Randomized Non-inferiority Trial of Continuous Thoracic Epidural Analgesia Versus Single Intercostal Nerve Block After Thoracotomy
Phase: PHASE4
Conditions: Pain Following Thoracotomy Surgery
Sponsor: Mayo Clinic

Cover Letter 
Study of Exparel Versus Epidural for Pain Control After Thoracotomy 
NCT02178553 
April 27, 2018

Study Protocol 
All patients will be screened by a study coordinator and written informed consent will be 
obtained at the preoperative visit. Inclusion criteria will be patients age 18 years and older 
undergoing thoracotomy (lobectomy, segmentectomy, wedge resection or pneumonectomy). We 
will stratify patients by surgeon and randomly assign them to receive either standard thoracic 
epidural analgesia or intercostal nerve injections with liposomal bupivacaine for perioperative 
pain control. Operations will be performed by any of 5 board certified general thoracic surgeons 
at our institution. Exclusion criteria will be planned chest wall resection or abdominal incision 
and/or gastroesophageal surgery; current enrollment in another post-thoracotomy analgesic 
research protocol; pre-existing pain syndrome (such as fibromyalgia, complex regional pain 
syndrome or postherpetic neuralgia in a thoracic distribution); daily opioid therapy; current 
gabapentin or pregabalin therapy; allergy to any study medication; coagulation or infectious 
issues that would preclude epidural catheter placement; severe psychological disorders or 
inability to understand the study protocol; prisoners or other institutionalized individuals; and 
severe hepatic, renal or cardiovascular disorders. Women who are pregnant will not be included 
in this study. 
Epidural Analgesia 
In the epidural catheter (TEC) group, a thoracic epidural catheter will be placed at the 
level of T6–T8 and advanced 5 cm into the epidural space and a 3 ml test dose of lidocaine 1.5% 
will be administered before the induction of general anesthesia. Patients will be excluded from 
the study if the catheter cannot be placed. A bolus dose of 0.5 mg hydromorphone plus 4.5 ml 
0.125% bupivacaine will be administered before surgical incision. An epidural infusion of 

0.075% bupivacaine and 10 mcg/ml hydromorphone, prepared by the hospital pharmacy, will be 
started intraoperatively at a rate of 5 ml/hr.  
Intercostal Nerve Block 
In the intercostal block (ICB) group,  liposomal bupivacaine 1.3% (4 ml) will injected by 
the surgeon under direct vision into the proximal intercostal space at the level of the thoracotomy 
and one interspace above and below. In addition, liposomal bupivacaine 1.3 % (4 ml) will be 
injected at each of the chest tube exit sites. Thus, a total of 20 ml liposomal bupivacaine 1.3% 
(260 mg) will be administered. 
General Anesthesia 
 
General anesthesia based on inhaled isoflurane will be administered to both groups. 
Intraoperative opioids, including up to 500 mcg of fentanyl and up to 1 mg of oxymorphone or 
up to 10 mg of morphine or up to 2 mg of hydromorphone may be given.  
Post-operative Care 
In the post-anesthesia care unit (PACU), IV fentanyl will be given for NRS > 4 as needed,  25 
mcg IV every 2 minutes up to a maximum 200 mcg. If additional analgesia was required, 15 mg 
of IV ketorolac will be given once for NRS > 4.  An IV fentanyl patient-controlled analgesic 
(PCA) will be initiated for all patients in the PACU on the ward. All patients will receive 
acetaminophen (1000 mg orally every 8 hours 6 hrs) during the first 48 hours postoperatively. IV 
ketorolac (15 mg every 6 hours) may also be administered depending on pain severity, urine 
output and renal function. The epidural infusion can be temporarily stopped due to hypotension, 
excessive sedation, or hypoventilation, and then restarted at 4 mL/hour. If the epidural catheter is 
suspected to be non-functioning, the treating anesthesiologist will be allowed to test and replace 
the epidural catheter as necessary. The inpatient pain service will follow both groups for pain 

management. Adjustments to the epidural infusion mixture and rate will be performed by the 
inpatient pain service depending on analgesic effect and side effect profile, according to the 
usual practice by standardized protocol.  
For the first 48 hours following surgery, nursing staff will collect NRS pain scores every 
4 hours at rest (primary outcome). Side effects such as nausea or vomiting, pruritus, sedation, 
dizziness, respiratory depression, and medication use will also be collected. Additional 
information on patient characteristics, surgical and hospital course will be collected 
prospectively from the medical record using a standardized data collection form by a study 
coordinator, who will contact the patient 3 months postoperatively to determine whether they 
experienced persistent pain following thoracotomy.  
 
 

Statistical analysis 
Demographic, intraoperative, postoperative, and three-month follow-up data from the 
epidural and the intercostal groups will be summarized and compared between groups.  Tabular 
summaries will be created to outline the patient and procedural characteristics. The primary 
outcome will be the 8 AM pain score with cough on the first postoperative day. Other pain scores 
recorded every 4 hours using the Numeric Rating Scale (NRS) for the first 48 hours following 
surgery will be analyzed as secondary outcomes. These endpoints will be compared between 
groups using an appropriate two-sample comparison (t-test or rank sum test).  In addition, a 90% 
confidence interval for the difference between groups will be constructed to assess whether the 
lower bound is above the non-inferiority limit (-1).  Secondary outcomes will include overall 
satisfaction with pain management, incidence of postoperative hypotension (defined as a systolic 
or diastolic blood pressure more than 20% below baseline), pruritus, nausea or vomiting, and 
postoperative sedation. Additional secondary outcomes will include postoperative complications 
(respiratory failure, myocardial infarction, and pneumonia), readmissions to the ICU, length of 
ICU stay, length of hospital stay, and in-hospital deaths. Groups will also be compared with 
respect to IV fentanyl PCA use and ketorolac use for 0-24 hours and 24-48 hours.  Additional 
secondary endpoints will include pain scores and medication use at three-month follow-up.  For 
all secondary and exploratory analyses, continuous variables will be compared between groups 
using the two-sample t-test (or rank sum test) and categorical variables will be compared using 
the chi-square test or Fisher’s exact test.  In all cases we will assess distributional assumptions 
and use transformations (e.g. log) or analysis of ranks as appropriate.  The level of statistical 
significance for all tests was P<0.05. 
Power Calculation 

 
The number of patients required in each group was determined from a power analysis on 
the basis of non-inferiority hypothesis (4) for the primary endpoint which is pain with cough at 
8:00 AM on postoperative day 1. For non-inferiority of the intercostal nerve block vs TEA, a 
maximum difference of 1 (margin of non-inferiority) on the NRS scale was considered as 
acceptable. On the basis of previously published data, a standard deviation of 2 was assumed for 
NRS distribution (3). If there is truly no difference between the standard and experimental 
treatment, then 138 patients (69 patients per group) are required to be 90% sure that the lower 
limit of a two-sided 90%  confidence interval (one-sided alpha=0.05) will be above the non-
inferiority limit of -1.  Thus the proposed sample-size of N=140 (70 per group) will provide 
adequate statistical power to detect a meaningful difference.