Inhaling penehyclidine to prevent perioperative respiratory adverse events in children at risk undergoing sevoflurane anesthesia (PEPSI trial): study protocol for a double-blind, randomized, placebo-controlled trial

Inhaling penehyclidine to prevent perioperative respiratory adverse events in children at risk undergoing sevoflurane anesthesia (PEPSI trial): study protocol for a double-blind, randomized, placebo-controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Inhaling penehyclidine to prevent perioperative respiratory adverse events in children at risk undergoing sevoflurane anesthesia (PEPSI trial): study protocol for a double-blind, randomized, placebo-controlled trial Yanling Zhu, Yongyi Wang, Yongjian Mai, Ting Huang, Jingxia Huang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5718305/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Apr, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Perioperative respiratory adverse events (PRAEs) remains a challenge for pediatric anesthesia, inhalation of penehyclidine has been showed to reduce postoperative pulmonary complications and enhance the recovery in high-risk surgical adults. Thus, prophylactic penehyclidine inhalation might show promising benefits against PRAEs in children with high risk factors. Aims To clarify the effectiveness of inhaling penehyclidine in reducing PRAEs in pediatric patients at risk scheduled for elective surgery following sevoflurane anesthesia with LMA. Methods This is a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Two hundred and four children, aged 3 to 7 years, undergoing ophthalmic surgery (minor surgery), will be randomized in a ratio of 1:1 to receive either inhaling penehyclidine hydrochloride (PHC, a dose of 0.05 mg/kg, diluted and mixed with normal saline to a total volume of 5 ml) or identical volumes and colour of normal saline before anesthesia. The primary outcome is the incidence of PRAEs between the 2 groups. Secondary outcomes include the airway hyperreactivity (AHR) score, and the severity of laryngospasm and bronchospasm if occurs. Moreover, ease of laryngeal mask airway (LMA) insertion, episode and degree of salivation during removal of LMA, anesthesia-related recovery time, postoperative pain score, incidence of emergence agitation (EA), hemodynamic parameters, other postoperative adverse events related to the study drug within the first 24 postoperative hours, and the development of respiratory infections within 7 days after surgery will be also collected. Discussion The results of this study will provide valuable insights into the potential role of inhaling PHC in reducing PRAEs in a high-risk pediatric cohort during sevofurane anesthesia with LMA, thereby promoting clinical practice. Trial registration ClinicalTrials.gov (NCT06624696). Registered on 30 September 2024. https://clinicaltrials.gov/study/NCT06624696 perioperative respiratory adverse events penehyclidine nebulization therapy high-risk patient pediatric anesthesia Figures Figure 1 Introduction Background and rationale Perioperative respiratory adverse events (PRAEs) are the most common critical complications in pediatric anesthesia, accounting for nearly one-third of anesthesia-related cardiac arrests [ 1 , 2 ]. A large cohort study reported that children with respiratory symptoms, such as nocturnal cough, cold, wheezing, or those with a family history of asthma, rhinitis, eczema, or exposure to passive smoking, can significantly increase the risks of PRAEs [ 3 ]. PRAEs can result in serious neurological damage due to hypoxia, which is strongly linked to prolonged hospital stays, increased medical costs, and perioperative mortality [ 4 ]. Consequently, identifying effective strategies to mitigate the incidence of PRAEs in high-risk children remains a key priority in pediatric anesthesia [ 5 ]. Optimizing airway management is crucial for preventing PRAEs during pediatric anesthesia. Although the use of laryngeal mask airway (LMA) has been advocated to reduce the risk of PRAEs as compared to endotracheal intubation, the incidence of PRAEs following LMA removal still remains high [ 6 ]. Karam et al. reported a PRAE incidence of 36.2% following LMA removal [ 7 ], with another study indicating further increase to 54% in high-risk preschool children [ 8 ]. In fact, there remains a debate over the optimal timing for LMA removal. Awake removal, in which the LMA is kept in place until the patient regained consciousness, is associated with a higher incidence of physical events such as bucking and coughing, while deep removal reduces these events but increases the risk of airway obstruction due to suppressed airway reflexes [ 9 , 10 ]. Regardless of awake or deep anesthesia stage at which the LMA is removed, airway secretions or stimulation are the major triggers for PRAEs particularly during the recovery phase, characterized by restoration of parasympathetic function leading to increased salivation and airway secretions, and gradual recovery of sympathetic activity resulting in airway smooth muscle hyperexcitability. Given the potential for airway secretions and hyperreactivity in high-risk patients, anesthesia management is aimed at minimizing stimulation of a potentially irritable airway [ 11 ]. Anticholinergic drugs are usually administered as premedication prior to anesthesia for the purpose of sedation, alleviating tension within various smooth muscles, facilitating tracheal and bronchial relaxation, and suppressing excessive glandular secretions through their action on both central and peripheral postganglionic cholinergic receptors [ 12 ]. In one survey of pediatric anesthesiologists, approximately one-third reported using anticholinergics on a frequent basis for children with URTIs [ 13 ]. Penehyclidine is a long-acting muscarinic antagonist with high selectivity for M3 receptor, a subtype of receptor that mediates airway smooth muscle contraction induced by acetylcholine [ 14 ]. Studies has demonstrated the benefits of inhaling penehyclidine hydrochloride (PHC) in reducing airway hyperreactivity, inhibiting inflammatory responses, and improving lung compliance in adults [ 15 – 17 ]. However, despite their use, there are no randomized studies to determine the effect of inhaling PHC on PRAEs in high-risk children as anticholinergic drugs may result in pediatric emergence agitation [ 18 ]. This randomized controlled study is therefore designed to test the hypothesis that, compared with placebo, prophylactic inhaling of PHC to high-risk children will reduce the incidence of PRAEs following sevoflurane anesthesia with LMA. Objectives Our goal is to evaluate the effectiveness of inhaling PHC in reducing PRAEs in children at risk undergoing sevoflurane anesthesia with LMA. Therefore, we will test the hypothesis that pediatric patients who exist at least 1 risk factor of PRAEs prophylactically to inhale PHC have a lower prevalence of PRAEs. Methods/design Trial design and setting This prospective, multicenter, double-blind, randomized, placebo-controlled trial is designed to explore the effect of the intervention. The study will be coordinated and conducted in Zhongshan Ophthalmic Center, Sun Yat-sen University (Guangzhou, China), and Shenzhen Eye Hospital (Shenzhen, China). The design of this study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 guideline. A detailed flow diagram of the trial is shown in Figure 1 . The study has received Institutional Review Board (IRB) approval (2024KYPJ108) and has been registered on ClinicalTrials.gov (NCT06624696). Patient recruitment and informed consent Annually, more than 10,000 pediatric patients present for elective surgery under general anesthesia at the two study institutions. All surgeons will be contacted before the start of the study to obtain their consent to allow their patients to be studied. Potential participants are identified and screened by staff anesthesiologists during preoperative evaluation the day before surgery. Then, an investigator of the research team will inform the guardian of the pediatric patients who meet the eligibility criteria, and explain the study protocol, including potential risks and benefits to the pediatrics. Once the investigator has obtained written informed consent from patient guardian, the trial will be proceeded further. We have begun recruitment in November 2024, and the enrolment period will extend to over 12 months. The timeline of enrolment, interventions and assessments for this trial is described in Table 1. Participants can withdraw from the trial at any time, and any reasons given for withdrawal will be recorded. Inclusion criteria are as follows: (1) pediatric patients aged 3 to 7 years. (2) scheduled to undergo ophthalmic surgery. (3) judged to be at risk of PRAEs (with at least one parentally reported risk factor for the PRAEs, including history of a recent cold, wheezing during exercise, wheezing more than three times in the past 12 months, nocturnal dry cough, eczema, or a family history of asthma, rhinitis, eczema, or exposure to passive smoke). Exclusion criteria are as follows: (1) American Society of Anesthesiologists (ASA) physical classification ≥ IV. (2) known cardiopulmonary diseases (eg. uncorrected congenital heart disease, primary or secondary pulmonary hypertension, tumors, or structural lung diseases). (3) severe renal dysfunction (requirement of renal replacement therapy) or severe hepatic dysfunction (Child-Pugh grade C); (4) neurological disorders. (5) neuromuscular diseases. (6) contraindication for PHC. (7) inhalation of β2-receptor activator, M-receptor blockers and/or glucocorticoids within 1 month before surgery. (8) allergy to anticholinergic drugs. (9) use of endotracheal tube (ETT) for ventilation. (10) known difficult airway. (11) severe upper respiratory tract infections (URTIs) and the anesthesiologist recommended delaying surgery. (12) participation in other clinical trial during the last month or within the six half-life periods of the study drug used in the last trial. (13) parents refusing to allow their children to participate. (14) obesity, with a body mass index (BMI) over 95th percentile according to the WHO guideline. Criteria of drop out include the following: (1) consent withdrawn by the parents. (2) loss to postoperative follow‐up. (3) ordered to exit by the investigators (eg., poor compliance, or occurrence of severe adverse events). (4) unplanned use of any prohibited drugs (anticholinergics or any medications other than the study drug) from study recruitment to postoperative day 2. Randomization and blinding After obtaining written informed consent, patients will be randomly assigned, in a 1:1 ratio randomized by OPERA Electronic Data Capture (EDC) System (Beijing Cloud Vision, Ltd., China) using blocked randomization with a block size of 4 or 6, to either treatment or placebo group. Group assignments will be concealed in sequentially numbered opaque envelopes that can only be opened on the morning of surgery and before anesthesia by a research nurse not further involving in the patient care. Then the study medication (penehyclidine hydrochloride, 1 ml: 0.5 mg, Jiangsu Nhwa Pharmaceutical Co., Ltd., China) and normal saline placebo will be prepared using identical 1-ml syringes by this nurse in a closed preparation room. In both groups, the trial drugs will be diluted and mixed with normal saline to 5 ml, added to nebulizers and provided for inhalation within 30 min before anesthesia. Consequently, except for this nurse, the patients, surgeons, anesthesiologists and outcome assessors will be masked to the treatment assignments during the study period. Blinding will be maintained unless it is considered necessary to unblind for safety reasons. These situations will be documented in the case report forms (CRFs). The unmasked patients will be included in the intention-to-treat population but excluded from the per-protocol analysis. Preoperative preparation On the morning of the surgical day, parents are administered a short questionnaire for documenting their child’s demographics (eg, age, height, weight, gender, family history) and medical history (including exiting risk factors of PRAEs) [3]. Preoperative anxiety will be evaluated with the modified Yale Preoperative Anxiety Scale (m-YPAS) score [19]. In addition, the “COLDS” score will be used to quantify the risk of PRAEs in patients presenting for elective surgery [20] ( eAppendix supplement table 1&2&3 ). Intervention and placebo Upon arrival in the preoperative holding room, patients are divided into 2 groups to receive either PHC (0.05 mg/kg of 0.05% solution) or equal volume of saline for nebulization therapy. Trial drugs will be diluted to a total volume of 5 mL with normal saline, added to the nebulizer cup for inhalation. Patients will be asked to inhale the entire volume of nebulized drugs within 30 min prior to surgery to maximize its efficacy. The trial drugs will be administered using a air-compressing nebulizer (403M, Jiangsu Yuyue Medical Equipment & Supply Co., Ltd., China). Each child will be intructed to begin the nebulization by using a face mask that covers the nose and mouth while the child is seated upright. Children will be encouraged to take deep and slow breaths, inhaling through the mouth and exhaling through the nose, to ensure the drugs effectively reaches the airway [21]. To improve the compliance of preschool children during nebulization, we will allow a guardian to accompany the child in the preoperative holding room, and supply age-appropriate cartoon videos to engage the children and help distract them during the procedure. Children who are unable to cooperate with nebulization treatment will be excluded from the study, but their subsequent medical rights will not be affected. General anesthesia protocol All participants are routinely required to fast 6 hours for solids and 4 hours for clear liquids before the surgery. Upon arrival at the operating room, all patients will be generally monitored by electrocardiogram, heart rate, non-invasive blood pressure, pulse oxygen saturation (SpO 2 ), and capnography. Anesthesia induction is performed via a face mask by sevoflurane inhalation given by a gradual increase in the concentration of