Effects of ultrasound-guided external oblique intercostal plane block on the postoperative analgesia after open liver surgery: study protocol for a randomised controlled trial

Abstract

Background

Open liver surgery remains a primary surgical approach for complex liver resections and liver transplantation. However, the postoperative pain management is still a major challenge. Ultrasound-guided external oblique intercostal (EOI) plane block is a novel approach of regional anaesthesia and has a great potential to relieve postoperative pain after upper abdominal surgeries. This study aims to investigate the efficacy and safety of ultrasound-guided EOI plane block in managing postoperative pain after open liver surgery.

Methods

Seventy-four participants scheduled for open liver surgery will be randomly assigned to either the intervention group, receiving an ultrasound-guided EOI plane block with a single dose of 30 ml 0.375% ropivacaine, or the control group, which will not receive this block. All participants will be provided with opioid-based patient-controlled intravenous analgesia (PCIA) postoperatively. The primary outcome is resting pain score at 3 h postoperatively, assessed using numerical rating scale. Secondary outcomes include pain score at 6, 24, 48, and 72 h postoperatively, perioperative opioid consumption, remedial analgesics within 72 h postoperatively, PCIA usage within postoperative 72 h, postoperative recovery, length of hospital stay, postoperative side effects, block-related complications, and ropivacaine plasma concentration of participants receiving the block.

Discussion

This study is a randomised controlled trial to evaluate the efficacy and safety of ultrasound-guided EOI plane block for postoperative analgesia after open liver surgery. As regional anaesthesia plays an important role in the multimodal pain management, EOI plane block may prove to be an effective regional technique for enhancing postoperative pain relief and contributing to enhanced recovery after open liver surgery.

Trial registration

Chinese Clinical Trial Registry ChiCTR2200065745. Registered on November 14, 2022.

Administrative information

Title {1}	Effects of ultrasound-guided external oblique intercostal plane block on the postoperative analgesia after open liver surgery: study protocol for a randomised controlled trial
Trial registration {2a and 2b}	ChiCTR2200065745 Chinese Clinical Trial Registry, November 14, 2022; https://www.chictr.org.cn/showprojEN.html?proj=184510
Protocol version {3}	Version 3, November 14, 2022
Funding {4}	Anaesthetic Research Project of Bethune Charitable Foundation (SX-2022–004)
Author details {5a}	Peking Union Medical College Hospital
Name and contact information for the trial sponsor {5b}	Trial sponsor is Dr Jiali Tang. Email address: tangjiali@pumch.cn
Role of sponsor {5c}	Sponsor is involved in the study design, performs ultrasound-guided external oblique intercostal plane block, maintains the final dataset, and participates in manuscript writing, submission, and data interpretation. However, sponsor does not participate in data collection, management, and analysis. Funder does not engage in study design, collection, management, analysis, interpretation of data, manuscript writing, or the decision to publish the results

Introduction

Background and rationale {6a}

Open liver surgery is still the main approach for complex liver resection referring to anatomically and/or technically major hepatectomy as well as liver transplantation. Open liver surgery is associated with significant postoperative pain. Research indicates that up to 66% of patients undergoing hepatectomy experienced moderate-to-severe postoperative acute pain [1], and 55–80% of patients having open abdominal surgery reported inadequate pain relief [2]. Consequently, postoperative analgesia after open liver surgery remains a major challenge. Effective pain management is crucial in enhanced recovery after surgery (ERAS) protocols, as it supports early mobilisation, reduces postoperative complications, lowers narcotic use, and shortens hospital stays [3,4,5,6].

In the context of ERAS, regional anaesthesia, such as neuraxial techniques and nerve/fascial plane blocks, play a key role in multimodal analgesic strategy [3, 5,6,7,8]. However, the usage of thoracic epidural analgesia is declining due to risks of postoperative hypotension and coagulopathy after liver resection [9]. This shift highlights the growing importance of nerve/fascial plane blocks. Common block techniques for open liver surgery include subcostal transversus abdominis plane block (TAPB), quadratus lumborum blocks (QLB), paravertebral blocks (PVB), and erector spinae plane blocks (ESPB) [4,5,6,7,8]. Each of these methods has limitations. Subcostal TAPB often inadequately covers the lateral abdominal wall, and local anaesthetics may leak due to the surgical incision [10]. QLB mainly covers lower abdominal wall [11], and ESPB’s effectiveness on the abdominal wall is debated [12]. Additionally, PVB is an advanced block technique and always calls for experienced performer, because of possibility of severe complications [13, 14]. QLB and ESPB may be challenging in obese patients [15].

