Clinical trial NCT02423876
Conditions: Intraoperative Complication Malignant Female Reproductive System Neoplasm Pain
Sponsor: University of Wisconsin, Madison
Start date: 2015-03-17; Completion date: 2022-01-03
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized clinical trial studies epidural anesthesia within an enhanced recovery pathway (ERP) in reducing pain in patients undergoing gynecologic surgery. An epidural analgesia (pain relief) is a small tube placed in the lower back that numbs the nerves and stops the feeling of pain. It stays in place for several days after surgery and may be helpful for pain control in patients with gynecologic cancer after surgery. ERP is a set of specific steps used before, during, and after surgery by health care providers to care for patients after surgery. ERPs include patient education, not using laxatives before surgery, increasing activity after surgery, and scheduled use of medications for pain and nausea. Giving epidural anesthesia as part of an ERP may improve pain control in patients undergoing gynecologic surgery.

Detailed description:
PRIMARY OBJECTIVES:

I. Mean postoperative pain score for the first 24 hours post-operatively, (measured by the Numeric Rating Scale \[NRS\], which rates pain on a 1-10 scale, collected routinely on the post-operative floor) will be compared between the epidural and no-epidural groups.

SECONDARY OBJECTIVES:

I. Total opioid use measured in oral morphine equivalents for the first two days post-surgery.

II. Length of hospital stay (measured in hours from admission to time of discharge order placement).

III. Post-operative antiemetic use and number of recorded episodes of emesis. IV. Return of bowel function (measured in hours from completion of surgery to passage of flatus).

V. Subject satisfaction at the 4 week post-operative visit (as measured by two pain satisfaction questions taken from the Hospital Consumer Assessment of Healthcare Providers and Systems \[HCAHPS\] survey).

VI. Post-operative complications (urinary tract infections \[UTIs\], thromboembolic events, pneumonia, blood transfusion, myocardial infarction, falls).

VII. Readmission rate. VIII. Epidural discontinuation rates prior to planned removal (in epidural group only).

IX. Stress and inflammation serum and saliva markers at baseline and the first day after surgery, as well as at their postoperative visit.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo epidural placement in the First Day Surgery pre-operative area or similar areas suitable for insertion of epidural catheters. In the post-operative anesthesia care unit, patients may receive medication via the epidural on an as needed basis, as determined by the anesthesia team. Dosing and rate of standardized medication will be managed by the anesthesia team until the epidural is removed. Patients complete the ERP comprising increased activity, dietary restrictions, fluid balance, as well as anti-nausea, anti-inflammatory and pain medications at specific times. Patients will have access to additional pain medications as needed to control their pain.

ARM II: Patients complete the ERP comprising increased activity, dietary restrictions, fluid balance, as well as anti-nausea, anti-inflammatory and pain medications at specific times. Patients will have access to additional pain medications as needed to control their pain.

Arms: arm 1: Patients undergo epidural placement in the First Day Surgery pre-operative area or similar areas suitable for insertion of epidural catheters. In the post-operative anesthesia care unit, patients may receive medication via the epidural on an as needed basis, as determined by the anesthesia team. Dosing and rate of standardized medication will be managed by the anesthesia team until the epidural is removed. Patients complete the ERP comprising increased activity, dietary restrictions, fluid balance, as well as anti-nausea, anti-inflammatory and pain medications at specific times. Patients will have access to additional pain medications as needed to control their pain. arm 2: Patients complete the ERP comprising increased activity, dietary restrictions, fluid balance, as well as anti-nausea, anti-inflammatory and pain medications at specific times. Patients will have access to additional pain medications as needed to control their pain.
Interventions: intervention 1: Epidural analgesia intervention 2: Intraoperative Complication Management and Prevention intervention 3: Pain Therapy
Intervention descriptions: intervention 1: Receive epidural placement. Standard epidural medications and dosage are as follows:

* 0.1% ropivicaine + 10 mcg/mL hydromorphone at 6 mL/hr continuous rate
* 3 mL/hr RN bolus, to be used as needed based on pain ratings
* 3 mL/30 minutes patient bolus, which is available on patient demand. intervention 2: Undergo ERP intervention 3: Undergo ERP

Protocol documents:
Prot_SAP_000.pdf: 
UW14030: Epidural Anesthesia Within an Enhanced Recovery Pathway in Reducing Pain in 
Patients Undergoing Gynecologic Surgery
NCT02423876
PI: Lisa Barroilhet, MD
11/14/2016


Protocol UW14030 
Version 3, 11/14/2016 
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UW14030: Epidural Analgesia as Part of an Enhanced Recovery Pathway in 
Gynecologic Surgery 
Protocol Version Date: November 14, 2016 
DESIGN: 
Single-center, randomized controlled trial 
PRIMARY INVESTIGATOR: 
Lisa M. Barroilhet, MD 
Department of Obstetrics and Gynecology 
Division of Gynecologic Oncology 
University of Wisconsin School of Medicine and Public Health 
CO-INVESTIGATORS: 
Kristopher Schroeder, MD 
Department of Anesthesiology 
University of Wisconsin School of Medicine and Public Health 
John Shepler, MD 
Department of Anesthesiology 
University of Wisconsin School of Medicine and Public Health 
Charles W. Ashley, MD 
Department of Obstetrics and Gynecology 
University of Wisconsin School of Medicine and Public Health 
Janessa Rohrbach, MD 
Department of Obstetrics and Gynecology 
University of Wisconsin School of Medicine and Public Health 
Caroline Kieserman-Schmokler, MD 
Department of Obstetrics and Gynecology 
University of Wisconsin School of Medicine and Public Health 
Mary Rysavy, MD 
Department of Obstetrics and Gynecology 
University of Wisconsin School of Medicine and Public Health 
Amanda Schwartz, MD 
Department of Obstetrics and Gynecology 
University of Wisconsin School of Medicine and Public Health 
Carley Zeal, MD MPH 
Department of Obstetrics and Gynecology 
University of Wisconsin School of Medicine and Public Health 
BIOSTATISTICIAN: 
Menggang Yu, PhD 


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Department of Biostatistics and Medical Informatics 
University of Wisconsin School of Medicine and Public Health 
 
ENROLLMENT: 
 
 
104 
 
STUDY LOCATION:   
 
University of Wisconsin Hospital and Clinics 
 
STUDY DURATION:   
 
36 months from initial subject enrollment 
 
PURPOSE:  
To test the hypothesis that epidural analgesia, when incorporated 
into an enhanced recovery pathway in gynecologic surgery, 
results in improved pain control, shorter hospital stay, decreased 
rate of complications, and increased patient satisfaction, than 
enhanced recovery pathway alone.  
 