up to 8% vol along with 100% oxygen, and the Pediatric Anesthesia Behavior (PAB) score ( eAppendix supplement table 4 ) is used to assess the degree of mask acceptance by an independent anesthesiologists who is blinded to the group assignment [22]. A PAB score of 2 or 3 is considered poor behavioral compliance and 1 mg/kg of propofol will be intravenously injected as a rescue method for rapid induction. Preoxygenation will not be used routinely as per routine clinical practice. After loss of consciousness, all patients will be consecutively administered intravenous fentanyl and cisatracurium, meanwhile, manually ventilated through a face mask with high flow (5-6 L/min) oxygen. Once the conditions are sufficiently satisfied for a supraglottic airway device insertion (loss of eyelash reflex, jaw relaxation or absence of body movement), a laryngeal mask airway (LMA; TuoRen medical, China) will be inserted using two-handed jaw-thrust maneuver [23]. The size of LMA is chosen based on the patient actual weight sizing for pediatric anesthesia (size 1 for weight<5 kg, size 1.5 for weight 5-10 kg, size 2 for weight 10-20 kg, size 2.5 for weight 20-30 kg, size 3 for weight 30-50 kg). The cuff of airway is inflated with air to obtain an intra-cuff pressure of 55-60 cmH 2 O (1 cmH 2 O=0.098 kPa). No more than 3 attempts at LMA insertion are allowed. The number of insertions attempts and repositioning will be recorded. In case of failure, an ETT is used to replace, and the patient was excluded from further analysis. Volume-controlled mode is applied with a tidal volume of 8-10 ml/kg and an inspiratory/expiratory ratio of 1:1.5-2. Respiratory rate is adjusted to maintain the end-tidal carbon dioxide (EtCO 2 ) within 35 to 45 mmHg (1 mmHg=0.133 kPa). Peak inspiratory pressure will be recorded. During the surgery, anesthesia is maintained with sevoflurane to reach an end-tidal concentration of 1-1.5 minimal alveolar concentration. At 15 min before the end of surgery, non-steroidal anti-inflammatory drugs (NSAIDs; flurbiprofen axetil, 1 mg/kg; Tidepharm Inc., China) is administered to all patients for postoperative analgesia. Upon completion of the surgery, sevoflurane will be discontinued, and patients with a LMA will be transferred to the postanesthesia care unit (PACU) for synchronized intermittent mandatory ventilation. None of patients will be administered acetylcholinesterase inhibitors or sugammadex for reversal of residual neuromuscular blockade. The LMA will be removed by a skilled pediatric anesthesiologist in the PACU, ensuring that the patient is awake and exhibits signs of facial grimace, adequate respiratory rate and volume, eye-opening, and purposeful movements. In the PACU, the patients are continuously monitored for HR and SpO 2 and cared for by PACU nurses. Postoperative pain is assessed using the Wong-Baker Pain Scale ( eAppendix supplement table 5 ), and if the score is greater than 4, fentanyl (0.5 mcg/kg) will be given to control the pain. Behavior on emergence will also be measured using the Aono’s Four Point Scale ( eAppendix supplement table 6 ) [24]; patients with a peak Aono’s score greater than 3 are diagnosed as emergence agitation (EA), and will be treated with an additional dose of propofol (10-20 mg). If patient displays persistent vomiting, droperidol 10 mcg/kg will be given for remission. The physiological criteria-based discharge scoring system will be assessed every 15 min [25]. Patients will be returned to the day-care ward when their physiological score achieve at 12 or higher points ( eAppendix supplement table 7 ). Primary outcome PRAEs are subdivided into two types: major (bronchospasm and laryngospasm) and minor (severe coughing, breath holding, desaturation, upper airway obstruction, and stridor) events. The primary outcome is the incidence of PRAEs. Patients will be considered positive for respiratory adverse events if at least 1 of the above adverse events occurs. PRAEs will be reported by a PACU nurse not involved in the study, and recorded against different phase of anesthesia (induction, maintenance, emergency, or recovery). The definitions of each respiratory adverse events are listed in Table 2 [26,27]. Secondary outcomes (1) The airway hyperreactivity score ( eAppendix supplement table 8) , which is used to assessed severity of PRAEs, accounting for the intensity of coughing, breath holding, and oxygen desaturation on a scale ranging from 0 (none) to 4 (severe). The maximum score is 12, and a score of ≤3 is categorized as mild, 4 to 8 as moderate, and ≥9 as severe [28]. (2) The severity of major respiratory adverse events if occurs, including laryngospasm and bronchospasm during the perioperative periods [7,29]. Laryngospasm will be scored according to its severity as follows: 1=none, 2=partial—reposition airway, 3=partial—continuous positive airway pressure (CPAP), 4=complete—muscle relaxant. In addition, bronchospasm will be scored according to its severity as follows: 1=none, 2= expiration only, 3= expiration and inspiration, 4=difficult to ventilate, require treatment. (3) Ease of LMA insertion, including time to successful insertion (from the beginning of the attempt until success of insertion), the number of insertion attempts, difficulty at insertion (defined as necessity for repositioning or reinsertion). No more than 3 attempts at LMA insertion are allowed. In case of failure, an ETT is used, and the patient will be excluded from further analysis. (4) The episode and degree of salivation during removal of LMA, which is evaluated as follows: 1=none, 2=minimal—no suction, 3=moderate—suction 1×, 4=copious—suction＞1×. (5) The anesthesia-related time, including time to LMA removal (the duration from termination of anesthetics to removal of LMA), and PACU stay time (the duration from arrival in PACU to the time of the physiological criteria-based discharge score achieves at least 12 points). (6) Postoperative pain score will be assessed within stay in the PACU using the Wong-Baker Pain Scale. A score of >4 is defined as moderate-to-severe pain which need to be timely managed. (7) EA will be evaluated within stay in PACU using the Aono’s four point scale (1: calm; 2: not calm but easily consolable; 3: not easily calmed restless or moderately agitated; 4: combative, disoriented, or excited) [24]. The scale scoring of 1 and 2 are considered as the absence of EA, and scale of 3 and 4 are considered as the presence of EA. (8) The development of URTIs within 7 days after surgery. Safety outcomes (1) Hemodynamic parameters (systolic blood pressure [SBP], heart rate [HR], and SpO 2 ) at eight time points (T0, baseline [without intervention]; T1, 5 minutes after inhaling PHC; T2, completion of inhaling PHC; T3, LMA insertion; T4, upon arrival in PACU; T5, pre-LMA mask removal; T6, post-LMA mask removal; T7, ready to discharge from PACU). (2) Other adverse events (AEs) potentially related to inhale the study drug from beginning of inhalation until the 24 postoperative hours, including postoperative nausea and vomiting (PONV), dry month, palpation, dizziness, fever, cough, urine retention, and flushing. Follow-up and withdrawal All participants will receive follow-up on postoperative 24 hours and 7 days via telephone consultants by a research coordinator. For patients and their guardians who no longer agree to participate in this trial can withdraw the informed consent at any time without need of further explanation. Nevertheless, in the case of drop-out patients who have undergone the intervention, the follow-up visits should continue to monitor any potential AEs. Data monitoring and management An independent research coordinator not involving in the intervention process will be dedicated to collect demographics and perioperative data. All data will be recorded in the EDC system under the supervision of the principal investigator. Data entry will be double-input and double-check for accuracy. The electronic database will be locked once the data registration is completed. Each enrolled patient will be assigned an identification number. Datasets without personally identifiable information will be sent to an independent statistician (not involved in the study procedure) for final analysis. The IRB of Zhongshan Ophthalmic Center, Sun Yat-sen University will complete the responsibility of monitoring the conduct of the study and the quality of data. Harm Severe adverse events, that is, those that might result in patient disability, prolonged hospital stay or life-threatening events, will be reported to the IRB within 24 hours. In such situation, the patients can be discontinued from the study, and medical treatment at the clinician discretion will be initiated as soon as possible. The compensation will be completed according to local laws and regulations. Further, the IRB will discuss and make recommendations on whether the study interventions should be modified and whether the study should be stopped. Sample size calculation The sample size was calculated based on a previously reported incidence of PRAEs of 36.2% in children who undergone sevoflurane anesthesia with awake LMA removal [7]. To achieve a 50% reduction in the occurrence of PRAEs by prophylactic inhalation of penehyclidine, a sample size of 91 participants in each group is required to detect a difference at a power of 0.8 and a 0.05 two-sided significance level. Allowing for a 10% dropout rate, a total of 204 participants will be enrolled in this study. The sample size calculation is performed using the PASS version 16.0 (NCSS, Kaysville, Utah, USA). Data analysis plan Statistical analyses will be conducted using IBM SPSS Statistics version 25.0 (Chicago, Illinois, USA). Outcome analyses will be performed in the intention-to-treat population, and a per-protocol analysis will be also conducted for the incidences of PRAEs in both groups. Descriptive analysis will be used for demographics and baseline characteristics of patients in each group. We will use Kolmogorov-Smirnov test to assess the normality distribution of the continuous data. Mean (standard deviation, SD) will be used for normally distributed data, and median (interquartile range, IQR) for data with skewed distribution. Categorical variables will be expressed as number (proportion). Independent t test or Mann-Whitney U test will be used to analyze the time to successful LMA insertion, the number of insertion attempts, the anesthesia-related time, AHR score, postoperative Wong-Baker pain score, and Aono’s four point scale score between the 2 groups. Pearson χ 2 test or Fisher’s exact test will be used to compare the incidences and severity of PRAEs, the degree of salivation during removal of LMA, difficulty at LMA insertion, and incidence of EA as well as any other AEs related to the study drug, besides, the development of respiratory infections within 7 days after surgery between the penehyclidine group and the saline group. Values of SBP, HR, and SpO 2 at different time points will be assessed using one-way repeated-measures analysis of variance. The primary outcome along with the post hoc outcomes will be assessed using binary logistic regression. A forward, stepwise multivariate logistic regression is used to identify significant confounding factors of PRAEs from the following variables: age, gender, body mass index, ASA physical status, family history, medical history, the m-YPAS score, the COLDS score, the PAB score, type and duration of surgery, usage of anesthetic methods. No interim analyses will be applied in this study. In cases of missing value for the primary and secondary outcomes, multiple imputation will be used for incomplete observations. A statistically significant difference is determined as a two-tailed p value < 0.05. Patient and public involvement Patients and public will not be involved in the design or conduct of the study. There is no plan to disseminate the results to study participants. Ethics, dissemination and data sharing This study protocol has been approved by the IRB of Zhongshan Ophthalmic Center, Sun Yat-sen University (2024KYPJ108 and 2024KYPJ108-2). The protocol has been registered at the ClinicalTrials.gov (NCT06624696) on 30 September 2024. All patient guardians will provide written informed consent, and the implementation of this study will conform to the Declaration of Helsinki. The results of this study will be disseminated via manuscript publication and peer-reviewed journals. Original data generated by this study will not be publicly available but on reasonable request to the corresponding author. Protocol amendments In principle, the established study protocol is not to be modified. Any proposed amendments to the study must be reviewed and approved by the principal investigators, clinical research center and IRB of the two study centers. Discussion The use of penehyclidine has been advocated to reduce salivary and respiratory secretions, and induce mild sedation prior to surgery [ 14 ]. The 2015 expert consensus in China concluded that penehyclidine not only effectively reduces mucus secretion but also relaxes airway smooth muscles, dilates bronchioles, and enhances pulmonary compliance [ 30 ]. Additionally, it prevents reflexive actions of the vagus nerve triggered by excessive acetylcholine release, such as abnormal airway contraction, thereby contributing to manage coughing and provide smoother breathing. With the increasing number of pediatric patients undergoing general anesthesia, the management of PRAEs has become a priority in pediatric anesthesia. We hypothesise that prophylactic penehyclidine inhalation would reduce the prevalence of PRAEs in high-risk padiatric patients undergoing sevoflurane anesthesia with LMA. Pediatric patients are exposed to a higher risk of PAREs due to predisposing risk factors, such as nocturnal cough, cold, wheezing, or those with a family history of asthma, rhinitis, eczema, or exposure to passive smoking; currently, the explanation for the development of respiratory adverse events is AHR [ 3 ]. AHR is considered a common response causing by various mechanisms, with significant attention given to the imbalance of neuro-receptors and the airway inflammation [ 31 , 32 ]. Muscarinic Ach receptor (mAchR) subtypes (M1, M2 and M3), widely expressed in the airway, are involved in airway remodeling and inflammation [ 33 ]. Accumulating evidences have indicated that muscarinic receptor antagonists may modulate airway contractility and AHR not only by blocking mAchRs expressed on the airway smooth muscle but also via anti-inflammatory mechanisms by blocking mAchRs expressed on inflammatory cells, submucosal glands, and epithelial cells [ 34 ]. An increasing number of studies have suggested that selective M1 and M3 receptor anticholinergic agents are more effective than β 2 receptor agonists in the treatment of acute episodes of COPD and asthma [ 35 , 36 ]. Thus, PHC may be a promising candidate for preventing respiratory adverse events in pediatric patients. A recent study involving 864 participants demonstrated that PHC can significantly decrease the occurrence of postoperative pulmonary complications in high-risk individuals [ 16 ]. Moreover, PHC moderates the release of inflammatory mediators such as TNF-α, IL-1β, IL-6, PGE2, and COX-2 because of its ability to attenuate Toll-like receptors [ 32 , 37 , 38 ]. These findings suggest that prophylactic use of PHC might benefit anesthetized patients with respiratory symptoms. Recently, nebulized inhalation has become a trend in the clinical application of PHC [ 16 , 17 ]. This way of administration directly targets the airways, allowing for a higher local concentration, which shortens the onset time and increases drug utilization while minimizing systemic side effects [ 21 , 39 ]. Moreover, the long-acting nature of penehyclidine with a half-life of 10.35 hours ensures a sustained pharmacologic effect throughout the perioperative period, reducing the need for repeated dosing as well as the risk of dose-related side effects [ 14 ]. This extended duration of action is particularly beneficial in procedures that involve extended periods of anaesthesia or postoperative recovery. This study is subject to several limitations. First, our inability to determine the blood concentration poses challenges in aligning the duration of action with penehyclidine inhalation. Second, due to the peak blood concentration time of PHC being 34 minutes, it may not achieve effectively preventive effects for pediatric patients undergoing short-time surgery. Third, for children with poor compliance who are unable to cooperate, the efficiency of nebulized inhalation may be affected, leading to measurement bias in the study outcomes. In the present study, we expect to definitively clarify the effect of inhaling penehyclidine in PRAEs for high-risk pediatric patients. The study results may support the idea that prophylactic penehyclidine inhalation reduces the prevalence of PRAEs in pediatric anesthetized patients, especially for those patients in high risks undergoing sevoflurane anaesthesia. Trial status The trial recruitment was initiated on November 1, 2024, and conducted on November 12, 2024. The recruitment of 204 patients at high-risk of PRAEs is expected to complete by December, 2025. Abbreviations PRAEs Perioperative respiratory adverse events AHR airway hyperreactivity LMA laryngeal mask airway EA emergence agitation PHC penehyclidine hydrochloride IRB Institutional Review Board ASA American Society of Anesthesiologists ETT endotracheal tube URTIs upper respiratory tract infections BMI body mass index EDC Electronic Data Capture CRFs case report forms m-YPAS modified Yale Preoperative Anxiety Scale PAB Pediatric Anesthesia Behavior NSAIDs non-steroidal anti-inflammatory drugs PACU postanesthesia care unit SpO2 oxygen saturation CPAP continuous positive airway pressure SBP systolic blood pressure HR heart rate AEs adverse events PONV postoperative nausea and vomiting SD standard deviation IQR interquartile range mAchR Muscarinic Ach receptor. Declarations Acknowledgements This study is supported by the National Natural Science Foundation of China (42276128 and 81901995), and the clinical research project of Zhongshan Ophthalmic Center of Sun Yat-sen University (3030901011175). The sponsors have no role in the study procedure. Authors’ contributions YZ, YW: conceptualisation, design, investigation and writing original draft. YM, TH: conceptualisation, design, investigation, and data curation. JH: conceptualisation, design, investigation, and funding acquisition. DZ: conceptualisation, design, and resources. XG: conceptualisation, design, resources, supervision, validation, writing review and editing. All authors read and approved this manuscript prior to submission. Funding None. Availability of data and materials As a multicenter study, the full analysis set is securely maintained by the lead research center. Investigators at sub-center have access to their own sub-center's dataset but not to the full analysis set. The dataset and statistical code will be made available upon reasonable request to the corresponding author after the study's completion. Ethics approval and consent to participate The first protocol (version 5.0) has received ethical approval from the IRB of Zhongshan Ophthalmic Center, Sun Yat-sen University (2024KYPJ108) on Sep 30, 2024. In the second protocol (version 6.0), the primary outcome was revised from the incidence of minor PRAEs to the incidence of PRAEs (including both minor and major AEs), and also, the sample size was increased, which was approved by the local Ethics Committee (2024KYPJ108-2) on Dec 10, 2024. The trial has been registered at ClinicalTrials.gov (NCT06624696). Prior to participation, legal guardians of the participants will provide informed consent. Results will be disseminated via an international peer-reviewed publication. Consent for publication Not applicable. Competing interests None declared. Author details 1 Department of Anesthesiology, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Sun Yat-sen University, Guangzhou, China. 2 Department of Anesthesiology, Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, China. References Murat I, Constant I, Maud'huy H. Perioperative anaesthetic morbidity in children: a database of 24,165 anaesthetics over a 30-month period. Paediatr Anaesth. 2004;14(2):158–66. 10.1111/j.1460-9592.2004.01167.x . Wudineh DM, Berhe YW, Chekol WB, Adane H, Workie MM. Perioperative Respiratory Adverse Events Among Pediatric Surgical Patients in University Hospitals in Northwest Ethiopia; A Prospective Observational Study. Front Pediatr. 2022;10:827663. 10.3389/fped.2022.827663 . von Ungern-Sternberg BS, Boda K, Chambers NA, Rebmann C, Johnson C, Sly PD, Habre W. Risk assessment for respiratory complications in paediatric anaesthesia: a prospective cohort study. Lancet. 2010;376(9743):773–83. 10.1016/S0140-6736(10)61193-2 . Hii J, Templeton TW, Sommerfield D, Sommerfield A, Matava CT, von Ungern-Sternberg BS. Risk assessment and optimization strategies to reduce perioperative respiratory adverse events in pediatric anesthesia-Part 1 patient and surgical factors. Paediatr Anaesth. 2022;32(2):209–16. 10.1111/pan.14377 . Subramanyam R, Yeramaneni S, Hossain MM, Anneken AM, Varughese AM. Perioperative Respiratory Adverse Events in Pediatric Ambulatory Anesthesia: Development and Validation of a Risk Prediction Tool. Anesth Analg. 2016;122(5):1578–85. 10.1213/ANE.0000000000001216 . Liu X, Cao H, Tan X, Qiao L, Zhang Q, Shi L. Comparison of the Effect of Laryngeal Mask Airway Versus Endotracheal Tube on Airway Management in Pediatric Patients with Tonsillar Hypertrophy. J Perianesth Nurs. 2021;36(2):142–6. 10.1016/j.jopan.2020.06.020 . Karam C, Zeeni C, Yazbeck-Karam V, Shebbo FM, Khalili A, Abi Raad SG, Beresian J, Aouad MT, Kaddoum R. Respiratory Adverse Events After LMA® Mask Removal in Children: A Randomized Trial Comparing Propofol to Sevoflurane. Anesth Analg. 2023;136(1):25–33. 10.1213/ANE.0000000000005945 . Ramgolam A, Hall GL, Zhang G, Hegarty M, von Ungern-Sternberg BS. Deep or awake removal of laryngeal mask airway in children at risk of respiratory adverse events undergoing tonsillectomy-a randomised controlled trial. Br J Anaesth. 2018;120(3):571–80. 10.1016/j.bja.2017.11.094 . Dolling S, Anders NR, Rolfe SE. A comparison of deep vs. awake removal of the laryngeal mask airway in paediatric dental daycase surgery. A randomised controlled trial. Anaesthesia. 2003;58(12):1224–8. 10.1046/j.1365-2044.2003.03413.x . Park JS, Kim KJ, Oh JT, Choi EK, Lee JR. A randomized controlled trial comparing Laryngeal Mask Airway removal during adequate anesthesia and after awakening in children aged 2 to 6 years. J Clin Anesth. 2012;24(7):537–41. 10.1016/j.jclinane.2012.03.004 . Templeton TW, Sommerfield D, Hii J, Sommerfield A, Matava CT, von Ungern-Sternberg BS. Risk assessment and optimization strategies to reduce perioperative respiratory adverse events in Pediatric Anesthesia-Part 2: Anesthesia-related risk and treatment options. Paediatr Anaesth. 2022;32(2):217–27. 10.1111/pan.14376 . Carlson AB, Kraus GP, Physiology CR. 2023 Aug 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Tait AR, Burke C, Voepel-Lewis T, Chiravuri D, Wagner D, Malviya S. Glycopyrrolate does not reduce the incidence of perioperative adverse events in children with upper respiratory tract infections. Anesth Analg. 2007;104(2):265–70. 10.1213/01.ane.0000243333.96141.40 . Wang Y, Gao Y, Ma J. Pleiotropic effects and pharmacological properties of penehyclidine hydrochloride. Drug Des Devel Ther. 2018;12:3289–99. 10.2147/DDDT.S177435 . Wang NA, Su Y, Che XM, Zheng H, Shi ZG. Penehyclidine ameliorates acute lung injury by inhibiting Toll-like receptor 2/4 expression and nuclear factor-κB activation. Exp Ther Med. 2016;11(5):1827–32. 10.3892/etm.2016.3154 . Yan T, Liang XQ, Wang GJ, Wang T, Li WO, Liu Y, Wu LY, Yu KY, Zhu SN, Wang DX, Sessler DI. Prophylactic Penehyclidine Inhalation for Prevention of Postoperative Pulmonary Complications in High-risk Patients: A Double-blind Randomized Trial. Anesthesiology. 2022;136(4):551–66. 10.1097/ALN.0000000000004159 . An MZ, Xu CY, Hou YR, Li ZP, Gao TS, Zhou QH. Effect of intravenous vs. inhaled penehyclidine on respiratory mechanics in patients during one-lung ventilation for thoracoscopic surgery: a prospective, double-blind, randomised controlled trial. BMC Pulm Med. 2023;23(1):353. 10.1186/s12890-023-02653-8 . Turkel S, Hanft A, Epstein D, Jacobson J. Review of delirium in the pediatric intensive care unit. J Pediatr Intensive Care. 2013;2(4):169–76. 10.3233/PIC-13070 . Kain ZN, Mayes LC, Cicchetti DV, Bagnall AL, Finley JD, Hofstadter MB. The Yale Preoperative Anxiety Scale: how does it compare with a gold standard? Anesth Analg. 1997;85(4):783–8. 10.1097/00000539-199710000-00012 . Lee BJ, August DA. COLDS: A heuristic preanesthetic risk score for children with upper respiratory tract infection. Paediatr Anaesth. 2014;24(3):349–50. 10.1111/pan.12337 . Martin AR, Finlay WH. Nebulizers for drug delivery to the lungs. Expert Opin Drug Deliv. 2015;12(6):889–900. 10.1517/17425247.2015.995087 . Chu L, Wang Y, Wang S, Su S, Guo Z, Wang G. Intranasal Dexmedetomidine Accompanied by Cartoon Video Preoperation for Reducing Emergence Delirium in Children Undergoing Strabismus Surgery: A Prospective Randomized Trial. Front Surg. 2021;8:754591. 10.3389/fsurg.2021.754591 . Huh H, Cho JE, Lee SW, Kim HC. The effects of two-handed jaw thrust on i-gel™ placement in anesthetized non-paralyzed patients. Minerva Anestesiol. 2021;87(10):1109–16. 10.23736/S0375-9393.21.15696-2 . Aono J, Ueda W, Mamiya K, Takimoto E, Manabe M. Greater incidence of delirium during recovery from sevoflurane anesthesia in preschool boys. Anesthesiology. 1997;87(6):1298–300. 10.1097/00000542-199712000-00006 . Armstrong J, Forrest H, Crawford MW. A prospective observational study comparing a physiological scoring system with time-based discharge criteria in pediatric ambulatory surgical patients. Can J Anaesth. 2015;62(10):1082–8. 10.1007/s12630-015-0428-6 . Ramgolam A, Hall GL, Sommerfield D, Slevin L, Drake-Brockman TFE, Zhang G, von Ungern-Sternberg BS. Premedication with salbutamol prior to surgery does not decrease the risk of perioperative respiratory adverse events in school-aged children. Br J Anaesth. 2017;119(1):150–7. 10.1093/bja/aex139 . Tait AR, Voepel-Lewis T, Burke C, Kostrzewa A, Lewis I. Incidence and risk factors for perioperative adverse respiratory events in children who are obese. Anesthesiology. 2008;108(3):375–80. 10.1097/ALN.0b013e318164ca9b . Pappas AL, Sukhani R, Lurie J, Pawlowski J, Sawicki K, Corsino A. Severity of airway hyperreactivity associated with laryngeal mask airway removal: correlation with volatile anesthetic choice and depth of anesthesia. J Clin Anesth. 2001;13(7):498–503. 10.1016/s0952-8180(01)00318-x . Tait AR, Malviya S, Voepel-Lewis T, Munro HM, Seiwert M, Pandit UA. Risk factors for perioperative adverse respiratory events in children with upper respiratory tract infections. Anesthesiology. 2001;95(2):299–306. 10.1097/00000542-200108000-00008 . Yu JG, Ma H, Wang DX, et al. Expert consensus on the perioperative airway management of penehyclidine hydrochloride. J Clin Anesthesiol. 2015;31:621–3. Bradding P, Porsbjerg C, Côté A, Dahlén SE, Hallstrand TS, Brightling CE. Airway hyperresponsiveness in asthma: The role of the epithelium. J Allergy Clin Immunol. 2024;153(5):1181–93. 10.1016/j.jaci.2024.02.011 . Xiao HT, Liao Z, Tong RS. Penehyclidine hydrochloride: a potential drug for treating COPD by attenuating Toll-like receptors. Drug Des Devel Ther. 2012;6:317–22. 10.2147/DDDT.S36555 . Calzetta L, Coppola A, Ritondo BL, Matino M, Chetta A, Rogliani P. The Impact of Muscarinic Receptor Antagonists on Airway Inflammation: A Systematic Review. Int J Chron Obstruct Pulmon Dis. 2021;16:257–79. 10.2147/COPD.S285867 . Mansfield L, Bernstein JA. Tiotropium in asthma: From bench to bedside. Respir Med. 2019;154:47–55. 10.1016/j.rmed.2019.06.008 . Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Criner GJ, Frith P, Halpin DMG, Han M, López Varela MV, Martinez F, Montes de Oca M, Papi A, Pavord ID, Roche N, Sin DD, Stockley R, Vestbo J, Wedzicha JA, Vogelmeier C. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019;53(5):1900164. 10.1183/13993003.00164-2019 . Wasilewski NV, Lougheed MD, Fisher JT. Changing face of β2-adrenergic and muscarinic receptor therapies in asthma. Curr Opin Pharmacol. 