Erector spinae plane block versus thoracic epidural analgesia in video-assisted thoracic surgery: a study protocol for a prospective randomized open label non-inferiority trial


 Background: Thoracic epidural analgesia is considered the gold standard for pain relief in video-assisted thoracoscopic surgery. This neuraxial technique blocks pain sensation by injecting local anesthetic in the epidural space near the spinal cord to block spinal nerve roots. Recently, the erector spinae plane block has been introduced as a practical alternative to the thoracic epidural. This interfascial regional anesthesia technique interrupts pain sensation by injecting local anesthetic in between the muscular layers of the thoracic wall. Several case series and three RCTs described it as an effective pain management technique in video-assisted thoracoscopic surgery. (1–5)The objective of this study is to test the hypothesis that a continuous erector spinae plane block is non-inferior in terms of the quality of recovery as measured by the Quality of Recovery-15 score compared to continuous thoracic epidural analgesia in patients undergoing elective unilateral video-assisted thoracoscopic surgery.Methods: This is a prospective randomized open label non-inferiority trial. A total of 90 adult patients undergoing video-assisted thoracoscopic surgery will be randomized 1:1 to receive either pain treatment with continuous erector spinae plane block (study group) or continuous thoracic epidural analgesia (control group). The primary endpoint is the quality of recovery as measured by the Quality of Recovery-15 score. Secondary endpoints are postoperative pain as Numerical Rating Score scores, length of hospital stay, failure of analgesic technique, postoperative morphine-equivalent consumption, itching, nausea and vomiting, total operative time, complications related to surgery, perioperative hypotension, complications related to pain treatment, duration of bladder catheterization, time of first assisted mobilization >20 meters and of mobilization to sitting in a chair. Discussion: This randomized controlled trial aims to confirm whether a continuous erector spinae plane block can equal analgesic effect as regional anesthesia technique compared with a thoracic epidural in patients undergoing video-assisted thoracoscopic surgery.


Title {1}
Erector spinae plane block versus thoracic epidural analgesia in video-assisted thoracic surgery: a study protocol for a prospective randomized open label non-inferiority trial A total of 90 patients are being randomly allocated to ESP (study group) or TEA (control group). Patients will be followed until 48 hours after surgery or until discharge from the hospital. Primary outcome is the Quality of Recovery 15 (QoR15) score. We hypothesize that the ESP is equally as effective as a TEA, without the disadvantages (bedrest, urinary catheter, rare but serious neurologic adverse events). systemic analgesic agents (opioids, acetaminophen, non-steroidal anti-inflammatory drugs, and cyclooxygenase-2-specific inhibitors) and analgesic adjuncts such as steroids, ketamine, α-2 agonists, and anticonvulsants (2). This so-called multimodal approach improves the analgesic effect because of the synergizing effect between the different analgesia techniques and/or drugs.

Status
Up until now, the epidural analgesia is the gold standard local anesthetic technique for VATS surgery (3). However, the invasiveness of this technique, the rare but serious neurologic complications and the failure rates up to 30% (4) have resulted in a search for alternatives.
Alternatives include lower thoracic catheter placement, intercostal nerve blocks, paravertebral blocks, intrapleural catheters, local anesthetic infiltration, and systemic analgesia with one or more agents (4). However, none of these techniques were able to replace the thoracic epidural as gold standard due to (5)  Thoracic epidural analgesia (TEA) is considered the gold standard analgesic technique for video-assisted thoracoscopic surgery (VATS).(6) The invasiveness of this technique, the rare but serious neurologic complications and the failure rates up to 30% (7), show the shortcomings of epidural analgesia. Also, neuraxial techniques are contra-indicated in patients using anticoagulation apart from acetylsalicylic acid and other non-steroidal anti-in ammatory drugs (NSAIDs). (8) Sepsis and infection are relative contraindications. (9) This has fuelled the interest in alternatives to TEA. Alternatives include intercostal nerve blocks, paravertebral blocks, intrapleural catheters, local anesthetic in ltration, and systemic analgesia with one or more agents. (6) However, none of these techniques were able to replace the thoracic epidural as gold standard due to being 'too technically challenging' (10) or providing 'insu cient analgesia'. (11) The most recently-described alternative to TEA is the erector spinae plane (ESP) block. The ESP block is a fascial plane block that aims to inject local anesthetic within a plane beneath the erector spinae muscle. or Maasstad Hospital Rotterdam will be asked for informed consent during the preoperative anesthesiology consultation. We plan to start recruitment in July 2020.
In order to be eligible to participate in this study, a subject must meet all of the following criteria: (1) age between 18 and 75 years old, (2) BMI between 18 and 30kg/m2, (3) scheduled for elective VATS, and (4) written informed consent.
Exclusion criteria are as follows: (1) ASA status 4 or 5, (2) chronic opioid use, de ned as > 3 months of opioid use (excluding tramadol and codeine), (3) renal or liver failure inhibiting the systematic use of paracetamol and/or NSAIDs, (4) contraindications to epidural analgesia including abnormal coagulation status, local infection, pre-existing neurological de cits of the torso or lower limbs, and spinal disease (5) allergy to study medication, (6) pregnancy, (7) cognitive impairment, (8) insu cient comprehension of the Dutch QoR-15 questionnaire.
Who will take informed consent? {26a} Informed consent will be obtained by an anesthesiologist during the preoperative anesthesiology consultation. An informed consent form will be signed by both the patient and the anesthesiologist.
Additional consent provisions for collection and use of participant data and biological specimens {26b} N/A, no biological specimens are collected.

