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Procedural sedation and analgesia versus general anesthesia for hysteroscopic myomectomy (PROSECCO trial): A multicenter randomized controlled trial [1]
['Julia F. Van Der Meulen', 'Department Of Obstetrics', 'Gynecology', 'Máxima Medical Centre', 'Veldhoven', 'The Netherlands', 'Grow School For Oncology', 'Reproduction', 'Maastricht University Medical Centre', 'Maastricht']
Date: 2024-01
Noninferiority of PSA for completeness of resection was not shown, though there were no significant differences in clinical outcomes and quality of life. In this study, hysteroscopic myomectomy for type 0 and 1 fibroids with PSA compared to GA was safe and led to shorter hospitalization. These results can be used for counseling patients by gynecologists and anesthesiologists. Based on these findings, we suggest that hysteroscopic myomectomies can be performed under PSA in an outpatient setting.
Hysteroscopic resection was complete in 86/98 women (87.8%) in the PSA group and 79/89 women (88.8%) in the GA group (risk difference −1.01%; 95% confidence interval (CI) −10.36 to 8.34; noninferiority, P = 0.09). No serious anesthesiologic complications occurred, and conversion from PSA to GA was not required. During the follow-up period, 15 serious adverse events occurred (overnight admissions). All were unrelated to the intervention studied. Main limitations were the choice of primary outcome and the fact that our study proved to be underpowered.
A total of 209 women participated in the study and underwent hysteroscopic myomectomy with PSA (n = 106) or GA (n = 103). Mean age was 45.1 [SD 6.4] years in the PSA group versus 45.0 [7.7] years in the GA group. For 98/106 women in the PSA group and 89/103 women in the GA group, data were available for analysis of the primary outcome.
The risk difference between both treatment arms was estimated, and a Farrington–Manning test was used to determine the p-value for noninferiority (noninferiority margin 7.5% of incomplete resections). Data were analyzed according to the intention-to-treat principle, including a per-protocol analysis for the primary outcome.
Primary outcome was the percentage of complete resections, assessed on transvaginal ultrasonography 6 weeks postoperatively by a sonographer blinded for the treatment arm and surgical outcome. Secondary outcomes were the surgeon’s judgment of completeness of procedure, menstrual blood loss, uterine fibroid related and general quality of life, pain, recovery, hospitalization, complications, and surgical reinterventions. Follow-up period was 1 year.
This was a multicenter, randomized controlled noninferiority trial conducted in 14 university and teaching hospitals in the Netherlands between 2016 and 2021. Inclusion criteria were age ≥18 years, maximum number of 3 type 0 or 1 fibroids, maximum fibroid diameter 3.5 cm, American Society of Anesthesiologists class 1 or 2, and having sufficient knowledge of the Dutch or English language. Women with clotting disorders or with severe anemia (Hb < 5.0 mmol/L) were excluded. Women were randomized using block randomization with variable block sizes of 2, 4, and 6, between hysteroscopic myomectomy under procedural sedation and analgesia (PSA) with propofol or under general anesthesia (GA).
Hysteroscopic resection is the first-choice treatment for symptomatic type 0 and 1 fibroids. Traditionally, this was performed under general anesthesia. Over the last decade, surgical procedures are increasingly being performed in an outpatient setting under procedural sedation and analgesia. However, studies evaluating safety and effectiveness of hysteroscopic myomectomy under procedural sedation are lacking. This study aims to investigate whether hysteroscopic myomectomy under procedural sedation and analgesia with propofol is noninferior to hysteroscopic myomectomy under general anesthesia.
Competing interests: No support from any organization for the submitted work was received, apart from the grant that was received from The Dutch organisation for Health Research and Development (ZonMW), as described in our funding statement; HvV received fees from Medtronic on an hourly basis for consultancy and lecturing on hysteroscopic morcellation. All the fees were donated to a foundation which promotes research in obstetrics and gynecology. NS received fees from Applied Medical for vNOTES courses and proctorship. These industries were not involved in the design, performance, analysis of this study nor the content or approval of this manuscript. All other authors report no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; SC is a board member of the Dutch gynaecologic endoscopy working party ‘Werkgroep gynaecologische endoscopie’. All other authors report no other relationships or activities that could appear to have influenced the submitted work.