PRIMARY ENDPOINT:   
Postoperative subject pain scores (mean pain score on a ten 
point scale in the first 24 hours following surgery)  
 
FUNDING SPONSOR:  
 
UW Department of Obstetrics and Gynecology 


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TABLE OF CONTENTS 
 
 
1.0 
PROJECT SUMMARY/ABSTRACT .............................................................................. 4 
2.0 
INTRODUCTION ........................................................................................................... 5 
3.0 
MATERIALS AND METHODS ...................................................................................... 8 
4.0 
STATISTICAL CONSIDERATIONS ............................................................................. 16 
5.0 
RECORDS TO BE KEPT ............................................................................................ 17 
6.0 
PATIENT CONSENT AND PEER JUDGMENT ........................................................... 19 
7.0 
DATA AND SAFETY MONITORING ........................................................................... 19 
8.0 
REFERENCES ............................................................................................................ 21 
 
 


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1.0 
PROJECT SUMMARY/ABSTRACT 
Epidural analgesia is commonly used for post-operative pain control in patients undergoing 
laparotomy. It has been associated with better pain control than patient-controlled analgesia 
with intravenous opioids and is considered the standard of care at our institution for patients 
undergoing surgery via vertical midline laparotomy. Epidurals are typically placed prior to the 
induction of general anesthesia but not used until the end of the surgery, when a combination 
of a local anesthetic and an opioid are started. The epidurals stay in place for several days 
after surgery, with a continuous dose of medication infused, and patient-controlled bolus 
dosing available. Once bowel function has returned, the epidural is removed and patients 
transition to a regimen of oral pain medications.  
 
Recently, the concept of enhanced recovery, in lieu of patient-controlled analgesia, has been 
validated in the colorectal and gynecologic surgical literature. Enhanced recovery pathways 
include pre-operative education, elimination of mechanical bowel prep, limited drain 
placement, early ambulation, and structured use of intra-operative and post-operative anti-
emetics and analgesics. The use of intravenous opioids is restricted.  
 
The role of epidural analgesia within an enhanced recovery pathway has not been studied. We 
will randomize participants undergoing laparotomy for gynecologic indications to epidural 
placement vs. no epidural placement. All patients will participate in an enhanced recovery 
pathway as described below. We will compare pain scores, opiate use, length of hospital stay, 
post-operative antiemetic use, return of bowel function, patient satisfaction, post-operative 
complications, and readmission rates in both groups. 
 
A translational correlate to our clinical endpoint will be examination of stress and inflammation 
response in patients receiving epidurals versus those who do not. There is evidence that 
neuroaxial blockade can decrease cytokine release (a marker for inflammation) and decrease 
cortisol release (a marker for stress). This is particularly important in patients with cancer, 
where immune function has the capability of affecting the tumor microenvironment. 
 


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1.1 
Research Schema 
 
 
2.0 
INTRODUCTION 
2.1 
Background and Rationale 
Historically, post-operative care has lacked evidence-based support. Common practices are 
adopted by individual surgeons and disseminated pedagogically. Consequently, much of the 
dogma surrounding post-operative care has been challenged in recent years. This can 
perhaps be best illustrated by looking at the use of post-operative nasogastric tubes. Once 
routinely used to prevent ileus in all post-operative patients, nasogastric tube use was 
subsequently shown to increase pneumonia, atelectasis and aspiration (1) and is now used 
only in select patients. New, evidence-based management pathways have been developed to 
attenuate the stress response associated with surgery and accelerate post-operative recovery 
(2,3). Termed ‘enhanced recovery pathways’ by Dr. Kehlet, a colorectal surgeon, aspects of 
these pathways have slowly disseminated and have been adapted across different surgical 


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subspecialties as more and more data have been published demonstrating their benefits.  Key 
elements common to all enhanced recovery pathways include: preoperative patient education, 
reduction of preoperative fasting, omission of bowel preparation, perioperative normovolemia, 
limited use of nasogastric tubes and drains, early removal of urinary catheters, aggressive 
multimodal analgesia to minimize opiate consumption, early postoperative mobilization, 
prokinetics to enhance gastrointestinal motility, and early oral intake. Recently, Kalogera et al. 
published a retrospective cohort study demonstrating the use of an enhanced recovery 
pathway in a gynecologic patient population (4). Patients undergoing laparotomy for debulking, 
staging and benign procedures (including vaginal prolapse surgery) were included. The 
described enhanced recovery pathway resulted in a 2-day reduction in mean length of hospital 
stay, use of fewer opioids for pain control, and significant cost savings (more than $500,000 in 
81 patients). Patient satisfaction scores and 30-day outcomes were similar in both groups (4). 
 
Individual surgeons currently adopt elements of different enhanced recovery pathways at our 
institution, but a rigorous multi-disciplinary system has yet to be enacted.  
 