Interventions
Explanation for the choice of comparators {6b} The control group will receive thoracic epidural analgesia (TEA). This is considered the gold standard analgesic technique for video-assisted thoracoscopic surgery (VATS). (6) Intervention description {11a} Investigational treatment During the study, patients will receive standard preoperative care. Both techniques will be performed after placement of an intravenous (IV) line and application of standard vital sign monitors (non-invasive blood pressure, electrocardiogram, and oxygen saturation). The TEA and the ESP block will be performed before the start of surgery, according to institutional protocol. The ESP block will be performed under ultrasound guidance and the thoracic epidural will be performed using the conventional landmark-guided technique in line with currently-accepted practice. All interventions will be performed consultant anesthesiologists experienced in the technique.

Intervention group: Continuous ESP block
The ESP block will be placed as described by Forero et al. (11) The patient will be installed in the lateral or sitting position. An ultrasound probe will be placed in a longitudinal position 2-3 cm lateral of the vertebral column. The erector spinae muscles will be identi ed in relation to the ipsilateral fth thoracic vertebra (T5) transverse process. A Tuohy needle will be inserted with an in-plane technique in a caudal to cephalad direction until bony contact with the transverse process is obtained. Hydrodissection with normal saline will be performed to identify and open up the correct plane for injection. A loading dose of ropivacaine will be injected followed by the insertion of an 18-gauge catheter 5 cm beyond the needle tip. Patients over 70 kg will receive 200 mg ropivacaine (40 ml), patients 50-70 kg will receive 150 mg ropivacaine (40 ml) and patients under 50 kg will receive ropivacaine 3 mg/kg (40 ml). At the end of surgery, ESP catheter is used at a continuous rate of 5 ml/h of bupivacaine 0.125% and an extra bolus of 10 ml bupivacaine 0.125% is given. Current institutional practice with other regional anesthesia techniques is to administer either ropivacaine at the start of surgery or bupivacaine at the end and continuous infusion on the ward. Because this techniques needs both a bolus at the start and end/ continuous infusion on the ward, we choose to adhere to known local practice as much as possible and use two different local anesthetics.

Control group: Continuous thoracic epidural analgesia
The epidural catheter will be inserted preoperatively at the T5-T7 vertebral level; the exact level will be at the discretion of the attending anesthesiologist. A loading dose of bupivacaine 0.25% (max 10 ml) or ropivacaine 0.75% (max 10 ml) will be administered, followed by an intraoperative infusion of 8-12 ml/h of bupivacaine 0.125 % with sufentanil 1 μg/ml or 5 ml/hour ropivacaine 0.2% with sufentanil 0.5 μg/ml. These dosing regimens are in line with existing individual institutional protocols; the speci c details will be left to the discretion of the attending anesthesiologist.
Postoperatively we will not measure blocked sensory dermatomes in both ESP and TEA group as part of standard treatment. For TEA it is our current practice to measure blocked sensory dermatomes only in patients who have a NRS >4. For ESP block patients, other studies showed highly variable sensory blockade. (18,19) Therefore, we do not measure it.