Funding: This study was funded by The Dutch organisation for Health Research and Development (ZonMW -
https://www.zonmw.nl/nl/ ), which is a governmental funding organisation. Grant number 843002603. This grant was awarded to MB, SC, HK, JvdM, CR, LO. Before receiving the grant this study protocol was peer-reviewed by ZonMW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright: © 2023 van der Meulen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
For gynecologic procedures, less literature on the use of PSA is available. A prospective cohort that was recently published showed that the performance of several therapeutic hysteroscopic procedures—including hysteroscopic myomectomy—is safe and feasible when performed under PSA with propofol: Complication rate and incompleteness rates were low, and the majority of patients was satisfied with the procedure [ 9 ]. However, the amount of myomectomies in this cohort was low, and a randomized controlled trial (RCT) comparing hysteroscopic myomectomy under PSA with the same procedure under GA is lacking. Although the advantages of an outpatient setting are present, it could be hypothesized that PSA, due to its higher level of consciousness compared to GA, could lead to more discomfort resulting in a higher number of incomplete procedures. This RCT was performed to investigate noninferiority of PSA with propofol as compared to GA for hysteroscopic myomectomy in terms of complete fibroid resection.
Procedural sedation and analgesia (PSA) is a technique of administering sedative agents with or without analgesics to create a decreased level of consciousness while maintaining cardiorespiratory functions so that patients can comfortably undergo unpleasant procedures [ 1 ]. Propofol is an intravenous anesthetic drug that can be used for moderate or deep sedation [ 2 ]. As a result of its short acting working mechanism, it leads to a rapid induction of sedation when started and a quick recovery when administration is stopped [ 13 ]. PSA with propofol is therefore used for a wide variety of procedures outside the operating room [ 7 , 10 , 13 , 14 , 30 ].
Hysteroscopic myomectomy is the treatment of first choice for submucous fibroids. Traditionally this procedure was performed in an operating room with general anesthesia (GA) [ 11 ]. However, in recent decades, the development of new and smaller diameter hysteroscopic instruments (without the need for cervical dilatation) has enabled the performance of many hysteroscopic procedures in an outpatient setting away from the operating theater [ 4 , 5 , 12 ]. This development leads to shorter admission time, faster recovery, and return to work, hereby reducing costs, whereas patient satisfaction and need for perioperative analgesia remain the same [ 20 , 24 ]. Office myomectomy techniques without anesthesia have been described for submucous fibroids with a diameter of less than 1.5 to 2 cm [ 11 ]. Nonetheless, for procedures that do require cervical dilatation, additional analgesia is necessary in an outpatient setting [ 11 ]. However, higher incompleteness rates have been described for hysteroscopic procedures performed under local anesthesia compared to GA. In addition, conversion from local anesthesia to GA might be required due to patient’s discomfort [ 8 , 33 ].
Methods
Ethics statement The study was conducted according to the principles of the Declaration of Helsinki (World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects, Version Fortaleza, Brazil, October 2013,) and ethical approval was granted by the ethics committee of the Máxima Medical Centre in Veldhoven, the Netherlands (registration number NL54779.015.15; reference number 15.106; date of approval 14 December 2015). Written informed consent was obtained from all patients before taking part.
Trial design The PROSECCO study was a multicenter noninferiority randomized controlled trial. The study was performed in 14 university and teaching hospitals in the Netherlands, collaborating in the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynecology, between 2016 and 2021. The study was registered prospectively in the Dutch Trial Register (NTR 5357; registration date: 11 August 2015). The full study protocol was published in 2019 [32]. During the course of the study, no major changes to the study protocol were made. Minor changes to our inclusion criteria were made (maximum number of submucous fibroids 3 instead of 2; maximum size 3.5 cm instead of 3.0 cm and inclusion of English speaking patients as well). These changes were all approved by the ethics committee of the Máxima Medical Centre in Veldhoven, the Netherlands, prior to implementation. This study is reported as per the consolidated standard of reporting trials (CONSORT) statement (S1 Consort Checklist).
Participants Women were found eligible for inclusion if they had a minimum age of 18 years and if symptomatic International Federation of Gynecology and Obstetrics (FIGO) type 0 or 1 fibroids [25] were present, with a maximum number of 3 type 0 or 1 fibroids and a maximum diameter of 3.5 cm. They had to be American Society of Anesthesiologists (ASA) class 1 or 2 and had to have sufficient knowledge of the Dutch or English language to comprehend the study information and questionnaires. Women with known clotting disorders or severe anemia (Hb < 5.0 mmol/L) were excluded. Eligible women were identified and informed about the study by gynecologists in the participating hospitals. They were counseled by research nurses, if available, or the local investigator, and written informed consent was obtained before randomization.
Interventions Patients were randomized to either PSA or GA. PSA was nonanesthesiologist-administered propofol (NAAP) sedation, administered and monitored by a qualified sedation practitioner according to the guidelines from the Health Care Inspectorate (IGZ) and Dutch Institute for Healthcare Improvement (CBO) [17]. Propofol was used for procedural sedation combined with alfentanil or remifentanil intravenously for analgesia. GA could be inhalational or total intravenously, with the use of a laryngeal mask or endotracheal tube. Hysteroscopic myomectomy was performed by an experienced surgeon with either a resectoscope or a morcellation device.
