life in 
patients undergoing liver and/or pancreatic resection between those 
receiving thoracic epidural analgesia (TEA) versus intravenous patient-
controlled analgesia (IVPCA). 
 
1.2 
Secondary Objectives: 
 
1.2.1 - To compare postoperative/surgical outcomes between TEA and 
IVPCA groups. 
 
1.2.2 - To validate survey instruments in the assessment of 
postoperative quality of recovery/satisfaction.  
 
1.2.3 - To compare parameters of immunological responses between 
TEA and IVPCA groups. 
 
2.0 
Background and Rationale 
 
2.1  
Introduction 
 
- Postoperative outcomes for surgical resection of cancer involving the liver and 
pancreas have significantly improved over the last few decades due to 
improvements in surgical techniques and perioperative care.[1-4] The advent of 
minimally invasive laparoscopic surgery has led to decreased postoperative pain 
compared to traditional open surgical procedures.[5, 6] However laparoscopy is 
not technically feasible and is oncologically inappropriate in the vast majority of 
these patients. Thus improved methods to limit the morbidity of postoperative 
pain and its sequelae are in critical need. Inadequate pain control after open 
abdominal procedures can result in increased complications, length of stay, and 
delay in overall recovery. This is of particular importance in cancer patients, 
many of whom require further intensive oncologic therapies after surgical 
resection. It has been found that a significant proportion of patients who may 
benefit from adjuvant therapy are unable to proceed due to prolongation of care 
secondary to surgical complications.[7, 8] An effective regimen of postoperative 
analgesia based on current evidence-based protocols, may attenuate the 
detrimental physiologic responses to resection, and contribute to improvement in 
patient outcomes and lower complications. As an example, uncontrolled 
postoperative pain may contribute to cardiac morbidity through activation of the 
sympathetic nervous system, surgical stress response, and coagulation cascade 
which can increase myocardial oxygen demand by increasing heart rate, 
contractility, 
arterial 
blood 
pressure, 
and 
enhance 
perioperative 
hypercoagulability.[9] Despite the availability of pain guidelines, postoperative 
pain continues to be undertreated.[10] Currently the two major analgesic options 
after inpatient abdominal surgery in the United States are intravenous patient-
controlled analgesia (IVPCA) using narcotics and thoracic epidural analgesia 
(TEA) using local anesthetics and/or narcotics. There has been considerable 
debate regarding the advantages and disadvantages between these two 

Protocol 2011-0146 
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standard of care modalities and how they should be applied in the postoperative 
setting. 
 
 
2.2 
Intravenous Opioids 
 
 
- Opioid-based analgesics work by binding to opioid receptors, which are found 
principally in the central nervous system and the gastrointestinal tract.[11] The 
analgesic effects of narcotics are due to decreased perception and reaction to 
pain.[12] By allowing individualization of postoperative analgesic requirements, 
IVPCA is considered to be the accepted standard by which opioids are delivered 
to the hospitalized surgical patient. IVPCA provides significantly superior 
analgesia compared with conventional “as needed” (intravenous, intramuscular, 
or subcutaneous) opioid administration.[13]  
 
- However, all systemic narcotic-based methods have certain drawbacks. The 
side effects in postoperative patients include significant nausea, sedation, cough 
suppression, respiratory depression, constipation, and delayed recovery of bowel 
function.[14] These effects may lead to increased postoperative complications 
and delayed recovery, particularly in older, higher-risk patients. Furthermore 
IVPCA has been found to have a higher incidence of interruptions in analgesic 
delivery due to system-related events compared to other forms of continuous 
analgesic delivery.[15] 
 
2.3 
Epidural Analgesia 
 
- Unlike that seen with systemic opioids, epidural local anesthetics can block 
nociceptive (pain) input into the central nervous system and with the addition of a 
low-dose epidural opioid, may provide an even greater analgesic effect.[16] Due 
to the potential reduced need for narcotics, post-operative epidural analgesia 
may decrease postoperative morbidity resulting from excessive narcotic use.  A 
recent systematic review found consistent evidence that TEA reduces risk of 
cardiovascular and pulmonary complications and hastens return of postoperative 
gastrointestinal function compared to other forms of intravenous narcotic 
regimens after abdominal surgery in subsets of high-risk patients.[9] As most 
adult solid cancers are diagnosed in the elderly, these can be at higher risk of 
operative complications. Epidural analgesia has been found to provide better 
pain relief in elderly patients, particularly for dynamic pain, and improves 
postoperative recovery with a lower incidence of adverse effects compared with 
IVPCA.[17] 
Epidural 
analgesia 
may 
provide 
additional 
humoral 
and 
immunological benefits. In patients receiving regional epidural analgesia, the 
neuroendocrine response has been found to be attenuated while NK-cell activity 
is preserved compared to those patients receiving IVPCA.[18, 19] Regional 
analgesia has been shown to markedly attenuate the neuroendocrine response 
to surgery, as evidenced by smaller perioperative concentrations of stress-
induced plasma catecholamines and cortisol.[20, 21] Similarly. NK and Th1-cell 
activity is better preserved with epidural techniques.[22, 23] 
 
- Epidural analgesia has its own set of potential drawbacks and can be 
complicated by pruritus, motor block, hypotension, catheter malfunction, and 
local infection.[24] Epidural hematoma formation, although very rare, can be a 
catastrophic complication of epidural catheterization. The risk is theoretically 