2014;16:148–56. 10.1016/j.coph.2014.05.007 . Lin D, Ma J, Xue Y, Wang Z. Penehyclidine Hydrochloride Preconditioning Provides Cardioprotection in a Rat Model of Myocardial Ischemia/Reperfusion Injury. PLoS ONE. 2015;10(12):e0138051. 10.1371/journal.pone.0138051 . Zhu R, Zhao Y, Li X, Bai T, Wang S, Wang W, Sun Y. Effects of penehyclidine hydrochloride on severe acute pancreatitis-associated acute lung injury in rats. Biomed Pharmacother. 2018;97:1689–93. 10.1016/j.biopha.2017.12.025 . Maccari JG, Teixeira C, Gazzana MB, Savi A, Dexheimer-Neto FL, Knorst MM. Inhalation therapy in mechanical ventilation. J Bras Pneumol. 2015;41(5):467–72. 10.1590/S1806-37132015000000035 . Tables Table 1 The schedule of enrolment, interventions, and assessments for this trial STUDY PERIOD Enrolment Allocation Post-allocation Close-out TIMEPOINT -t 1 0 t 1 t 2 t 3 t 4 t 5 t 6 Preoperative Nebulisation Anaesthesia induction Anaesthesia maintenance Anaesthesia emergence Anaesthesia recovery Postoperative 24 hours Postoperative 1 week ENROLMENT Eligibility screen × Informed consent × Random allocation × Demographics × Baseline data × INTERVENTIONS Inhaling penehyclidine × Inhaling normal saline × ASSESSMENTS PRAEs and severity Ease of LMA insertion × Salivation and severity × The AHR score × The anaesthesia-related time × × Postoperative pain × × Emergence agitation × Haemodynamic data Other adverse events Development of URI × PRAEs, perioperative respiratory adverse events; LMA, laryngeal mask airway; AHR, airway hyperreactivity; URI, upper respiratory infection. Table 2 Definitions of PRAEs Adverse events Definition Severe coughing A series of pronounced, persistent coughs lasting >10 seconds. Breath holding Apnea longer than 5 seconds. Desaturation: oxygen saturation (SpO 2 ) < 95% The limit of 95% is chosen in line with institutional guidelines based on post-anaesthesia care unit discharge criteria. Upper airway obstruction Presence of airway obstruction in combination with a snoring noise, respiratory efforts, or both. Stridor High-pitched sound during breathing. Laryngospasm Complete airway obstruction with associated muscle rigidity of the abdominal and chest wall. Bronchospasm Increased respiratory effort, particularly during expiration and wheeze on auscultation. PRAEs, perioperative respiratory adverse events Supplementary Files SPIRITchecklist.doc Supplementtables.docx Cite Share Download PDF Status: Published Journal Publication published 02 Apr, 2026 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 31 Aug, 2025 Reviewers invited by journal 29 Aug, 2025 Editor invited by journal 03 Mar, 2025 Editor assigned by journal 02 Mar, 2025 First submitted to journal 28 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5718305","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507377329,"identity":"1df9c4b6-14f7-4d4b-9af5-a78755ebca6e","order_by":0,"name":"Yanling Zhu","email":"","orcid":"","institution":"Sun Yat-Sen University Zhongshan Ophthalmic Center","correspondingAuthor":false,"prefix":"","firstName":"Yanling","middleName":"","lastName":"Zhu","suffix":""},{"id":507377330,"identity":"2c2094c3-b307-4284-a5fe-e8ee94a7e861","order_by":1,"name":"Yongyi Wang","email":"","orcid":"","institution":"Sun Yat-Sen University Zhongshan Ophthalmic Center","correspondingAuthor":false,"prefix":"","firstName":"Yongyi","middleName":"","lastName":"Wang","suffix":""},{"id":507377331,"identity":"0878ffd6-06be-4e97-bad2-a40cf031c28e","order_by":2,"name":"Yongjian Mai","email":"","orcid":"","institution":"Sun Yat-Sen University Zhongshan Ophthalmic Center","correspondingAuthor":false,"prefix":"","firstName":"Yongjian","middleName":"","lastName":"Mai","suffix":""},{"id":507377332,"identity":"7edd753a-7fa6-4a6d-b491-ecf57b0f3e30","order_by":3,"name":"Ting Huang","email":"","orcid":"","institution":"Sun Yat-Sen University Zhongshan Ophthalmic Center","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Huang","suffix":""},{"id":507377333,"identity":"c5f58447-92c0-4ddf-87b6-5a8397a0fc61","order_by":4,"name":"Jingxia Huang","email":"","orcid":"","institution":"Sun Yat-Sen University Zhongshan Ophthalmic Center","correspondingAuthor":false,"prefix":"","firstName":"Jingxia","middleName":"","lastName":"Huang","suffix":""},{"id":507377334,"identity":"38107cc5-2502-4460-900b-91124200fe99","order_by":5,"name":"Lin Yiquan","email":"","orcid":"","institution":"Sun Yat-Sen University Zhongshan Ophthalmic Center","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Yiquan","suffix":""},{"id":507377335,"identity":"5afd0642-ab25-490b-b2c4-fab1a93625b4","order_by":6,"name":"Dongsheng Zhao","email":"","orcid":"","institution":"Shenzhen Eye Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dongsheng","middleName":"","lastName":"Zhao","suffix":""},{"id":507377336,"identity":"06b5fec4-f5a9-4199-8018-ec01897db6fd","order_by":7,"name":"Xiaoliang Gan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYLCCBxUMDGzscG4CEVoSzgC1MJOkJbENSBCtRd797DGJxHnb5PmYGZg/8/w5zMDPnmPA8HMHbi2GZ/KSDRK33TZsY2Zgk+ZtO8wg2fPGgLH3DB4tDTmGD4BaGEFamHkbDjMY3MgxYGZsw6Ol/43BgcQ5t+3bYA6zJ6RFXgJkS8PtRKAWBmkeNqAtEgS0GEi8MTZIOHY7uQ2oTHJuWzqPxJlnBQd78dnSn2Mm8aHmtu389ubDH978sZbjb0/e+OAnPlsOwJmMDUw8DAw8IOYBHKohtjQgcRh/4FM6CkbBKBgFIxYAAOzhTFtcYyljAAAAAElFTkSuQmCC","orcid":"","institution":"Sun Yat-Sen University Zhongshan Ophthalmic Center","correspondingAuthor":true,"prefix":"","firstName":"Xiaoliang","middleName":"","lastName":"Gan","suffix":""}],"badges":[],"createdAt":"2024-12-27 01:07:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5718305/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5718305/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-026-09671-x","type":"published","date":"2026-04-02T15:59:41+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90879804,"identity":"9421607c-6e90-44f4-a831-12b8a18ed7ac","added_by":"auto","created_at":"2025-09-09 09:37:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49812,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT Flow Diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5718305/v1/1be249a6c1443204a465c552.png"},{"id":106343601,"identity":"af9f2278-e423-45b1-9a64-6d07d0e2a47d","added_by":"auto","created_at":"2026-04-07 16:07:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1173155,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5718305/v1/68a8cf6a-5b82-43e3-ad72-8c401ab8db6c.pdf"},{"id":90881528,"identity":"11a26ee7-87ca-4332-be62-4465017618d9","added_by":"auto","created_at":"2025-09-09 09:45:11","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":124132,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-5718305/v1/e3aa325a4a4a9dfdd6bb783f.doc"},{"id":90879811,"identity":"db30fa3d-baa8-40d7-afc8-949292b2fb44","added_by":"auto","created_at":"2025-09-09 09:37:11","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":355843,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementtables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5718305/v1/ee51f023d6cb7cf823b3e58b.docx"}],"financialInterests":"","formattedTitle":"Inhaling penehyclidine to prevent perioperative respiratory adverse events in children at risk undergoing sevoflurane anesthesia (PEPSI trial): study protocol for a double-blind, randomized, placebo-controlled trial","fulltext":[{"header":"Introduction","content":"\u003ch2\u003eBackground and rationale\u003c/h2\u003e\u003cp\u003ePerioperative respiratory adverse events (PRAEs) are the most common critical complications in pediatric anesthesia, accounting for nearly one-third of anesthesia-related cardiac arrests [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A large cohort study reported that children with respiratory symptoms, such as nocturnal cough, cold, wheezing, or those with a family history of asthma, rhinitis, eczema, or exposure to passive smoking, can significantly increase the risks of PRAEs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. PRAEs can result in serious neurological damage due to hypoxia, which is strongly linked to prolonged hospital stays, increased medical costs, and perioperative mortality [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Consequently, identifying effective strategies to mitigate the incidence of PRAEs in high-risk children remains a key priority in pediatric anesthesia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOptimizing airway management is crucial for preventing PRAEs during pediatric anesthesia. Although the use of laryngeal mask airway (LMA) has been advocated to reduce the risk of PRAEs as compared to endotracheal intubation, the incidence of PRAEs following LMA removal still remains high [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Karam et al. reported a PRAE incidence of 36.2% following LMA removal [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], with another study indicating further increase to 54% in high-risk preschool children [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In fact, there remains a debate over the optimal timing for LMA removal. Awake removal, in which the LMA is kept in place until the patient regained consciousness, is associated with a higher incidence of physical events such as bucking and coughing, while deep removal reduces these events but increases the risk of airway obstruction due to suppressed airway reflexes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Regardless of awake or deep anesthesia stage at which the LMA is removed, airway secretions or stimulation are the major triggers for PRAEs particularly during the recovery phase, characterized by restoration of parasympathetic function leading to increased salivation and airway secretions, and gradual recovery of sympathetic activity resulting in airway smooth muscle hyperexcitability. Given the potential for airway secretions and hyperreactivity in high-risk patients, anesthesia management is aimed at minimizing stimulation of a potentially irritable airway [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAnticholinergic drugs are usually administered as premedication prior to anesthesia for the purpose of sedation, alleviating tension within various smooth muscles, facilitating tracheal and bronchial relaxation, and suppressing excessive glandular secretions through their action on both central and peripheral postganglionic cholinergic receptors [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In one survey of pediatric anesthesiologists, approximately one-third reported using anticholinergics on a frequent basis for children with URTIs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Penehyclidine is a long-acting muscarinic antagonist with high selectivity for M3 receptor, a subtype of receptor that mediates airway smooth muscle contraction induced by acetylcholine [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Studies has demonstrated the benefits of inhaling penehyclidine hydrochloride (PHC) in reducing airway hyperreactivity, inhibiting inflammatory responses, and improving lung compliance in adults [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e–\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, despite their use, there are no randomized studies to determine the effect of inhaling PHC on PRAEs in high-risk children as anticholinergic drugs may result in pediatric emergence agitation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This randomized controlled study is therefore designed to test the hypothesis that, compared with placebo, prophylactic inhaling of PHC to high-risk children will reduce the incidence of PRAEs following sevoflurane anesthesia with LMA.\u003c/p\u003e\n\u003ch3\u003eObjectives\u003c/h3\u003e\n\u003cp\u003eOur goal is to evaluate the effectiveness of inhaling PHC in reducing PRAEs in children at risk undergoing sevoflurane anesthesia with LMA. Therefore, we will test the hypothesis that pediatric patients who exist at least 1 risk factor of PRAEs prophylactically to inhale PHC have a lower prevalence of PRAEs.\u003c/p\u003e"},{"header":"Methods/design","content":"\u003cp\u003e\u003cstrong\u003eTrial design and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective, multicenter, double-blind, randomized, placebo-controlled trial is designed to explore the effect of the intervention. The study will be coordinated and conducted in Zhongshan Ophthalmic Center, Sun Yat-sen University (Guangzhou, China), and Shenzhen Eye Hospital (Shenzhen, China). The design of this study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 guideline. A detailed flow diagram of the trial is shown in \u003cstrong\u003eFigure 1\u003c/strong\u003e. The study has received Institutional Review Board (IRB) approval (2024KYPJ108) and has been registered on ClinicalTrials.gov (NCT06624696).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient recruitment and informed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnnually, more than 10,000 pediatric patients present for elective surgery under general anesthesia at the two study institutions. All surgeons will be contacted before the start of the study to obtain their consent to allow their patients to be studied. Potential participants are identified and screened by staff anesthesiologists during preoperative evaluation the day before surgery. Then, an investigator of the research team will inform the guardian of the pediatric patients who meet the eligibility criteria, and explain the study protocol, including potential risks and benefits to the pediatrics. Once the investigator has obtained written informed consent from patient guardian, the trial will be proceeded further. We have begun recruitment in November 2024, and the enrolment period will extend to over 12 months. The timeline of enrolment, interventions and assessments for this trial is described in\u003cstrong\u003e\u0026nbsp;Table 1.\u003c/strong\u003e Participants can withdraw from the trial at any time, and any reasons given for withdrawal will be recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria are as follows:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1)\u0026nbsp; \u0026nbsp;\u0026nbsp;pediatric patients aged 3 to 7 years.\u003c/p\u003e\n\u003cp\u003e(2) \u0026nbsp; \u0026nbsp;scheduled to undergo ophthalmic surgery.