Paravertebral vs. Epidural Analgesia for Liver Surgery (PEALS): Protocol for a randomized controlled pilot study

Sample size

Non-inferiority trials typically require larger samples than superiority trials^49,50; thus, we anticipate the need to include multiple centres to secure enough participants. Therefore, we propose a single-centre pilot study to generate the data needed to estimate the sample size required for a large, multi-centre trial. Based upon previous studies that compared TEA versus PVB for postoperative analgesia in patients undergoing thoracotomy,^45,51 we will aim for a convenience sample of 25 patients per group to generate pilot data upon which to base a larger, multi-centre trial. Our non-inferiority margin will be set at 20% for cumulative opioid consumption at 72 hours postoperatively since we do not consider a difference of <20% to be clinically relevant.

Participants, setting and recruitment

A convenience sample of 50 patients scheduled to undergo a hepatectomy through a right subcostal incision will be recruited from our medium-sized (~407 beds), tertiary care academic centre. Eligible patients will be approached by research personnel at the preoperative screening clinic or, because of COVID concerns, via telephone at least 24-48 hours before surgery and given information about the study. For patients who are eligible and willing, research personnel will obtain signed consent while they are waiting to be taken to the operating room (OR). In all cases, both the anaesthesiologist and the attending surgeon will be made aware at least one to three days before surgery of the potential involvement of the patient, and time will be allowed for discussion and withdrawal at their request. With the volume of liver resection surgical patients at our centre (i.e., ~30/year), we anticipate recruitment/data collection for 50 patients to require two to three years.

Eligibility criteria

Randomisation

This is a randomised, controlled, non-inferiority pilot study. Eligible patients will be randomised using a computer-generated randomisation table prepared by the institutional biostatistician with assignments concealed in envelopes. Participants, surgeons, and dedicated research personnel collecting the data (i.e., study nurses/research assistants) will be blinded to allocation. Anaesthesiologists performing TEA/PVB will not be blinded but will have no involvement in patient assessments/data collection.

Data collection and storage

To protect confidentiality, patient data on collection sheets/spreadsheets will be identified only by a study identification number that will be linked to the patient identity only on a master sheet/spreadsheet kept securely and separately from the data. Patient data will then be entered into a password-protected REDCAP file and stored on the institutional server behind a firewall. All study data will be retained for the 15-year storage period required by Health Canada following which, it will be permanently deleted and/or destroyed. Only study personnel will have access to identifiable study data and it will not be shared with a third party. Final data may be placed in a public depository but no publicly accessible information will be identifiable.

Descriptive demographic data including patient height, weight, age, sex, ASA physical classification, MELD score, comorbidities, type and length of surgical procedure, number of resected liver segments, estimated blood loss, intraoperative complications, surgeon, the main surgical indication, and preoperative functional liver status will be recorded.

Study design and ethical approval

Ethical approval was provided by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (ANAE-270-15) and the study registered on Clinicaltrials.gov (NCT02909322 09-21-2016) available at URL: https://clinicaltrials.gov/ct2/show/NCT02909322. This non-inferiority pilot RCT in which hepatectomy patients will be randomly assigned to receive either TEA or PVB for postoperative analgesia, is also in compliance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. As clearly stated in the informed consent, in the unlikely event that participants are injured due to participation in the current study, medical care will be provided to them free of charge until resolution of the problem. By providing consent to participate, they are not waiving their legal rights or releasing the investigator(s) and sponsors from their legal and professional responsibilities.

Interventions

Control group: TEA

TEA procedures will follow the standard of care at our centre. The TEA catheter will be sited preoperatively at T7-T9 using the landmark technique, and a lignocaine test dose (4-6 mL of 2% lignocaine with epinephrine 1:200,000) will be given. After GA induction, bupivacaine 0.1% with hydromorphone 10 μg/mL will be infused at 6-10 mL/h and five mL boluses will be allowed at 30 min intervals at the discretion of the anaesthesiologist. Upon admission to the PACU, patient-controlled epidural analgesia (PCEA) will be initiated. The PCEA bolus of the same solution will be set at three mL with a lockout period of 30 min, and the epidural infusion of the same solution will be set at six mL/h and adjusted in two mL/h increments (or decrements) up to 10 mL/h depending upon pain scores and sensory block tested with ice in the PACU.

