https://orcid.org/0000-0002-1208-1923
Figures
Abstract
Background
Postoperative nausea and vomiting (PONV) is a common complication of general anesthesia. This affects 30–80% of patients, and leads to discomfort and extended hospital stays. The effectiveness of penehyclidine for preventing PONV remains a subject of debate in the literature. Therefore, the present systematic review and meta-analysis will evaluate the efficacy of penehyclidine in preventing PONV in patients who received general anesthesia.
Methods
The present systematic review and meta-analysis is registered in PROSPERO (CRD42024523798). The present study will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) guidelines. The search will be conducted across multiple databases, including MEDLINE, PubMed, Cochrane Library, Embase, Scopus, Web of Science, and CQVIP. This will comprise articles published from the inception of the databases to April 1, 2024. Eligible randomized controlled trials (RCTs) that meet the inclusion criteria would be searched. The main outcome measure is the incidence of PONV. The secondary outcome measures include the incidence of postoperative nausea, incidence of postoperative vomiting, severity of nausea, severity of vomiting, patient satisfaction, length of hospital stay and adverse effects. Two researchers will independently evaluate the quality of the selected literature, and extract the data. The quality assessment of each RCT will be independently conducted by two researchers using the GRADE approach, as recommended in the Cochrane Handbook for Risk of Bias Assessment. The meta-analysis will be conducted using RevMan 5.4.
Citation: Yuan Y, Zhou J, Zhang Y, Zhong W, Xi G, Ma H, et al. (2025) Penehyclidine for postoperative nausea and vomiting in patients receiving general anesthesia: A systematic review and meta-analysis protocol. PLoS ONE 20(1): e0318093. https://doi.org/10.1371/journal.pone.0318093
Editor: Kuo-Cherh Huang, Taipei Medical University, TAIWAN
Received: July 16, 2024; Accepted: January 8, 2025; Published: January 30, 2025
Copyright: © 2025 Yuan 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.
Data Availability: Deidentified research data will be made publicly available when the study is completed and published.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CI, confidence interval; OR, odds ratio; PACU, postanesthesia care unit; PONV, postoperative nausea and vomiting; RCTs, randomized control trials; RR, risk ratio; SMD, standard mean difference; WMD, weighted mean difference
1. Introduction
Postoperative nausea and vomiting (PONV) is a common complication of general anesthesia that can lead to adverse reactions, such as water/electrolyte imbalance, wound dehiscence, and even aspiration, endangering the life, and significantly affecting the physiological, psychological and postoperative recovery and prognosis of patients [1]. An epidemiological report revealed that the incidence of PONV is approximately 30%, reaching 80% in high-risk populations [2]. At present, the preventive and therapeutic effects of commonly used antiemetic drugs during the perioperative period, such as corticosteroids, selective 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, and dopamine receptor antagonists, remains unsatisfactory, and may result in adverse reactions, including sedation, headache, dizziness and arrhythmias [3].
Penehyclidine is a novel long-acting anticholinergic drug that selectively acts on the M1 and M3 subtypes of acetylcholine receptors, with no significant effect on the M2 subtype (mainly distributed in the heart and presynaptic membranes of neurons) [4]. As a selective blocker of the M1 and M3 subtypes of acetylcholine receptors, phenehyclidine can potently inhibit glandular secretion, has long-lasting central sedative effects, and can improve the microcirculation [5,6]. A study reported that the M3 and M5 subtypes of acetylcholine receptors are associated to motion sickness, which is a risk factor for PONV [7]. Furthermore, the M1 subtype of acetylcholine receptors is primarily distributed in the solitary beam nucleus, emetic chemosensory area, and vestibular system. The activation of these receptors can induce nausea and vomiting [8]. Previous studies have suggested that the preoperative administration of penehyclidine can help to prevent PONV [9]. Due to its elimination half-life that exceeds 10 hours, penehyclidine has a prolonged duration of action, potentially providing sustained efficacy in preventing PONV.
