Laparoscopically guided transversus abdominis plane block versus local wound analgesia in laparoscopic surgery for peritoneal endometriosis: study protocol for a prospective randomized controlled double-blinded LTAP-trial

Data will be collected prospectively on an electronic SPSS-database designed for this study. Validated questionnaires (NRS and EHP-30) will be used at the baseline and for collecting outcome data concerning postoperative pain and 6-month follow-up. These are filled in on paper questionnaires by the patients and transferred into SPSS database by two authors who double-check each other’s work. Any trial participant lost to follow-up will be contacted in order to complete the 6-month follow-up. All data will be handled with utmost care and confidentiality. Data will be stored electronically with passwords and any manual data will be stored behind locked doors in the department. Data entry is possible only for the authoring investigators. The unique personal ID codes given by the Finnish government at birth or immigration will be used to link data originated at different phases of the study. For analyses, only pseudonymized data will be handled, using ID codes generated for this study. A separate key file connecting the unique personal ID codes and the study ID codes will be created and stored in hospital server where only primary investigators (AT, SK) have access. Not applicable. No biological specimens will be collected.

This is the protocol number one. The recruitment will begin in April 2021 and will be completed by the end of 2022.

Not applicable. This study is a single-center clinical trial with a short follow-up time and low risks for the participating patients. No data monitoring committee will be needed for this single-center study. Possible adverse events and other unintended effects of the trial will be documented on trial data and medical records. All significant adverse events will be listed specifically. Lethal or severe adverse events will be reported to the Finnish Medicines Agency (Fimea) as soon as possible or within 7 days from getting informed of the adverse event. All suspected severe adverse events and a statement regarding the safety of the trial participants will be reported to Fimea once a year. Any significant novel perceptions of the medicinal product will be reported to Fimea immediately. In case of possible future protocol modifications, The Ethical Committee at Oulu University Hospital as well as Fimea will be informed. The trial results will be published in international peer-reviewed journals focusing on the investigatory field in question.

Trial participants, surgeons, and the anesthesiologist will be blinded to interventions. All participants will be administered both LTAP and local wound injections (analgesic and placebo) as described earlier. The injectable analgesics will be prepared by the OR nurse and the anesthetic nurse, who also open the sealed envelopes. The needles, the syringes, and the injectable amounts are the same in both groups. In case of a severe allergic reaction after levobupivacaine infiltration, unblinding will be performed in order to reveal the exact dosage of levobupivacaine administered.

The purpose of this study is to evaluate the efficacy and safety of laparoscopically guided transversus abdominis plane block (LTAP) in comparison to trocar site local analgesia in laparoscopic surgery for suspected or diagnosed superficial endometriosis. Previously, it has been shown that women with chronic pelvic pain or endometriosis have altered pain experience in form of lower pressure-pain threshold and lower maximal pain tolerance than controls, widespread myofascial dysfunction and pain sensitization beyond the pelvic area [ 17 – 19 ]. Additionally, severe dysmenorrhea, a leading symptom of endometriosis, has been noted to predict the severity of postoperative pain after gynecological laparoscopy [ 3 ]. Thus, there is a need for effective postoperative pain management regimen with minimal side effects allowing ERAS. So far, knowledge on LTAP in gynecologic surgery is sparse and inconsistent [ 12 – 14 ]. However, data from gastrointestinal surgery, mainly from laparoscopic cholecystectomies, have shown promising results after using LTAP in postoperative analgesia [ 7 , 8 , 11 ]. This study will offer knowledge on whether LTAP is an efficient tool for postoperative pain management for gynecological patients that would carry minimal risks and diminish postoperative opioid consumption as well as support enhanced recovery and discharge.

Statistical analyses will be performed on an intention-to-treat basis using IBM SPSS software by the study statistician who does not participate in patient care or data collection. Continuous variables will be described as mean with standard deviation (SD) or as median with 25th–75th percentiles and categorical variables as numbers and percentage of proportions. Comparison between the study groups will be conducted using the Student’s t -test or Welch test for continuous variables, Mann-Whitney U test for variables measured at ordinal scale, and the chi-square or Fisher’s test for categorical variables. Furthermore, continuous variables with measurements both pre- and postoperatively will be analyzed using linear regression model with preoperative measurement as an adjusting factor. The statistical significance limit is set at two-sided p -value < 0.05. No interim analyses will be performed. No preplanned subgroup analyses will be performed. Per-protocol analyses will be performed as sensitivity analyses when protocol violations occur. In the case of missing data, a multiple imputation (MI) method will be used. If the results of the MI analysis differ from the original, then both results will be presented. In the case of an arbitrary missing case pattern, the fully conditional specification will be used as an imputation method. In the case of a monotone missing case pattern, the regression imputation will be used. Health data is sensitive data and cannot be delivered even if pseudonymized. Statistical code and output may be presented if asked.

