Successful Deep Sedation with Remimazolam and Alfentanil in a Child Susceptible to Malignant Hyperthermia: A Case Report

Successful Deep Sedation with Remimazolam and Alfentanil in a Child Susceptible to Malignant Hyperthermia: A Case Report | 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 Case Report Successful Deep Sedation with Remimazolam and Alfentanil in a Child Susceptible to Malignant Hyperthermia: A Case Report Kailai Zhu, Shuangwei Wu, Xianglin Hao, Chuanguang Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6150816/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Apr, 2025 Read the published version in BMC Anesthesiology → Version 1 posted 10 You are reading this latest preprint version Abstract Background Malignant hyperthermia (MH) is a life-threatening autosomal-dominant disorder caused by mutations in the ryanodine receptor 1 (RYR1) gene, leading to calcium dysregulation in skeletal muscle. Patients with genetically confirmed MH susceptibility must strictly avoid volatile anesthetics and succinylcholine. Intravenous deep sedation presents a viable alternative, yet evidence supporting remimazolam use in pediatric MH patients remains scarce. Case presentation We report the first case of a 1-year-old male patient with genetically confirmed MH susceptibility undergoing orchidopexy under remimazolam-alfentanil deep sedation combined with caudal block. The patient had no MH manifestations intraoperatively or postoperatively and recovered uneventfully. Conclusion This case demonstrates the feasibility of remimazolam-based deep sedation in genetically confirmed pediatric MH patients, supporting its safety profile in this population. Further multicenter studies are needed to establish standardized protocols. Malignant hyperthermia Remimazolam Pediatric anesthesia RYR1 mutation Deep sedation Figures Figure 1 Background Malignant hyperthermia (MH) is a rare but fatal pharmacogenetic disorder primarily caused by pathogenic variants in the RYR1 gene, which disrupts calcium release from the sarcoplasmic reticulum [ 1 ] . Exposure to triggering agents (volatile anesthetics and succinylcholine) induces a hypermetabolic crisis characterized by hypercarbia, hyperthermia, muscle rigidity, and rhabdomyolysis [ 2 ] . Current guidelines recommend Total Intravenous Anesthesia(TIVA) as the standard anesthetic approach for MH-susceptible patients to avoid these triggers [ 3 ] . Remimazolam, a short-acting benzodiazepine, has emerged as a potential alternative to propofol-based TIVA in MH-susceptible individuals. Previous cellular studies demonstrated that remimazolam does not induce calcium release in RYR1-mutant cells at clinical concentrations, and limited clinical data suggest its safety in adult MH-susceptible patients [ 4 ] . However, its application in pediatric populations remains understudied due to age-related pharmacokinetic differences and the rarity of confirmed MH cases in this group. This case report describes the successful use of remimazolam-alfentanil deep sedation combined with caudal block in a 1-year-old patient with genetically confirmed MH susceptibility, providing new insights into the anesthetic management of MH in pediatrics. Case presentation A 1-year-old male infant (weight 9 kg, height 75 cm) was admitted for scheduled orchidopexy. The patient presented with right-sided cryptorchidism noted at birth, followed by progressive feeding difficulties, hypotonia, and global developmental delay observed during postnatal growth. The genetic testing revealed that the patient carried two heterozygous RYR1 mutations (c.11608 + 1G > A and c.13660-29G > A), while the father exhibited a heterozygous mutation (c.13660-29G > A) and the mother a heterozygous mutation (c.11608 + 1G > A). These mutations (c.11608 + 1G > A and c.13660-29G > A) are not listed in the ClinVar database. According to the American College of Medical Genetics and Genomics(ACMG) guidelines, these variants were classified as Variant of Uncertain Significance (VUS), but may still be considered potentially pathogenic(Fig. 1 ). During the preoperative evaluation, the patient exhibited right ptosis with limited eye-opening, inability to stand or walk independently, and growth and development delay compared to age-matched peers.Preanesthetic examination and laboratory evaluation results were within the normal range. According to the European Malignant Hyperthermia Group (EMHG) guidelines [3], we prepared using an anesthesia machine previously free of volatile agents, strictly avoided volatile anesthetics and succinylcholine, and implemented remimazolam-alfentanil deep sedation combined with caudal block for intraoperative analgesia to minimize reliance on systemic opioids. Preoperative measures included having dantrolene readily available per Chinese drug labeling recommendations (initial dose: 1 mg/kg, with