Thoracic Epidural Analgesia vs Surgical Site Infiltration With Liposomal Bupivacaine Following Open Gynecologic Surgery

Study Overview
=================
Brief Summary
-----------------
The goal of this study is to test the hypothesis that surgical site infiltration with liposomal bupivacaine (LB) is non-inferior to and more cost effective than thoracic epidural analgesia (TEA) for patients undergoing open gynecologic surgery on an established enhanced recovery program (ERP) using a non-inferiority randomized trial design. The impact of TEA and surgical site infiltration with LB on neuroendocrine and inflammatory mediators of surgical stress response (SSR) will also be investigated as a translational endpoint.

Official Title
-----------------
A Non-Inferiority Randomized Trial Comparing the Impact of Thoracic Epidural Analgesia Versus Surgical Site Infiltration With Liposomal Bupivicaine on the Postoperative Recovery of Patients Following Open Gynecologic Surgery

Conditions
-----------------
Surgery, Analgesia

Intervention / Treatment
-----------------
* Drug: Liposomal bupivacaine
* Other: Thoracic epidural analgesia (bupivacaine)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Individuals ≥ 18 years of age Planned laparotomy by the gynecologic oncology service at the sponsor institution. Exclusion Criteria: Individuals who have a contraindication to thoracic epidural analgesia Individuals with a coagulation disorder Individuals with an infection at the site of epidural placement Individuals with intracranial pathology such as non-communicating increased intracranial pressure or obstruction of cerebrospinal fluid flow related to mass lesions Individuals with spinal pathology: abnormal spine anatomy, surgical fusion, or spinal column lesions Individuals who have a contraindication to liposomal bupivacaine Individuals with a known allergic reaction to liposomal bupivacaine Individuals with Childs-Pugh Class B or C liver disease Individuals who have a history of long-term opioid use for chronic pain, defined as use of opioid pain medications for ≥4 weeks prior to surgery.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Thoracic Epidural Analgesia with bupivicaine<br>Thoracic epidural analgesia (TEA): 0.125 % Bupivicaine infusion (5-7 milliliter [mL] per hour) intraoperatively with a 3 mL bolus at the end of the operative procedure just prior to emergence from general anesthesia. Postoperatively 0.0625% Bupivicaine until patient-controlled epidural analgesia (PCEA) pump. PCEA pump 0.0625% bupivacaine at 5-7 mL per hour infusion with a 3 mL q20 minutes demand. PCEA discontinuation with oral tolerance. | Other: Thoracic epidural analgesia (bupivacaine)<br>* Perioperative bupivacaine based thoracic epidural placed preoperatively.<br>|
| Experimental: Arm 2: Surgical Site Infiltration with Liposomal Bupivacaine<br>Liposomal bupivacaine (LB) surgical site infiltration: A single 20 mL liposomal bupivacaine vial containing 266 mg of free-base bupivacaine will be mixed with 60 mL of 0.25% bupivacaine hydrochloride (HCl) and then diluted in preservative-free sterile 0.9% saline for maximal volume not to exceed 300 mL. Dilution with 0.9% saline will be dependent upon length of surgical incision per protocol. The solution will be injected using 22-gauge needle in equal distribution into the peritoneum, along the fascia and into the subcutaneous tissues of the surgical wound by trained faculty surgeons. | Drug: Liposomal bupivacaine<br>* Surgical site infiltration with 20 mL liposomal bupivacaine prior to laparotomy closure.<br>* Other names: Exparel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analgesia as assessed by pain intensity scores on a visual analog scale | Pain intensity will be measured using visual analog scale (VAS) pain intensity scores. The VAS scores pain intensity on a scale of 0-10, where 0 is no pain and 10 is the most severe pain. | 0 to 48 hours postoperatively | 
| Total opioid consumption | Total opioid consumption in IV mg morphine equivalents from 0 to 48 hours postoperatively will be compared between the two arms. | 0 to 48 hours postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-perceived quality of recovery as assessed by the Quality of Recovery-15 instrument (QoR-15) | Mean patient-perceived quality of recovery scores using the Quality of Recovery-15 instrument (QoR-15) on postoperative days 1 to 7 will be compared between the two arms. The QoR-15 is a validated instrument designed to measure the major domains of postoperative recovery including functional independence, physical comfort/pain, psychological/emotional well-being, cognition and satisfaction with a score of 0 indicating the poorest patient-perceived quality of recovery and 150 indicating the highest patient-perceived quality of recovery. | Days 1 through 7 post-intervention | 