Endometriosis is a chronic disease affecting about 10% of women during their fertile years. Patients often suffer from chronic pelvic pain that decreases markedly their quality of life. Conservative hormonal medication, being the primary treatment option, is often insufficient due to persisting pain, contraindications, or side-effects such as irregular bleeding. Hence, there is also need for surgical treatment of peritoneal endometriosis [ 1 ]. Clinical observations have shown that patients with endometriosis tend to suffer from more severe postoperative pain after pelvic surgery than other patients [ 2 ]. This may be due to hypersensitization of sensory pelvic nerves, which is caused by the inflammatory nature of endometriosis. Dysmenorrhea, which is the leading symptom of endometriosis, is a prognostic factor for the severity of postoperative pain [ 3 ]. The use of epidural or local wound analgesia after endometriosis surgery has been common practice. However, local wound analgesia is often insufficient for endometriosis patients, who tend to suffer from more severe postoperative pain [ 2 ]. Epidural analgesia carries a risk of potentially harmful complications and may also prohibit enhanced recovery after surgery (ERAS) and prolong time to discharge. In addition, postoperative opioid consumption also predisposes to complications such as nausea, vomiting, and respiratory depression. Dorsally inserted transversus abdominis plane block (TAP) has been used as a part of multimodal analgesia in abdominal surgery since the beginning of twenty-first century [ 4 ]. TAP blocks the sensory nerves of the abdominal wall unilaterally between the costal margin and the inguinal ligament (T6–L1), and it provides analgesia to the parietal peritoneum, muscles, and abdominal skin accordingly [ 5 ]. When inserted in a blind fashion, it carries a risk of visceral injury. To avoid complications, ultrasound-guided transversus abdominis plane block technique (UTAP) was adopted by anesthesiologists. Both methods have been shown to serve as an effective postoperative analgesia reducing postoperative opioid consumption and opioid-related side effects after open and laparoscopic abdominal surgery [ 6 ]. Laparoscopically inserted transversus abdominis plane block (LTAP) is a novel technique that has been used by gastrointestinal surgeons, especially in laparoscopic cholecystectomies and colorectal surgery [ 7 , 8 ] with equally good results in comparison to UTAP [ 9 ]. According to a recent meta-analysis, LTAP is safe and superior to local wound analgesia in adults undergoing minimally invasive surgery (such as laparoscopic or robotic abdominal procedures) regarding early pain control, opioid consumption, and patient satisfaction [ 10 ]. In another study, a reduction in postoperative pain score measured by visual analog scale was noted even at 1 week after laparoscopic cholecystectomy with LTAP in comparison to local wound analgesia [ 11 ]. LTAP has been suggested to reduce postoperative pain and opioid need in gynecologic and endometriosis laparoscopic surgery, but the results of previously published studies have been inconsistent [ 12 – 14 ]. The purpose of this study is to investigate whether LTAP provides a post-laparoscopic opioid-sparing effect in comparison to local wound analgesia, thus diminishing opioid related side-effects and improving ERAS. The objective of this prospective, randomized, controlled, double-blinded study is to examine whether LTAP is superior, i.e., reduces the postoperative opioid consumption compared to local wound analgesia in treating post-laparoscopic pain in patients suffering from pelvic pain because of suspected endometriosis.