Protocol 2011-0146 
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increased in patients with impaired hemostasis because of coagulopathy or 
therapeutic anticoagulation. However, the results of several studies looking at 
over 3000 patients undergoing TEA found the incidence of epidural hematoma to 
be less than 0.001%.[25-27] Early recognition of these problems can improve 
outcome and these low-frequency complications need to be balanced against the 
potentially serious hypoxemia and other postoperative complications associated 
with intravenous opioids used for postoperative pain relief.[28] Epidural analgesia 
is labor intensive and needs the support of an Acute Pain Service in order to use 
this technique safely. Overall, thoracic epidural analgesia has been found to be 
safe for use on surgical wards.[29]  
 
2.4 
Evidence-Based Postoperative Analgesia 
 
- Results of numerous randomized controlled studies comparing these two 
modalities have shown that TEA results in improved pain scores compared to 
IVPCA. These studies evaluated analgesic outcomes in a variety of operative 
procedures: 
thoracic, 
spinal, 
orthopedic, 
gynecologic, 
and 
abdominal 
surgery.[30-36] A recent meta-analysis found that for all types of surgery and 
pain assessments, all forms of epidural analgesia (both continuous epidural 
infusion and patient-controlled epidural analgesia) provided significantly superior 
postoperative 
analgesia 
compared 
with 
intravenous 
patient-controlled 
analgesia.[13] The authors concluded that almost without exception, epidural 
analgesia, regardless of analgesic agent, epidural regimen, and type and time of 
pain assessment, provided superior postoperative analgesia compared to 
intravenous patient-controlled analgesia (IVPCA). Although none of these studies 
included patients specifically undergoing liver and/or pancreatic surgery. 
 
2.5 
Non-analgesic Benefits 
 
- The advantages of TEA over IVPCA are not only represented by better 
analgesic scores. Numerous studies have found that there is reduced sedation 
with less respiratory complications, improved out-of-bed mobilization, faster 
return of bowel function (ileus) with improved food intake, long-lasting effects on 
exercise capacity, as well as significant reductions in hospital stay, all of which 
led to the added benefit of cost effective healthcare with decreased hospital 
costs.[37-42] Epidural analgesia was found to protect against postoperative 
pneumonia following abdominal surgery in a recent meta-analysis.[43] One of the 
more recent measures of postoperative recovery has to do with patient 
satisfaction and overall perioperative quality of life. Several recent studies found 
improved impact on overall patient satisfaction and superior perioperative quality 
of life (QOL) scores in those receiving TEA compared to IVPCA.[31, 39] 
Additional research is needed to validate these claims in patients undergoing 
liver and/or pancreatic surgery as well as to develop optimal measures of 
postoperative recovery and satisfaction in all surgical patients. 
 
2.6 
Analgesic Regimens in Cancer 
 
- The use of epidural analgesia versus IVPCA has specifically been studied in the 
cancer patient population. Epidural analgesia was found to have superior 
postoperative pain control compared to traditional IVPCA in a large series of 
patients undergoing surgery for malignancy. Furthermore patients receiving 

Protocol 2011-0146 
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epidural analgesia experienced faster recovery as judged by shorter mechanical 
ventilation time and decreased SICU and hospital stays resulting in significantly 
lower hospitalization costs.[38, 44] There is also recent speculation that opioid 
narcotics may play a significant role in cancer recurrence with clinical data 
suggesting that methods of analgesic technique may play a role in tumor 
dissemination and recurrence.[45-47] In an animal model of surgical-induced 
tumor seeding and metastasis, researchers found that the addition of regional 
analgesia (spinal blockade) reduced retention of shed tumor cells by over 70%. A 
similar benefit was observed when studying the actual development of 
metastasis.[48] In addition to the clinical observations, there is also evolving 
basic science literature suggesting that narcotics affect tumor growth.[49] 
Considerable evidence suggests that narcotics facilitate metastasis both via 
suppression of critical anti-tumor immune functions and by mechanisms 
independent of immune suppression. Acute and chronic administration of opioids 
is now known to mediate immune response by a combination of central and 
peripheral mechanisms. Peripherally exogenous opioids inhibit components of 
the cellular and humoral immune function such as antibody production, NK-cell 
activity, cytokine secretion, lymphocyte proliferative responses to mitogens, and 
phagocytic activity.[50] Signals of central origin may be relayed through 1) the 
hypothalamic-pituitary-adrenal axis resulting in the production of glucocorticoids, 
which are immunosuppressive, and 2) the sympathetic nervous system eliciting 
the 
release 
of 
biologic 
amines, 
which 
in 
turn, 
also 
reduces 
immunocompetence.[51] Alternative mechanisms by which opioids might 
promote metastasis are: induction of nitric-oxide (NO) upregulation and 
angiogenesis by opioids. NO also mediates increased vascular permeability, 
which could both increase the release of cancer cells into the circulation and 
increase extravasation of circulating tumor cells and the formation of new 
metastases. Nitric oxide also regulates endothelial cell proliferation, migration, 
and protease release – all of which are important for angiogenesis.[52] Vascular 
Endothelial Growth Factor (VEGF) plays a key role in angiogenesis. Recent 
evidence indicates that opioids promote VEGF-induced angiogenesis, an effect 
that is nearly completely blocked by opioid antagonists.[53] A large, multicenter, 
prospective, randomized trial investigating the influence of type of analgesia 
(intravenous narcotics versus epidural analgesia) on cancer recurrence is 
currently underway.[54]  
 
2.7 
Analgesia in Liver and Pancreatic Surgery 
 
- Despite the overwhelming evidence supporting its use in a variety of other 
surgical procedures, postoperative epidural analgesia is universally underutilized 
in patients undergoing liver and/or pancreatic surgery at most centers. This is 
due for a variety of reasons such as concerns of longer procedure times, greater 
initial costs, invasiveness of the procedure, fear of increased complications in this 
unique subset of patients, and clinical benefits that may in fact be 
underwhelming. No randomized controlled trials have been performed evaluating 
the efficacy or safety of epidural analgesia versus IVPCA in this specific patient 
population.  
 