The external oblique intercostal (EOI) plane block is a relatively new fascial plane block technique with potential advantages over traditional methods for postoperative analgesia in open liver surgery [16, 17]. The EOI plane block covers the anterior and lateral abdominal walls from T6 to T10, matching sensation area of the typical incision in open liver surgery [16, 17]. Additionally, its target fascial plane is relatively shallow, making it potentially more effective in obese patients compared to QLB, PVB, and ESPB [15].

However, there are only a few anatomic study and case reports pointing out the potential benefits of EOI plane block in analgesia after epigastric surgery. This randomised controlled trial aims to evaluate the efficacy and safety of the ultrasound-guided EOI plane block in patients undergoing open liver surgery, examining its impact on postoperative analgesia, narcotic consumption, side effects, postoperative recovery, and safety of EOI plane block including block-related complications and ropivacaine plasma concentrations.

Objectives {7}

It is hypothesised that ultrasound-guided EOI plane block will lead to lower postoperative pain score, reduced opioid consumption, and improved postoperative recovery in patients undergoing open liver surgery. Additionally, it is anticipated that this block technique will demonstrate a safety profile with a low incidence of complications.

Trial design {8}

This study is a single centre, randomised, double-blind, controlled superiority trial with a concealed 1:1 allocation. Participants will be assigned to receive either an ultrasound-guided EOI plane block (0.375% ropivacaine 30 ml) or no block. The study protocol flow chart is illustrated in Fig. 1.

Fig. 1

Participant flow chart. EOI, external oblique intercostal

Methods: participants, interventions, and outcomes

Study setting {9}

This trial will be carried out in Peking Union Medical College Hospital.

Eligibility criteria {10}

Participants will be eligible for enrolment if they meet the following criteria and provide informed consent: (1) age 18 and 80 years; (2) scheduled for elective open liver surgery under general anaesthesia; (3) classified as American Society of Anaesthesiologists (ASA) physical status I to III.

Exclusion criteria include (1) refusal to participate; (2) inability to cooperate; (3) presence of skeletal muscle or nervous system disorders; (4) allergy or hypersensitivity to local anaesthetics; (5) history of opioid abuse; (6) skin infection at the injection site; (7) abnormal coagulation, defined as prothrombin time (PT) or activated partial thromboplastin time (aPTT) prolonged or international normalised ratio (INR) > 1.4, or platelet count < 80 × 10^9; (8) severe organ dysfunction (renal, liver or cardiac); (9) pregnancy or breastfeeding; and (10) any other conditions deemed inappropriate for participation.

Who will take informed consent? {26a}

An investigator will obtain written informed consent from potential participants in the reception room prior to allocation. The investigator will explain background, purpose, method, and procedures of the study, as well as any possible benefits and risks. Participants will have the opportunity to ask questions to ensure they fully understand and can make a decision.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Blood samples will be collected from participants in the intervention group at various time points to analyse ropivacaine plasma concentration. This provision is included in informed consent form. Additional consent will be obtained if relevant blood analysis is required in future research.

Interventions

Explanation for the choice of comparators {6b}

At Peking Union Medical College Hospital, the standard perioperative pain management for patients undergoing open liver resection involves multimodal analgesia without regional anaesthesia. After surgery, patients typically receive opioid-based PCIA with additional medications such as non-steroid anti-inflammatory drug, acetaminophen, tramadol, and extra opioid as needed. This standard regimen is used as comparator to evaluate whether the EOI plane block provides superior postoperative analgesia, reduces opioid consumption, and improves recovery after surgery.

To maintain blinding, all participants will receive local infiltration anaesthesia with 1 ml of 1% lidocaine. Participants in the intervention group will then receive EOI plane block, while those in the control group will not receive any block.

Intervention description {11a}

Before surgery, participants will be placed in pre-anaesthesia room for monitoring, including non-invasive blood pressure, continuous electrocardiography, and pulse oximetry. Supplemental oxygen will be provided via nasal cannula. One to 2 mg of midazolam will be administered. A radial arterial catheter will be placed for continuous arterial blood pressure monitoring and arterial blood gas analysis during operation. Blood samples for ropivacaine plasma concentration testing will also be obtained through this catheter.

Participants will be placed in the supine position, and their skin will be disinfected with povidone-iodine 5% solution. A linear ultrasound transducer (6–13 MHz, X-Porte, SonoSite, Bothell, MA, USA) will be covered by sterile sleeve. Ultrasound-guided EOI plane block will be performed as described previously [17]. In brief, the transducer will be placed slightly medial to the anterior axillary line between the sixth and seventh ribs on the right side. The cranial end of transducer points slightly medially, while the caudal end laterally. The local anaesthetic will be administered between the external oblique and intercostal muscles. Participants in the EOI plane block group will receive a single shot of 30 ml of 0.375% ropivacaine after a subcutaneous infiltration anaesthesia with 1 ml of 1% lidocaine. Participants in the control group will receive only the subcutaneous infiltration anaesthesia with 1 ml of 1% lidocaine.