Penehyclidine has been shown to have antiemetic properties, and may be effective in preventing PONV in patients who undergo general anesthesia. However, evidence for the effectiveness of penehyclidine in preventing PONV remains limited and conflicting [10]. Therefore, a systematic review and meta-analysis are needed to evaluate the preventive effect of penehyclidine on PONV, in patients who receive general anesthesia.
The present protocol outlines the methods for conducting a systematic review and meta-analysis, in order to assess the effectiveness of penehyclidine in preventing PONV in patients who undergo general anesthesia. The findings of the present review will provide clinicians and researchers with valuable information on the use of penehyclidine, as a preventive measure for PONV, in patients who undergo general anesthesia.
2. Materials and methods
2.1. Study registration
The present systematic review and meta-analysis is registered on the PROSPERO platform of the National Institute for Health and Care Research (NHS), with registration number CRD42024523798. The present study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (S1 Checklist) [11], and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) guidelines [12]. The present systematic review will be a secondary research study conducted on previously published literature, thereby meeting the criteria for ethical exemption. Any amendments to the information provided at registration or in the protocol will be approved by the NHS.
2.2. Inclusion criteria for the literature
2.2.1. Types of literature.
Randomized controlled trials (RCTs) provide high-quality evidence, and are essential for assessing the efficacy of penehyclidine for the prevention of PONV in patients who receive general anesthesia. Therefore, the present study will only include RCTs. The following studies will be excluded: (1) studies on non-general anesthesia surgical patients; (2) studies that cannot be accessed in full text, or have incomplete outcome measures; (3) studies that include non-RCTs, case reports, systematic reviews, meta-analyses, mechanistic studies, conference abstracts, and animal studies; (4) duplicate publications.
2.2.2. Types of participants.
The study subjects will comprise of adult patients, who underwent surgical procedures under general anesthesia, with no restrictions on gender, type of surgery, nationality, or race.
2.2.3. Types of interventions.
The intervention will involve the trial group that received penehyclidine, and the control group that received saline, atropine, placebo, or no treatment. Furthermore, the comparison will include the different doses of penehyclidine.
2.2.4. Types of outcome measures.
The main outcome measure is the incidence of PONV, which includes both the incidence rate and cumulative incidence. The study will include both inpatients and patients who underwent day surgery, in order to provide a comprehensive analysis of PONV across different patient populations. Based on the different time points for assessment, this outcome will be divided into three subgroups: (1) incidence rate (studies that only reported the incidence rate, without specifying the assessment period, or with a broad assessment time span that cannot be categorized as early or late, such as within 0–24 hours, 0–48 hours, 0–72 hours, and beyond); (2) early incidence rate (within 0–6 hours, postoperatively, in the postanesthesia care unit [PACU]); (3) late incidence rate (6–24 hours, postoperatively, in the ward, after discharge from day surgery). If multiple time intervals are reported within the early or late incidence rate subgroup (e.g., studies that reported incidence rates for 0–2 hours and 2–6 hours, separately, for early incidence rate), merely the highest incidence rate will be recorded. In addition, dry retching (with retching, but no expulsion of gastric contents) will be considered as vomiting.
The secondary outcome measures will include the following: (1) Severity of PONV: assessment of the severity of nausea and vomiting experienced by patients in the penehyclidine group, when compared to the control group, using a numeric rating scale (NRS): the NRS ranges from 0 to 10, with 0 indicating no nausea and 10 indicating extremely severe nausea, where a higher score represents a more severe degree. In addition to scoring the severity of nausea, the number of vomiting episodes must also be recorded to comprehensively assess the severity of PONV. (2) Patient satisfaction: evaluation of patient satisfaction with the antiemetic effect of penehyclidine, when compared to standard care or other antiemetic agents. (3) Length of hospital stay: comparison of the duration of hospital stay between patients who received penehyclidine, and subjects in the control group. (4) Adverse effects: analysis of any adverse effects associated to the use of penehyclidine for the prevention of PONV. In addition, patients who experienced combined nausea and vomiting, as well as patients who suffered from less common presentations, such as vomiting without previous nausea, will be considered, in order to capture the full spectrum of PONV experiences.