- There is little data available regarding epidural analgesia in pancreatic surgery. 
In a retrospective analysis of patients undergoing pancreatic resection epidural 
analgesia was associated with a modest reduction in postoperative pain scores, 

Protocol 2011-0146 
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however those patients were more likely to require intensive care unit admissions 
and required more frequent alterations of analgesics. In that series epidural 
analgesia was associated with a non-significant increase in blood losses and 
fluid requirements. The groups (TEA vs. IVPCA) did not differ in bowel function, 
lengths of stay, morbidities, or mortalities.[55] Others found, also retrospectively, 
that epidural analgesia after pancreatic resection was associated with 
hemodynamic 
instability, 
which 
may 
theoretically 
compromise 
enteric 
anastomoses, gastrointestinal recovery, and respiratory function.[56] In contrast, 
another analysis in those undergoing pancreatic procedures found that patients 
treated with epidural analgesia experienced better pain relief, compared with 
subjects receiving IV analgesia who demonstrated a higher incidence of opioid-
related adverse effects such as sedation and respiratory depression.[57] 
 
- The data on epidural analgesia in liver surgery is also sparse and contradictory. 
In a retrospective analysis of patients comparing epidural analgesia to traditional 
IVPCA, epidural analgesia was independently associated with increased risk of 
packed red blood cell transfusion after hepatectomy and did not appear to 
minimize complications or shorten hospital stay.[58] Data from liver 
transplantation literature has identified a high prevalence of hemostatic 
abnormalities in patients undergoing major hepatic resection while receiving 
epidural analgesia.[59] In contrast, a recent study found that epidural anesthesia 
does not lead to changes in intravascular volume, but only promotes 
redistribution of blood, thus decreasing both venous return and portal vein 
pressure, which in fact may contribute to reduced hepatic congestion and 
reduced surgical blood loss.[60] None of these studies evaluated effective pain 
control. 
 
 
2.8 
Current Institutional Practice 
 
- The primary indication for TEA should be pain relief for open abdominal or 
thoracic surgery as there is sufficient Level 1 evidence that it may provide 
improved analgesia than intravenous opioids. In our current practice the decision 
for epidural versus IVPCA is both patient and physician dependent. Based on our 
institution’s extensive experience, the use of perioperative epidural techniques 
should be considered to expedite recovery of surgical patients and has the added 
value benefit of being cost effective by reducing hospital stays. Observed 
advantages of this approach are higher patient postoperative pain satisfaction, 
increased efficiency, less sedation, lower opioid dosage, and decrease in 
postoperative complications, particularly in higher-risk patients. We believe as 
others, that the clinical advantages of TEA outweigh the greater initial cost and 
invasiveness of this technique.[61] Due to our significant experience with both 
local-regional anesthetic techniques (>2000 TEA/year) and systemic opioid 
administration, as well as our established dedicated inpatient Acute Pain Service, 
patients undergoing liver and/or pancreatic surgery at this institution currently 
receive either IVPCA or TEA for management of their postoperative pain as 
standard of care. 
 
- The choice of postoperative analgesic regimens has implications for our current 
analgesic practice, particularly when considering the use of an indwelling 
epidural catheter in patients undergoing liver and/or pancreatic resection. We 
currently understand that disorders of coagulation occur after hepatic resection 

Protocol 2011-0146 
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Page 9 
 
even in patients who have normal preoperative coagulation and liver function 
tests. In our experience, the PT returns to normal within 5 days. Transiently 
impaired hepatic synthesis after major liver resection may account for this 
imbalance in hemostatic mechanisms.[62] In addition, due to prolonged biliary 
obstruction in patients with pancreatic head malignancies, abnormalities in 
vitamin K dependent coagulation factors are common.[63] The safe conduct of 
care for liver and/or pancreatic resection patients must take into account the 
possibility of these phenomena. Until these hemostatic abnormalities are better 
understood, the anesthesiologist and surgeon caring for patients undergoing liver 
and/or pancreatic surgery must weigh the theoretical risk of epidural hematoma 
formation against the benefits of epidural analgesia in this unique population. 
Further studies to characterize the hemostatic abnormalities after liver and/or 
pancreatic resection are warranted. Important considerations include discussion 
with the surgical team, measuring perioperative coagulation, and heightened 
clinical monitoring in the postoperative period. In our experience we have not had 
any significant epidural complications and have not had a single epidural 
hematoma in over 20,000 catheter placements. 
 