Many aspects of the enhanced recovery pathway are focused on hastening the return of 
gastrointestinal function after surgery, including minimizing opiate consumption (5). At our 
institution, return of bowel function after laparotomy is often the rate limiting factor impacting 
length of hospital stay. Like many institutions, we have explored the potential benefit of 
epidural analgesia to reduce systemic opioid use. The benefit of epidural analgesia in post-
laparotomy pain management has been demonstrated in a number of randomized controlled 
trials and meta-analyses (6, 7). The 2005 Cochrane review on this subject concluded that 
although there was improved pain control with continuous epidural analgesia vs. patient 
controlled analgesia, there was no statistically significant difference in the length of hospital 
stay or time until return of bowel function (8). Despite data supporting its use, epidural 
analgesia has not been universally accepted, attributable to regional trends and physician 
preference. In our institution, we do not often utilize epidurals in patients who have undergone 
bowel resection, fearing that postoperative hypotension may lead to anastamotic ischemia and 
subsequent bowel leak. Many surgeons find that the frequency of epidurals being discontinued 
is unacceptable, and preferentially use patient-controlled analgesia (PCA), typically with 
hydromorphone or morphine. Epidural placement also can delay surgical start times, 
dependent on the availability of anesthesia staff. Further, no prospective data have been 
collected regarding the use of epidural analgesia within an enhanced recovery pathway. 
 
We will test the hypothesis that patients who receive epidural analgesia as part of an 
enhanced recovery pathway do not experience better pain control than those who participate 
in an enhanced recovery pathway without regional analgesia. We have identified an 
exploratory translational endpoint, which examines the role of epidural analgesia in immune 
cell function and stress response. Serum markers of inflammation (IL-2, IL-6, TNF, CRP) will  
be compared between the two groups. Salivary cortisol levels (as a marker of stress) will also 
be obtained to make comparisons. This may be of particular interest for our subjects with a 
cancer diagnosis, as stress and inflammation have been shown to negatively affect tumor 
behavior, promoting invasion, angiogenesis and metastases.  
 


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2.2 
Study Purpose 
We propose to perform a randomized controlled trial to test the hypothesis that epidural 
analgesia in combination with an enhanced recovery pathway is not superior in providing post-
operative pain control when compared with an enhanced recovery protocol alone among 
patients undergoing laparotomy for gynecologic surgery. We will also measure the impact of 
epidural analgesia on the following secondary outcomes: opiate use, length of hospital stay, 
post-operative antiemetic use, return of bowel function, patient satisfaction, post-operative 
complications, and readmission rate. To test our hypothesis that epidural analgesia decreases 
stress response to surgery, we will also measure serum levels of several biomarkers 
associated with stress, such as C-reactive protein (CRP) and salivary cortisol levels.  
 
2.3 
Study Design 
Our study will be a single-center, non-blinded, randomized control trial. The study will be 
conducted at the University of Wisconsin Hospital and Clinics. Gynecologic patients 
undergoing laparotomy via midline vertical skin incision will be eligible. Given the nature of this 
study, it will be impossible for researchers or subjects to be blinded to research interventions.   
 
2.4 
Study Endpoints 
2.4.1 Primary Endpoint 
Mean postoperative pain score for the first 24 hours post-operatively, measured  by the 
Numeric Rating Scale (NRS), which rates pain on a 1-10 scale (collected routinely on 
the post-operative floor) will be compared between the epidural and no-epidural 
groups. 
2.4.2 Secondary Endpoints 
2.4.2.1 
Total opioid use measured in oral morphine equivalents for the first two days 
post-surgery  
 
2.4.2.2 
Length of hospital stay (measured in hours from admission to time of 
discharge order placement) 
 
2.4.2.3 
Post-operative antiemetic use and number of recorded episodes of emesis 
 
2.4.2.4 
Return of bowel function (measured in hours from completion of surgery to 
passage of flatus) 
 
2.4.2.5 
Subject satisfaction at the 4 week post-operative visit (as measured by two 
pain satisfaction questions taken from the Hospital Consumer Assessment 
of Healthcare Providers and Systems (HCAHPS) survey) 
 


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2.4.2.6 
Post-operative complications (urinary tract infections (UTIs), 
thromboembolic events, pneumonia, blood transfusion, myocardial 
infarction, falls) 
 
2.4.2.7 
Readmission rate  
 
2.4.2.8 
Epidural discontinuation rates prior to planned removal (in epidural group 
only) 
  
2.4.2.9 
Stress and inflammation serum markers at baseline and the first day after 
surgery, as well as saliva markers the first day after surgery.  
 
3.0 
MATERIALS AND METHODS 
3.1 
Selection of Subjects 
 
Subjects included in this study will be women who are undergoing an exploratory laparotomy 
via midline vertical skin incision for gynecologic indications at UW Hospital. 
 
3.2 
Eligibility Criteria 
Potential subjects will be introduced to the study during their pre-operative assessment with 
their operating surgeon. Eligible subjects will have a discussion with the study team about the 
goals and objectives of the study, and will be consented for the study at their preoperative 
clinic visit. There is a chance that subjects will be approached after their pre-operative 
assessment regarding this study.  This would be conducted via phone contact by a clinical 
member of the research team. This would only be in circumstances that the study team is 
unable to initially approach a subject at her clinical pre-operative assessment, and the study 
team feels that the subject would be a good candidate for this study.   
3.2.1 Inclusion Criteria 
1. 
Patients undergoing gynecologic surgery via midline vertical laparotomy at 
UWHC. 
2. 
Patients must be ≥18 years old. 
3. 
Patients must be English speaking. 
4. 
Patients must have the ability to understand visual and verbal pain scales. 
5. 
Patients must be eligible for epidural placement  
3.2.2 Exclusion Criteria 
1. 
Known allergy to local anesthetics. 
2. 
Known history of chronic pain disorders and/or chronic opioid use defined as >     
10mg of PO morphine or equivalent used daily for at least 30 days prior to 
enrollment 


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3. 
Patient is a prisoner or incarcerated. 
4. 
Significant liver disease that would inhibit prescription of opioids 
5. 
Significant kidney disease that would inhibit administration of gabapentin 
6. 
Patient has a history of opioid dependence requiring rehabilitation or the use of 
opioid antagonists  
7. 
Patient is pregnant 
8. 
Patients with a planned exploration with biopsies (no organs removed) will be 
excluded from the study.  
 