incremental doses of 1 mg/kg as needed, up to a maximum of 7 mg/kg), along with rapid cooling equipment such as ice packs, cold saline infusion, and continuous blood gas monitoring. The surgery was performed using a minimally invasive open surgical technique. After establishing intravenous access in the ward, the patient was transferred to the operating room. Upon arrival, electrocardiography, pulse oximetry, and non-invasive blood pressure monitoring were applied. No premedication was administered before anesthesia. Considering the patient’s non-cooperation, remimazolam 0.2 mg/kg (actual dose: 1.8 mg) was administered first, followed by the placement of a nasal cannula with capnographic monitoring of end-tidal carbon dioxide (EtCO₂). Alfentanil 10 µg/kg (actual dose: 90 µg) was then administered, followed by continuous infusions of remimazolam at 1–2 mg/kg/h (total ≈ 11 mg) and alfentanil at 10–20 µg/kg/h (total ≈ 90 µg).Rectal temperature probes and radial artery catheters were placed for continuous core temperature and blood pressure monitoring. Caudal block with 0.25% ropivacaine (10 mL) provided effective intraoperative analgesia, reducing the need for additional anesthetic agents and minimizing hemodynamic fluctuations. Throughout the 40-minute procedure, the patient maintained spontaneous ventilation without the use of a laryngeal mask or endotracheal intubation. Vital signs remained stable, with EtCO₂ levels fluctuating between 37–47 mmHg and body temperature ranging from 36.5–37.2°C, with no signs of MH. The depth of sedation was consistent with deep sedation as defined by the ASA, with spontaneous ventilation, airway patency, and stable hemodynamics adequately maintained under remimazolam and alfentanil anesthesia combined with regional block.The patient spontaneously recovered 5 minutes after discontinuing anesthetics, and maintained stable vital signs in the postanesthesia care unit(PACU) for 30 minutes, followed by transfer to the general ward. On postoperative day 2, a follow-up ultrasound confirmed successful testicular fixation, with no evidence of hyperthermia, myalgia, or hematuria. The patient was discharged on postoperative day 3. Discussion​ This case report demonstrates the feasibility of remimazolam-based deep sedation in genetically confirmed MH-susceptible children, with no MH-related clinical manifestations observed during or after surgery. Malignant hyperthermia (MH), primarily triggered by volatile anesthetics and succinylcholine, poses life-threatening risks in susceptible individuals. Our approach using intravenous deep sedation circumvents these triggers while adhering to EMHG guidelines, as evidenced by the successful management of a 1-year-old patient with heterozygous RYR1 mutations. Remimazolam, a novel benzodiazepine acting through GABAA receptor activation [ 5 ] , offers distinct advantages over traditional anesthetics. Compared to midazolam, it exhibits faster onset and shorter duration due to ester hydrolysis metabolism, minimizing postoperative recovery time and residual sedation [ 6 ] . Moreover, remimazolam demonstrates superior cardiovascular safety compared to propofol-based TIVA: lower incidence of injection site pain, less hemodynamic instability, and reversibility with flumazenil [ 7 – 8 ] .Notably, in vitro experiments at concentrations exceeding 100 times the clinical dose demonstrated that neither remimazolam nor propofol enhanced caffeine sensitivity or RYR1-mediated calcium release in mutant RYR1-expressing cells, supporting their safety in MH-susceptible patients. [ 9 ] . Although adult MH-susceptible patients have been reported to tolerate remimazolam [ 10 , 11 ] , this case represents the first genetically confirmed pediatric application, highlighting the paucity of data in infants (< 2 years old). The multimodal strategy incorporating alfentanil and caudal block further optimized outcomes: alfentanil reduced opioid-related respiratory depression and hemodynamic fluctuations [ 12 , 13 ] , while caudal block minimized systemic anesthetic exposure, mitigating potential calcium dyshomeostasis in MH-susceptible patients. The two RYR1 gene mutations identified in the patient (c.11608 + 1G > A and c.13660-29G > A) were classified as variants of uncertain significance (VUS) due to their absence from ClinVar and other genomic databases. Despite being annotated as potentially pathogenic based on ACMG guidelines and functional prediction algorithms (SIFT/PolyPhen-2), direct functional validation remains lacking, including calcium release assays (CICR) and in vitro contracture tests (IVCT) [ 14 ] . The diagnostic limitation was further compounded by the infant’s young age (1-year-old) and parental refusal to consent to invasive procedures, precluding tissue sampling for direct assessment of calcium homeostasis via muscle biopsy. In conclusion, this case