Approximately 30 min after local anaesthetic injection, participants will be transferred to the operating room. Monitoring will include electrocardiography, pulse oximetry, bispectral index, and invasive blood pressure. General anaesthesia will be induced with propofol (2–2.5 mg/kg), sufentanil (0.15 μg/kg), and rocuronium (0.6 mg/kg), followed by endotracheal intubation and mechanical ventilation. Two to 3 vol% sevoflurane/oxygen/air mix inhalation, sufentanil (0.1 μg/kg/h), remifentanil (0.1–0.2 μg/kg/min), and rocuronium (0.1–0.2 mg/kg /h) will be applied to maintain anaesthesia. Hemodynamic fluctuation will be kept within 20% of baseline values.

Criteria for discontinuing or modifying allocated interventions {11b}

Participants may withdraw from the study at any stage. The risks associated with ultrasound-guided EOI plane block are considered low, as no publication reported the complications. In the event of complications, appropriate medical treatment will be administered. Participant who wishes to continue despite any issues will remain in their original study group,

Strategies to improve adherence to interventions {11c}

The interventions and tests related to ropivacaine plasma concentration will be provided at no cost. Additionally, participants will benefit from enhanced postoperative pain management, which often increases their engagement and adherence to the study. The ultrasound-guided EIO blocks will be performed exclusively in the operating room, and any other regional blocks performed perioperatively will be documented in the electric system. This ensures that any deviations from the allocated procedures can be identified, allowing for effective monitoring of adherence.

Relevant concomitant care permitted or prohibited during the trial {11d}

Any postoperative pain management including opioid, non-steroid anti-inflammatory drug, acetaminophen, tramadol, and other medicines are permitted. However, any form of regional anaesthesia is prohibited, including wound infiltration, transversus abdominis plane block, quadratus lumborum blocks, paravertebral blocks, erector spinae plane blocks, and thoracic epidural analgesia.

Provisions for post-trial care {30}

The ultrasound-guided EOI plane block is generally a safe procedure. If a participant experiences an injury related to this clinical trial, it will be documented, evaluated, and treated with appropriate medical care. The costs of such care will be covered by Clinical Trial Insurance.

Outcomes {12}

Primary outcome

• The primary outcome is the resting pain score, assessed using the numerical rating scale (NAS) at 3 h after surgery.

Secondary outcomes include

• (1) NRS pain scores at rest and during movement at postoperative 6, 24, 48, and 72 h, and during movement at postoperative 3 h.

• (2) Perioperative opioid consumption.

• (3) Remedial analgesics within 72 h postoperatively.

• (4) PCIA pump usage within 72 h postoperatively.

• (5) Recovery milestones, including time to removal of urinary catheter, time to first ambulation, time to first flatus, and length of hospital stay.

• (6) Postoperative side effects, such as nausea, vomiting, dizziness, drowsiness, and pruritus.

• (7) Block-related complications, including pneumothorax, local anaesthetic systemic toxicity, and hematoma.

Exploratory outcome

• Ropivacaine plasma concentration in participants from intervention group.

Participant timeline {13}

The participant timeline is shown in Fig. 2.

Fig. 2

Schedule of enrolment, interventions, and assessment (SPIRIT figure). EOI, external oblique intercostal

Sample size {14}

The sample size was calculated based on data from a pilot study with 8 participants, which indicated that resting pain score at 3 h postoperatively was 3.5 (± 1.3) in the control group and 2.8 (± 0.5) in the intervention group. To achieve a statistical power of 0.80 with a two-sided α level of 0.05, a minimal sample of 33 participants per group was required. Accounting for a dropout rate of approximately 10%, we plan to recruit 37 participants per group.

Recruitment {15}

Participants are all inpatients scheduled for elective open liver surgery. The day before the surgery, an investigator will review the list of scheduled operation to identify potential subjects. Those who meet all inclusion criteria and none of the exclusion criteria will be eligible for the study. The investigator will introduce this study to the participants and their families. Informed consent will be obtained subsequently. Close cooperation between anaesthesiology and liver surgery departments ensures effective participant enrolment.

Assignment of interventions: allocation

Sequence generation {16a}

Participants will be equally randomly assigned into two groups (control group; intervention group) using a computer-generated simple random sequence. No block or stratification will be used.