- The decrease in the use of TEA for patients undergoing liver and/or pancreatic 
resection at other institutions may paradoxically result in more complications, as 
loss of expertise in this technique becomes an issue, thus a critical need for level 
1 data to support the use of this modality in these patients. Our hypothesis is that 
TEA is improves pain control compared to IVPCA in patients undergoing liver 
and/or pancreatic resection with improved patient satisfaction and perioperative 
quality of life without significant risk of epidural related complications. In addition 
the limitation of systemic opioids in the postoperative setting may lead to 
decreased postoperative complications as well as improved immunological 
function that may correlate with oncologic outcomes, As a result of the following 
motivational factors: concerns about the effectiveness of TEA and safety in those 
patients undergoing liver or pancreatic resection, the lack of randomized 
controlled data supporting its use in this patient population, the increasing 
evidence regarding potential immunologic benefits of regional analgesia in 
cancer patients, the recent national demand for assessment of optimal patient 
recovery and perioperative satisfaction, our considerable experience and 
expertise with both modalities of postoperative analgesia, and the appropriate 
infrastructure and organizational leadership already in place at this institution, we 
have proposed a novel and much needed clinical postoperative analgesic trial 
with associated laboratory and patient-directed correlates in this subset of 
patients.  We have designed this study to reflect the current clinical practice 
standards of postoperative analgesia in patients undergoing liver/and or 
pancreatic surgery. 
 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria: 
 
3.1.1 - Patients undergoing liver and/or pancreatic surgical resection for 
malignancy at MD Anderson Cancer Center. 
 

Protocol 2011-0146 
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3.1.2 - Patients 18 years of age and older. There will be no upper age 
restriction. 
 
3.1.3 - Patients must sign a study-specific consent form. 
 
3.1.4 - Adequate coagulation function within 30 days of surgery: 
• 
Platelets >= 100,000/ml 
• 
INR <= 1.5 
• 
aPTT <= 40 
 
3.1.5 - Patients must have no fever or evidence of infection or other 
coexisting medical condition that would preclude epidural placement. 
 
3.2 
Exclusion criteria: 
 
3.2.1 - Evidence of severe uncontrolled systemic disease or other 
comorbidity that precludes liver or pancreatic surgery. 
 
3.2.2 - History of chronic pain, long-term narcotic use or being 
considered for chronic pain consultation postoperatively. 
 
3.2.3 - Anaphylaxis to local anesthetics or narcotics. 
 
3.2.4 - Previous or current neurologic disease affecting the lower 
hemithorax or below. 
 
3.2.5 - Major open abdominal/thoracic surgery in the previous 30 days 
under general anesthesia, except for TIVA (total intravenous anesthesia). 
 
3.2.6 - Technical contraindications to epidural placement: previous 
thoracic spinal surgery or local skin or soft tissue infection at proposed 
site for epidural insertion. 
 
3.2.7 - Ongoing use or planned peri-operative use of anticoagulants (not 
including DVT prophylaxis). 
 
3.2.8 - Known bleeding diasthesis or coagulopathy. 
 
3.2.9 - Educational, psychiatric (untreated or poorly controlled 
schizophrenia, major depression, or bipolar disorder), or communication 
(language) barrier that would preclude accurate assessment of 
postoperative pain and/or ability to answer questionnaires (need to be 
able to read, comprehend, and answer questions).  
 
3.2.10 - Inability to comply with study and/or follow-up procedures. 
 
3.2.11 - Patient refusal to participate in randomization. 
 
3.2.12 - Pregnant women are excluded from this study; women of 
childbearing potential (defined as those who have not undergone a 
hysterectomy or who have not been postmenopausal for at least 12 

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Page 11 
 
consecutive months) must agree to practice adequate contraception and 
to refrain from breast-feeding, as specified in the informed consent. 
 
3.2.13 - Patients with obvious unresectable disease prior to signing 
informed consent. 
 
4. 
Treatment Plan - Analgesic Regimens 
 
4.1 
IVPCA 
 
4.1.1 - Immediately following surgery, the OR Anesthesia team will 
titrate intravenous narcotics in the PACU for pain down to an acceptable 
level prior to initiating IVPCA. All patients assigned to IVPCA group will be 
started on intravenous patient-controlled analgesia protocol according to 
current institutional policy following surgical procedures. All patients will 
be given hydromorphone as the opioid of choice per current practice, 
unless there are contraindications. Fentanyl or Morphine will be 
secondary alternatives. Initial recommended starting doses are: no basal 
rate, 0.2mg  every 10 minutes demand dosing, and a 0.5mg nursing bolus 
every 1 hour as needed for additional pain control (Appendix A). 
Adjunctive use oral, rectal, or intravenous non-narcotic analgesics 
(acetaminophen, non-steroidals, etc.) will be utilized at the discretion of 
the Primary Surgical Team.  
 
4.1.2 - Patients whose IVPCA’s are not functioning or not providing 
adequate analgesia will be considered for possible postoperative 
placement of TEA (coagulation studies permitting) as an alternative 
analgesic regimen (patient crossover). 
 
4.1.3 - Further drug information can be found in the MDACC formulary 
and the FDA approved package inserts of the medications as they are all 
commercially available. 
 