\u003c/p\u003e\n\u003cp\u003e(3) \u0026nbsp; \u0026nbsp;judged to be at risk of PRAEs (with at least one parentally reported risk factor for the PRAEs, including history of a recent cold, wheezing during exercise, wheezing more than three times in the past 12 months, nocturnal dry cough, eczema, or a family history of asthma, rhinitis, eczema, or exposure to passive smoke).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;are as follows:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1)\u0026nbsp; \u0026nbsp;\u0026nbsp;American Society of Anesthesiologists (ASA) physical classification \u0026ge; IV.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(2)\u0026nbsp; \u0026nbsp;known cardiopulmonary diseases (eg. uncorrected congenital heart disease, primary or secondary pulmonary hypertension, tumors, or structural lung diseases).\u003c/p\u003e\n\u003cp\u003e(3)\u0026nbsp; \u0026nbsp;\u0026nbsp;severe renal dysfunction (requirement of renal replacement therapy) or severe hepatic dysfunction (Child-Pugh grade C);\u003c/p\u003e\n\u003cp\u003e(4)\u0026nbsp; \u0026nbsp;\u0026nbsp;neurological disorders.\u003c/p\u003e\n\u003cp\u003e(5)\u0026nbsp; \u0026nbsp;\u0026nbsp;neuromuscular diseases.\u003c/p\u003e\n\u003cp\u003e(6)\u0026nbsp; \u0026nbsp;\u0026nbsp;contraindication for PHC.\u003c/p\u003e\n\u003cp\u003e(7)\u0026nbsp; \u0026nbsp;\u0026nbsp;inhalation of \u0026beta;2-receptor activator, M-receptor blockers and/or glucocorticoids within 1 month before surgery.\u003c/p\u003e\n\u003cp\u003e(8)\u0026nbsp; \u0026nbsp;\u0026nbsp;allergy to anticholinergic drugs.\u003c/p\u003e\n\u003cp\u003e(9)\u0026nbsp; \u0026nbsp;\u0026nbsp;use of endotracheal tube (ETT) for ventilation.\u003c/p\u003e\n\u003cp\u003e(10)\u0026nbsp;\u0026nbsp;known difficult airway.\u003c/p\u003e\n\u003cp\u003e(11)\u0026nbsp;\u0026nbsp;severe upper respiratory tract infections (URTIs) and the anesthesiologist recommended delaying surgery.\u003c/p\u003e\n\u003cp\u003e(12)\u0026nbsp;\u0026nbsp;participation in other clinical trial during the last month or within the six half-life periods of the study drug used in the last trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(13) \u0026nbsp;parents refusing to allow their children to participate.\u003c/p\u003e\n\u003cp\u003e(14) \u0026nbsp;obesity, with a body mass index (BMI) over 95th percentile according to the WHO guideline.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria of drop out include the following:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1)\u0026nbsp; \u0026nbsp;\u0026nbsp;consent withdrawn by the parents.\u003c/p\u003e\n\u003cp\u003e(2)\u0026nbsp; \u0026nbsp;\u0026nbsp;loss to postoperative follow‐up.\u003c/p\u003e\n\u003cp\u003e(3) \u0026nbsp; \u0026nbsp;ordered to exit by the investigators (eg., poor compliance, or occurrence of severe adverse events).\u003c/p\u003e\n\u003cp\u003e(4) \u0026nbsp; \u0026nbsp;unplanned use of any prohibited drugs (anticholinergics or any medications other than the study drug) from study recruitment to postoperative day 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization and blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter obtaining written informed consent, patients will be randomly assigned, in a 1:1 ratio randomized by OPERA Electronic Data Capture (EDC) System (Beijing Cloud Vision, Ltd., China) using blocked randomization with a block size of 4 or 6, to either treatment or placebo group. Group assignments will be concealed in sequentially numbered opaque envelopes that can only be opened on the morning of surgery and before anesthesia by a research nurse not further involving in the patient care. Then the study medication (penehyclidine hydrochloride, 1 ml: 0.5 mg, Jiangsu Nhwa Pharmaceutical Co., Ltd., China) and normal saline placebo will be prepared using identical 1-ml syringes by this nurse in a closed preparation room. In both groups, the trial drugs will be diluted and mixed with normal saline to 5 ml, added to nebulizers and provided for inhalation within 30 min before anesthesia. Consequently, except for this nurse, the patients, surgeons, anesthesiologists and outcome assessors will be masked to the treatment assignments during the study period. Blinding will be maintained unless it is considered necessary to unblind for safety reasons. These situations will be documented in the case report forms (CRFs). The unmasked patients will be included in the intention-to-treat population but excluded from the per-protocol analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreoperative preparation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn the morning of the surgical day, parents are administered a short questionnaire for documenting their child\u0026rsquo;s demographics (eg, age, height, weight, gender, family history) and medical history (including exiting risk factors of PRAEs) [3]. Preoperative anxiety will be evaluated with the modified Yale Preoperative Anxiety Scale (m-YPAS) score [19]. In addition, the \u0026ldquo;COLDS\u0026rdquo; score will be used to quantify the risk of PRAEs in patients presenting for elective surgery [20] (\u003cstrong\u003eeAppendix supplement table 1\u0026amp;2\u0026amp;3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention and placebo\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUpon arrival in the preoperative holding room, patients are divided into 2 groups to receive either PHC (0.05 mg/kg of 0.05% solution) or equal volume of saline for nebulization therapy. Trial drugs will be diluted to a total volume of 5 mL with normal saline, added to the nebulizer cup for inhalation. Patients will be asked to inhale the entire volume of nebulized drugs within 30 min prior to surgery to maximize its efficacy. The trial drugs will be administered using a air-compressing nebulizer (403M, Jiangsu Yuyue Medical Equipment \u0026amp; Supply Co., Ltd., China). Each child will be intructed to begin the nebulization by using a face mask that covers the nose and mouth while the child is seated upright. Children will be encouraged to take deep and slow breaths, inhaling through the mouth and exhaling through the nose, to ensure the drugs effectively reaches the airway [21].\u003csup\u003e\u0026nbsp;\u003c/sup\u003eTo improve the compliance of preschool children during nebulization, we will allow a guardian to accompany the child in the preoperative holding room, and supply age-appropriate cartoon videos to engage the children and help distract them during the procedure. Children who are unable to cooperate with nebulization treatment will be excluded from the study, but their subsequent medical rights will not be affected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral anesthesia protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants are routinely required to fast 6 hours for solids and 4 hours for clear liquids before the surgery.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eUpon arrival at the operating room, all patients will be generally monitored by electrocardiogram, heart rate, non-invasive blood pressure, pulse oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e), and capnography. Anesthesia induction is performed via a face mask by sevoflurane inhalation given by a gradual increase in the concentration of up to 8% \u003cem\u003evol\u003c/em\u003e along with 100% oxygen, and the Pediatric Anesthesia Behavior (PAB) score (\u003cstrong\u003eeAppendix supplement table 4\u003c/strong\u003e) is used to assess the degree of mask acceptance by an independent anesthesiologists who is blinded to the group assignment [22]. A PAB score of 2 or 3 is considered poor behavioral compliance and 1 mg/kg of propofol will be intravenously injected as a rescue method for rapid induction. Preoxygenation will not be used routinely as per routine clinical practice.\u003c/p\u003e\n\u003cp\u003eAfter loss of consciousness, all patients will be consecutively administered intravenous fentanyl and cisatracurium, meanwhile, manually ventilated through a face mask with high flow (5-6\u0026nbsp;L/min) oxygen. Once the conditions are sufficiently satisfied for a supraglottic airway device insertion (loss of eyelash reflex, jaw relaxation or absence of body movement), a laryngeal mask airway (LMA; TuoRen medical, China) will be inserted using two-handed jaw-thrust maneuver [23]. The size of LMA is chosen based on the patient actual weight sizing for pediatric anesthesia (size 1 for weight\u0026lt;5\u0026nbsp;kg, size 1.5 for weight 5-10\u0026nbsp;kg, size 2 for weight 10-20\u0026nbsp;kg, size 2.5 for weight 20-30\u0026nbsp;kg, size 3 for weight 30-50\u0026nbsp;kg). The cuff of airway is inflated with air to obtain an intra-cuff pressure of 55-60 cmH\u003csub\u003e2\u003c/sub\u003eO (1 cmH\u003csub\u003e2\u003c/sub\u003eO=0.098 kPa). No more than 3 attempts at LMA\u0026nbsp;insertion are allowed. The number of insertions attempts and repositioning will be recorded. In case of failure, an ETT is used to replace, and the patient was excluded from further analysis. Volume-controlled mode is applied with a tidal volume of 8-10\u0026nbsp;ml/kg and an inspiratory/expiratory ratio of 1:1.5-2. Respiratory rate is adjusted to maintain the end-tidal carbon dioxide (EtCO\u003csub\u003e2\u003c/sub\u003e) within 35 to 45\u0026nbsp;mmHg (1 mmHg=0.133 kPa). Peak inspiratory pressure will be recorded.\u003c/p\u003e\n\u003cp\u003eDuring the surgery, anesthesia is maintained with sevoflurane to reach an end-tidal concentration of 1-1.5 minimal alveolar concentration. At 15 min before the end of surgery, non-steroidal anti-inflammatory drugs (NSAIDs; flurbiprofen axetil, 1 mg/kg; Tidepharm Inc., China) is administered to all patients for postoperative analgesia. Upon completion of the surgery, sevoflurane will be discontinued, and patients with a LMA will be transferred to the postanesthesia care unit (PACU) for synchronized intermittent mandatory ventilation. None of patients will be administered acetylcholinesterase inhibitors or sugammadex for reversal of residual neuromuscular blockade. The LMA will be removed by a skilled pediatric anesthesiologist in the PACU, ensuring that the patient is awake and exhibits signs of facial grimace, adequate respiratory rate and volume, eye-opening, and purposeful movements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the PACU, the patients are continuously monitored for HR and SpO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003eand cared for by PACU nurses. Postoperative pain is assessed using the Wong-Baker Pain Scale (\u003cstrong\u003eeAppendix supplement table 5\u003c/strong\u003e), and if the score is greater than 4, fentanyl (0.5 mcg/kg) will be given to control the pain. Behavior on emergence will also be measured using the Aono\u0026rsquo;s Four Point Scale (\u003cstrong\u003eeAppendix supplement table 6\u003c/strong\u003e) [24]; patients with a peak Aono\u0026rsquo;s score greater than 3 are diagnosed as emergence agitation (EA), and will be treated with an additional dose of propofol (10-20 mg). If patient displays persistent vomiting, droperidol 10 mcg/kg will be given for remission. The \u0026nbsp;physiological criteria-based discharge scoring system will be assessed every 15 min [25]. Patients will be returned to the day-care ward when their physiological score achieve at 12 or higher points (\u003cstrong\u003eeAppendix supplement table 7\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Primary outcome","content":"\u003cp\u003ePRAEs are subdivided into two types: major (bronchospasm and laryngospasm) and minor (severe coughing, breath holding, desaturation, upper airway obstruction, and stridor) events. The primary outcome is the incidence of PRAEs. Patients will be considered positive for respiratory adverse events if at least 1 of the above adverse events occurs. PRAEs will be reported by a PACU nurse not involved in the study, and recorded against different phase of anesthesia (induction, maintenance, emergency, or recovery). The definitions of each respiratory adverse events are listed in \u003cstrong\u003eTable 2\u003c/strong\u003e [26,27].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1) The airway hyperreactivity score (\u003cstrong\u003eeAppendix supplement table 8)\u003c/strong\u003e, which is used to assessed severity of PRAEs, accounting for the intensity of coughing, breath holding, and oxygen desaturation on a scale ranging from 0 (none) to 4 (severe). The maximum score is 12, and a score of \u0026le;3 is categorized as mild, 4 to 8 as moderate, and \u0026ge;9 as severe [28].\u003c/p\u003e\n\u003cp\u003e(2) The severity of major respiratory adverse events if occurs, including laryngospasm and bronchospasm during the perioperative periods [7,29]. Laryngospasm will be scored according to its severity as follows: 1=none, 2=partial\u0026mdash;reposition airway, 3=partial\u0026mdash;continuous positive airway pressure (CPAP), 4=complete\u0026mdash;muscle relaxant. In addition, bronchospasm will be scored according to its severity as follows: 1=none, 2= expiration only, 3= expiration and inspiration, 4=difficult to ventilate, require treatment.\u003c/p\u003e\n\u003cp\u003e(3) Ease of LMA insertion, including time to successful insertion (from the beginning of the attempt until success of insertion), the number of insertion attempts, difficulty at insertion (defined as necessity for repositioning or reinsertion). No more than 3 attempts at LMA insertion are allowed. In case of failure, an ETT is used, and the patient will be excluded from further analysis.\u003c/p\u003e\n\u003cp\u003e(4) The episode and degree of salivation during removal of LMA, which is evaluated as follows: 1=none, 2=minimal\u0026mdash;no suction, 3=moderate\u0026mdash;suction 1\u0026times;, 4=copious\u0026mdash;suction＞1\u0026times;.\u003c/p\u003e\n\u003cp\u003e(5) The anesthesia-related time, including time to LMA removal (the duration from termination of anesthetics to removal of LMA), and PACU stay time (the duration from arrival in PACU to the time of the physiological criteria-based discharge score achieves at least 12 points).