Outcomes The primary outcome was the percentage of complete resections, evaluated by transvaginal ultrasonography (TVU) (contrast sonography when TVU was inconclusive) 6 weeks postoperatively. Complete resection was defined as the absence of an intracavitary remnant of the fibroid (s) resected during hysteroscopic myomectomy. TVU was performed by an experienced sonographer or gynecologist blinded for the treatment arm and the surgery outcome. If it was concluded that resection was incomplete based on TVU, the images were adjudicated by an independent review committee, blinded for the type of anesthesia and the surgeon’s judgment on completeness during the procedure. When applicable, the result of the TVU was recorded as complete after adjudication. Secondary outcomes were as follows: completeness of resection as judged by the surgeon during the procedure; pain (Numeric Rating Scale (NRS)) score postprocedure, at discharge and 24 hours postoperatively as measured through a self-tailored questionnaire (Appendix 1 in S1 Text); recovery and return to daily activities at 24 hours, 2 weeks and 8 weeks postoperatively as measured through the Recovery Index (RI) Questionnaire [19]; duration of hospitalization; peri- and postoperative complications until 6 weeks follow-up; the need for surgical reinterventions at 12 months follow-up as measured through a self-tailored questionnaire (Appendix 1 in S1 Text); amount of menstrual blood loss at baseline, 8 weeks and 12 months follow-up as measured through Pictorial Blood Loss Assessment Chart (PBAC) score [16]; quality of life at baseline, 24 hours, 2 weeks, 8 weeks, 6 months, 12 months, as measured through the EQ-5D-5L questionnaire [15]; Uterine Fibroids Symptoms and health-related Quality of Life (UFS-QoL) at baseline and 8 weeks follow-up as measured through the UFS-QoL questionnaire [18,31]. All questionnaires were completed online. Local research nurses in the participating hospitals were responsible for collection of baseline and follow-up data from the patients’ medical records. Serious adverse events (SAEs) were reported by the local investigator to the principal investigator, who then informed the ethics committee within 15 days.
Sample size Prior to the study, the incidence of incomplete resections was estimated to be 2.5% in both treatment groups based on expert opinion and previous literature [21,22,26]. An upper limit of the noninferiority margin at a risk difference of 7.5% incomplete resections was considered to prove clinical noninferiority sufficiently. With an alpha of 0.025 and accounting for a loss to follow-up rate of 10%, 206 women had to be recruited to achieve 90% power.
Randomization and blinding Randomization was performed by using an internet-based randomization program in a 1:1 ratio with random permuted blocks of sizes 2, 4, or 6 and was stratified by the surgical technique used (morcellation or resection). Treating physicians and patients were not blinded for the allocated treatment. However, the sonographer assessing the primary outcome 6 weeks postoperatively was blinded for the treatment arm and the surgical outcome.
Statistical methods Data were analyzed according to the intention-to-treat (ITT) principle. Given the noninferiority design of the study, we also performed a per-protocol (PP) for the primary outcome. Imputation of missing data was not used. The primary outcome was evaluated by estimating the risk difference between both treatment arms, with adjustment for stratification factor (resection technique). A Farrington–Manning test was used to determine the p-value for noninferiority. For adjustment of stratification factor, a generalized linear model was used with identity link and binomial distribution where the stratification factor was used as a covariable. Prespecified exploratory subgroup analyses were performed for parity and fibroid size (<20/≥20 mm), based on the largest fibroid seen preoperatively when >1 fibroid was present in 1 patient. A significance level of 0.05 was used for two-sided testing. Relative risks were estimated for categorical secondary outcomes, with 95% confidence intervals (CIs), and χ2 tests or Fisher’s exact tests as appropriate. Continuous data were described as means with standard deviation if normally distributed, or medians with interquartile ranges; tests for significance were t tests or Mann–Whitney U tests, respectively. The Hodges–Lehman estimator was used to calculate the CI for the difference in medians. PBAC scores were analyzed longitudinally using a generalized estimating equations model for repeated measures and Poisson distribution. For UFS-QoL, EQ-5D-5L, RI, and NRS scores, this was not possible since data did not fit distribution assumptions. For those outcomes, the Hodges–Lehmann estimator for difference in median between groups at the different time points with p-value for Mann–Whitney test was estimated. A sign test for within-group change from baseline was used. Data were analyzed using SPSS Statistics for Windows (version 22.0; IBM, Armonk, NY). For the longitudinal analysis and the noninferiority analysis SAS (version 9.4; SAS Institute, Cary, NC) was used. Details on the statistical analyses can be found in the statistical analysis plan (Statistical Analysis Plan in S1 Text).
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