 
3.3 
Conduct of Study 
3.3.1 Study Procedure Overview 
Informed consent will be obtained at the pre-operative visit, during which time all 
participants will receive standardized preoperative teaching and carbohydrate loading 
in line with the enhanced recovery protocol. Post-surgical expectations and additional 
measurements within the context of the study will be explained to all participants.  
 
They will also be informed of the risks and benefits of epidural analgesia. Subjects 
would leave with printed information regarding the enhanced recovery pathway, 
including when to drink the carbohydrate-loading drink and how to manage their daily 
medications in the preoperative and postoperative periods.  
 
In the event that the initial introduction regarding the study was not completed at the 
subject’s pre-operative assessment, the potential subject may be contacted via phone 
by a clinical member of the research team. An IRB-approved basic introductory 
telephone script will be used.  If the subject is interested in learning more about the 
study, the study team may mail the subject a consent form and/or invite the subject to 
come in for a research visit. Two attempts will be made to call the potential subject. If 
the subject does not answer the phone, does not return the phone calls, or is not 
interested in participating, the study team will not make additional attempts to contact 
the subject.  
 
Additionally, if a patient is admitted directly to the hospital for a laparotomy or was not 
recruited at the pre-op visit, she may be recruited and consented in the hospital. This is 
relatively rare in our patient population. Recruitment and consenting would only be 
considered if the patient were admitted the day prior to surgery and adequate time 
were available to discuss the study and obtain consent. In the hospital setting, a 
member of the clinical/surgical team who is also a member of the research team (e.g., 
resident, surgeon, fellow) would approach the potential subject. Consent would then be 
obtained by that same individual or another member of the research team (e.g., study 
coordinator). 
 
The study staff will provide the anesthesiology team with regular notifications regarding 
consented subjects and their planned surgery dates.  Subjects will be considered 


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enrolled at the time of randomization, which will preferably occur on the day of surgery, 
but could be performed at any time after consent. Randomization will be computer-
generated via OnCore and will be performed by one of the study team members.  
 
Sections 3.3.2-3.3.3 outline the recommended procedures to be followed throughout 
the pre-, peri- and post-operative periods. These guidelines are consistent with 
standard clinical care, for which strict adherence is not feasible. Therefore, variations 
from these guidelines will not be considered protocol deviations.  
 
3.3.2 Intervention Period 
Upon arrival to the hospital on the day of surgery, standard First Day Surgery 
procedures will be followed. Subjects will be cleared physically fit for surgery by both 
anesthesiology and gynecology per standard clinical practice. A peripheral intravenous 
catheter will be placed preoperatively, as this is customary for any operative procedure.  
For subjects randomized to receive an epidural, the regional anesthesiology faculty, 
fellow or resident will discuss the nature of epidural analgesia with the subject. If the 
subject is still amenable, they will be consented for the epidural per standard practice 
(part of the surgical consent form) in a semi-enclosed space in the pre-operative 
holding area normally used for consenting all surgical and anesthetic procedures.  
 
Subjects in both arms will receive the following medications in our pre-operative 
holding area: 
● 
Celecoxib 400mg PO x 1 
● 
Acetaminophen 1,000 mg PO x 1 
● 
Gabapentin 600 mg PO x 1. Patients over 60 years old will be given 300 
mg PO x 1 of gabapentin to avoid over-sedation. 
For subjects randomized to the epidural group, an epidural will be placed in the First 
Day Surgery pre-operative area or similar areas suitable for insertion of epidural 
catheters. Subjects will receive sedative and opioid prior to epidural placement, per the 
anesthesia team’s standard practices. The epidural will be placed by the anesthesia 
team using the standard protocol. The epidural will not be turned on (no medications 
running other than the test dose) until the end of the surgery. The first bolus dose will 
be given while the skin incision is being closed. 
 
During the operation, all patients will receive the following anti-emetics: 
● Haldol 1 mg IV x 1 
● Dexamethasone 4 mg IV x 1 
● Zofran 4 mg IV 30 minutes before skin incision closure. 
Alternative medications of similar classes may be utilized in the event of a drug 
shortage.  
 
The non-epidural subjects will receive an injection of a local anesthetic (.25% 
bupivacaine or equivalent) into their incision after fascial closure. IV opioid medication 
will be administered at the discretion of the anesthesiologist. 


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In the post-operative anesthesia care unit, subjects with epidurals may receive 
medication via the epidural in boluses on an as needed basis, as determined by the 
anesthesia team. Medications will be titrated based on patient comfort and blood 
pressures.  
 
Standard epidural medications and dosage are as follows: 
● 0.1% ropivicaine + 10 mcg/mL hydromorphone at 6 mL/hr continuous rate 
● 3 mL/hr RN bolus, to be used as needed based on pain ratings 
● 3 mL/30 minutes patient bolus, which is available on patient demand.  
 
Hypotension is a common side effect of epidural analgesia, and is the most common 
reason that epidurals are turned off post-operatively. In order to standardize dose 
adjustments related to hypotension, hypotension will be defined as follows: 
● >20mmHg drop in systolic blood pressure from the patient’s pre-operative 
ambulatory clinic visit.  
● Other evidence of hypotension, such as evidence of reduced end-organ 
perfusion (ie neurologic changes, demand cardiac ischemia, urine output of < 
10 mL/hr) 
 
If subjects with epidurals develop hypotension, they will be evaluated by the 
gynecology resident on-call. Other causes of hypotension (hypovolemia, acute 
hemorrhage) will be ruled out. An intravenous fluid bolus will be given based on the 
MD’s clinical evaluation. If the patient’s blood pressure does not respond, the 
anesthesia team will be called and the epidural rate will be decreased from 6 mL/hr to 
4 mL/hr. In the event of severe hypotension of instability, the epidural may be 
discontinued or halted as dictated by standard clinical practice. If these interventions 
fail to normalize the patient’s blood pressure to within 20 mmHg of their baseline, the 
epidural will be turned off. The patient will continue to receive medications through the 
enhanced recovery pathway and may receive patient controlled opioid analgesia if 
indicated. The future use of the epidural will be determined by the surgical and 
anesthesia team.  
 