\u003c/p\u003e\n\u003cp\u003e(6) Postoperative pain score will be assessed within stay in the PACU using the Wong-Baker Pain Scale. A score of \u0026gt;4 is defined as moderate-to-severe pain which need to be timely managed.\u003c/p\u003e\n\u003cp\u003e(7) EA will be evaluated within stay in PACU using the Aono\u0026rsquo;s four point scale (1: calm; 2: not calm but easily consolable; 3: not easily calmed restless or moderately agitated; 4: combative, disoriented, or excited) [24]. The scale scoring of 1 and 2 are considered as the absence of EA, and scale of 3 and 4 are considered as the presence of EA.\u003c/p\u003e\n\u003cp\u003e(8) The development of URTIs within 7 days after surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1) Hemodynamic parameters (systolic blood pressure [SBP], heart rate [HR], and SpO\u003csub\u003e2\u003c/sub\u003e) at eight time points (T0, baseline [without intervention]; T1, 5 minutes after inhaling PHC; T2, completion of inhaling PHC; T3, LMA insertion; T4, upon arrival in PACU; T5, pre-LMA mask removal; T6, post-LMA mask removal; T7, ready to discharge from PACU).\u003c/p\u003e\n\u003cp\u003e(2) Other adverse events (AEs) potentially related to inhale the study drug from beginning of inhalation until the 24 postoperative hours, including postoperative nausea and vomiting (PONV), dry month, palpation, dizziness, fever, cough, urine retention, and flushing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up and withdrawal\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants will receive follow-up on postoperative 24 hours and 7 days via telephone consultants by a research coordinator. For patients and their guardians who no longer agree to participate in this trial can withdraw the informed consent at any time without need of further explanation. Nevertheless, in the case of drop-out patients who have undergone the intervention, the follow-up visits should continue to monitor any potential AEs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData monitoring and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn independent research coordinator not involving in the intervention process will be dedicated to collect demographics and perioperative data. All data will be recorded in the EDC system under the supervision of the principal investigator. Data entry will be double-input and double-check for accuracy. The electronic database will be locked once the data registration is completed. Each enrolled patient will be assigned an identification number. Datasets without personally identifiable information will be sent to an independent statistician (not involved in the study procedure) for final analysis. The IRB of Zhongshan Ophthalmic Center, Sun Yat-sen University will complete the responsibility of monitoring the conduct of the study and the quality of data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHarm\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSevere adverse events, that is, those that might result in patient disability, prolonged hospital stay or life-threatening events, will be reported to the IRB within 24 hours. In such situation, the patients can be discontinued from the study, and medical treatment at the clinician discretion will be initiated as soon as possible. The compensation will be completed according to local laws and regulations. Further, the IRB will discuss and make recommendations on whether the study interventions should be modified and whether the study should be stopped.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size was calculated based on a previously reported incidence of PRAEs of 36.2% in children who undergone sevoflurane anesthesia with awake LMA removal [7]. To achieve a 50% reduction in the occurrence of PRAEs by prophylactic inhalation of penehyclidine, a sample size of 91 participants in each group is required to detect a difference at a power of 0.8 and a 0.05 two-sided significance level. Allowing for a 10% dropout rate, a total of 204 participants will be enrolled in this study. The sample size calculation is performed using the PASS version 16.0 (NCSS, Kaysville, Utah, USA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis plan\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses will be conducted using IBM SPSS Statistics version 25.0 (Chicago, Illinois, USA). Outcome analyses will be performed in the intention-to-treat population, and a per-protocol analysis will be also conducted for the incidences of PRAEs in both groups. Descriptive analysis will be used for demographics and baseline characteristics of patients in each group. We will use Kolmogorov-Smirnov test to assess the normality distribution of the continuous data. Mean (standard deviation, SD) will be used for normally distributed data, and median (interquartile range, IQR) for data with skewed distribution. Categorical variables will be expressed as number (proportion). Independent\u003cem\u003e\u0026nbsp;t\u003c/em\u003e test or Mann-Whitney \u003cem\u003eU\u003c/em\u003e test will be used to analyze the time to successful LMA insertion, the number of insertion attempts, the anesthesia-related time, AHR score, postoperative Wong-Baker pain score, and Aono\u0026rsquo;s four point scale score between the 2 groups. Pearson \u0026chi;\u003csup\u003e2\u003c/sup\u003e test or Fisher\u0026rsquo;s exact test will be used to compare the incidences and severity of PRAEs, the degree of salivation during removal of LMA, difficulty at LMA insertion, and incidence of EA as well as any other AEs related to the study drug, besides, the development of respiratory infections within 7 days after surgery between the penehyclidine group and the saline group. Values of SBP, HR, and SpO\u003csub\u003e2\u003c/sub\u003e at different time points will be assessed using one-way repeated-measures analysis of variance. The primary outcome along with the post hoc outcomes will be assessed using binary logistic regression. A forward, stepwise multivariate logistic regression is used to identify significant confounding factors of PRAEs from the following variables: age, gender, body mass index, ASA physical status, family history, medical history, the m-YPAS score, the COLDS score, the PAB score, type and duration of surgery, usage of anesthetic methods. No interim analyses will be applied in this study. In cases of missing value for the primary and secondary outcomes, multiple imputation will be used for incomplete observations. A statistically significant difference is determined as a two-tailed \u003cem\u003ep\u003c/em\u003e value \u0026lt; 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient and public involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients and public will not be involved in the design or conduct of the study. There is no plan to disseminate the results to study participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics, dissemination and data sharing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study protocol has been approved by the IRB of Zhongshan Ophthalmic Center, Sun Yat-sen University (2024KYPJ108 and 2024KYPJ108-2). The protocol has been registered at the ClinicalTrials.gov (NCT06624696) on 30 September 2024. All patient guardians will provide written informed consent, and the implementation of this study will conform to the Declaration of Helsinki. The results of this study will be disseminated via manuscript publication and peer-reviewed journals. Original data generated by this study will not be publicly available but on reasonable request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol amendments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn principle, the established study protocol is not to be modified. Any proposed amendments to the study must be reviewed and approved by the principal investigators, clinical research center and IRB of the two study centers.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe use of penehyclidine has been advocated to reduce salivary and respiratory secretions, and induce mild sedation prior to surgery [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The 2015 expert consensus in China concluded that penehyclidine not only effectively reduces mucus secretion but also relaxes airway smooth muscles, dilates bronchioles, and enhances pulmonary compliance [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Additionally, it prevents reflexive actions of the vagus nerve triggered by excessive acetylcholine release, such as abnormal airway contraction, thereby contributing to manage coughing and provide smoother breathing. With the increasing number of pediatric patients undergoing general anesthesia, the management of PRAEs has become a priority in pediatric anesthesia. We hypothesise that prophylactic penehyclidine inhalation would reduce the prevalence of PRAEs in high-risk padiatric patients undergoing sevoflurane anesthesia with LMA.\u003c/p\u003e\u003cp\u003ePediatric patients are exposed to a higher risk of PAREs due to predisposing risk factors, such as nocturnal cough, cold, wheezing, or those with a family history of asthma, rhinitis, eczema, or exposure to passive smoking; currently, the explanation for the development of respiratory adverse events is AHR [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. AHR is considered a common response causing by various mechanisms, with significant attention given to the imbalance of neuro-receptors and the airway inflammation [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Muscarinic Ach receptor (mAchR) subtypes (M1, M2 and M3), widely expressed in the airway, are involved in airway remodeling and inflammation [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Accumulating evidences have indicated that muscarinic receptor antagonists may modulate airway contractility and AHR not only by blocking mAchRs expressed on the airway smooth muscle but also via anti-inflammatory mechanisms by blocking mAchRs expressed on inflammatory cells, submucosal glands, and epithelial cells [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. An increasing number of studies have suggested that selective M1 and M3 receptor anticholinergic agents are more effective than β\u003csub\u003e2\u003c/sub\u003e receptor agonists in the treatment of acute episodes of COPD and asthma [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Thus, PHC may be a promising candidate for preventing respiratory adverse events in pediatric patients.\u003c/p\u003e\u003cp\u003eA recent study involving 864 participants demonstrated that PHC can significantly decrease the occurrence of postoperative pulmonary complications in high-risk individuals [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Moreover, PHC moderates the release of inflammatory mediators such as TNF-α, IL-1β, IL-6, PGE2, and COX-2 because of its ability to attenuate Toll-like receptors [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. These findings suggest that prophylactic use of PHC might benefit anesthetized patients with respiratory symptoms. Recently, nebulized inhalation has become a trend in the clinical application of PHC [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This way of administration directly targets the airways, allowing for a higher local concentration, which shortens the onset time and increases drug utilization while minimizing systemic side effects [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Moreover, the long-acting nature of penehyclidine with a half-life of 10.35 hours ensures a sustained pharmacologic effect throughout the perioperative period, reducing the need for repeated dosing as well as the risk of dose-related side effects [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This extended duration of action is particularly beneficial in procedures that involve extended periods of anaesthesia or postoperative recovery.\u003c/p\u003e\u003cp\u003eThis study is subject to several limitations. First, our inability to determine the blood concentration poses challenges in aligning the duration of action with penehyclidine inhalation. Second, due to the peak blood concentration time of PHC being 34 minutes, it may not achieve effectively preventive effects for pediatric patients undergoing short-time surgery. Third, for children with poor compliance who are unable to cooperate, the efficiency of nebulized inhalation may be affected, leading to measurement bias in the study outcomes. In the present study, we expect to definitively clarify the effect of inhaling penehyclidine in PRAEs for high-risk pediatric patients. The study results may support the idea that prophylactic penehyclidine inhalation reduces the prevalence of PRAEs in pediatric anesthetized patients, especially for those patients in high risks undergoing sevoflurane anaesthesia.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\u003ch2\u003eTrial status\u003c/h2\u003e\u003cp\u003eThe trial recruitment was initiated on November 1, 2024, and conducted on November 12, 2024. The recruitment of 204 patients at high-risk of PRAEs is expected to complete by December, 2025.