 
4.2 
TEA 
 
4.2.1 - All patients assigned to TEA will have thoracic epidurals placed 
preoperatively in either the holding area or in the operating room 
according to current institutional protocol. Epidural catheters will be 
placed between the Thoracic 5th-Thoracic 10th interspinous levels using 
standard technique according to institutional practices. All epidural 
catheters will be tested for correct placement and level of block 
documented and secured as is currently practiced. The epidural will be 
initially dosed according to current practices with hydromorphone (10 
mcg/kg for pts 65 yrs or younger and 5 mcg/kg for pts > 65yrs) after 
induction of anesthesia. Standard epidural solutions are: Hydromorphone 
(10 mcg/ml for pts 65yrs or younger and 5 mcg/ml for pts > 65yrs) and 
Bupivicaine (0.075%) at 10 ml/hr continuous infusion and a 3ml every 10 
minutes demand dosing, and a 5ml every 3 hours clinician bolus as 
needed for additional pain control (Appendix B). Fentanyl with Bupivicaine 

Protocol 2011-0146 
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Page 12 
 
will be secondary alternatives. Adjunctive use of oral, rectal, or 
intravenous non-narcotic analgesics (acetaminophen, non-steroidals, 
etc.) will be utilized at the discretion of Acute Pain Service and/or Primary 
Surgical Team. Epidural catheters will remain in place a maximum of 7 
days postoperatively. Epidural catheters will be removed once patients 
are successfully tolerating a full diet or tube feeds and are transitioned to 
oral/enteral analgesics. Indwelling urinary catheters will be removed after 
TEA removal per current policy. 
 
4.2.2 - Patients whose TEA’s are not functioning or not providing 
adequate analgesia will be considered for IVPCA as an alternative 
analgesic regimen (patient crossover). 
 
4.2.3 - Further drug information can be found in the MDACC formulary 
and the FDA approved package inserts of the medications as they are all 
commercially available. 
 
5. 
Treatment Plan – Perioperative Monitoring 
 
 
5.1 
Intraoperative Monitoring 
 
 
 
5.1.1 - Patient in both groups will have arterial lines placed per current 
procedural policy. As is currently practiced hemodynamic and 
physiologic parameters will be monitored. If available, LiDCO-Rapid 
technology will be used to track other hemodynamic parameters during 
the duration of the procedure. Perioperative fluids, vasoactive medication 
administration, urine output, and blood product transfusions will be 
documented as per current guidelines. Central venous pressure will be 
recorded in those patients that have central venous catheters.  
 
 
5.2 
Postoperative Monitoring 
 
5.2.1 - After surgery, patients in both groups will be initially admitted to 
the PACU and subsequent disposition to either intensive care unit, 
overnight recovery suite, or general surgical floor dictated by patient 
status and the anesthesia and primary surgical team discretion. Patient 
monitoring in ICU, overnight recovery, or floor will be per current practice. 
 
5.2.2 - 15cc of blood will be drawn intraoperatively prior to anesthesia 
induction and daily every other day (POD# 1, 3, 5) postoperatively with 
other standard postoperative tests, for laboratory correlates of analgesic 
mediated immune function. 5cc of blood will be drawn into purple top 
(ETDA) tubes and 5cc will be drawn into 2 green top 
(Heparinized) tubes. All blood samples will be kept on ice for transport (up 
to 8hrs). After blood draw (performed at same time as routine daily 
postoperative labs) samples will be sent to laboratory Y6.25 (pager -713-
404-2911). Laboratory personnel involved include Javier Valenzuela and 
Juan Cata. For cell separation a Ficoll gradient technique will be used 
and for plasma collection, we will spin each EDTA sample for 10 min at 

Protocol 2011-0146 
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Page 13 
 
2000 rpm at 4 degrees C. Samples will be stored until processing at  -80 
degrees C in laboratory freezer with samples de-identified for 
confidentiality. These correlative studies are optional however will not 
require additional blood draws to the patient as they are being drawn 
simultaneously to the routine perioperative blood draws. 
 
6. 
Postoperative Assessments 
 
6.1 
Postoperative Epidural Assessment (TEA only) 
 
6.1.1 - The Acute Pain Service will monitor epidural site daily for 
evidence of hematoma, cellulitis, abscess, CSF leak, and malfunction as 
is current practice. 
 
 
6.2 
Postoperative Motor Block Assessment (TEA only) 
 
6.2.1 - Motor status will be assessed approximately every nursing shift 
and before ambulation as is current practice (Appendix C). 
 
 
6.3 
Postoperative Sensory Block Assessment (TEA only) 
 
 
6.3.1 - Sensory status will be assessed approximately every nursing 
shift to ensure adequate epidural function and that block is within 
expected dermatome levels as is current practice (Appendix D). 
 
6.4 
Postoperative Sedation Assessment (TEA and IVPCA) 
 
6.4.1 - Sedation will be assessed using Richmond Agitation Sedation 
Scale (RASS) approximately every nursing shift per current practice 
(Appendix E). 
 
 
6.5 
Postoperative Pain Assessment (Both TEA and IVPCA Groups) 
 
6.5.1 - Pain scores will be assessed in both groups with a 
Numeric/Visual Pain Scale (0-10) at various time points in the clinical 
record per current inpatient policies (Appendix F). Beginning in the PACU 
after surgery, pain will be assessed by nursing staff approximately every 
hour per current practice until disposition to inpatient care units. In the 
overnight recovery suite and general floor pain will be assessed by 
nursing staff approximately every 4 hours per current practice. In the 
SICU pain will be assessed by nursing staff approximately every hour per 
current practice. The pain assessments that are being used for analysis 
are average pain scores within first 6hrs postop, the next 18hrs, and each 
24hr period thereafter. The pain scores for each 24 hour period after this 
will be averaged (as many as are collected). Pain will re-assessed by 
nursing staff approximately 1 hour after every analgesic intervention per 
current practice on all nursing floors. All dosing alterations, changes, and 
total narcotic/analgesic use will be documented in the clinical record per 
current practice. 
 