3.3.3 Postoperative Care Guidelines: For all subjects 
 
3.3.3.1 
Activity 
 
Patients will spend >2 hours out of bed (including 1 or more walk and sitting 
in chair) within the first 12 hours following surgery. From POD 1 until 
discharge, the patient will be out of bed greater than 8 hours including four 
or more walks and sitting in chair each day. The patient will be up in a chair 
for all meals. The urinary catheter will be removed as soon as the patient 
demonstrates the ability to walk with assistance and the treating team does 
not have a clinical indication to measure urine output with the accuracy of a 
catheter. In the case of radical hysterectomy, where post-operative bladder 


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dysfunction is common, the catheter will be removed at the physician’s 
discretion. 
 
3.3.3.2 
Diet 
 
If a gastric emptying device (orogastric or nasogastric tube) was used 
intraoperatively, it will be removed at extubation. The first meal of low 
residual diet will be ordered 4 hours after completion of surgery (or upon 
arrival to floor). Within the first 12 hours after surgery, one box of liquid 
Ensure will be ordered for the patient. Patients will be encouraged to have 
oral intake of at least 800mL, but not more than 2,000mL on POD 0. 
Continue 2 boxes of liquid Ensure per day until discharge. There will be a 
daily oral intake goal of 1500-2500mL of fluids. Scheduled senna, docusate 
and polyethylene glycol will be ordered to promote post-operative bowel 
function. 
 
3.3.3.3 
Fluid balance 
 
Upon arrival to the floor IV fluids will be infused at 40 mL/h. A nursing 
communication will be sent to peripheral lock IV when patient has had 600 
mL orally intake or at 8:00 AM on post-operative day (POD) #1, whichever 
comes first. Fluid boluses will be given at the discretion of the physician. 
 
3.3.3.4 
Analgesia 
 
There will be a goal of no IV patient-controlled analgesia. In the epidural 
group, dosing and rate of standardized medication will be managed by the 
anesthesia team until the epidural is removed. This will include the standard 
order set for patients who receive epidurals on any hospital service. 
Medications will include the epidural solution of local anesthetic and 
narcotic, oral narcotic on an as needed basis, scheduled acetaminophen, 
and as-needed anti-emetics. The dose of ropivicaine (either the 
concentration or the rate) can be increased on post-operatively based on 
blood pressures, pain scores and sensory exam. In the non-epidural group 
(and in the epidural group after epidural removal), suggested pain 
medication regimen guidelines are as follows: 
 
 
Oral opioids 
Oxycodone 5–15 mg orally will be administered every 3 hours as needed for 
pain rated 4 or greater or greater than patient stated comfort goal (5 mg for 
pain rated 4–5, 10 mg for pain rated 6-7, or 15 mg for pain rated 8-10). If 15 
mg every 3 hours is inadequate for pain control as evidenced by a need for 
IV opioids the dose will be escalated by increasing the dose available by 
10mg increments.   
 
Scheduled acetaminophen 


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Acetaminophen 1,000 mg will be given orally every 8 hours for subjects with 
no or mild hepatic disease (acetaminophen 1,000 mg orally twice daily for 
patients with moderate hepatic disease). Maximum acetaminophen should 
not exceed 3,000 mg/24 hours from all sources 
 
Scheduled NSAIDs 
Ketorolac 15 mg IV will be given every 6 h for four doses (start no sooner 
than 6 hours after last intraoperative dose). Six hours after last dose of 
ketorolac, ibuprofen 800 mg will be given orally every 6 hours on a 
scheduled basis.  
 
If a subject is unable to take NSAIDs, Tramadol 100 mg will be given orally 
4 times a day (start at 6:00 AM POD 1) for subjects younger than 65 years 
of age with no history of renal impairment or hepatic disease. The dose of 
tramadol will be reduced to 100 mg orally twice daily for subjects 65 years 
of age or older or whose creatinine clearance is less than 30 mL/min  
 
All medications above may be substituted for a similar drug in the same 
class if a medication shortage occurs or an allergic reaction is documented.  
 
Breakthrough pain  
If pain is rated greater than 7 more than 30 minutes after receiving 15 mg 
oxycodone, the subject will receive an IV narcotic as a rescue dose. This 
dose may be repeated after 20 minutes of the first dose if the pain score 
remains above 5. Patient-controlled analgesia utilizing an IV opioid will be 
initiated if the 2 IV narcotic doses are deemed insufficient to keep the 
patient's pain score less than 5 using the NRS.  
 
 
3.3.4 Biological outcome measures 
 
Biological correlates will include assessment of salivary cortisol levels, systemic levels 
of inflammatory cytokines (IL-2, IL-6, TNF and CRP), and changes in the phenotype of 
circulating immune cells, in order to quantify changes in stress and inflammation in 
patients who receive epidural analgesia versus those who do not. 
 
Blood samples from enrolled subjects will be collected at the following specific time-
points: prior to surgery and the 1st day following surgery. Whenever possible, these 
research blood draws will coincide with routine laboratory draws in order to avoid 
additional venipuncture. We will collect 3 tubes of blood (~30mL) at each time point to 
measure serum markers for inflammation and stress response (IL-2, IL-6, TNF, CRP). 
Salivary cortisol levels will also be measured three times on the first post-operative day 
(morning, afternoon, evening).  
    


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The standard of care for patients on our gynecologic service is to draw a routine set of 
serum laboratory studies, including blood count and comprehensive metabolic panel, 
on the first post-operative day.  
 
 
3.3.5 Post-operative data collection 
 
 
The Pain Numeric Rating Scale (NRS) is routinely performed by nursing staff at least 
once per shift and is included in the electronic medical record. In addition, a member of 
the research team will collect a Brief Pain Inventory (short form) on the first post-
operative day.  Missed pain scores will not constitute a protocol violation, though every 
attempt will be made by the study team to ensure they are collected. Total opioid 
equivalents used will be recorded. Total anti-emetic use and episodes of emesis will be 
recorded. Post-operative complications, including infections, bowel obstructions, deep 
vein thromboses, and pulmonary emboli, will be recorded. Time until return of bowel 
function (as defined by passage of flatus or gas visualized in the ostomy bag) will be 
recorded.  
 