General treatment regimen
Induction of anesthesia, intraoperative hemodynamic management, and mechanical ventilation will follow current standards of care for both groups. In the operating room, general anesthesia is induced with propofol, sufentanil for analgesia and rocuronium for paralysis. The trachea is intubated, and the lungs are mechanically ventilated with pressure-regulated volume-controlled ventilation. After induction, general anesthesia is maintained with a propofol infusion and supplemented as needed by additional boluses of sufentanil for intraoperative analgesia. A radial arterial line and an internal jugular central venous line will be inserted at the discretion of the attending anesthesiologist. A urinary catheter is inserted for the patients in the TEA group but only if indicated in patients in the ESP group. All patients without urinary catheter will receive a bladder scan in the post-anesthetic care unit (PACU) before discharge to the ward as part of standard postoperative care. Cefuroxime 1500mg is administered prior to incision.

Postoperative analgesia regimen
Intervention group: erector spinae plane Patients in the intervention group will receive continuous ESP analgesia with an infusion of 5 ml/h bupivacaine 0.125% and a nurse administered bolus of 10 ml bupivacaine 0.125% every 3 hours. The nurse will get an automated order to give the bolus at regular 3-hour intervals. They also receive a patientcontrolled intravenous analgesia (PCIA) pump with piritramide and droperidol. Settings of the PCIA pump will be according to local institutional protocols. When ESP does not provide a NRS < 4, the patient will be titrated piritramide intravenous until NRS <4.

Control group: thoracic epidural analgesia
Patients in the control group will receive TEA through a continuous epidural analgesia (CEA) pump with either bupivacaine 0.125% + sufentanil 1 μg/ml (8-12 ml/h with the possibility of a bolus of 4 ml every hour) or ropivacaine 0.2% + sufentanil 0.5 μg/ml (rate of 5 ml/h with a 2 ml bolus on demand with a lockout of 20 minutes) according to local institutional protocols. When CEA does not provide a NRS < 4, an extra bolus of 5 ml of bupivacaine 0.125% + sufentanil 1 μg/ml or ropivacaine 0.2% + sufentanil 0.5 μg/ml will be given.
Discontinuation of ESP or CEA is planned on the morning of day 2, after APS assessment, unless sideeffects or safety issues mandate discontinuation or removal earlier. Patients will receive a daily visit by the acute pain service (APS) team, who will convert the patients to oral analgesics (paracetamol, NSAID and oxycodone) after removal of ESP or CEA.
Use of co-intervention All patients will receive the standard pain treatment with paracetamol and NSAIDs following the in house protocol. The attending anesthesiologist will decide if IV titration of piritramide at the end of the surgery is necessary for smooth transition to the post anesthesia care unit. In the PACU ward, intravenous piritramide will be titrated until NRS ≤4. If this is insu cient, intravenous clonidine 1mcg/kg will be added.
The APS team will visit the patient daily and adjust the analgesic regimen as described above to manage inadequate analgesia. They will systematically screen for side effects, failure of analgesic technique, need for rescue medication and need for specialist intervention.

Summary of known and potential risks
In a prospective audit report from the UK, the incidence of permanent injury from neuraxial anesthesia In our current expertise, which follows the available literature, we perceive that ESP block is safe compared to the standard treatment, epidural analgesia. It is conducted in an environment with extensive monitoring of vital parameters and direct presence of experts in the eld able to provide immediate support if required. The dosing with catheters in the postoperative phase resembles treatment, which is current standard practice in peripheral nerve blocks and postoperative epidural analgesia.
Criteria for discontinuing or modifying allocated interventions {11b} We will exclude patients to participate in the study in case of failure of primary insertion of the ESP or TEA catheter. This will be documented as technical failure. (Table 1) Secondary failures, such as catheter dislodgement, migration or leakage leading to premature removal of the catheter will be documented.
Need for rescue medication and need for specialist intervention will also be reported. When the surgical technique changes intra operatively, e.g. conversion to open procedure, the patient will be replaced and will not be used in the intention to treat analysis. The APS team will visit the patient daily and adjust the analgesic regimen as described above to manage inadequate analgesia. They will systematically screen for side effects, failure of analgesic technique, need for rescue medication and need for specialist intervention.

Relevant concomitant care permitted or prohibited during the trial {11d}
Postoperative pain strategy is outlined in the study protocol. Concomitted care of any other kind is permitted during the trial, if necessary.
Provisions for post-trial care {30} The sponsor/investigator has liability insurance, which is in accordance with article 7 of the WMO. This insurance provides cover for damage to research subjects through injury or death caused by the study.

Outcomes {12}
Primary endpoint The primary outcome in this study is the Quality of Recovery-15 (QoR-15) score. This score is a compound measure of overall postoperative patient recovery. The score comprises a 15-item questionnaire that provides an evaluation across ve dimensions: patient support, comfort, emotions, physical independence and pain. The questionnaire has been validated extensively and a minimal clinically important difference has been de ned. intervention (e.g., epidural hematoma and abscess or local anesthetic toxicity), duration of bladder catheterization, time of rst assisted mobilization (>20 meters and to sitting in a chair).