Protocol 2011-0146 
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6.5.2 - The Acute Pain Service team/nurse will assess all patients in 
both groups (TEA and IVPCA). Therapeutic analgesic interventions in the 
TEA group will be per discretion of the Acute Pain Service per current 
practice. Therapeutic interventions in the IVPCA group will be per 
discretion of the primary surgical team per current practice and the 
primary surgical team will be blinded to the Acute Pain Service 
assessment of patients in IVPCA group. 
 
 
6.6 
Postoperative Quality of Life and Recovery Questionnaires 
 
- Several postoperative Quality of Life and Surgical Recovery instruments 
will be filled out by participating patients in both groups. Please refer to 
7.2.2 for details. 
 
 
7. 
Measured Outcomes (TEA and IVPCA) 
 
7.1 
Primary Endpoints 
 
 
7.1.1 - Pain scores (Numeric/Visual Pain Scale) 
 
Pain score AUC within the first 48 hours will be used as the 
primary endpoint. The AUC for each patient will be computed 
using the trapezoidal method using the pain score versus time 
curve.  The mean AUC pain scores within the first 48 hours will 
be compared between TEA and IVPCA groups for the primary 
analysis. 
 
 
7.1.2 - Quality of Life 
 
- Patients will complete a validated SF-8, Acute Recall 
QOL survey (preoperatively and then at approximately 
24hrs after surgery) (Appendix G) 
 
- Patients will complete a validated SF-36v2, Acute Recall 
QOL survey (preoperatively and then prior to discharge or 
at approximately 1 week after surgery – whichever is first)  
(Appendix H). 
 
 
7.2 
Secondary Endpoints 
 
7.2.1 - Postoperative complications 
 
- Hospital stay 
 
 
 
- ICU admissions 
 
 
 
- Postoperative bleeding 
 
 
 
- Infection 
 
 
 
- Anastomotic leak 
 
 
 
- Respiratory complications 
 
 
 
- Cardiac complications 
 
 
 
- DVT/VTE 
 
 
 
- Recovery of bowel function 

Protocol 2011-0146 
November 12, 2015 
Page 15 
 
 
 
 
- Time to ambulation 
 
 
 
- Epidural complications 
 
 
 
7.2.2 - Quality of Recovery/Patient Satisfaction 
 
- Several short (5-10 minute), simple survey instruments 
will be utilized in this study to assess patient-centered 
perioperative 
pain 
control, 
and 
overall 
recovery, 
satisfaction. Although all of these survey instruments have 
been validated in other studies, none have been applied in 
the evaluation of patients undergoing liver and/or 
pancreatic surgery. The use of multiple instruments with 
some overlap in measures allows for redundancy in 
assessments and the determination of the accuracy of 
patient reporting. Such data will assist in comparing the 
efficacy of these various instruments in capturing the “true” 
quality of recovery in this subset of patients. Any variations 
and discrepancies in the reported redundant measures will 
assist in the formulation of a subsequent improved 
instrument for validation on a greater scale. 
 
- The Health Outcomes Recovery Questionnaire (HORQ), 
a validated postoperative recovery instrument, will be 
administered daily for the first 5 postoperative days and 
includes questions regarding patient satisfaction, daily 
activities, and opioid-related symptoms (Appendix I).[64] 
 
- The Postoperative Pain Survey (PPS), an outcome-
oriented validated survey to assess quality improvement in 
postoperative pain management, will be administered daily 
for the first 5 postoperative days (Appendix J).[65] 
 
- The Opioid-related Symptom Distress Scale (SDS), a 
validated and reliable measurement tool that measures 
twelve opioid-related symptoms, will be administered daily 
for the first 5 postoperative days (Appendix K).[66] 
 
- The Quality of Recovery Survey (QoR), a useful and 
validated summary measure of recovery after anesthesia 
and surgery, will be administered daily for the first 5 
postoperative days (Appendix L).[67] 
 
7.2.3 - Immunologic correlates 
 
-Cytotoxicity assays will be performed to detect NK and 
NKT killing activity. These assays will be done by flow 
cytometry. These assays will be from optional blood 
collected as described in 5.2.2. 
 
-Cytokine determination will be done by ELISA technique 
using commercially available kits for each cytokine. These 

Protocol 2011-0146 
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assays will be from optional blood collected as described in 
5.2.2. 
 
7.2.4 - Pain score at each time point 
 
- Mean pain scores at various time points will be compared 
between groups (TEA vs. IVPCA). There will be 6 specific 
timepoints that will be used for secordary analysis as each 
timepoint will be an independent measure and may differ 
between groups dependent on duration from surgery as 
was found in previous studies: 1). mean pain scores 
compared between groups at 6 hrs postop; 2). mean pain 
scores compared between groups for subsequent 18hrs 
postop; 3). mean pain scores compared between groups 
over 24hrs on postop day #2;  4). mean pain scores 
compared between groups over 24hrs on postop day #3;  
5). mean pain scores compared between groups over 
24hrs on postop day #4; and 6). mean pain scores 
compared between groups over 24hrs on postop day #5.  
 