Stress and inflammation serum markers will be drawn as part of the standard POD#1 
morning lab draw. Salivary cortisol levels will be measured at three time-points on the 
first post-operative day (morning, afternoon and night). A Perceived Stress Scale (PSS) 
will be administered on the first day after surgery, to correlate perceived stress with 
salivary cortisol levels. Subjects will fill out a patient satisfaction survey related to pain 
control (HCAHPS) at their post-operative visit. BPI will also be collected at this visit. If 
the study team is unable to administer the questionnaires at the time of the post-
operative clinic visit, the study team may call the patient to administer the 
survey/questionnaires over the phone or mail the survey/questionnaires to the subject 
within one month of the postoperative clinic visit.  


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3.3.6 Study Table of Events 
 
 
 
Pre-op 
Visit1 
Day of 
Surgery 
Post-Op 
Day 1 
Discharge 
Post-Op 
Clinic Visit 
Consent 
X 
 
 
 
 
Eligibility  
X 
 
 
 
 
Randomization 
 
X2 
 
 
 
Enhanced 
Recovery 
Pathway (ERP) 
X 
X 
X 
X 
X 
Epidural 
placement 
 
X3 
 
 
 
Serum (~ 
30mL)6 
X4 
 
X 
 
 
Salivary swab6 
 
 
X5 
 
 
Pain Numeric 
Rating Scale 
(NRS) 
 
X7 
X 
X7 
 
Brief Pain 
inventory 
 
 
X 
 
X8 
Perceived 
Stress Scale 
 
 
X 
 
 
AE check 
 
 
 
X 
 
Patient 
Satisfaction 
Survey 
(HCAHPS) 
 
 
 
 
X8 
 
1. 
Study recruitment may occur over the phone after the pre-operative assessment using an 
IRB approved phone script, or recruited from the hospital if admitted the day prior to 
surgery.  
2. 
Randomization to occur at any point after consent and eligibility is determined, but as close 
to surgery as possible. Preferably to occur the morning of surgery. 
3. 
For subjects randomized to receive an epidural 
4. 
Pre-op serum sample may be collected at the pre-operative visit or on the day of surgery.  
5. 
Salivary swab will be performed on POD #1 at three time points: morning, afternoon and 
evening 
6. 
Every attempt should be made to collect blood and salivary samples as outlined. However, if 
a subjects refuses or the sample is unable to be collected for another reason (e.g., no lab 
staff available to process sample, or unable to obtain sufficient sample), it will not be 
considered a protocol violation.  
7. 
Every attempt will be made to collect the Pain Numeric Rating Scale (NRS) on Day of 
Surgery and Discharge date, if available. The Pain Numeric Rating Scale (NRS) will be 
collected daily during admission.  
8.       If the study team is unable to administer the questionnaires at the time of the post-operative 
clinic visit, the study team may call the patient to administer the survey/questionnaires over 


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the phone or mail the survey/questionnaires to the subject within one month of the 
postoperative clinic visit. 
4.0 
STATISTICAL CONSIDERATIONS 
4.1 
Randomization 
 
Simple unstratified complete randomization will be performed electronically by study staff using 
OnCore after consent, as close to surgery as possible, preferably on the day of surgery.  
 
 
4.2 
Analyses 
The primary endpoint of relative pain scores between the epidural and non-epidural group will 
be analyzed by calculating a two-sided 95% confidence interval on the difference in mean 
scores between the two groups and concluding non-inferiority if this lies entirely below 2 points 
(mean non-epidural pain score proven, within a 95% confidence limit, to be at most 2 points 
worse than mean pain score in the epidural group). Secondary outcomes of length of hospital 
stay, patient satisfaction scores, average daily pain score for two days following surgery, length 
of time until return of bowel function, total opioid use, and stress and inflammation serum 
markers will be compared using two-sided 95% confidence intervals for their mean differences. 
Superiority tests at the two-sided .05 level, where specified in Section 2.4, will be conducted 
by determining whether these confidence intervals overlap 9. Post-operative complications 
and epidural discontinuation rates will be tabulated and presented for each group (where 
applicable).  
 
All analyses will be performed on an intent-to-treat basis, although as stated below 
noncompliance and losses follow-up are expected to be rare.  
 
 
4.3 
Sample Size Calculations 
With 52 patients in each group and using a two-sided 0.5 critical value, there is 87% power to 
detect non-inferiority of the non-epidural group to the epidural group as defined by a mean 
difference in post-operative pain scores of 2 points or less, under the alternative hypothesis 
that the treatments are identical. Thus this study is well-powered to show non-inferiority of the 
patient group who does not receive an epidural as part of the enhanced recovery pathway, 
with respect to postoperative pain within a margin of 2 points. These calculations used a post-
operative pain score standard deviation or 3.3 units, obtained from unpublished data on similar 
patients at this institution.  
 
Because randomization will be performed as close to surgery as possible and the primary 
outcome is obtained within one day of surgery, minimal loss to follow-up is anticipated. We will 
increase the number of subjects enrolled in order to meet our power calculations if a subject is 
lost to follow-up. Therefore, up to 6 additional subjects may be accrued.  
 
 


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4.4 
Interim Analysis 
No formal interim analysis will be made for efficacy or futility.  Adverse events and other 
aspects of safety will be monitored as described in Section 7.  
 
 
5.0 
RECORDS TO BE KEPT  
 
All subjects will be entered into OnCore, the UWCCC research database. The following fields 
will be completed in OnCore: demographics, MR number, insurance type, consent information, 
study ID#, subject statuses and dates, disease site and histology, enrolling staff.  Subject data 
will be managed by the PI, resident researchers (Co-Investigators) and the UW Gyn-Oncology 
Research Office.  
  
