Study design

The Epidurals in Pancreatic Resection Outcomes (E-PRO) study is a prospective, single-centre, randomised controlled trial. In total, 150 patients undergoing either pancreaticoduodenectomy or distal pancreatectomy will be randomised to receive an epidural infusion of 0.125% bupivacaine starting at 5 mL/hour (range of 5–8 mL/hour) following anaesthetic induction followed by a standard epidural infusion of 0.1% bupivacaine at 4–6 mL/hour postoperatively in addition to the institutional standardised pain regimen of hydromorphone patient-controlled analgesia (PCA), intravenous acetaminophen and ketorolac (intervention group) or no epidural infusion and only the standardised postoperative pain regimen (control group). Follow-up information will be collected from the medical record for up to 2 years postoperatively. The study design is outlined in figure 1.

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Figure 1

Study design. IL, interleukin; QST, quantitative sensory testing; TNF, tumour necrosis factor; VAS, visual analogue scores.

Eligibility criteria

Patients 18 years old or older who are able to understand and sign an institutional review board (IRB)-approved informed consent form and who are undergoing either pancreaticoduodenectomy or distal pancreatectomy will be eligible for study inclusion. Patients will be excluded if they fulfil any one of the following criteria: indication for operative intervention being chronic pancreatitis, currently on warfarin with an international normalised ratio (INR) >1.4 or clopidogrel that cannot be discontinued 7 days prior to surgery, most recent INR prior to surgery >1.4, most recent platelet count prior to surgery <70 000/μL, chronic opioid use as defined by use of >20 mg oxycodone, or equivalent, daily, history of pre-existing neuropathic pain conditions, known medical history of significant psychiatric or cognitive impairment, or history of HIV, hepatitis B and/or hepatitis C. Patients will be consented and enrolled during a clinic or preoperative evaluation appointment.

Baseline assessment

Each study participant will be randomised into the control group with standard of care pain management regiment or the intervention group with the addition of epidural analgesia. Randomisation will occur via a randomised number generation by the principal investigator (PI).

Patients will have the standard of care preoperative evaluation at the Barnes Jewish Hospital Center for Preoperative Assessment and Planning. Routine laboratory tests including complete blood count, comprehensive metabolic panel and coagulation studies will be obtained and reviewed.

In patients receiving chronic antiplatelet or anticoagulant medications, the following procedure will be practised to minimise the risk of bleeding (per American Society of Regional Anesthesia and Pain Medicine guidelines37).

Acetyl salicylic acid (aspirin) or other non-steroidal anti-inflammatory drugs may be continued prior to epidural catheter insertion. Clopidogrel use must be discontinued 7 days before the procedure. The study participant’s treating physician (eg, surgeon, cardiologist, neurologist) will be consulted prior to the discontinuation of clopidogrel. Participants receiving warfarin will proceed with the following schedule: if INR <1.4, subject may proceed with epidural catheter insertion. If INR >1.4, the participant’s treating physician will be consulted whether warfarin can be discontinued until INR reaches <1.4 or the subject can be switched to low-molecular weight heparin, which can be discontinued 36 hours before catheter insertion. INR and prothrombin time (PTT) will be assessed on the day of epidural catheter insertion in all patients on anticoagulant (but not antiplatelet) therapy.

Study participants will undergo a complete medical history and physical examination, and the following baseline assessments:

1. Evaluation of hypersensitivity or dynamic mechanical allodynia to brush stimulation in the upper abdomen.38

2. Quantitative sensory testing (QST) to assess warm and cold detection thresholds, heat and cold pain thresholds, mechanical detection and pain thresholds, presence of wind-up (enhanced temporal summation) to pinprick (online supplementary file 1).

3. Screening for psychological risk factors for acute and chronic pain using Hospital Anxiety and Depression Scale.39

4. Baseline assessment for delirium using the 3D-CAM instrument.40

5. Baseline assessment of serum inflammatory markers (IL-1β, IL-6, TNF-α, IL-10).

Interventions

Postoperatively, all patients will receive a standardised pain regimen including a hydromorphone PCA (initial settings of no bolus dose, 0.25 mg per demand dose, minimal interval dose time of 10 min), acetaminophen (1000 mg every 6 hours for 24 hours) and ketorolac (15 mg every 6 hours for 72 hours) per surgeon’s preference. Study group patients will have an epidural bupivacaine infusion beginning in the operating room (OR).

An epidural infusion of 0.125% bupivacaine starting at 5 mL/hour (range of 5–8 mL/hour) will be started after induction of anaesthesia. Epidural narcotic consisting of fentanyl 50 μg will be administered with sterile precaution by the anaesthesia provider before starting the epidural infusion. Epidural boluses of 0.125% bupivacaine may be administered as guided clinically. A phenylephrine infusion can be used to maintain adequate blood pressure maintaining mean arterial pressures (MAP) >60 mm Hg. The epidural infusion can be paused if vasopressor requirements exceed 1 μg/kg/min of phenylephrine or 0.1 μg/kg/min of norepinephrine. The epidural infusion is to be paused if haemodynamics become unstable, either due to excessive blood loss or MAP consistently below 60 mm Hg. The epidural infusion can be resumed when haemodynamics are stable.