Other study parameters
Upon inclusion we will collect gender, age, weight, height, American Society of Anesthesiologists (ASA) risk score, type of surgery, opioids in home medication

Participant timeline {13}
Patients will be asked to enroll in the study during the preoperative anesthesiology consultation. They will be randomized in an ESP group and a TEA group. A baseline assessment of the QoR-15 upon inclusion will be done. Patients will undergo placement of TEA of ESP catheter just prior to surgery on the preoperative ward in the pre-anesthesia room. After surgery, on the recovery ward or ICU, the NRS score will be taken by the recovery nurse or ICU nurse. Pain medication will be given, according to this protocol. Patients will receive a daily visit by the acute pain service (APS) team until they can be converted to oral analgesics: paracetamol, NSAID and oxycodon. Patients will be followed until POD2 or until (earlier) discharge from the hospital. A owchart of the study design is presented in gure 1.

Recruitment {15}
Patients will be asked to participate in the study during the preoperative anesthesiology consultation.

Sequence generation {16a}
In this open label study, patients will be randomly allocated in a 1:1 ratio to receive either an ESP block (study group) or a TEA block (control group) by using a predetermined computer-generated randomized schedule. Only the investigators will have access to this list. Permutated block randomization with varying permuted block sizes will be used to divide the lobectomy and wedge resections in homogenous strata to manage for any surgical variation. Separate randomization lists will be used for the two hospitals, to reduce bias. This blocked randomization list will be created with Sealed EnvelopeTM software.

Concealment mechanism {16b}
Participants will be randomised using Research Manager, My Data Manager which is an online, central randomisation service within the program Research Manager. Allocation concealment will be ensured, as the service will not release the randomisation code until the patient has been recruited into the trial, which takes place after all baseline measurements have been completed.

Implementation {16c}
The person who will generate the allocation sequence is not involved in the study. The attending anesthesiologist on the preoperative anesthesiology clinic will enroll participants. The researchers will assign participants to interventions, according to the randomization.

Assignment of interventions: Blinding
Who will be blinded {17a} Blinding of the trial participants and study personnel engaged in patient care to group allocation is not possible due to the different clinical characteristics and invasive nature of the two study interventions.
Statistical analysis will be performed by a third-party who is not otherwise involved in the conduct of the study; they will be fully blinded to the hypothesis of the study and to the group allocation.

Procedure for unblinding if needed {17b} N/A Data collection and management
Plans for assessment and collection of outcomes {18a} Patients' demographical data will be collected upon inclusion assessment during the preoperative anesthesiology consultation. The attending anesthesiologist will collect data with regard to the anesthesia and surgical procedure. Nurses will collect the data at the Post Anesthesia Care Unit (PACU).
The APS team will collect QoR15 scores, opioid consumption, NRS scores and adverse events. The amount and frequency of the opioid usage will be extracted out of the PCA pump. NRS scores and additional administration of analgesia will be extracted out of the medical chart of the patient as collected by the nurses at the ward. Complications will be assessed on POD 2 or earlier at discharge. Some of the data will be registered on paper. After termination of the trial, the data will be directly registered in the software program My Research Manager.

Plans to promote participant retention and complete follow-up {18b}
To reduce non-retention, the APS team will stimulate the participants to complete the questionnaires.
Also, most data except for the questionnaires is registered on a regular basis for all patients who have epidural analgesia, therefore this limits registration burden and prevents missing data.
Non-adherence to protocol is described in the lower section on page 8 'Criteria for discontinuing or modifying allocated interventions {11b}'. All non-adherence will be documented and reported.

Data management {19}
The Monitoring team of the Catharina Hospital Eindhoven will provide the monitoring and quality assurance of this study. Data entry, coding and storage will be done according to GCP-standards.
Publication of data will be done anonymously.

Con dentiality {27}
The data of each patient will be noted on an individual case report form. Data will be coded using a numerical code, the key to this code is only available to the research team and is stored in the investigator site le in accordance with the Dutch law 'Algemene Vordering Gegevensbescherming (AVG; Personal Data Protection Act) and GCP. All patient data will be handled con dentially and anonymously. Data will then be inserted into a database (GCP validated), and a second investigator will control correctness of entries. All data, including case report forms and consent forms, will be stored for fteen years after completion of the study. Data, both anonymous or not, will always be stored securely, in a locked cabinet (hard copy) or on password secured computers Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} N/A, biological specimens are not used in this study.