Local wound infiltration with levobupivacaine has been the most commonly used mode of postoperative analgesia in laparoscopic surgery in our clinic. To explore the possibilities of improving the efficacy of postoperative pain management after peritoneal endometriosis surgery, we decided to choose LTAP with levobupivacaine as a comparator. Administration of LTAP has a fast learning curve and it does not increase the operative time markedly. After giving informed consent, study participants will fill in preoperative validated questionnaires regarding pain (Numeric Rating Scale, NRS) and endometriosis-related health (Endometriosis Health Profile, EHP-30). Total intravenous anesthesia will be administered to both groups in a standardized fashion using propofole and remifentanil infusions. No inhalation anesthetics will be used. Dexamethasone 5 mg iv will be administered for the prevention of postoperative nausea and vomiting (PONV). Operating room (OR) nurse will randomize participants to intervention or control group with an allocation ratio of 1:1 by fetching a sealed opaque numbered envelope from the office of the operating ward. The envelope will be opened and sealed again and the levobupivacaine and saline will be prepared in identical looking syringes according to allocation before the operating surgeon enters the OR. The LTAP and local wound analgesia will both be administered at the beginning of the operation under laparoscopic vision by the surgeon. LTAP will be infiltrated bilaterally at the upper and lower quadrants between front axillary and mid-clavicular lines in the depth reaching the space between transverse abdominal and internal oblique muscles. Local wound infiltration will be administered to all trocar sites prior to incision. The study group will be given LTAP with 20 ml levobupivacaine 2.5 mg/ml bilaterally and local wound infiltration with saline 10 ml in total as placebo. The control group will be administered with saline 20 ml bilaterally as placebo to the sites corresponding LTAP and local wound infiltration with levobupivacaine 5 mg/ml 10 ml in total. Standard surgical care according to our protocol in laparoscopic surgery of suspected peritoneal endometriosis will be given. Peritoneal endometriosis implants will be resected using a monopolar hook. Bipolar energy instrument may be used to ensure hemostasis where needed. At the end of the procedure, 50 mg of dexketoprofen iv and fentanyl 0.5 μg/kg iv will be administered as remifentanil infusion is discontinued. As the patient arrives in the recovery room, a PCA pump (Delta Legacy iv) will be started with oxycodone 3 mg/ml with 1.5 mg boluses maximum of 4 per hour. Iv oxycodone may be administered in addition to the PCA-pump as a rescue analgesia. Paracetamol 1 g × 3 po and ibuprofen 600 mg × 3 po are started. Early mobilization and other ERAS protocols will be implemented. Not applicable. Allocation and allocated intervention are done minutes apart on anesthetized patients, so no need for modification is expected. The preoperative data as well as the outcome measure data during the hospital stay will be collected by the hospital staff. The study participants that have not returned the 6-month questionnaires will be contacted by the investigators to improve the response rate using their contact details (address, phone number) that can routinely be found in the clinical patient notes in Finland. Treatment of the patient will be conducted by standard care protocols regardless of the trial participation. Ancillary and post-trial care including the care of possible complications will be given according to standard medical practice irrespective to the trial itself. Every patient receiving medical or surgical care in Finland is covered by the Finnish Patient Insurance Centre. Possible complications caused by the study interventions are compensated via the center. Primary outcome is the overall 24 h postoperative opioid consumption compared between the study groups. The amount of oxycodone administered via the PCA-pump and possible rescue analgesics (oxycodone administered in addition to the PCA-pump) will be converted to morphine equivalents. As secondary outcomes, the following will be measured: Postoperative pain using NRS scaled from 0 to 10 (0 meaning no pain and 10 meaning “worst imaginable pain”). The maximum experienced pain will be recorded at the recovery room. Additional NRS will be recorded at the ward every six hours up to 24 h (if the patient is discharged before 24 h, they are requested to fill in the NRS at home). Factors related to ERAS (nausea, vomiting, peroral intake, mobilization, complications, time of discharge, readmission to hospital) will serve as other outcomes and will be documented and analyzed accordingly. A 6-month postoperative follow-up will be conducted using NRS pain inquiry and EHP-30 questionnaire being sent to participants. Postoperative pain using NRS scaled from 0 to 10 (0 meaning no pain and 10 meaning “worst imaginable pain”). The maximum experienced pain will be recorded at the recovery room. Additional NRS will be recorded at the ward every six hours up to 24 h (if the patient is discharged before 24 h, they are requested to fill in the NRS at home). Factors related to ERAS (nausea, vomiting, peroral intake, mobilization, complications, time of discharge, readmission to hospital) will serve as other outcomes and will be documented and analyzed accordingly. A 6-month postoperative follow-up will be conducted using NRS pain inquiry and EHP-30 questionnaire being sent to participants. Sample size was calculated based on the assumption that LTAP would decrease the postoperative opioid consumption by 50%, which was thought to be a clinically relevant difference. The calculation was based on previous literature showing a 15.4 mg ± 9.2 postoperative opioid consumption after local wound analgesia [ 15 ]. With 80% power and 0.05 alpha error, the sample size of 46 (23 + 23) was obtained to detect a decrease of 7.7 mg in opioid consumption from 15.4 mg in the control group to 7.7 mg in the intervention group, assuming a standard deviation of 9.2 mg. Sample size was calculated according to Chow et al. [ 16 ], and the calculation was performed with statistical program R. All eligible patients referred to gynecological outpatient clinic at the Oulu University Hospital with diagnosed or suspected peritoneal endometriosis needing laparoscopic evaluation or surgery because of insufficient response to medical management will be considered as potential trial participants. After receiving thorough information on the study protocol including possible advantages and disadvantages, and after voluntary signing of the informed consent, the trial participants will be enrolled to the LTAP-trial.