highlights the potential of remimazolam-based deep sedation as a safe and effective anesthetic strategy for genetically confirmed MH-susceptible children. Despite the absence of MH manifestations, further multicenter studies are warranted to validate its broader applicability in pediatric populations. Abbreviations MH: Malignant Hyperthermia RYR1: Ryanodine Receptor 1 TIVA: Total Intravenous Anesthesia ACMG:American College of Medical Genetics and Genomics VUS:Variant of Uncertain Significance EMHG: European Malignant Hyperthermia Group EtCO₂: End-Tidal Carbon Dioxide PACU: Postanesthesia Care Unit CICR:Calcium release assays IVCT:In vitro contracture tests Declarations Ethics approval and consent to participate This work has been carried out by the Declaration of Helsinki (2013) of the World Medical Association. This study was approved by the Ethics Committee of Lishui Municipal Central Hospital, and all participants provided written informed consent. Consent for publication Written informed consent was obtained from the patient's parents for publication of clinical details, intraoperative images (Figure 1), and genetic data. The consent form explicitly states that the patient's identifiable features have been anonymized in all published materials. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding None. Author's contributions Collection and compilation of the case and pictures: Kailai Zhu.Literature search: Shuangwei Wu, Xianglin Hao.Drafting the article and revising it critically for important intellectual content: Chuanguang Wang. All the authors reviewed and approved the final version of the manuscript. References Yu KD, Betts MN, Urban GM, et al. Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program. Anesthesiology. 2024. 140(1): 52-61. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010. 110(2): 498-507. Rüffert H, Bastian B, Bendixen D, et al. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021. 126(1): 120-130. Kondo H, Mukaida K, Sasai K, et al. Remimazolam-based total intravenous anesthesia in a patient with a confirmed diagnosis of malignant hyperthermia: a case report. JA Clin Rep. 2024. 10(1): 26. Wang M, Zhao X, Yin P, Bao X, Tang H, Kang X. Profile of Remimazolam in Anesthesiology: A Narrative Review of Clinical Research Progress. Drug Des Devel Ther. 2022. 16: 3431-3444. Pastis NJ, Yarmus LB, Schippers F, et al. Safety and Efficacy of Remimazolam Compared With Placebo and Midazolam for Moderate Sedation During Bronchoscopy. Chest. 2019. 155(1): 137-146. Chen S, Wang J, Xu X, et al. The efficacy and safety of remimazolam tosylate versus propofol in patients undergoing colonoscopy: a multicentered, randomized, positive-controlled, phase III clinical trial. Am J Transl Res. 2020. 12(8): 4594-4603. Chen SH, Yuan TM, Zhang J, et al. Remimazolam tosylate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial. J Gastroenterol Hepatol. 2021. 36(2): 474-481. Watanabe T, Miyoshi H, Noda Y, et al. Effects of Remimazolam and Propofol on Ca(2+) Regulation by Ryanodine Receptor 1 with Malignant Hyperthermia Mutation. Biomed Res Int. 2021. 2021: 8845129. Uchiyama K, Sunaga H, Katori N, Uezono S. General anesthesia with remimazolam in a patient with clinically suspected malignant hyperthermia. JA Clin Rep. 2021. 7(1): 78. Matsumoto T, Sakurai K, Takahashi K, Kawamoto S. Use of remimazolam in living donor liver transplantation: a case report. JA Clin Rep. 2022. 8(1): 65. Xin Y, Chu T, Wang J, Xu A. Sedative effect of remimazolam combined with alfentanil in colonoscopic polypectomy: a prospective, randomized, controlled clinical trial. BMC Anesthesiol. 2022. 22(1): 262. Huang B, Li NP, Tan GK, Liang N. Effectiveness and safety of remimazolam combined with alfentanil in hysteroscopic examination: A prospective, randomized, single-blind trial. Medicine (Baltimore). 2024. 103(15): e37627. Frassanito L, Sbaraglia F, Piersanti A, et al. Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review. J Clin Med. 2023. 12(12): 3869. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 23 Apr, 2025 Read the published version in BMC Anesthesiology → Version 1 posted Editorial decision: Revision requested 08 Apr, 2025 Reviews received at journal 04 Apr, 2025 Reviewers agreed at journal 03 Apr, 2025 Reviews received at journal 02 Apr, 2025 Reviewers agreed at journal 02 Apr, 2025 Reviews received at journal 02 Apr, 2025 Reviewers agreed at journal 02 Apr, 2025 Reviewers invited by journal 02 Apr, 2025 Submission checks completed at journal 01 Apr, 2025 First submitted to journal 30 Mar, 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-6150816","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":437538824,"identity":"e7804d7c-018b-438c-897b-19e93739fec2","order_by":0,"name":"Kailai