Statistical methods
Statistical methods for primary and secondary outcomes {20a} All statistical analyses will be done in consultation with a senior statistician. The primary analysis will be an intention to treat analysis. Secondary analyses will include a per protocol analysis to identify any protocol deviations or other safety signals. Continuous data will be presented as mean and standard deviation or median and interquartile range. Normality of distributions for continuous variables will be assessed with skewness and kurtosis measures. Continuous data will be assessed using a Student's t-test if they are normally distributed or a Mann Whitney U test if otherwise. Dichotomous data will be presented in percentages. Categorical data will be analyzed using a Chi-square test or Fisher exact test.
Primary study parameter(s) We will compare the (mean) score of QoR15 of each day separately between the standard and the intervention group using the Student's t-test. Repeated-measures analysis will be used to assess changes over time in the study parameters.
Secondary study parameter(s) Continuous data (postoperative morphine-equivalent consumption per day, postoperative NRS score on POD 1 and 2; length of hospital stay, requirement of rescue medication, failure of anesthetic technique, total operative time, complications related to surgery or pain treatment, duration of bladder catheterization, rst assisted mobilization to chair and >20meters, 30 day postsurgical evaluation) will be assessed using a Student's t-test if they are normally distributed or a Mann Whitney U test if otherwise.
Categorical data (e.g., gender) will be analyzed using a Chi-square test or Fisher exact test. The mean difference between the two groups will be presented together with the 95% con dence interval.

Interim analyses {21b}
An interim-analysis will be performed after randomization of 50% of the patients. This analysis will be performed by the Education and Research team of our hospital, more speci cally a professional in statistical analysis, who is not engaged in the anesthesiology practice or with our (study) patients.
Criteria for terminating the study prematurely are indicators of insu cient patient comfort and are de ned as mean NRS>6 of all patients during more than 2 consecutive measurements in the study group in the rst 24 hours or mean QoR15 <83 in the study group on POD2.
Methods for additional analyses (e.g. subgroup analyses) {20b} N/A Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Primary analysis will be an intention to treat analysis. Secondary analysis will include a per protocol analysis. Within the 7% drop out safety buffer, there will be no replacement of study patients. A drop out is de ned as a patient not completing the full duration of the study. When the surgical technique changes intra operatively, e.g. conversion to open procedure, the patient will be replaced and will not be used in the intention to treat analysis.
There will be no follow-up of patients withdrawn from the treatment if they withdrawal before at least the QoR15 score on POD1 is registered. In that case, the patient will be replaced after we exceeded the 7% withdrawal safety buffer. Data of the dropouts with a QoR15 score on POD1 will be used in the intention to treat analysis.
Plans to give access to the full protocol, participant level-data and statistical code {31c} The datasets generated during and/or analyzed during the current study will be made available from the corresponding author on reasonable request and will only be accessible to personnel involved in the trial.
Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} The Catharina Hospital is the coordinating centre. Arthur Bouwman is lead investigator. Renee van den Broek is the main researcher at the Catharina Hospital, Seppe Koopman is the main researcher at the Maasstad Hospital. They are responsible for identi cation, recruitment, data collection and completion of CRFs, along with follow up of study patients and adherence to study protocol. A senior statistician will be consulted for statistical analysis. All protocol contributors will draft and/or revise the manuscript.
Composition of the data monitoring committee, its role and reporting structure {21a} The Monitoring team of the Catharina Hospital Eindhoven will provide the monitoring and quality assurance of this study. The monitor for this study is Sylvie