2.3. Search strategy
The English search terms used will be determined based on the MeSH thesaurus provided by PubMed (MeSH Database). The MEDLINE, PubMed, Cochrane Library, Embase, Scopus, Web of Science, and CQVIP databases will search to identify RCTs that meet the inclusion criteria, from the inception of the database, until April 1, 2024. The search strategy will be finalized after multiple iterations. In addition, manual searches that involve the tracing of references and unpublished literature will be conducted. The search strategy will combine the subject headings and free terms. The English search terms will include the following: “penehyclidine, cholinergic antagonists, postoperative period, postanaesthetic, nausea, emetics, vomiting, randomized controlled trial, controlled clinical trial”. The search language will be in the English language. Cross-referencing will be performed using the references in the retrieved literature, expert comments, and publicly available correspondence, in order to identify potential literature. The search strategy, as exemplified by the PubMed database, is shown in Table 1 and the supplementary material (S1 Table).
2.4. Literature selection
Literature screening will be independently conducted by two researchers. Endnote X9 (Thomson ResearchSoft, Stanford, Connecticut, USA) will be used for the deduplication of the literature. After deduplication, the titles and abstracts of the literature will be reviewed, and based on the predefined inclusion criteria, the literature will be preliminarily screened to exclude those that clearly do not meet the inclusion criteria. Then, the results of the initial screening will be subjected to full-text reading. For literature with inclusion disputes, a discussion will be held, or a decision will be made with a third researcher to determine whether the literature can be included. The process of study selection is depicted in the form of a flowchart, which is labeled as Fig 1.
2.5. Data extraction
Two researchers will independently extract the data from each included study using the same information extraction form. The following aspects of the data will be extracted: (1) the basic information of the articles, including the first author, publication date, and information of the included subjects, such as age, gender, body weight or body mass index (BMI), and type of surgery; (2) the clinical characteristics of each group after subject grouping; (3) the administration route and dose of penehyclidine and control drugs; (4) the primary and secondary outcome measures; (5) the key elements for evaluating the quality of the study design. Information extracted from each literature will be displayed in a table (S2 Table). If the two researchers have differing opinions, these differences will be discussed and resolved with the participation of a third researcher.
2.6. Dealing with missing data
During this review process, incomplete, suppressed, or missing data will be addressed by initially contacting the authors to request clarification or data. If unavailable, the affected studies will be excluded to ensure integrity and reliability. This exclusion will be disclosed in the methodology, and its implications on the interpretation and generalizability of the results will be discussed, maintaining the rigor and transparency of the review process.
2.7. Risk of bias
The Cochrane handbook-recommended bias risk assessment criteria, which mainly include the generation of random sequences, allocation concealment, blinding of researchers and participants, blinding assessment of study outcomes, completeness of outcome data, selective reporting of study results, and other sources, will be used to evaluate the bias risk in the included studies [13].
2.8. Data analysis
The criteria to quantitatively synthesize the study data for the present systematic review and meta-analysis protocol will include the study design, population characteristics, intervention and comparison, outcomes of interest, data quality and reporting, risk of bias assessment, and statistical methods. Merely RCTs with clear inclusion criteria, comparable interventions, and sufficient data reporting will be included in the quantitative synthesis. The literature data will be analyzed using the RevMan 5.4 software (Cochrane Collaboration, Oxford, UK). For continuous data, if different studies used the same measurement tool and units, the analysis will be conducted using the weighted mean difference (WMD). If different measurement tools or units were used, the standardized mean difference (SMD) will be chosen for the analysis, and the 95% confidence interval (95% CI) will be calculated. Heterogeneity will be tested for each study. If there is statistical heterogeneity among the studies (p ≤ 0.10, I2 ≥ 50%), a sensitivity analysis will be conducted to further explore the possible sources of heterogeneity and eliminate it. Then, the evaluation and analysis will be conducted. If the sources of heterogeneity cannot be identified, a random-effects model will be used for the statistical analysis. If there is no statistical heterogeneity (p > 0.10 and I2 < 50%), a fixed-effects model will be used for the statistical analysis. If the number of included studies exceeds 10, a funnel plot will be generated to assess the risk of publication bias. When quantitative synthesis is not suitable, a narrative synthesis will be planned. This approach will qualitatively and descriptively summarize multiple studies, and be especially effective for heterogeneous studies with varying designs, populations, interventions and outcomes, making the quantitative synthesis challenging.
