This randomized, single-blind clinical trial of patients scheduled to undergo elective gynecological laparoscopy will use concealed allocation. The patients will be allocated to receive either OFA (dexmedetomidine and lidocaine) or a standard anesthesia protocol (remifentanil). This study will be conducted at Seoul St. Mary’s Hospital, Catholic University Medical College, South Korea. Figure 1 and 2 provide an overview of the study schedule, which was designed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.
The inclusion criteria for this study are as follows: adults (aged 20–65 years) scheduled for elective gynecological laparoscopy including hysterectomy, uterus myomectomy, oophorectomy, salpingectomy, cyst enucleation, and cystectomy. Postoperative IV patient-controlled analgesia (PCA) will be applied in all the patients. The exclusion criteria are refusal to participate in the study, emergent surgery, cancer surgery, chronic pain requiring a pain killer, psychiatric disease, preoperative bradycardia (heart rate [HR] < 50 bpm), hypotension, atrioventricular block, intraventricular or sinoatrial block, body mass index > 35 kg/m2, allergy or history of adverse events to study drug, pregnancy, or lactation.
Randomization and blinding
The enrolled participants will be randomized to one of two groups (study or control group). The block randomization scheme will be generated using a web-based random number generator (at www.random.org) by a research nurse. Participants will be randomized to receive OFA or standard general anesthesia at a 1:1 allocation ratio using stratified block randomization with a fixed block size. Once a patient has been enrolled, the medical staff will open an opaque, sequentially numbered envelope containing the group allocation.
The participants and surgeons will be kept blinded to the group allocation throughout the study period. The medical staff providing postoperative care and evaluating outcomes in the post-anesthesia care unit (PACU) and the ward will also be unaware of the group allocation. The anesthesiologists performing general anesthesia will be the only unblinded staff. However, they will not participate in the postoperative care or assessment of postoperative outcomes.
This study has two arms (Figure 2). Both arms include general anesthesia for gynecological laparoscopy and postoperative care, according to clinical practice guidelines. Before starting the study, the participants will be instructed in how to assess their pain intensity using a visual analog scale (VAS; 0 cm = no pain, 10 cm = worst pain imaginable), and how to use IV PCA. To improve adherence to the protocol, participants will be asked to request analgesia without hesitation if the VAS pain score is > 4.
None of the patients will receive premedication. Electrocardiography, non-invasive blood pressure measurements, pulse oximetry, neuromuscular monitoring using train-of-four (TOF) stimulation, bispectral index (BIS VISTA Monitoring System; Aspect Medical Systems, Inc., Norwood, MA, US) monitoring of anesthesia depth, and surgical pleth index (SPI: General Electric Healthcare, Helsinki, Finland) measurements of nociception will be applied in the operating room. General anesthesia will be induced with 1.5–2 mg/kg IV propofol. After unconsciousness is confirmed (BIS value < 60), absence of an eyelash reflex, and no response to verbal stimulation, 0.8 mg/kg rocuronium will be injected and orotracheal intubation will be performed using a direct laryngoscope when there are zero TOF twitches. Ventilation will be controlled mechanically and then adjusted to maintain the end-tidal CO2 value at 25–40 mmHg throughout the surgery. Additional rocuronium will be administered as required. Anesthesia will be maintained with 4–6% desflurane (expired concentration) in 40% air/oxygen (total flow, 4 L/min) to maintain the BIS at 30–60. Ephedrine (4 mg IV) will be injected in the cases with systolic blood pressure (SBP) < 80 mmHg or mean arterial pressure (MAP) < 60 mmHg. If the HR decreases to < 45 bpm, atropine (0.25 mg IV) will be administered.
All the enrolled the patients will be allocated to one of the following two groups; Study group (OFA using dexmedetomidine and lidocaine) and Control group (standard general anesthesia using remifentanil).
The study group will receive dexmedetomidine 0.7 µg/kg IV for 10 min before the propofol injection. Immediately after inducing anesthesia, a 1.5 mg/kg IV lidocaine bolus will be injected followed by a 1.5 mg/kg/h infusion. The dexmedetomidine infusion will be started at 0.5 µg/kg/h and adjusted in steps of 0.1 µg/kg/h to maintain the SBP baseline within ± 20%. The dexmedetomidine and lidocaine infusion will be stopped when skin suturing begins.
The control group will receive 3.5 ng/ml remifentanil using a target-controlled infusion (Orchestra Base Primea, Fresenius Vial, Brezins, France) before the propofol injection. After inducing anesthesia, the remifentanil infusion will be adjusted in increments of 0.5 ng/ml to maintain the SBP baseline within ± 20%. The remifentanil infusion will be stopped at the end of skin suturing.
The laparoscopy will be performed under video guidance with three punctures in the abdomen. Intraperitoneal pressure will be maintained at about 12 mmHg. All patients will receive 5 mg dexamethasone at the start, and palonosetron 75 µg at the end, of surgery to prevent PONV. Acetaminophen (1 g via an IV drip) and ketorolac (30 mg IV) will be administered 30 min before the end of surgery for postoperative pain control. After confirming self-respiration, patients will be extubated and transferred to the PACU. If the patient complains of pain (VAS score > 4) in the PACU, fentanyl 0.5–1 µg/kg will be administered immediately. Once the acute pain is under control, IV PCA (fentanyl 15 µg/kg in 100 mL normal saline, basal rate 0 mL/h, bolus 1 mL, lock-out time 10 min) will be applied in all patients, and no loading dose will be administered. Metoclopramide 10 mg IV will be injected in cases of PONV. The patients will be discharged to the general ward when their Aldrete score is ≥ 9 .