| Time (days) to return of bowel function (ROBF) | Time to ROBF is defined as the time lapse from the day of surgery (DOS) to the day oral intake is consistently tolerated for 48 hours without vomiting. | Up to 7 days post-intervention | 
| Number of participants with postoperative ileus | Ileus is defined as the occurrence of postoperative nausea and vomiting requiring cessation of oral intake and initiation of intravenous hydration +/- nasogastric tube placement following documented ROBF or the persistence of these symptoms beyond postoperative day 5 in the absence of ROBF. | Up to 7 days post-intervention | 
| Mobility as assessed by the Johns Hopkins Highest Level of Mobility (JH-HLM) scale | The Johns Hopkins Highest Level of Mobility scale is an ordinal scale from 1 to 8, with numbers representing mobility milestones that patients accomplish, based on observation. Patients who score a 2 have some type of bed mobility, while those scoring an 8 can walk more than 250 feet. | Up to 7 days post-intervention | 
| Degree of sedation as assessed by the Pasero Opioid-Induced Sedation Scale | The Pasero Opioid-induced Sedation Scale (POSS) is a valid, reliable tool used to assess sedation when administering opioid medications to manage pain. It uses an ordinal scale of 1-4 with a POSS of 1 or 2 indicating an acceptable level of sedation and a score of 3 or 4 indicating over-sedation and the need for intervention, such as the administration of a reversal agent in the case of a score of 4. | Up to 7 days post-intervention | 
| Length of stay | The duration of the index inpatient postoperative admission in days. | Up to 1 year | 
| Time to postoperative diuresis | Time to diuresis is defined as the recovery time in hours to achieve a net negative fluid balance sustained over a 24 hour time period. | Arrival in recovery through hospital discharge, up to 1 year | 
| Total intravenous fluids administered in mL |  | Arrival in recovery through hospital discharge, up to 1 year | 
| Amount of Vasopressor required | Total amount (micrograms) of vasopressor required. | Start of operation through hospital discharge, up to 1 year | 
| Duration of Vasopressor administration | Duration (minutes) of vasopressor administration. | Start of operation through hospital discharge, up to 1 year | 
| Number of postoperative complications | Number of postoperative complications (Maryland Hospital Acquired Conditions). | Day of admission through postoperative day 30 | 
| Total direct cost of TEA placement and LB surgical site infiltration | Pharmacy and equipment costs, professional fees and the dollar-value of total OR time required for administration of each intervention will be compared. | Up to 1 year | 
| Post-discharge narcotic utilization | Patient reported total outpatient narcotic use in IV morphine (mg) equivalents on nurse phone survey administered on postoperative day 14. | Postoperative day 14 | 
| Change in Serum adrenocorticotropic hormone (ACTH) | Serum ACTH level in pg/mL. | Baseline and postoperative day 7 | 
| Change in Epinephrine level (pg/mL) |  | Baseline and postoperative day 7 | 
| Change in Total cortisol level (microgram/dL) |  | Baseline and postoperative day 7 | 
| Change in Anti-diuretic hormone (ADH) level | ADH level in pg/mL. | Baseline and postoperative day 7 | 
| Change in Interleukin-6 level (pg/mL) |  | Baseline and postoperative day 7 | 
| Change in Atrial natriuretic peptide (ANP) level | ANP level in pg/mL. | Baseline and postoperative day 7 | 
| Change in Syndecan-1 level (pg/mL) |  | Baseline and postoperative day 7 | 
| Change in Glycosaminoglycans level (ng/mL) |  | Baseline and postoperative day 7 | 
| Change in Endothelial glycocalyx constituents (ng/mL) |  | Baseline and postoperative day 7 | 
| Change in C-reactive protein level (ng/mL) |  | Baseline and postoperative day 7 | 
| Change in Tumor necrosis factor alpha (TNF-α) level | TNF-α level in pg/mL. | Baseline and postoperative day 7 | 
| Change in Salivary cortisol (microgram/dL) level |  | Baseline and postoperative day 7 | 
| Rate of 30-day hospital readmission | Rate of 30-day hospital readmission assessed as the number of participants who get readmitted within 30 days of discharge from the initial admission. | Up to 30 days post discharge from index admission |