In the event of variability in the standardized scales used to measure PONV across the included studies, the following measures will be taken: First, an attempt will be made to standardize the data to a common scale, where possible. Second, a subgroup analysis will be conducted based on the type of scale used. Furthermore, a sensitivity analysis will be performed to assess the impact of the scale variation on the present findings. Lastly, the different scales used will be reported, and their potential impact will be discussed in the “Discussion” section.
2.9. Sensitivity analysis
A sensitivity analysis will be conducted to assess the robustness of the results, and identify the potential biases or outliers that may have influenced the overall findings. For the present review, the sensitivity analysis will be performed by excluding studies with high risks of bias (e.g., lack of blinding, small sample size, and incomplete data reporting), and re-analyzing the data to determine whether the results remain consistent.
2.10. Subgroup analysis
A subgroup analysis will be performed to explore the potential heterogeneity in the effects of penehyclidine on PONV across different patient populations or study characteristics. The subgroup analysis will be conducted based on the type of surgery, anesthesia regimen, and patient characteristics.
2.11. Evaluation of evidence quality
The assessment of evidence quality of each randomized controlled trial will be undertaken independently by two researchers, employing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach as endorsed in the Cochrane Handbook for assessing the risk of bias [14]. This methodical evaluation will involve the application of GRADE criteria to downgrade the quality of evidence in instances of risk of bias, inconsistency, indirectness, imprecision, and publication bias, and to upgrade it in cases of significant effect sizes or dose-response gradients, as shown in Table 2. Should any disagreements arise between the two researchers, a third researcher will be engaged to arbitrate and determine the final assessment. The GRADE approach is selected for its comprehensive framework in evaluating the quality and risk of bias within the included studies, ensuring a rigorous and transparent process that aligns with current best practices in evidence-based research.
3. Discussion
Through the present systematic review and meta-analysis, the comprehensive evaluation of the effect of penehyclidine in preventing PONV after general anesthesia surgery will help in more comprehensively understanding its effectiveness and safety.
PONV, which is a prevalent issue, particularly in patients who receive general anesthesia, not only leads to physical discomfort, but can also extend hospital stays and recovery periods. Hence, the prevention and management of PONV are vital for enhancing patient well-being, and expediting the postoperative recovery process. The occurrence of PONV is multifactorial, and may be associated to various factors, such as the type of anesthetic agent used, the surgical site, the duration of surgery, patient age, gender, and individual susceptibility [15]. In the prevention of PONV, common strategies involve the selection of suitable anesthetic agents, such as diazepam and propofol, which are known to potentially decrease the PONV rates, while opioids may increase the risk of PONV [16]. Furthermore, maintaining an optimal anesthesia depth can help mitigate PONV by preventing complications associated to excessive anesthesia [17]. Prophylactic medications, such as serotonin receptor antagonists (e.g., ondansetron) and dopamine receptor antagonists, are effective in reducing the occurrence of PONV [18]. In addition, postoperative care plays a crucial role in the timely administration of appropriate fluid replacement, the management of triggers for nausea and vomiting, and the provision of a comfortable postoperative environment [19]. These measures are essential for preventing PONV.