Zhu","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kailai","middleName":"","lastName":"Zhu","suffix":""},{"id":437538826,"identity":"3803ba6f-7183-4d9c-a311-6b66f7c6dc73","order_by":1,"name":"Shuangwei Wu","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuangwei","middleName":"","lastName":"Wu","suffix":""},{"id":437538828,"identity":"b6501678-d72f-4f25-840c-24ff8d73db67","order_by":2,"name":"Xianglin Hao","email":"","orcid":"","institution":"The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xianglin","middleName":"","lastName":"Hao","suffix":""},{"id":437538830,"identity":"e2b74688-30f4-4643-84f2-4ba015d16a61","order_by":3,"name":"Chuanguang Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYJCCAwk/auQgTDbidDA++NhzzJgkLcyGM9iYExuI1mJw/Pg1aR4etvQN184YMHwoO8zAP7uBgJYzOWXSPBYyuRtu5xgwzjh3mEHizgH8Wsxu8KSBbMndBtTCzNt2mMFAIoEYLWzM6WYgLX+J08J+GOT9BLAWRmK02J/JAQey4f7baQUHe86l80jcIKBFsv34A1BUykvOTt744EeZtRz/DAJaGBh4DODMAyAuIfVAwP6ACEWjYBSMglEwogEAkYZE1OM74GUAAAAASUVORK5CYII=","orcid":"","institution":"The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital","correspondingAuthor":true,"prefix":"","firstName":"Chuanguang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-03-04 04:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6150816/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6150816/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12871-025-03076-0","type":"published","date":"2025-04-23T15:57:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79907842,"identity":"53f17a2a-557d-4353-9db4-404dd96b92af","added_by":"auto","created_at":"2025-04-04 11:15:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":220150,"visible":true,"origin":"","legend":"\u003cp\u003eThe patient exhibited two heterozygous mutations in the RYR1 gene:\u003c/p\u003e\n\u003cp\u003e① c.11608+1G\u0026gt;A: A guanine-to-adenine substitution at the +1 nucleotide position following codon 11608 in the coding sequence, resulting in a heterozygous mutation.\u003c/p\u003e\n\u003cp\u003e② c.13660-29G\u0026gt;A: A guanine-to-adenine substitution at the -29 nucleotide position preceding codon 13660 in the coding sequence, also classified as a heterozygous mutation.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6150816/v1/7c1184e57b5427a64c1b6d18.png"},{"id":81569594,"identity":"e3ff6d0e-e250-42a8-b8ca-5daa3680789c","added_by":"auto","created_at":"2025-04-28 16:07:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":567594,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6150816/v1/d0afca1a-efbd-4c36-88bd-7c0860db9878.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful Deep Sedation with Remimazolam and Alfentanil in a Child Susceptible to Malignant Hyperthermia: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eMalignant hyperthermia (MH) is a rare but fatal pharmacogenetic disorder primarily caused by pathogenic variants in the RYR1 gene, which disrupts calcium release from the sarcoplasmic reticulum\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Exposure to triggering agents (volatile anesthetics and succinylcholine) induces a hypermetabolic crisis characterized by hypercarbia, hyperthermia, muscle rigidity, and rhabdomyolysis\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Current guidelines recommend Total Intravenous Anesthesia(TIVA) as the standard anesthetic approach for MH-susceptible patients to avoid these triggers \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRemimazolam, a short-acting benzodiazepine, has emerged as a potential alternative to propofol-based TIVA in MH-susceptible individuals. Previous cellular studies demonstrated that remimazolam does not induce calcium release in RYR1-mutant cells at clinical concentrations, and limited clinical data suggest its safety in adult MH-susceptible patients\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. However, its application in pediatric populations remains understudied due to age-related pharmacokinetic differences and the rarity of confirmed MH cases in this group.\u003c/p\u003e \u003cp\u003eThis case report describes the successful use of remimazolam-alfentanil deep sedation combined with caudal block in a 1-year-old patient with genetically confirmed MH susceptibility, providing new insights into the anesthetic management of MH in pediatrics.