The bupivacaine 0.125% epidural infusion is to be discontinued in the OR at the end of surgery and a standard epidural infusion of 0.1% bupivacaine at 4–6 mL/hour will be started in the post-anaesthesia care unit (PACU). The epidural infusion is followed up by an Acute Pain Service in the postoperative period that will titrate the infusion based on the patients’ self-reported pain scores and MAP values.

Outcomes

Sample size

Sample size estimation was performed based on the study primary outcome of postoperative opioid consumption. Based on our prior experience, this estimation will be based on the following assumptions41: expected morphine consumption is 30 mg intraoperatively, 30 mg on postoperative day 1 (POD1), 20 mg on POD2 and 10 mg on POD3. Therefore, expected total morphine consumption in the first 72 hours is, on average, 80 mg. Then, assuming that the SD of morphine consumption is 30 mg, that a 20 mg difference in morphine consumption between groups is a clinically meaningful reduction of opioid use and assuming normal distribution of morphine consumption in both patient groups, the proposed sample size for a=0.05 and b=0.2 would be 37 patients per group (74 patients in total). However, we propose to increase the sample size of the study to 150 total patients to account for patients lost to follow-up, inability to complete the scheduled pancreatic resection, data errors and other unanticipated study problems.

Recruitment

Participants will be recruited primarily through the Washington University Hepatobiliary-Pancreatic Surgery clinics. Subjects will be given verbal (initially) and then written descriptions of the study aims, procedures, risks and benefits, and will be required to give written informed consent. A member of the investigative team provides all study descriptions, informed consent and answers all questions. No deception is required for the purposes of this study. All subjects will be aware of the randomisation used in this study to either the control or intervention group. Subjects are informed verbally and in writing that participation is voluntary and they may refuse to participate and may withdraw from the study at any time without penalty.

Allocation

Participants will be randomised in a 1:1 ratio into the control group with standard of care pain management regimen or the intervention group with the addition of epidural analgesia. Randomisation will occur via randomised number generation.

This is a single-blind study. Patients and the primary investigative team will be aware of the randomisation. However, all study members performing data collection will be blinded to the randomisation.

Data analysis and management

Data analysis for this study will focus on the comparison of patient outcomes (postoperative morphine/morphine-equivalent consumption, measures of postoperative recovery, inflammatory markers, 3D-CAM/CAM-ICU assessments, QST) between the intervention and control study groups. Based on data distribution, continuous variables will be compared between the two groups using Student’s t-test or the Mann-Whitney U test as appropriate. When appropriate, significance of findings will be adjusted for multiple comparisons using the Bonferroni correction method.

The Center for Biomedical Informatics at Washington University will be used as the central location for data collection and management. Since 2008, Washington University has hosted Research Electronic Data Capture (REDCap), a secure, web-based application for building and storing online research and clinical trial databases. The REDCap servers are securely housed in an on-site limited access data centre managed by the Center for Biomedical Informatics at Washington University. All web-based information transmission is encrypted, and all data are stored on a private firewall-protected network. All users are assigned individual user IDs, and passwords and individual access is restricted on a role-specific basis. REDCap was developed specifically around Health Insurance Portability and Accountability Act (HIPAA) guidelines and is also implemented and maintained in accordance with institutional security guidelines.

Monitoring

The study team will monitor all study participants for adverse events. The PI will report all unanticipated problems or adverse events, all conditions of non-compliance and any new information that may affect the continued or current enrolment of study participants to the IRB. All events will be reported to the IRB within 10 working days of the event or of notification of the PI of the event. The death of a study participant must be reported to the IRB within one working day of the event or of notification of the PI of the event.

The specific monitoring plan for this investigation is commensurate with the risks and the size and complexity of the investigations planned. The potential risks are attributable to performing insertion of the epidural catheter and the use of bupivacaine for neuraxial analgesia. Based on these considerations, the monitoring plan involves engaging a colleague from the Department of Anesthesiology not involved in the study to serve in a monitoring capacity. Based on the small size and relatively low-risk nature of the protocol, only a third person (the colleague), rather than a full Data Safety Monitoring Board, will be used. The colleague will be an anaesthesiologist knowledgeable in the risks associated with nerve blocks and local anaesthetic administration. This individual will review the annual summary of adverse events. In addition, this colleague will review all reports of a serious adverse event or an unexpected adverse event.

Ethics approval and consent

The E-PRO trial was provided ethical approval by the Washington University in St. Louis’s IRB which serves Washington University and Barnes-Jewish Hospital. Study recruitment and enrolment began in May 2016 and will continue through the end of 2017. Potential study participants will be given verbal and then written descriptions of the study aims, procedures, risks and benefits, and written informed consent will be obtained for all participants. All participants are informed verbally and in writing that participation is voluntary and they may refuse to participate and may withdraw from the study at any time without penalty.

Confidentiality

Only the investigators and research team will have access to any protected health information of study participants and any study data. All subjects will be assigned a study ID number. All study data and samples will be coded with the assigned study ID number. A key to the code linking code numbers to patient names will be kept at a separate location, under lock and key; this link will be destroyed at the conclusion of this study. All data will be recorded by a member of the research team and will be stored in a password-protected electronic database stored on the departmental network drive. Study data will not be entered into participants’ medical records.

Dissemination

Dissemination plans include presentations at scientific conferences and scientific publications.