 
8.0 
Statistical Considerations 
 
 
8.1 
Methodology 
 
- 
This is a two-arm randomized non-blinded study whose primary 
objectives are to compare postoperative pain scores and quality of life 
(QOL) scores in patients undergoing liver and/or pancreatic resection 
between those receiving TEA versus IVPCA. Eligible patients will be 
randomized in a 3:1 allocation ratio to the treatment group of TEA or 
IVPCA group (to represent our current institutional practice as well as 
to allow a more accurate determination of overall TEA failures and 
complications). Randomization will be stratified by the resection type 
(liver or pancreatic - 1:1). The randomization will be conducted by the 
CORE prior to surgery and after consent and registration. Pain will be 
assessed using a numeric/visual pain score at various timepoints. The 
pain scores will be averaged for each patient and be compared 
between TEA and IVPCA groups at specific time points as follows: 
pain scores for the first 6 hours after surgery, pain scores for the next 
18hrs after surgery, pain scores for each subsequent 24hr period after 
surgery until postoperative day #5 or epidural removed, whichever 
occurs first. QOL will be assessed pre- and postoperatively using SF-
8 and SF-36v2. These validated instruments will score 8 domains that 
will be reduced to two summary measures scales, Physical 
Component Summary (PCS) and the Mental Health Component 
Summary (MCS). Scoring will be performed utilizing proprietary 
certified scoring software from the vendor. QOL scores will be 
calculated and compared between the two groups of patients. 
 
- 
Categorical data will be tabulated with frequency and percentages, 
and continuous variables will be summarized using descriptive 
statistics mean, standard deviation, median and range. The primary 

Protocol 2011-0146 
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Page 17 
 
endpoint for pain scores is mean pain scores within the first 48 hours, 
computed as the AUC the pain score vs. time curve for each 
individual. In case there is missing data, we will compute the AUC 
while using last value carried forward to fill in the missing data. For 
primary analysis, 2-sample t-tests or Wilcoxon rank sum test will be 
used to compare mean pain scores within 48 hours post operation 
between TEA and IVPCA arms. The same methods will also be 
applied to compare mean pain scores at each time point between 
TEA and IVPCA.  Linear mixed models including treatment, evaluation 
time, and interaction of treatment and evaluation time will be fit to 
determine the treatment effect on pain scale. Each pain score in PPS 
form will be analyzed for the primary analysis.  Chi-square test or 
Fisher’s exact test will be used to compare the binary outcomes 
between the two arms, which are related to effects of pain on patients’ 
movement or mood, such as pain’s influence on mobility or 
movement, cough or breath deeply, sleep and mood. Generalized 
estimating equation (GEE) regression models will be fit to estimate 
the treatment effects on the listed binary outcomes. Chi-square test 
will be used to compare the categorical items of QOL pre and post 
surgery between the two treatment arms, the same method will also 
be used to compare the changes pre-postoperative  in items of QOL 
between the two arms as well. 
 
8.2 
Sample Size 
 
- A total of 200 liver and pancreatic resection patients will be enrolled in 
order to achieve 140 evaluable patients.  As these surgical procedures 
are for resection of malignancy, a proportion of patients will be identified 
with unresectable or metastatic disease at the time of planned resection 
either during initial laparoscopy or after open exploration.  Those patients 
deemed unresectable at laparoscopy will not undergo open exploration, 
and thus, will be inevaluable for postoperative pain due to differences in 
incision type.  Furthermore those patients that do undergo an open 
exploration but are deemed unresectable due to local or metastatic 
disease found intraoperatively will have markedly different prognoses 
compared to those that have a successful resection, which may bias their 
response to pain and quality of recovery and bias the questionnaire 
responses.  Based on previous work at our and other institutions, it is 
expected that up to 30% of patients will not be evaluable due to various 
reasons, including ineligibility, patient withdrawal from the study, 
unresectable disease, and failure to complete or inaccurate completion of 
questionnaires.  Based on historical information, if the difference in mean 
pain score between the two evaluable treatment groups of patients is 1 
and the common standard deviation is 1.5, with a total of 140 evaluable 
patients (105 in TEA group and 35 in IVPCA group), the study will yield a 
92% power to detect the difference, using a two-sample t-test at a two-
sided significance level of 0.05.  Furthermore, the study will have a 99% 
power to detect a difference of 10 in QOL score with a corresponding 
standard deviation of 9 using a two-sided Student’s t-test with a type I 
error of 0.05.  All statistical analyses will be performed with an intent to 

Protocol 2011-0146 
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treat methodology, including those patients who cross over between 
treatment groups.  
 
- Patients undergoing major hepatectomy are a subset population of 
interest, since they are at higher risk of perioperative complications.  
Major hepatectomy is defined as resection of 3 or more segments of the 
liver, while minor hepatectomy is resection of 1 or 2 segments.  With a 
target accrual to 200 patients and 140 evaluable patients, we anticipate 
enrolling 70 patients undergoing major hepatectomy.  Based on our 
previous work it is expected that half of the 140 patients will undergo 
major hepatectomy.  With 70 patients who undergo major hepatectomy 
and assuming a 3:1 randomization to the experimental arm and control 
arm (51 in TEA group and 17 in IVPCA group), this sample size will have 
80% power to detect an effect size of 0.796 (i.e. 0.796-SD) in the mean 
pain scores between the two treatment arms, using a two-sample t-test at 
a two-sided significance level of 0.05.  Two-sample t-tests or Wilcoxon 
rank sum test will be used to compare mean pain scores within 48 hours 
postoperatively between TEA and IVPCA arms. 
 