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 1-year-old male infant (weight 9 kg, height 75 cm) was admitted for scheduled orchidopexy. The patient presented with right-sided cryptorchidism noted at birth, followed by progressive feeding difficulties, hypotonia, and global developmental delay observed during postnatal growth. The genetic testing revealed that the patient carried two heterozygous RYR1 mutations (c.11608\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A and c.13660-29G\u0026thinsp;\u0026gt;\u0026thinsp;A), while the father exhibited a heterozygous mutation (c.13660-29G\u0026thinsp;\u0026gt;\u0026thinsp;A) and the mother a heterozygous mutation (c.11608\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A). These mutations (c.11608\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A and c.13660-29G\u0026thinsp;\u0026gt;\u0026thinsp;A) are not listed in the ClinVar database. According to the American College of Medical Genetics and Genomics(ACMG) guidelines, these variants were classified as Variant of Uncertain Significance (VUS), but may still be considered potentially pathogenic(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDuring the preoperative evaluation, the patient exhibited right ptosis with limited eye-opening, inability to stand or walk independently, and growth and development delay compared to age-matched peers.Preanesthetic examination and laboratory evaluation results were within the normal range. According to the European Malignant Hyperthermia Group (EMHG) guidelines [3], we prepared using an anesthesia machine previously free of volatile agents, strictly avoided volatile anesthetics and succinylcholine, and implemented remimazolam-alfentanil deep sedation combined with caudal block for intraoperative analgesia to minimize reliance on systemic opioids. Preoperative measures included having dantrolene readily available per Chinese drug labeling recommendations (initial dose: 1 mg/kg, with incremental doses of 1 mg/kg as needed, up to a maximum of 7 mg/kg), along with rapid cooling equipment such as ice packs, cold saline infusion, and continuous blood gas monitoring. The surgery was performed using a minimally invasive open surgical technique. After establishing intravenous access in the ward, the patient was transferred to the operating room. Upon arrival, electrocardiography, pulse oximetry, and non-invasive blood pressure monitoring were applied. No premedication was administered before anesthesia. Considering the patient\u0026rsquo;s non-cooperation, remimazolam 0.2 mg/kg (actual dose: 1.8 mg) was administered first, followed by the placement of a nasal cannula with capnographic monitoring of end-tidal carbon dioxide (EtCO₂). Alfentanil 10 \u0026micro;g/kg (actual dose: 90 \u0026micro;g) was then administered, followed by continuous infusions of remimazolam at 1\u0026ndash;2 mg/kg/h (total\u0026thinsp;\u0026asymp;\u0026thinsp;11 mg) and alfentanil at 10\u0026ndash;20 \u0026micro;g/kg/h (total\u0026thinsp;\u0026asymp;\u0026thinsp;90 \u0026micro;g).Rectal temperature probes and radial artery catheters were placed for continuous core temperature and blood pressure monitoring. Caudal block with 0.25% ropivacaine (10 mL) provided effective intraoperative analgesia, reducing the need for additional anesthetic agents and minimizing hemodynamic fluctuations. Throughout the 40-minute procedure, the patient maintained spontaneous ventilation without the use of a laryngeal mask or endotracheal intubation. Vital signs remained stable, with EtCO₂ levels fluctuating between 37\u0026ndash;47 mmHg and body temperature ranging from 36.5\u0026ndash;37.2\u0026deg;C, with no signs of MH. The depth of sedation was consistent with deep sedation as defined by the ASA, with spontaneous ventilation, airway patency, and stable hemodynamics adequately maintained under remimazolam and alfentanil anesthesia combined with regional block.The patient spontaneously recovered 5 minutes after discontinuing anesthetics, and maintained stable vital signs in the postanesthesia care unit(PACU) for 30 minutes, followed by transfer to the general ward. On postoperative day 2, a follow-up ultrasound confirmed successful testicular fixation, with no evidence of hyperthermia, myalgia, or hematuria. The patient was discharged on postoperative day 3.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e "},{"header":"Discussion​","content":"\u003cp\u003eThis case report demonstrates the feasibility of remimazolam-based deep sedation in genetically confirmed MH-susceptible children, with no MH-related clinical manifestations observed during or after surgery. Malignant hyperthermia (MH), primarily triggered by volatile anesthetics and succinylcholine, poses life-threatening risks in susceptible individuals. Our approach using intravenous deep sedation circumvents these triggers while adhering to EMHG guidelines, as evidenced by the successful management of a 1-year-old patient with heterozygous RYR1 mutations.