Each subject will be assigned a unique, study ID number. Study data will be stored with study 
ID numbers and will be kept indefinitely. Study data will be collected and managed using 
REDCap electronic data capture tools hosted at the University of Wisconsin-Madison, School 
of Medicine and Public Health. REDCap (Research Electronic Data Capture) is a secure, web-
based application designed to support data capture for research studies, providing: 1) an 
intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from external sources. Once the 
study is complete and REDCap is no longer needed, data will be exported from the system 
and stored on the departmental network, which is secure and password protected. Access is 
limited to the study team and IT support staff. Data within REDCap is maintained and archived 
per ICTR policy.  
 
Data will be collected directly from subjects, from study interventions and from medical record 
review. Data elements to be collected will include demographics, details of the enhanced 
recovery protocol, details of surgery and hospital course, diagnosis, pain scores, and adverse 
events (a complete data sheet is attached). 
             
Blood and salivary samples are collected as part of this study. Tissue banking is optional for 
study participants. All specimens will be stored at UW Hospital in the Division of Gynecologic 
Oncology laboratories. These laboratory areas have limited access and remain locked when 
no laboratory personnel are present. Subject samples will be coded, removed of all direct 
identifiers, and linked to the password-protected study database.   
Since the UW Gyn-Oncology lab does not have the ability to test for cortisol levels, saliva 
samples will be sent to an outside lab for testing.  The UW lab will extract saliva from the 
collection swabs and then store the samples for batch shipment to the Laboratory for 
Biological Health Psychology at Brandeis University where cortisol measurements are 
conducted on a fee-for-service basis.  Samples for shipment will be labeled with study number, 
subject ID number, specimen code (e.g., morning, afternoon, evening). Brandeis will not have 
access to any direct identifiers or the code that links samples back to identifiers. Salivary 
samples will be exhausted or discarded after testing at Brandeis and only cortisol results will 
be returned to the UW study team.  


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Additionally, 1-2 mL of serum will be sent to an outside laboratory at Brigham and Women’s 
Hospital in Boston, MA. Samples for shipment will be labeled with study number, subject ID 
number, specimen code (e.g., pre-op or POD#1). The lab will not have access to any direct 
identifiers or the code that links samples back to identifiers. Samples will be exhausted or 
discarded after testing at Brigham and only results will be returned to the UW study team. 
Samples will be centrifuged and then frozen at -70-80°C and held for batch shipment to the lab 
of: 
Kevin Elias, MD and Kathy Hasselblatt, MS 
Brigham and Women’s Hospital 
221 Longwood Avenue 
Boston, MA 02115 
 
After the available protocol testing from blood samples is complete, leftover samples will be 
stored for future IRB-approved research if subjects consent to specimen banking.  Future 
research will be limited to research studying cancer and surgical stress and immune response. 
No future research will be conducted on leftover samples without obtaining separate IRB 
approval. Subjects may request to withdraw samples at any time by contacting our research 
office.  
Blood samples will be used to analyze soluble molecules present in the serum and plasma. 
We will isolate immune and other cells present in the blood to determine if epidural analgesia 
affects immune response. The soluble molecules present in the blood will be analyzed by 
using techniques such as mass spectroscopy, NMR, ELISA, western blotting, and biochemical 
activity assays. The cells present in the blood will also be used in different immunological 
assays. At the lab at Brigham and Women’s Hospital, serum will be analyzed for circulating 
microRNAs. Serum cytokine, CRP and cortisol levels may also be evaluated, to ensure results 
are similar to those collected in our own laboratories. Salivary samples will be used to 
measure cortisol levels. Cortisol is a marker of physiologic stress, which also may be altered 
by epidural analgesia. 
Blood collection: 30 mL of blood will be drawn from the patient prior to surgery. We will use this 
blood to examine the patient’s baseline immune response, by measuring natural killer cell and 
other immune activity. A second blood draw (again, 30mL) will occur the first day after surgery. 
Whenever possible, blood samples will be drawn in conjunction with other clinically required 
blood tests in order to avoid unnecessary venipuncture.  
Salivary collection: A cotton swab will be brushed against the inside of the mouth (the buccal 
mucosa) at three different time points (morning, afternoon, and evening) on the first post-
operative day.  
 
 
 
 


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6.0 
PATIENT CONSENT AND PEER JUDGMENT  
 
Current FDA, NCI, state, federal and institutional regulations concerning informed consent will 
be followed.  
 
 
7.0 
DATA AND SAFETY MONITORING 
 
7.1 
Oversight and Monitoring Plan 
 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for monitoring 
data quality and subject safety for all UWCCC clinical studies.  A summary of DSMC activities 
follows: 
• 
Reviews all clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity. 
• 
Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as defined in 
the protocol, for all clinical trials conducted at the UWCCC, and studies conducted at 
external sites for which UWCCC acts as an oversight body. 
• 
Reviews all reports generated through the UWCCC DSMS elements (Internal Audits, 
Quality Assurance Reviews, Response Reviews, Compliance Reviews, and Protocol 
Summary Reports) described in Section II of this document. 
• 
Notifies the protocol Principal Investigator of DSMC decisions and, if applicable, any 
requirements for corrective action related to data or safety issues. 
• 
Notifies the CRC of DSMC decisions and any correspondence from the DSMC to the 
protocol Principal Investigator. 
• 
Works in conjunction with the UW Health Sciences IRB in the review of relevant safety 
information as well as protocol deviations, non-compliance, and unanticipated 
problems reported by the UWCCC research staff.  
• 
Ensures that notification is of SAEs requiring expedited reporting is provided to 
external sites participating in multi-institutional clinical trials coordinated by the 
UWCCC. 
  
 
7.2 
Monitoring and Reporting Guidelines 
 
Subjects will be assessed for toxicity throughout the study period. All grade 3 or greater 
adverse events, regardless of causality, that occur during hospitalization will be collected. Data 
Safety Monitoring Protocol Summary Reports will be provided to the UWCCC DSMC annually. 
 