\u003c/p\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePRAEs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePerioperative respiratory adverse events\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAHR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eairway hyperreactivity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLMA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003elaryngeal mask airway\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eemergence agitation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePHC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epenehyclidine hydrochloride\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIRB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInstitutional Review Board\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eASA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmerican Society of Anesthesiologists\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eETT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eendotracheal tube\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eURTIs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eupper respiratory tract infections\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebody mass index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEDC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectronic Data Capture\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCRFs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecase report forms\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003em-YPAS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emodified Yale Preoperative Anxiety Scale\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePAB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePediatric Anesthesia Behavior\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNSAIDs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003enon-steroidal anti-inflammatory drugs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePACU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epostanesthesia care unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSpO2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eoxygen saturation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCPAP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003econtinuous positive airway pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esystolic blood pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eheart rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAEs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eadverse events\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePONV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epostoperative nausea and vomiting\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003estandard deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003einterquartile range\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003emAchR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMuscarinic Ach receptor.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by the National Natural Science Foundation of China (42276128 and 81901995), and the clinical research project of Zhongshan Ophthalmic Center of Sun Yat-sen University (3030901011175). The sponsors have no role in the study procedure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYZ, YW: conceptualisation, design, investigation and writing original draft. YM, TH: conceptualisation, design, investigation, and data curation. JH: conceptualisation, design, investigation, and funding acquisition. DZ: conceptualisation, design, and resources. XG: conceptualisation, design, resources, supervision, validation, writing review and editing. All authors read and approved this manuscript prior to submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs a multicenter study, the full analysis set is securely maintained by the lead research center. Investigators at sub-center have access to their own sub-center\u0026apos;s dataset but not to the full analysis set. The dataset and statistical code will be made available upon reasonable request to the corresponding author after the study\u0026apos;s completion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe first protocol (version 5.0) has received ethical approval from the IRB of Zhongshan Ophthalmic Center, Sun Yat-sen University (2024KYPJ108) on Sep 30, 2024. In the second protocol (version 6.0), the primary outcome was revised from the incidence of minor PRAEs to the incidence of PRAEs (including both minor and major AEs), and also, the sample size was increased, which was approved by the local Ethics Committee (2024KYPJ108-2) on Dec 10, 2024. The trial has been registered at ClinicalTrials.gov (NCT06624696). Prior to participation, legal guardians of the participants will provide informed consent. Results will be disseminated via an international peer-reviewed publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Anesthesiology, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Sun Yat-sen University, Guangzhou, China. \u003csup\u003e2\u003c/sup\u003eDepartment of Anesthesiology, Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMurat I, Constant I, Maud'huy H. Perioperative anaesthetic morbidity in children: a database of 24,165 anaesthetics over a 30-month period. Paediatr Anaesth. 2004;14(2):158\u0026ndash;66. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1460-9592.2004.01167.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1460-9592.2004.01167.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWudineh DM, Berhe YW, Chekol WB, Adane H, Workie MM. Perioperative Respiratory Adverse Events Among Pediatric Surgical Patients in University Hospitals in Northwest Ethiopia; A Prospective Observational Study. Front Pediatr. 2022;10:827663. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fped.2022.827663\u003c/span\u003e\u003cspan address=\"10.3389/fped.2022.827663\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evon Ungern-Sternberg BS, Boda K, Chambers NA, Rebmann C, Johnson C, Sly PD, Habre W. Risk assessment for respiratory complications in paediatric anaesthesia: a prospective cohort study. Lancet. 2010;376(9743):773\u0026ndash;83. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(10)61193-2\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(10)61193-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHii J, Templeton TW, Sommerfield D, Sommerfield A, Matava CT, von Ungern-Sternberg BS. Risk assessment and optimization strategies to reduce perioperative respiratory adverse events in pediatric anesthesia-Part 1 patient and surgical factors. Paediatr Anaesth. 2022;32(2):209\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/pan.14377\u003c/span\u003e\u003cspan address=\"10.1111/pan.14377\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSubramanyam R, Yeramaneni S, Hossain MM, Anneken AM, Varughese AM. Perioperative Respiratory Adverse Events in Pediatric Ambulatory Anesthesia: Development and Validation of a Risk Prediction Tool. Anesth Analg. 2016;122(5):1578\u0026ndash;85. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1213/ANE.0000000000001216\u003c/span\u003e\u003cspan address=\"10.1213/ANE.0000000000001216\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu X, Cao H, Tan X, Qiao L, Zhang Q, Shi L. Comparison of the Effect of Laryngeal Mask Airway Versus Endotracheal Tube on Airway Management in Pediatric Patients with Tonsillar Hypertrophy. J Perianesth Nurs. 2021;36(2):142\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jopan.2020.06.020\u003c/span\u003e\u003cspan address=\"10.1016/j.jopan.2020.06.020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaram C, Zeeni C, Yazbeck-Karam V, Shebbo FM, Khalili A, Abi Raad SG, Beresian J, Aouad MT, Kaddoum R. Respiratory Adverse Events After LMA\u0026reg; Mask Removal in Children: A Randomized Trial Comparing Propofol to Sevoflurane. Anesth Analg. 2023;136(1):25\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1213/ANE.0000000000005945\u003c/span\u003e\u003cspan address=\"10.1213/ANE.0000000000005945\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRamgolam A, Hall GL, Zhang G, Hegarty M, von Ungern-Sternberg BS. Deep or awake removal of laryngeal mask airway in children at risk of respiratory adverse events undergoing tonsillectomy-a randomised controlled trial. Br J Anaesth. 2018;120(3):571\u0026ndash;80. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bja.2017.11.094\u003c/span\u003e\u003cspan address=\"10.1016/j.bja.2017.11.094\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDolling S, Anders NR, Rolfe SE. A comparison of deep vs. awake removal of the laryngeal mask airway in paediatric dental daycase surgery. A randomised controlled trial. Anaesthesia. 2003;58(12):1224\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1046/j.1365-2044.2003.03413.x\u003c/span\u003e\u003cspan address=\"10.1046/j.1365-2044.2003.03413.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePark JS, Kim KJ, Oh JT, Choi EK, Lee JR. A randomized controlled trial comparing Laryngeal Mask Airway removal during adequate anesthesia and after awakening in children aged 2 to 6 years. J Clin Anesth. 2012;24(7):537\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jclinane.2012.03.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jclinane.2012.03.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTempleton TW, Sommerfield D, Hii J, Sommerfield A, Matava CT, von Ungern-Sternberg BS. Risk assessment and optimization strategies to reduce perioperative respiratory adverse events in Pediatric Anesthesia-Part 2: Anesthesia-related risk and treatment options. Paediatr Anaesth. 2022;32(2):217\u0026ndash;27. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/pan.14376\u003c/span\u003e\u003cspan address=\"10.1111/pan.14376\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCarlson AB, Kraus GP, Physiology CR. 2023 Aug 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTait AR, Burke C, Voepel-Lewis T, Chiravuri D, Wagner D, Malviya S. Glycopyrrolate does not reduce the incidence of perioperative adverse events in children with upper respiratory tract infections. Anesth Analg. 2007;104(2):265\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1213/01.ane.0000243333.96141.40\u003c/span\u003e\u003cspan address=\"10.1213/01.ane.0000243333.96141.40\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang Y, Gao Y, Ma J. Pleiotropic effects and pharmacological properties of penehyclidine hydrochloride. Drug Des Devel Ther. 2018;12:3289\u0026ndash;99. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/DDDT.S177435\u003c/span\u003e\u003cspan address=\"10.2147/DDDT.S177435\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang NA, Su Y, Che XM, Zheng H, Shi ZG. Penehyclidine ameliorates acute lung injury by inhibiting Toll-like receptor 2/4 expression and nuclear factor-κB activation. Exp Ther Med. 2016;11(5):1827\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3892/etm.2016.3154\u003c/span\u003e\u003cspan address=\"10.3892/etm.2016.3154\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYan T, Liang XQ, Wang GJ, Wang T, Li WO, Liu Y, Wu LY, Yu KY, Zhu SN, Wang DX, Sessler DI. Prophylactic Penehyclidine Inhalation for Prevention of Postoperative Pulmonary Complications in High-risk Patients: A Double-blind Randomized Trial. Anesthesiology. 2022;136(4):551\u0026ndash;66. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/ALN.0000000000004159\u003c/span\u003e\u003cspan address=\"10.1097/ALN.0000000000004159\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAn MZ, Xu CY, Hou YR, Li ZP, Gao TS, Zhou QH. Effect of intravenous vs. inhaled penehyclidine on respiratory mechanics in patients during one-lung ventilation for thoracoscopic surgery: a prospective, double-blind, randomised controlled trial. BMC Pulm Med. 2023;23(1):353. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12890-023-02653-8\u003c/span\u003e\u003cspan address=\"10.1186/s12890-023-02653-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTurkel S, Hanft A, Epstein D, Jacobson J. Review of delirium in the pediatric intensive care unit. J Pediatr Intensive Care. 2013;2(4):169\u0026ndash;76. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3233/PIC-13070\u003c/span\u003e\u003cspan address=\"10.3233/PIC-13070\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKain ZN, Mayes LC, Cicchetti DV, Bagnall AL, Finley JD, Hofstadter MB. The Yale Preoperative Anxiety Scale: how does it compare with a gold standard? Anesth Analg. 1997;85(4):783\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00000539-199710000-00012\u003c/span\u003e\u003cspan address=\"10.1097/00000539-199710000-00012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee BJ, August DA. COLDS: A heuristic preanesthetic risk score for children with upper respiratory tract infection. Paediatr Anaesth. 2014;24(3):349\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/pan.12337\u003c/span\u003e\u003cspan address=\"10.1111/pan.12337\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartin AR, Finlay WH. Nebulizers for drug delivery to the lungs. Expert Opin Drug Deliv. 2015;12(6):889\u0026ndash;900. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1517/17425247.2015.995087\u003c/span\u003e\u003cspan address=\"10.1517/17425247.2015.995087\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChu L, Wang Y, Wang S, Su S, Guo Z, Wang G. Intranasal Dexmedetomidine Accompanied by Cartoon Video Preoperation for Reducing Emergence Delirium in Children Undergoing Strabismus Surgery: A Prospective Randomized Trial. Front Surg. 2021;8:754591. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fsurg.2021.754591\u003c/span\u003e\u003cspan address=\"10.3389/fsurg.2021.754591\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuh H, Cho JE, Lee SW, Kim HC. The effects of two-handed jaw thrust on i-gel\u0026trade; placement in anesthetized non-paralyzed patients. Minerva Anestesiol. 2021;87(10):1109\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.23736/S0375-9393.21.15696-2\u003c/span\u003e\u003cspan address=\"10.23736/S0375-9393.21.15696-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAono J, Ueda W, Mamiya K, Takimoto E, Manabe M. Greater incidence of delirium during recovery from sevoflurane anesthesia in preschool boys. Anesthesiology. 1997;87(6):1298\u0026ndash;300. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00000542-199712000-00006\u003c/span\u003e\u003cspan address=\"10.1097/00000542-199712000-00006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArmstrong J, Forrest H, Crawford MW. A prospective observational study comparing a physiological scoring system with time-based discharge criteria in pediatric ambulatory surgical patients. Can J Anaesth. 2015;62(10):1082\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12630-015-0428-6\u003c/span\u003e\u003cspan address=\"10.1007/s12630-015-0428-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRamgolam A, Hall GL, Sommerfield D, Slevin L, Drake-Brockman TFE, Zhang G, von Ungern-Sternberg BS. Premedication with salbutamol prior to surgery does not decrease the risk of perioperative respiratory adverse events in school-aged children. Br J Anaesth. 