Penehyclidine, which is an anticholinergic medication, exerts its effect by selectively blocking the M1 and M3 subtypes of acetylcholine receptors, which are implicated in the pathophysiology of PONV [4]. This blockade would result in reduced cholinergic neurotransmission, leading to the decreased contraction of gastrointestinal smooth muscles, and lowered gastrointestinal motility. Consequently, penehyclidine has been shown to significantly decrease the incidence of PONV, and enhance the postoperative quality of life of patients in several clinical trials [20–23]. However, it is important to acknowledge the limitations of the present evidence base, which include the lack of long-term follow-up data and standardized outcome measures.
Furthermore, the potential adverse effects of penehyclidine, such as the risk of addiction and withdrawal symptoms, have not been thoroughly explored in existing literature [22–24]. These factors are crucial for healthcare professionals to consider when evaluating the overall risk-benefit profile of penehyclidine for PONV prevention. Therefore, the present systematic review and meta-analysis protocol aims to provide a more comprehensive analysis of the available evidence, while also identifying gaps in the present research, which warrant further investigation. By doing so, it is hoped that this would offer valuable insights to the role of penehyclidine in preventing PONV, and contribute to the development of more effective and safe treatment strategies for this common postoperative complication.
In the present protocol for the systematic review and meta-analysis of penehyclidine for PONV in patients who received general anesthesia, several potential limitations related to publication bias, heterogeneity of studies, quality of included studies, incomplete data extraction, lack of long-term follow-up, language and geographic bias, and the use of aggregate data should be acknowledged. These limitations will be considered when interpreting the results of the review and meta-analysis. Efforts will be made to mitigate these limitations as much as possible through rigorous methodology and transparent reporting.
In conclusion, the present systematic review and meta-analysis provides preliminary evidence that support the use of penehyclidine for the prevention of PONV in patients who undergo general anesthesia. However, further high-quality research is needed to confirm these findings, and provide more definitive recommendations for clinical practice.
Supporting information
S1 Checklist. Preferred Reporting Items for Systematic review and MetaAnalysis Protocols (PRISMA-P) 2015 checklist: Recommended items to address in a systematic review protocol.
https://doi.org/10.1371/journal.pone.0318093.s001
(DOCX)
S2 Table. Suggested table of data collection.
https://doi.org/10.1371/journal.pone.0318093.s003
(DOCX)
Acknowledgments
The authors acknowledge the contributions of the anesthesiologists and nurses of the Department of Anesthesiology, Henan Provincial Chest Hospital & Affiliated Chest Hospital of Zhengzhou University. We also acknowledge Nature Research Editing Service (https://authorservices.springernature.com/) for the English language editing.
References
- 1. Benhamou D. Postoperative nausea and vomiting: Is the big little problem becoming a smaller little problem?. Br J Anaesth. 2023;131(1):22–5. pmid:37179157
- 2. Jin Z, Gan TJ, Bergese SD. Prevention and treatment of postoperative nausea and vomiting (PONV): a review of current recommendations and emerging therapies. Ther Clin Risk Manag. 2020;16:1305–17. pmid:33408475
- 3. Weibel S, Schaefer MS, Raj D, Rücker G, Pace NL, Schlesinger T, et al. Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: an abridged Cochrane network meta-analysis. Anaesthesia. 2021;76(7):962–73. pmid:33170514
- 4. Sun X, Sun C, Zhai L, Dong W. A selective M1 and M3 receptor antagonist, penehyclidine hydrochloride, exerts antidepressant-like effect in mice. Neurochem Res. 2019;44(12):2723–32. pmid:31606838