9. 
Data and Protocol Management 
 
After obtaining informed consent, patients will be registered by an 
Anesthesia/Surgery Research Nurse, who will register them on the MDACC 
computerized Protocol System. The PI, Dr. Vauthey, and Dr. Mark Truty at Mayo 
Clinic College of Medicine will analyze the data once the study is closed. Only 
Limited Data Sets (LDS) will be sent to Dr. Truty at Mayo Clinic College of 
Medicine, however, Mayo Clinic will not participate in the analysis or in any part 
of the study. LDS is Protected Health Information that excludes the sixteen (16) 
direct identifiers listed in the U.S. Department of Health and Human Services 
Health Insurance Portability and Accountability Act (HIPAA). A Data Use 
Agreement will be used to send the data to Dr. Truty. All data obtained will be de-
identified after the conclusion of the study.  
 
10. 
Data Safety and Monitoring Board 
 
This study will be monitored by The Data Safety and Monitoring Board (DSMB), 
through routine reviews and/or institutional audits. The DSMB reports to the 
President, or his designee, as the on-campus representative of The University of 
Texas Board of Regents. It oversees the data and patient safety issues for 
randomized Phase III clinical trials that originate at UTMDACC; that are 
coordinated or analyzed by UTMDACC and are not being monitored by any other 
DSMB; or has been designated as the DSMB for any trial at the request of the 
IRB, the CRC, or institution. The primary objectives of the DSMB are to ensure 
that patients’ rights pertaining to participation in a research study are protected, 
and that patients’ interests are prioritized over the interests of the scientific 
investigation. Responsibilities include: 
 
 
(a) 
Review interim analyses of outcome data after 60 evaluable patients 
are enrolled (prepared by the study statistician or other responsible 
person at the time points defined in the study) approved by the IRB 
and additional time points as determined by the DSMB, and to 

Protocol 2011-0146 
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Page 19 
 
recommend, if necessary, whether the study needs to be changed 
or terminated based on these analyses; 
 
(b) 
Determine whether, and to whom, outcome results should be 
released prior to the reporting of study results; 
 
(c) 
Review interim toxicity data and efficacy of treatment; 
 
(d) 
Review major research modifications proposed by the investigator 
or appropriate study committee prior to implementation (e.g., 
termination, dropping an arm based on toxicity results from the 
study or results of other studies, increasing target sample size). 
 
The DSMB consists of not more than 15 members (including the Chair) as 
recommended by the President, or his designee, for each fiscal year. The 
committee includes physicians, statisticians and lay member(s), and will be 
selected based on their experience, reputation for objectivity, absence of conflicts 
of interest (or the appearance of the same), and knowledge of good clinical trial 
methodology.  The committee meets 5 times per year, and may schedule 
additional meetings if needed.  
 
11. 
Confidentiality 
 
- This study will be conducted in accordance with all applicable privacy laws, 
rules and regulations.  The Principal Investigator will take steps to guard against 
any loss of confidentiality. Only the Principal Investigator, Study Co-Chairs, and 
the authorized research team will have access to the identifiable information from 
this study.   
 
- Identifiers (such as name and medical record number) will be collected but will 
be replaced by study numbers in the analytic file. The key linking to these 
numbers will be retained in a secure computer file. Access to this file will be 
limited to the Principal Investigator, Study Co-Chairs, and the authorized 
research team. All computer files are password-protected and stored on 
institution computers behind the institution firewall to further ensure database 
security and all records are kept confidential. Any reports or publications resulting 
from this study will not include any personal identifiers. 
 
 
 

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Myles, P.S., et al., Development and psychometric testing of a quality of recovery 
score after general anesthesia and surgery in adults. Anesth Analg, 1999. 88(1): 
p. 83-90. 
 
 
 
 

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Appendix A: Inpatient IVPCA Orders  
 
 
 
 
 
 
 
 
 
 
 

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Appendix B: Inpatient TEA Orders 
 
 
 
 
 
 
 
 
 

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Appendix C: Motor Block Scale 
 
 
Bromage Motor Block Scale 
(0/5 complete motor block; 5/5 no motor block) 
 
 
Right Leg 
 
Left Leg 
 
Hip Flexion 
 
0 - 5 
0 - 5 
 
Knee Extension 
 
0 - 5 
0 - 5 
 
Ankle Dorsiflexion 
 
0 - 5 
0 - 5 
 
Ankle Plantar Flexion 
 
0 - 5 
0 - 5 
 
Great Toe Dorsiflexion 
 
0 - 5 
0 - 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix D: Dermatome Sensory Block Map 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix E: Richmond Agitation Symptom Scale 
 
+4 
 
Combative 
 
Violent, immediate danger to self or staff 
 
+3 
Very Agitated 
 
Pulls or removes tube(s) or catheter(s); 
aggressive behavior 
 
+2 
Agitated 
 
Frequent non-purposeful movement, fights 
ventilator 
 
+1 
Restless 
 
Anxious, apprehensive but movements not 
aggressive or vigorous 
 
0 
Alert & Calm 
 
 
-1 
Drowsy 
 
Not fully alert, but has sustained awakening to 
voice (eye opening & contact > sec) 
 
-2 
Light Sedation 
 
Briefly awakens to voice (eye opening & 
contact < 10 sec) 
 
-3 
Moderate Sedation 
 
Movement or eye-opening to voice (but no 
eye contact) 
 
-4 
Deep Sedation 
 
No response to voice, but movement or eye 
opening to physical stimulation 
 
-5 
Unarousable 
 
No response to voice or physical stimulation 
 
 
 
 
 
 
 
 
 
 
 

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Appendix F: Numeric/Visual Analog Pain Scale