Adverse event reporting and harms {22}
In accordance to section 10, subsection 4, of the WMO, the sponsor (in this investigator-initiated study, the investigator) will suspend the study if there is su cient ground that continuation of the study will jeopardize subject health or safety. The investigator will notify the accredited MREC (Medical Research Ethics Committee) without undue delay of a temporary halt including the reason for such an action. The study will be suspended pending a further positive decision by the accredited MREC. The investigator will take care that all subjects are kept informed.
Adverse events are de ned as any undesirable experience occurring to a subject during the study, whether or not considered related to the trial procedure. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded.
A serious adverse event is any untoward medical occurrence or effect that results in death; is life threatening (at the time of the event); -requires hospitalization or prolongation of existing inpatients' hospitalization; -results in persistent or signi cant disability or incapacity; is a congenital anomaly or birth defect; or any other important medical event that did not result in any of the outcomes listed above due to medical or surgical intervention but could have been based upon appropriate judgment by the investigator.
An elective hospital admission will not be considered as a serious adverse event.
The investigator will report all SAEs to the sponsor without undue delay after obtaining knowledge of the events, except for the following SAEs: surgical or other complications unrelated to the anesthetic procedure.
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited MREC that approved the protocol, within 7 days of rst knowledge for SAEs that result in death or are life threatening followed by a period of maximum of 8 days to complete the initial preliminary report. All other SAEs will be reported within a period of maximum 15 days after the sponsor has rst knowledge of the serious adverse events.
Follow-up of adverse events All AEs will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. SAEs need to be reported till end of study within the Netherlands, as de ned in the protocol Frequency and plans for auditing trial conduct {23} The Monitoring team of the Catharina Hospital Eindhoven will provide the monitoring and quality assurance of this study. The monitor will perform an initiation visit and will audit the overall quality and completeness of the data, examine source documents and con rm that the clinical centers have complied with the requirements of the protocol. The monitor will verify that all adverse events were documented in the correct format, and are consistent with protocol de nition.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, Amendments are changes made to the research protocol after a favorable opinion by the accredited ethics committee. All amendments will be noti ed to the ethics committee.

Dissemination plans {31a}
The trial's results will be submitted to a peer-reviewed journal regardless of the outcome.

Discussion
Although the ESP block is gaining popularity as analgesia in thoracic surgery, there has been limited study of its clinical e cacy compared with the current gold standard of thoracic epidural analgesia (TEA). However, these preliminary results are promising. (2)(3)(4)(26)(27)(28) This prompted us to speculate that ESP block may have a similar analgesic pro le to TEA, and in turn to conduct a trial to compare these two techniques and further validate the theory from a clinical aspect.
The expected results will provide clinical evidence to verify the analgesic mechanism of ESP and promote its application in minimally invasive thoracic surgery. Furthermore, if the e cacy of ESP is equal to that of TEA, ESP could replace TEA in minimally-invasive thoracic surgery because it is relatively safe and convenient to perform, while TEA carries risks of failure, dural puncture and epidural abscess or hematoma. (14,20,21,29) Furthermore, unlike TEA, ESP does not require routine urinary catheterization to manage urinary retention and thus facilitates the early mobilization of the patient after surgery.
The proposed trial is a prospective, randomized trial with rigorous methodology to avoid potential risk of bias. Since the nature of the intervention makes it impossible for the participant, the investigator performing the block, and the outcome assessor to be blinded, only the statistician will be blinded to the allocation to keep the data analysis unbiased.
In contrast to epidural analgesia, ESP analgesia can only induce a unilateral sensory block of thoracic dermatomes. Nonetheless, this unilateral thoracic block is expected to achieve adequate control of chest pain after minimally invasive thoracic surgery, especially when combined with patient-controlled intravenous opioid analgesia as an escape for breakthrough discomfort. (3)(4)(5) If ESP analgesia in fact achieves adequate pain control, the avoidance of epidural-related side-effects likely facilitates fast recovery after minimally invasive thoracic surgery, which is the primary interest of this study. Since postoperative recovery is multifactorial, a composite endpoint was considered to be most appropriate and therefore the QoR-15 questionnaire was chosen as primary outcome. The QoR-15 consists of 15 questions that are divided in separate sections that aim to evaluate the presence and extent of pain, symptoms, comfort, emotional well-being, physical independence, and satisfaction with treatment. (30) As the hypothesized advantages of ESP analgesia are expected to impact several of these sections, the composite QoR-15 score is considered to be a good parameter for postoperative recovery.
Our evaluation through the QoR15 score matches the call for more patient-centered outcomes in ESP block studies. (15,31) The reduction in pain scores itself may not equate to an improvement in patients experience. Factors other than only analgesia, such as general well-being, nausea, itching, being able to get out of bed, appetite and the need for a bladder catheter also matter in the patients' perspective on good recovery, and contribute to enhanced recovery and earlier hospital discharge.
If our trial yields positive results, there is potential that ESP could be recommended as an alternative block for postoperative analgesia in minimally invasive thoracic surgery, to circumvent the need for TEA.

Trial Status
This document is based on version 5 of the original protocol, approved by the MET-U (ethics committee) on 26 th February 2020, registration number R18.022. We anticipate randomizing the rst patient in July 2020 and plan to complete the study in December 2021.   Figure 1 Schedule of enrolment, interventions, and assessments.

Figure 2
Flow chart of the study design.