- 5. Wang Z, Lin D, Zhang L, Liu W, Tan H, Ma J. Penehyclidine hydrochloride prevents anoxia/reoxygenation injury and induces H9c2 cardiomyocyte apoptosis via a mitochondrial pathway. Eur J Pharmacol. 2017;797:115–23. pmid:28089921
- 6. Wang Y, Gao Y, Ma J. Pleiotropic effects and pharmacological properties of penehyclidine hydrochloride. Drug Des Devel Ther. 2018;12:3289–99. pmid:30323561
- 7. Moraitis A, Hultin M, Walldén J. Risk of postoperative nausea and vomiting in hip and knee arthroplasty: a prospective cohort study after spinal anaesthesia including intrathecal morphine. BMC Anesthesiol. 2020;20(1):242. pmid:32972366
- 8. Tolaymat M, Sundel MH, Alizadeh M, Xie G, Raufman J-P. Potential role for combined subtype-selective targeting of M1 and M3 muscarinic receptors in gastrointestinal and liver diseases. Front Pharmacol. 2021;12:786105. pmid:34803723
- 9. Sun J, Cao X, Lu T, Li N, Min X, Ding Z. Penehyclidine mitigates postoperative nausea and vomiting and intraoperative oculocardiac reflex in patients undergoing strabismus surgery: a prospective, randomized, double-blind comparison. BMC Anesthesiol. 2021;21(1):49. pmid:33581727
- 10. Ding X, Chen D, Che J, Xu S, Liang H, Gui B. Penehyclidine hydrochloride for treating postoperative nausea and vomiting after laparoscopic bariatric surgery: a double-blinded randomized controlled trial. BMC Anesthesiol. 2023;23(1):135. pmid:37095439
- 11. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. pmid:33782057
- 12. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. pmid:28935701
- 13. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. pmid:22008217
- 14. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6. pmid:21208779
- 15. Stoops S, Kovac A. New insights into the pathophysiology and risk factors for PONV. Best Pract Res Clin Anaesthesiol. 2020;34(4):667–79. pmid:33288117
- 16. Khanna SS, Mohammed Abdul MS, Fatima U, Garlapati H, Qayyum MA, Gulia SK. Role of general anesthetic agents in postoperative nausea and vomiting: a review of literature. Natl J Maxillofac Surg. 2022;13(2):190–4. pmid:36051800
- 17. Corner H, Barley M, Metodiev Y. The use of processed electroencephalography (pEEG) in obstetric anaesthesia: a narrative review. Int J Obstet Anesth. 2023;54:103650. pmid:36934515
- 18. Weibel S, Rücker G, Eberhart LH, Pace NL, Hartl HM, Jordan OL, et al. Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis. Cochrane Database Syst Rev. 2020;10(10):CD012859. pmid:33075160
- 19. Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, et al. Fourth consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2020;131(2):411–48. pmid:32467512
- 20. Gao P-F, Zhao L, Li S-Y, Li Y, Chen M-K, Fu J, et al. Prevention of postoperative nausea and vomiting after orthognathic surgery: a scoping review. BMC Anesthesiol. 2024;24(1):121. pmid:38539078
- 21. Lu T, Li R, Sun J, Chen J. Evaluation of penehyclidine for prevention of post operative nausea and vomitting in patients undergoing total thyroidectomy under total intravenous anaesthesia with propofol-remifentanil. BMC Anesthesiol. 2022;22(1):317. pmid:36241968
- 22. Zhao K, Gao Y, Zhang J, Wang S, Chen J, Guo F, et al. Penehyclidine for prevention of postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery under combined intravenous and inhalation anesthesia: a randomized, double-blind, placebo-controlled trial. Drug Des Devel Ther. 2024;18:685–97. pmid:38445065
- 23. Wang L-K, Cheng T, Yang X-D, Xiong G-L, Li N, Wang D-X. Penehyclidine for prevention of postoperative nausea and vomiting following bimaxillary orthognathic surgery: a randomized, double-blind, controlled trial. J Anesth. 2022;36(1):122–36. pmid:34738161
- 24. Zhang Z, Zhuang Y, Ouyang F, Zhang A, Zeng B, Gu M. Penehyclidine enhances the efficacy of tropisetron in prevention of PONV following gynecological laparoscopic surgery. J Anesth. 2012;26(6):864–9. pmid:22878869