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/ ). Title {1} Laparoscopically guided transversus abdominis plane block versus local wound analgesia in laparoscopic peritoneal endometriosis surgery: a prospective, randomized, double-blinded LTAP-trial Trial registration {2a and 2b}. ClinicalTrials.gov , ID: NCT04735770 . Prospectively registered, February 2021. European Union Drug Regulating Authorities Clinical Trials Database: Eudra-CT 2020-004353-80. Registered 2020. Protocol version {3} March 9, 2021, version 1. Funding {4} No external funding. Author details {5a} MD, Anna Terho, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland MD, Terhi Puhto, Oulu University Hospital and Research unit of Surgery, Anesthesia and Intensive care, University of Oulu, PL 21, 90029 OYS, Finland MD, Johanna Laru, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland MD, PhD, Outi Uimari, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland Pasi Ohtonen, Division of Operative Care, Oulu University Hospital and Research unit of Surgery, Anesthesia and Intensive care, University of Oulu, PL 21, 90029 OYS, Finland Professor (a recent nomination), Tero Rautio, Oulu University Hospital and Research unit of Surgery, Anesthesia and Intensive care, University of Oulu, PL 21, 90029 OYS, Finland MD, PhD, Sari Koivurova, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland Name and contact information for the trial sponsor {5b} Oulu University Hospital and University of Oulu. Principal Investigator Dr. Sari Koivurova, M.D., Ph.D. Address: PL 24, 90029 OYS, Oulu, Finland Email: [email protected] Tel: +358 8 3153082 Role of sponsor {5c} This is a researcher-driven study carried out in Oulu University Hospital, with no outside sponsor or funding. The Principal Investigator is actively involved in planning and executing of the study. MD, Anna Terho, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland MD, Terhi Puhto, Oulu University Hospital and Research unit of Surgery, Anesthesia and Intensive care, University of Oulu, PL 21, 90029 OYS, Finland MD, Johanna Laru, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland MD, PhD, Outi Uimari, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland Pasi Ohtonen, Division of Operative Care, Oulu University Hospital and Research unit of Surgery, Anesthesia and Intensive care, University of Oulu, PL 21, 90029 OYS, Finland Professor (a recent nomination), Tero Rautio, Oulu University Hospital and Research unit of Surgery, Anesthesia and Intensive care, University of Oulu, PL 21, 90029 OYS, Finland MD, PhD, Sari Koivurova, Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center, University of Oulu, Oulu, Finland Oulu University Hospital and University of Oulu. Principal Investigator Dr. Sari Koivurova, M.D., Ph.D. Address: PL 24, 90029 OYS, Oulu, Finland Email: [email protected] Tel: +358 8 3153082

This is a prospective, randomized, controlled, double-blinded clinical study evaluating the effectiveness and safety of LTAP compared to local wound analgesia in laparoscopic gynecological surgery for superficial peritoneal endometriosis. Randomization at patient level is done with an allocation ratio of 1:1. The active LTAP group will receive a long-acting local anesthetic, levobupivacaine, administered at LTAP points and saline infiltrated at the sites of laparoscopic ports. The control group will receive saline at LTAP points and levobupivacaine at the sites of laparoscopic ports. The patient and the surgeon remain blinded to the allocated group until the end of the study data collection. The aim of this study is to explore whether LTAP is superior, i.e., offers opioid-sparing effect when compared to local wound analgesia in postoperative pain after laparoscopic gynecological surgery for peritoneal endometriosis. The power calculation for this study was based on 50% reduction in the consumption of opioids during the postoperative period, which we estimated to be clinically relevant. The study protocol flow chart and time of collection of outcomes are described in Figs. 1 and 2 , respectively. Fig. 1 Flow chart describing the study protocol Fig. 2 Time of collection of outcomes Flow chart describing the study protocol Time of collection of outcomes This is a single-center trial located in a tertiary university hospital in Finland. The inclusion criteria are as follows: Age 18–50 years Diagnosed or suspected peritoneal endometriosis and laparoscopic surgery indicated ASA 1–3 Age 18–50 years Diagnosed or suspected peritoneal endometriosis and laparoscopic surgery indicated ASA 1–3 The exclusion criteria: Sleep apnea ASA > 3 Contraindications to opioids or non-steroidal anti-inflammatory drugs Continuous opioid intake preoperatively Sleep apnea ASA > 3 Contraindications to opioids or non-steroidal anti-inflammatory drugs Continuous opioid intake preoperatively The laparoscopies and LTAP administration will be performed by two experienced laparoscopists, who work within a multi-professional team focusing on endometriosis surgery in a tertiary hospital setting. Informed consent will be obtained during the preoperative clinical review at the outpatient clinic by the operating gynecologist. Not applicable. No biological specimens will be collected.