If at any time point during the first 72 hours post-surgery patients complain of moderate-severe pain (i.e., >4/10 on a numeric rating scale (NRS) where 0 = no pain, 10 = worst pain imaginable) despite maximal epidural infusion (10 mL/h), a bolus of five mL bupivacaine 0.25% will be given, provided the patient is haemodynamically stable, and the block height will then be re-tested. If two boluses of five mL bupivacaine 0.25% over 60 min (30 min. apart) fail to control pain and there is no demonstrable sensory block upon testing with ice, the catheter will be removed (if coagulation profile allows). The decision to remove the epidural catheter will be made by the clinical management team. Therapeutic failure is defined as catheter removal and/or discontinuation of infusion prior to completion of the study (72 hours postoperative). In this case, patients will be started on a standard i.v. PCA (hydromorphone 0.2 mg/mL, 0.2 mg demand dose, 8 min lockout interval).

Intervention group: PVB

PVB will be performed following our standard of care protocol. In the institutional block room, a preoperative paravertebral catheter will be sited on the right side at T7-T9 using the landmark technique or under ultrasound guidanceIn the landmark technique, once the appropriate thoracic level is identified, the needle is inserted at 2.5-3 cm lateral to the most cephalad aspect of the spinous process and advanced perpendicular to the skin in all planes to contact the transverse process of the vertebra below. The needle is then walked above the transverse process and gradually advanced until a loss of resistance to saline is felt as the needle tip traverses the thin superior costotransverse ligament.⁵² For US-guided PVB, a high-frequency linear US transducer is placed 2.5-3 cm lateral to the most cephalad aspect of the spinous process and oriented vertically at the target thoracic level. Once the transverse process is identified as a “squared” bony structure (note, the identification of a “round” bony structure is usually consistent with the rib, indicating that the probe should be slowly moved medially), the superior/cephalad aspect of the probe is maintained static, while its inferior/caudal aspect is slightly (~30°) rotated counterclockwise until the costotransverse ligament (usually ~0.5 cm superficial to the pleura) is brought into view. The block needle is carefully advanced in plane with the probe in a cephalad direction until it pierces the costotransverse ligament. Correct LA deposition is evidenced by the inferior displacement of the pleura under direct US visualization. A bolus of 20 mL ropivacaine 0.25% will be administered through the block needle followed by catheter advancement into the paravertebral space. An infusion of ropivacaine 0.25% at a rate of 0.1 mL/kg/h will be started shortly after induction of GA. In addition, 5 mL boluses of ropivacaine 0.25% will be allowed at 30 min intervals intraoperatively at the discretion of the anaesthesiologist. Upon transfer to the PACU, patient-controlled paravertebral analgesia (PCPA) will be started. The PCPA bolus will be 5 mL ropivacaine 0.25% with a lockout period of 2 h, and an infusion of ropivacaine 0.25% will be continued at 0.1 mL/kg/h and increased in 2 mL/h increments up to 10 mL/h, depending on the pain scores and sensory block to ice tested in the PACU. This initial infusion will be continued for the first 24 h after surgery, and then reduced by 25% on postoperative day (POD) two, and further reduced another 25% on POD3 to reduce the risk of LAST. Notably, the difference in LA solutions between the TEA (bupivacaine 0.1% with hydromorphone 10 μg/mL) and the PVB (ropivacaine 0.25%) groups aligns with industry as well as our institutional standard practice and accounts for the fact that the paravertebral space, being anatomically larger than the epidural space, requires higher volume and concentration of LA to achieve similar analgesia. In addition, PVB has traditionally only involved the use of LA without opioids.