Concealment mechanism {16b}

An investigator not involved in clinical care or outcome assessment will prepare sealed opaque envelopes for each participant. Upon arrival in the pre-anaesthesia room, the investigator responsible for block will open these envelopes and administer the interventions as assigned. The investigator who performs the block will not involve in outcome assessment. The surgical team, anaesthesiologists, participants, and outcome assessors will all be blinded to the group allocation.

Implementation {16c}

Random sequence will be generated by an independent clinical epidemiology not involved in the participant recruitment. On the day before surgery, an investigator will enrol participants and obtain the informed consents. On the day of surgery, the sealed opaque envelope will be handed to the investigator responsible for performing the EOI plane block.

Assignment of interventions: blinding

Who will be blinded {17a}

Trial participants, care providers, outcome assessor, data analyst, and surgical team will be blinded to group allocation.

Procedure for unblinding if needed {17b}

If severe block-related complications are suspected, such as pneumothorax, severe local anaesthetic systemic toxicity, or severe hematoma, the allocation will be revealed. The surgeon will contact the investigator who performed EOI plane block. This investigator will then confirm whether the participant received the block. Diagnosis and treatment of complications will follow standard protocols.

Data collection and management

Plans for assessment and collection of outcomes {18a}

An investigator will follow up with participants and collect data. Baseline data will be obtained from the hospital’s electric system, while pain score, side effects, block-related complications, and recovery condition will be collected during face-to-face interview.

NRS pain score will be used to assess pain, ranging from 0 (no pain) to 10 (worst pain). Ropivacaine plasma concentration will be analysed using liquid chromatography-tandem mass spectrometry (LC–MS/MS) following a standardised protocol [18].

Plans to promote participant retention and complete follow-up {18b}

Participants will be followed for 72 h after surgery. Usually, participants will be monitored in hospital for more than 3 days postoperatively. If a participant is discharge before 72 h, follow-up will be conducted via telephone interviews to ensure all outcome data are collected.

Data management {19}

The investigator responsible for participant follow-up will complete the case report form (CRF) and input data into a designed Excel table. Another investigator will review the Excel table and perform range checks on data values to ensure quality. Both the CRFs and Excel table will be securely stored for 5 years. Data will not be transferred or disclosed to unauthorised individuals.

Confidentiality {27}

All investigators will be trained about data and privacy protection. Personal information of potential and enrolled participants will be collected from electronic hospital records and through face-to-face interviews. During face-to-face interviews, it will be arranged in a quiet office for privacy protection.

Each enrolled participant will be assigned a trial number. This number will serve as their ID and will be used in all documentations and labelling of samples. Access to collected information and data will be restricted to the investigation team. Data will be shared only within the investigation team during the trial. After the trial, data without personal information will be available for analysis.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

For participants receiving EOI plane block, blood samples will be collected at six time points: 5, 10, 30, 60, 120, and 180 min after block. Plasma will be separated and stored at − 20 °C for ropivacaine concentration analysis. The remaining blood components will be discarded, and these specimens will not be used for future research.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

Data analysis will use an intention-to-treat approach. Baseline characteristics of the two groups will be summarised with appropriate descriptive statistics. For primary outcome, rest pain scores at 3 h postoperatively will be compared using Student’s t-test, and mean difference with 95% confidence interval will be reported. For secondary outcomes, intraoperative opioid consumption will be compared using a Student’s t-test. Pain scores and opioid consumption at various time points will be analysed with repeated-measures analysis of variance, with sphericity tested using Mauchly’s test. The number of remedial analgesic administrations and PCIA pump compressions within 72 h postoperatively will be compared using Poisson regression, with overdispersion tested using Cameron and Trivedi’s test, and negative binomial regression applied if needed. Cox regression will be applied to analyse time to removal of urinary catheter, ambulation, flatus, and length of hospital stay. The incidence of postoperative side effects and block-related complications will be analysed with Pearson χ² test. Statistical significance will be defined as a two-sided p value of less than 0.05.

Interim analyses {21b}

There is no interim analysis.

Methods for additional analyses (e.g. subgroup analyses) {20b}

The subgroups will be defined by gender and age.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

The main data analysis will use a complete cases dataset. Missing data for the primary outcome will be addressed through multiple imputation, and relevant findings will be regarded as sensitivity analysis. For missing pain scores and opioid consumption data at various time points, a generalised estimating equation model will be used, which accommodates incomplete observations. No imputation will be conducted for other outcomes.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

Data without private information of participants may be shared upon reasonable request. There are no plans to make participant data publicly accessible. After the manuscript is published, statistical codes will be available through an open-source repository on GitHub.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

There is no coordinating centre or trial steering committee. The trial is managed daily by the investigation team, which includes the principal investigator, a resident, a nurse, and a master student. This team will meet weekly. Additionally, the Research Board of Peking Union Medical College Hospital regularly oversees the trial to ensure protocol adherence, adverse events, and unanticipated problems.