2017;119(1):150\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/bja/aex139\u003c/span\u003e\u003cspan address=\"10.1093/bja/aex139\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTait AR, Voepel-Lewis T, Burke C, Kostrzewa A, Lewis I. Incidence and risk factors for perioperative adverse respiratory events in children who are obese. Anesthesiology. 2008;108(3):375\u0026ndash;80. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/ALN.0b013e318164ca9b\u003c/span\u003e\u003cspan address=\"10.1097/ALN.0b013e318164ca9b\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePappas AL, Sukhani R, Lurie J, Pawlowski J, Sawicki K, Corsino A. Severity of airway hyperreactivity associated with laryngeal mask airway removal: correlation with volatile anesthetic choice and depth of anesthesia. J Clin Anesth. 2001;13(7):498\u0026ndash;503. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0952-8180(01)00318-x\u003c/span\u003e\u003cspan address=\"10.1016/s0952-8180(01)00318-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTait AR, Malviya S, Voepel-Lewis T, Munro HM, Seiwert M, Pandit UA. Risk factors for perioperative adverse respiratory events in children with upper respiratory tract infections. Anesthesiology. 2001;95(2):299\u0026ndash;306. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00000542-200108000-00008\u003c/span\u003e\u003cspan address=\"10.1097/00000542-200108000-00008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYu JG, Ma H, Wang DX, et al. Expert consensus on the perioperative airway management of penehyclidine hydrochloride. J Clin Anesthesiol. 2015;31:621\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBradding P, Porsbjerg C, C\u0026ocirc;t\u0026eacute; A, Dahl\u0026eacute;n SE, Hallstrand TS, Brightling CE. Airway hyperresponsiveness in asthma: The role of the epithelium. J Allergy Clin Immunol. 2024;153(5):1181\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaci.2024.02.011\u003c/span\u003e\u003cspan address=\"10.1016/j.jaci.2024.02.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXiao HT, Liao Z, Tong RS. Penehyclidine hydrochloride: a potential drug for treating COPD by attenuating Toll-like receptors. Drug Des Devel Ther. 2012;6:317\u0026ndash;22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/DDDT.S36555\u003c/span\u003e\u003cspan address=\"10.2147/DDDT.S36555\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCalzetta L, Coppola A, Ritondo BL, Matino M, Chetta A, Rogliani P. The Impact of Muscarinic Receptor Antagonists on Airway Inflammation: A Systematic Review. Int J Chron Obstruct Pulmon Dis. 2021;16:257\u0026ndash;79. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/COPD.S285867\u003c/span\u003e\u003cspan address=\"10.2147/COPD.S285867\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMansfield L, Bernstein JA. Tiotropium in asthma: From bench to bedside. Respir Med. 2019;154:47\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.rmed.2019.06.008\u003c/span\u003e\u003cspan address=\"10.1016/j.rmed.2019.06.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Criner GJ, Frith P, Halpin DMG, Han M, L\u0026oacute;pez Varela MV, Martinez F, Montes de Oca M, Papi A, Pavord ID, Roche N, Sin DD, Stockley R, Vestbo J, Wedzicha JA, Vogelmeier C. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019;53(5):1900164. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1183/13993003.00164-2019\u003c/span\u003e\u003cspan address=\"10.1183/13993003.00164-2019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWasilewski NV, Lougheed MD, Fisher JT. Changing face of β2-adrenergic and muscarinic receptor therapies in asthma. Curr Opin Pharmacol. 2014;16:148\u0026ndash;56. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.coph.2014.05.007\u003c/span\u003e\u003cspan address=\"10.1016/j.coph.2014.05.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin D, Ma J, Xue Y, Wang Z. Penehyclidine Hydrochloride Preconditioning Provides Cardioprotection in a Rat Model of Myocardial Ischemia/Reperfusion Injury. PLoS ONE. 2015;10(12):e0138051. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0138051\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0138051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhu R, Zhao Y, Li X, Bai T, Wang S, Wang W, Sun Y. Effects of penehyclidine hydrochloride on severe acute pancreatitis-associated acute lung injury in rats. Biomed Pharmacother. 2018;97:1689\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.biopha.2017.12.025\u003c/span\u003e\u003cspan address=\"10.1016/j.biopha.2017.12.025\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaccari JG, Teixeira C, Gazzana MB, Savi A, Dexheimer-Neto FL, Knorst MM. Inhalation therapy in mechanical ventilation. J Bras Pneumol. 2015;41(5):467\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1590/S1806-37132015000000035\u003c/span\u003e\u003cspan address=\"10.1590/S1806-37132015000000035\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"101%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eThe schedule of enrolment, interventions, and assessments for this trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTUDY PERIOD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnrolment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAllocation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-allocation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClose-out\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTIMEPOINT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e-t\u003csub\u003e1\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003et\u003csub\u003e1\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003et\u003csub\u003e2\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003et\u003csub\u003e3\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003et\u003csub\u003e4\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003et\u003csub\u003e5\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003et\u003csub\u003e6\u003c/sub\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreoperative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNebulisation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnaesthesia induction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnaesthesia maintenance\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnaesthesia emergence\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnaesthesia recovery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostoperative 24 hours\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostoperative 1 week\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eENROLMENT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eEligibility screen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eRandom allocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eDemographics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eBaseline data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eINTERVENTIONS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eInhaling penehyclidine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eInhaling normal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eASSESSMENTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003ePRAEs and severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.4757%;\" colspan=\"5\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003cimg src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img1757083116.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eEase of LMA insertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eSalivation and severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eThe AHR score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eThe anaesthesia-related time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003ePostoperative pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eEmergence agitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eHaemodynamic data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72.4826%;\" colspan=\"7\"\u003e\n \u003cp\u003e\u0026nbsp;\u003cimg src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img1757083191.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eOther adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61.8924%;\" colspan=\"6\"\u003e\u003cimg src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img1757083219.png\"\u003e\u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eDevelopment of URI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003ePRAEs, perioperative respiratory adverse events; LMA, laryngeal mask airway; AHR, airway hyperreactivity; URI, upper respiratory infection.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Definitions of PRAEs\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eAdverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003eDefinition\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eSevere coughing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003eA series of pronounced, persistent coughs lasting \u0026gt;10 seconds.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eBreath holding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003eApnea longer than 5 seconds.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eDesaturation: oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e) \u0026lt; 95%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003eThe limit of 95% is chosen in line with institutional guidelines based on post-anaesthesia care unit discharge criteria.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eUpper airway obstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003ePresence of airway obstruction in combination with a snoring noise, respiratory efforts, or both.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eStridor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003eHigh-pitched sound during breathing.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eLaryngospasm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003eComplete airway obstruction with associated muscle rigidity of the abdominal and chest wall.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 223px;\"\u003e\n \u003cp\u003eBronchospasm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 441px;\"\u003e\n \u003cp\u003eIncreased respiratory effort, particularly during expiration and wheeze on auscultation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003ePRAEs, perioperative respiratory adverse events\u003c/em\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"perioperative respiratory adverse events, penehyclidine, nebulization therapy, high-risk patient, pediatric anesthesia","lastPublishedDoi":"10.21203/rs.3.rs-5718305/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5718305/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003ePerioperative respiratory adverse events (PRAEs) remains a challenge for pediatric anesthesia, inhalation of penehyclidine has been showed to reduce postoperative pulmonary complications and enhance the recovery in high-risk surgical adults. Thus, prophylactic penehyclidine inhalation might show promising benefits against PRAEs in children with high risk factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAims \u003c/strong\u003eTo clarify the effectiveness of inhaling penehyclidine in reducing PRAEs in pediatric patients at risk scheduled for elective surgery following sevoflurane anesthesia with LMA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis is a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Two hundred and four children, aged 3 to 7 years, undergoing ophthalmic surgery (minor surgery), will be randomized in a ratio of 1:1 to receive either inhaling penehyclidine hydrochloride (PHC, a dose of 0.05 mg/kg, diluted and mixed with normal saline to a total volume of 5 ml) or identical volumes and colour of normal saline before anesthesia. The primary outcome is the incidence of PRAEs between the 2 groups. Secondary outcomes include the airway hyperreactivity (AHR) score, and the severity of laryngospasm and bronchospasm if occurs. Moreover, ease of laryngeal mask airway (LMA) insertion, episode and degree of salivation during removal of LMA, anesthesia-related recovery time, postoperative pain score, incidence of emergence agitation (EA), hemodynamic parameters, other postoperative adverse events related to the study drug within the first 24 postoperative hours, and the development of respiratory infections within 7 days after surgery will be also collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e The results of this study will provide valuable insights into the potential role of inhaling PHC in reducing PRAEs in a high-risk pediatric cohort during sevofurane anesthesia with LMA, thereby promoting clinical practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration \u003c/strong\u003eClinicalTrials.gov (NCT06624696). Registered on 30 September 2024.\u003c/p\u003e\n\u003cp\u003ehttps://clinicaltrials.gov/study/NCT06624696\u003c/p\u003e","manuscriptTitle":"Inhaling penehyclidine to prevent perioperative respiratory adverse events in children at risk undergoing sevoflurane anesthesia (PEPSI trial): study protocol for a double-blind, randomized, placebo-controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 09:37:06","doi":"10.21203/rs.3.rs-5718305/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-08-31T05:42:27+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-29T09:56:13+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Trials","date":"2025-03-03T13:45:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-02T07:39:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-02-28T10:37:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2218fe2e-02dc-41e4-927a-d908d9b456e4","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T16:03:11+00:00","versionOfRecord":{"articleIdentity":"rs-5718305","link":"https://doi.org/10.1186/s13063-026-09671-x","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-04-02 15:59:41","publishedOnDateReadable":"April 2nd, 2026"},"versionCreatedAt":"2025-09-09 09:37:06","video":"","vorDoi":"10.1186/s13063-026-09671-x","vorDoiUrl":"https://doi.org/10.1186/s13063-026-09671-x","workflowStages":[]},"version":"v1","identity":"rs-5718305","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5718305","identity":"rs-5718305","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}