If at any time point during the first 72 hours post-surgery, patients complain of moderate to severe pain (NRS >4/10) despite maximal PVB infusion (10 mL/h) and if there are no signs of LAST, a bolus of five mL ropivacaine 0.25% will be given, and the sensory block distribution will be re-tested with ice. If two boluses of 5 mL ropivacaine 0.25% over 60 min are unsuccessful in maintaining pain scores <4/10, and there is no demonstrable block on sensory testing with ice, the PVB infusion will be discontinued and the catheter removed (if coagulation profile allows), and the case will be counted as a PVB failure. The decision to remove the PVB catheter will be made by the clinical management team. Therapeutic failure in the PVB group is defined as PVB catheter removal prior to completion of the study at 72 h postoperative. In this case, patients will be started on a standard i.v. PCA (hydromorphone 0.2 mg/mL, 0.2 mg demand dose, eight min lockout interval).

All patients will be offered subcutaneous hydromorphone (0.5-1.0 mg) every 1-2 h and upon patient request until they are able to tolerate oral fluids/medications, at which point they will be given oral hydromorphone (1-2 mg every 4 h) as required starting on the morning of POD2. A member of the research team (blinded to randomisation) will assess the presence/severity of pain and PONV. The assessment will be performed 30 min after arrival to the PACU, and at 4, 8, 24, 48, and 72 h postoperatively. We will ask all patients to rate their pain (NRS scale) at rest and with coughing and their PONV at each of the above listed time points. An antiemetic will be offered to any patients with a PONV score ≥ 2 (where 0 = none, 1 = mild, 2 = moderate, 3 = severe (retching/vomiting)). At 72 hours postoperatively, patient satisfaction with analgesia will be assessed.

As alluded to, our protocol follows the standard institutional practice for TEA and PVB, including specific LAs used and infusion regimens. Any changes to the study protocol will be amended to the approved ethics application and communicated to all involved in study execution.

Adverse events

Serious adverse events (SAEs) such as epidural haematoma or abscess, pneumothorax, LAST, serious respiratory depression, massive transfusion, refractory hypotension, myocardial infarction, will be reported as per standard of care for our centre and also to the institutional research ethics board as required. All SAEs will be documented and discussed by investigators. If deemed to have potentially resulted from the study protocol, the study will be halted pending further independent investigation.

Statistical analyses

Data will be entered into REDCAP and then imported to SPSS (ver. 29.0 for Windows, Armonk, NY, 2022) for data analysis. Data will be analysed using an intent-to-treat strategy, regardless of whether the catheter is removed early. Since intent-to-treat strategies are often “anti-conservative” when used in non-inferiority trials,⁵³ we will also analyse our data using the per-protocol strategy, excluding those participants who were excluded, lost, or deviated from the protocol. All continuous data will be checked for normality using the Shapiro-Wilk test. The two groups will be compared using Student’s t-tests for normally distributed data, and the Mann-Whitney U for non-normally distributed data. Continuous data collected at several points in time, such as pain, PONV, patient satisfaction, and sedation scores, will be compared using the repeated measures ANOVA (Tukey’s post hoc test for comparisons between individual time points), or the Friedman test (Wilcoxon signed rank test with Bonferroni adjustment for comparison between individual time points) for non-normally distributed data. Categorical data will be compared using Pearson’s Chi Square test, or the Fisher’s Exact test, as appropriate. No adjustments will be made for multiple comparisons, no adjustment or imputation will be made for missing data, and a p-value of <0.05 will be used as the criteria for statistical significance.

Dissemination plans

This study will be used to design a powered, multi-centre RCT comparing TEA to PVB in hepatectomy patients. This work has a high potential to positively impact the quality and safety of care in the liver resection patient population with a reduction in associated costs. Upon completion, study results will be disseminated through international conferences and peer reviewed publication(s). Results will also be communicated to anaesthesiologists and hepatic surgeons at other centres.