The primary outcome is the quality of postoperative recovery according to the QoR-40 questionnaire scores on postoperative day (POD) 1. The QoR-40 questionnaire includes five dimensions of recovery: physical comfort (12 items), emotional state (9 items), physical independence (5 items), psychological support (7 items), and pain (7 items). Each item is scored on a 5-point Likert scale (none of the time, some of the time, usually, most of the time, and all of the time). The total score on the QoR-40 ranges from 40 (poorest possible recovery) to 200 (best possible recovery). The QoR-40 will be completed the day before surgery and on POD 1.
To determine whether OFA provides the same effects as remifentanil-used general anesthesia, such as hemodynamic stability and sedation, we will obtain intraoperative hemodynamic data (SBP, MAP, and HR), and anesthetic depth (BIS) and nociception severity (SPI) data, at baseline, before intubation (at the time of unconsciousness), immediately after intubation, at the time of the incision, and immediately after tracheal extubation. Additionally, to assess intraoperative complications, episodes of bradycardia (< 45 bpm) in association with administration of atropine, hypotension (SBP < 80 mmHg or MAP < 60 mmHg), hypertension (MAP > 90 mmHg), and shock (anaphylactic, septic, cardiac, or hemorrhagic) will be recorded.
Pain severity will be assessed using a VAS upon arrival in the PACU, and every 15 min thereafter. Additionally, sedation severity (none / sedated and responsive to verbal stimuli / sedated and unresponsive to verbal stimuli), the incidence of PONV and shivering, the requirement for analgesics and antiemetics, and the PACU stay will be assessed. These outcomes will be evaluated again 24 hours after surgery. Additionally, the time to first flatus or defecation will be recorded.
Ancillary cytokine study
To determine the potential involvement of OFA in neuroinflammation, an ancillary study will be performed in the 50 enrolled patients (n=25 in each group). Blood samples will be measured for cytokines at baseline, immediately after tracheal intubation, at the time of the incision, immediately after tracheal extubation, and 24 hours after surgery. The cytokines to be measured include pro-inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, and IL-6), an anti-inflammatory cytokine (IL-10), reactive oxygen species (ROS; manganese superoxide dismutase, matrix metalloproteinase [MMP]-9), and stress hormones (norepinephrine and epinephrine). All blood samples will be placed in tubes and centrifuged within 1 hour, and the plasma will be separated and stored at −70°C until analysis. All plasma specimens will be discarded after completion of the study.
The primary outcome is the QoR-40 score on POD 1. Based on a previous study that reported a 13-point difference in QoR-40 scores between different anesthetic techniques , a sample size of 34 was calculated to be as necessary to achieve a power of 80% with a type 1 error of 0.05. An additional 15% of participants is added to account for possible loss to follow-up. Thus, the final sample size will be 78 participants (39 in each group).
A researcher blinded to the group allocation will perform the statistical analysis of all randomized patients (intention-to-treat analysis) using SPSS for Windows software (ver. 18.0; SPSS Inc., Chicago, IL, USA). Data will be expressed as frequencies or percentages for categorical variables and means with standard deviations for quantitative variables. The Kolmogorov–Smirnov test will be used to check the normality of the distribution of the quantitative variables. Student’s t-test or the Mann–Whitney U test will be used to analyze quantitative variables, including the primary outcome. The chi-square or Fisher’s exact test will be used to analyze qualitative variables. Continuous endpoints repeatedly measured during the study period will be analyzed using repeated measures two-way analysis of variance. A P-value < 0.05 will be considered significant.
Analyses will be performed between groups as randomized. Participants who withdraw from the trial will be followed up, according to routine clinical practices. To reduce missing data in the intention-to-treat analysis, the investigator may ask the participants which specific aspects of the trial they want to withdraw from.
Missing data will be tested if they are missing at random; otherwise, the last observation carried forward method will be applied . A sensitivity analysis will also be performed to check for inconsistencies. A subgroup analysis will be performed to check for differences in outcomes according to the surgeon. No interim analyses are planned, and no serious adverse effects are expected to arise during the study, because the protocols have been used previously without any such effects [6, 7, 15].
Data collection and monitoring
Clinical data will be entered into paper-based case report forms. After each assessment, the identifiers (e.g., name and birth date) will be anonymized, coded, and stored on a secure server. The files will be backed up on a password-protected computer. Data will be handled according to Korean law.
The project team designed and prepared the trial, and will disseminate the results. The team will meet every month to discuss the progress of the study. A data monitoring committee, comprised of two independent professors (anesthesiologists) and a physician pharmacologist, will meet three times a year throughout the study. This committee is responsible for safeguarding the interests of the trial participants, assessing the safety of the interventions, and monitoring the overall conduct of the trial. Any deviation from the protocol will be documented in a report. All significant protocol modifications will be communicated to the relevant parties and updated in the trial register.
The results obtained from this study will be disseminated at anesthesia conferences (local and international meetings). The key findings will be reported in the trial registry. A full study report will be submitted for publication in an anesthesia journal, preferably an open-access journal.