 


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7.3 
Review and Oversight Guidelines  
7.3.1 Serious Adverse Event – Reported Within 48 hours 
Serious Adverse Events requiring reporting within 48 hours (as described in the 
protocol) must also be reported to the Data and Safety Monitoring Committee (DSMC) 
Chair via an email to saenotify@uwcarbone.wisc.edu within one business day.  A 48 hr. 
initial “SAE Details” Report, generated in the UWCCC database, must be attached to 
the email along with any pertinent information available at the time of initial reporting. 
The Committee Chair will review the information and determine if immediate action is 
required. Within 10 working days, all subsequent SAE documentation must be 
submitted electronically along with a 48 hour follow-up “SAE Details” Report and a 
completed UWCCC SAE Routing Form to saenotify@uwcarbone.wisc.edu. All 
information is entered and tracked in the UWCCC database. 
 
The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB (as necessary) and provides documentation of these notifications to 
the DSMC. 
 
See Section 7.4 for detailed instructions on SAE reporting.  
7.3.2 Serious Adverse Event – Reported Within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described in the 
protocol) must be reported to the Data and Safety Monitoring Committee (DSMC) Chair 
via an email to saenotify@uwcarbone.wisc.edu.  The OnCore SAE Details Report must 
be submitted along with other report materials as appropriate (any documentation 
available at that time of initial reporting). The DSMC Chair will review the information 
and determine if further action is required. All information is entered and tracked in the 
UWCCC database. 
 
The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB (as necessary) and provides documentation of these notifications to 
the DSMC. 
 
See Section 7.4 for detailed instructions on SAE reporting.  
 
7.3.3 Study Progress Review 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC in the 
timeframe determined by the risk level of the study (quarterly; semi-annually; or 
annually). The PSR provides a cumulative report of SAEs, as well as instances of non-
compliance, protocol deviations, and unanticipated problems, toxicities and responses 
that have occurred on the protocol in the timeframe specified.  PSRs for those 
protocols scheduled for review are reviewed at each DSMC meeting. 
 


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Protocol Summary Reports enable DSMC committee members to assess whether 
significant benefits or risks are occurring that would warrant study suspension or 
closure. This information is evaluated by the DSMC in conjunction with other reports of 
quality assurance activities (e.g., reports from Internal Audits, Quality Assurance 
Reviews, etc.) occurring since the prior review of the protocol by the DSMC.  
Additionally, the DSMC requires the study team to submit external DSMB or DSMC 
reports, external monitoring findings for industry-sponsored studies, and any other 
pertinent study-related information.  
 
In the event that there is significant risk warranting study suspension or closure, the 
DSMC will notify the PI of the DSMC findings and ensure the appropriate action is 
taken for the protocol (e.g., suspension or closure).  The DSMC ensures that the PI 
reports any temporary or permanent suspension of a clinical trial to the sponsor (e.g., 
NCI Program Director, Industry Sponsor Medical Monitor, Cooperative Group Study 
Chair, etc.) and other appropriate agencies. DSMC findings and requirements for 
follow-up action are submitted to the CRC. 
 
 
7.4 
Expedited Reporting of Serious Adverse Events 
Subjects will be assessed for SAEs in real-time during the hospital admission until the time of 
discharge. All Grade 3 events considered at least possibly related to the study intervention 
(except grade 3 hypotension) will be reported to the UWCCC DSMC within at least 10 working 
days. Grade 4-5 events considered as least possibly related (including hypotension) must be 
reported within 48 business hours. All SAEs must be reported to the UWCCC Data and Safety 
Monitoring Committee Chair (as above) and the UW IRB (if applicable; consult the UW-IRB 
website for reporting guidelines).  For submission of SAEs on this protocol, reference the 
UWCCC SAE SOP and the SAE Reporting Workflow for DOWGs on the UWCCC website 
(http://www.uwccc.wisc.edu) for specific instructions on how and what to report to the UWCCC.   
 
For this protocol, the following entities are required to be notified: 
a) 
saenotify@uwcarbone.wisc.edu 
b) 
Study PI (Dr. Lisa Barroilhet) 
c) 
Study Co-Investigators 
d) 
UWCCC Gynecologic Oncology Research Program Manager 
e) 
Any other appropriate parties listed on the SAE Routing Form (for follow-up 
reports only) 
 
For each SAE, research staff will consult the UW-IRB website to determine if reporting to the 
IRB is required.  
 
8.0 
REFERENCES 
 
1. Cheatham ML, Chapman WC, Key SP, et al: A meta-analysis of selective versus 
routine nasogastric decompression after elective laparotomy. Ann Surg 221:469, 1995 


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2. Kehlet H. Multimodal approach to control postoperative pathophysiology and 
rehabilitation. Br J Anaesth 1997;78:606–17. 
 
3. Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J Surg 
2002;183:630–41. 
 
4. Kalogera E, BAkkum-Gamez J, Joankowski C, et al. Enhanced Recovery in 
Gynecologic Surgery. Gyn Onc Vol 2013: 122: 319-328. 
 
5. D.A. Scott, D. Blake, M. Buckland et al. A comparison of epidural ropivacaine infusion 
alone and in combination with 1, 2, and 4 microg/mL fentanyl for seventy-two hours of 
postoperative analgesia after major abdominal surgery. Anesth. Analg., 88 (1999), pp. 
857–864 
 
6. C.L. Wu, S.R. Cohen, J.M. Richman. Efficacy of postoperative patient-controlled and 
continuous infusion epidural analgesia versus intravenous patient-controlled analgesia 
with opioids: a meta-analysis. Anesthesiology, 103 (2005), pp. 1079–1088 
 
7. B.M. Block, S.S. Liu, A.J. Rowlingson, A.R. Cowan, J.A. Cowan Jr., C.L. Wu. Efficacy 
of postoperative epidural analgesia: a meta-analysis. JAMA, 290 (2003), pp. 2455–
2463 
 
8. T. Werawatganon, S. Charuluxanun.  Patient controlled intravenous opioid analgesia 
versus continuous epidural analgesia for pain after intra-abdominal surgery.  Cochrane 
Database Syst. Rev. (2005) CD004088