Composition of the data monitoring committee, its role and reporting structure {21a}

Data monitoring committee (DMC) consists of an anaesthesiologist who has experience of clinic trial and a statistician. DMC monitors study conduct and participations’ safety. Regular reports on study progress and adverse event will be presented at the meetings attended by all investigators and DMC members. DMC operates independently from the sponsor and competing interests.

Adverse event reporting and harms {22}

In the operating room, participants will be closely monitored by anaesthesiologist. After surgery, participants will be monitored by surgical team. Additionally, the investigation team will visit participants at 3, 6, 24, 48, and 72 h postoperatively. Complains and abnormalities can be reported by participants or identified by the surgical and investigation teams. Any confirmed adverse event will be documented, reported, and managed with appropriate treatment.

Frequency and plans for auditing trial conduct {23}

DMC will oversee the progress of this study and conduct audits every 6 months through interviews or phone calls. This auditing process will be independent of both the investigators and sponsor. The DMC retains the right to audit participant recruitment and data collection at any time.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

Any protocol amendments must be submitted to the IRB of Peking Union Medical College Hospital with written documentations. Once approved by IRB, the revised protocol and approval certification will be submitted to Chinese Clinical Trial Registry. After updating the registry, participants will be provided with a modified informed consent form reflecting the revised protocol.

Dissemination plans {31a}

Results of this research will be published in a peer-reviewed journal and presented at scientific conferences.

Discussion

Pain relief after open liver surgery has often been inadequate [1]. In the era of ERAS, the challenge is to reduce both pain and opioid use. Consequently, a multimodal analgesia strategy is widely recommended for postoperative pain management [5, 7, 8]. Regional anaesthesia plays an essential role in this strategy [5, 7, 8].

The EOI plane block is a novel regional anaesthesia technique with promising potential for managing pain after upper abdominal surgeries [12, 19]. Anatomic studies have shown that EOI plane block can effectively target the lateral and anterior branches of intercostal nerves from T7 to T10 [16, 17] and can achieve sensory loss from the posterior axillary line (T6–T10) to the midline (T6–T9) [17]. Observational studies indicated that EOI plane block can significantly reduce opioid requirement and lower pain scores [15, 20, 21]. However, most of these studies involved either laparoscopic or open abdominal surgeries with small sample sizes, leaving its efficacy in open liver surgery uncertain. Given its sensory coverage, the EOI plane block might be beneficial for open liver surgery [17], warranting further investigation through this randomised controlled trial to assess its effects on pain scores, analgesic consumption, and recovery quality.

The safety of the EOI plane block is also not well established. While ultrasound guidance has minimised risks of blood vessels, nerves, and organ injuries [22], the potential for local anaesthetic systemic toxicity remains a concern due to the large volumes used in plane blocks [23, 24]. This study will also evaluate safety of EOI plane block by measuring ropivacaine plasma concentrations, in addition to assessing block-related complications such as pneumothorax and hematoma.

This study protocol has several limitations. First, to blind the participants, dermatomal coverage of EOI plane block will not be assessed, which may include cases of incomplete analgesia, thereby potentially understating the benefit of block. Second, the sample size, calculated based on resting pain scores at 3 h post-surgery, may be insufficient to detect rare severe complications. Third, comparing EOI plane block with other regional techniques, such as subcostal TAPB and PVB, could provide additional insights, but is complex due to the distinct advantages of each technique. Thus, the participants in control group will receive placebo treatments rather than an alternative regional technique.

In conclusion, this trial represents the first prospective, randomised, double-blind controlled study to evaluate the efficacy and safety of ultrasound-guided EOI block for postoperative analgesia following open liver surgery. If the EOI plane block demonstrates superior pain relief and safe ropivacaine levels, it could offer a valuable option for pain management in open liver surgery and support the broader use of this regional technique.

Trial status

This protocol (version 2.0, September 29, 2022) was approved by IRB of Peking Union Medical College Hospital on October 12, 2022. The current protocol is version 3.0 (November 14, 2022), which was approved by IRB on November 17, 2022. The trial was registered on November 14, 2022. Participant recruitment began on November 21, 2022, and is anticipated to be completed by November 20, 2026.