\u003c/p\u003e \u003cp\u003eRemimazolam, a novel benzodiazepine acting through GABAA receptor activation \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, offers distinct advantages over traditional anesthetics. Compared to midazolam, it exhibits faster onset and shorter duration due to ester hydrolysis metabolism, minimizing postoperative recovery time and residual sedation\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Moreover, remimazolam demonstrates superior cardiovascular safety compared to propofol-based TIVA: lower incidence of injection site pain, less hemodynamic instability, and reversibility with flumazenil\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.Notably, in vitro experiments at concentrations exceeding 100 times the clinical dose demonstrated that neither remimazolam nor propofol enhanced caffeine sensitivity or RYR1-mediated calcium release in mutant RYR1-expressing cells, supporting their safety in MH-susceptible patients. \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Although adult MH-susceptible patients have been reported to tolerate remimazolam \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, this case represents the first genetically confirmed pediatric application, highlighting the paucity of data in infants (\u0026lt;\u0026thinsp;2 years old).\u003c/p\u003e \u003cp\u003eThe multimodal strategy incorporating alfentanil and caudal block further optimized outcomes: alfentanil reduced opioid-related respiratory depression and hemodynamic fluctuations \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, while caudal block minimized systemic anesthetic exposure, mitigating potential calcium dyshomeostasis in MH-susceptible patients.\u003c/p\u003e \u003cp\u003eThe two RYR1 gene mutations identified in the patient (c.11608\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A and c.13660-29G\u0026thinsp;\u0026gt;\u0026thinsp;A) were classified as variants of uncertain significance (VUS) due to their absence from ClinVar and other genomic databases. Despite being annotated as potentially pathogenic based on ACMG guidelines and functional prediction algorithms (SIFT/PolyPhen-2), direct functional validation remains lacking, including calcium release assays (CICR) and in vitro contracture tests (IVCT)\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. The diagnostic limitation was further compounded by the infant\u0026rsquo;s young age (1-year-old) and parental refusal to consent to invasive procedures, precluding tissue sampling for direct assessment of calcium homeostasis via muscle biopsy.\u003c/p\u003e \u003cp\u003eIn conclusion, this case highlights the potential of remimazolam-based deep sedation as a safe and effective anesthetic strategy for genetically confirmed MH-susceptible children. Despite the absence of MH manifestations, further multicenter studies are warranted to validate its broader applicability in pediatric populations.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMH: Malignant Hyperthermia\u003c/p\u003e\n\u003cp\u003eRYR1: Ryanodine Receptor 1\u003c/p\u003e\n\u003cp\u003eTIVA: Total Intravenous Anesthesia\u003c/p\u003e\n\u003cp\u003eACMG:American College of \u0026nbsp;Medical Genetics and Genomics\u003c/p\u003e\n\u003cp\u003eVUS:Variant of Uncertain Significance\u003c/p\u003e\n\u003cp\u003eEMHG: European Malignant Hyperthermia Group\u003c/p\u003e\n\u003cp\u003eEtCO₂: End-Tidal Carbon Dioxide\u003c/p\u003e\n\u003cp\u003ePACU: Postanesthesia Care Unit\u003c/p\u003e\n\u003cp\u003eCICR:Calcium release assays\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIVCT:In vitro contracture tests\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work has been carried out by the Declaration of Helsinki\u003c/p\u003e\n\u003cp\u003e(2013) of the World Medical Association. This study was approved by the Ethics\u003c/p\u003e\n\u003cp\u003eCommittee of Lishui Municipal Central Hospital, and all participants\u003c/p\u003e\n\u003cp\u003eprovided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient\u0026apos;s parents for publication of clinical details, intraoperative images (Figure 1), and genetic data. \u0026nbsp;The consent form explicitly states that the patient\u0026apos;s identifiable features \u0026nbsp;have been anonymized in all published materials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article. \u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026apos;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCollection and compilation of the case and pictures: Kailai Zhu.Literature search: Shuangwei Wu, Xianglin Hao.Drafting the article and revising it critically for important intellectual content: Chuanguang Wang. All the authors reviewed and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYu KD, Betts MN, Urban GM, et al. Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program. Anesthesiology. 2024. 140(1): 52-61.\u003c/li\u003e\n\u003cli\u003eLarach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010. 110(2): 498-507.\u003c/li\u003e\n\u003cli\u003eR\u0026uuml;ffert H, Bastian B, Bendixen D, et al. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021. 126(1): 120-130.\u003c/li\u003e\n\u003cli\u003eKondo H, Mukaida K, Sasai K, et al. Remimazolam-based total intravenous anesthesia in a patient with a confirmed diagnosis of malignant hyperthermia: a case report. JA Clin Rep. 2024. 10(1): 26.\u003c/li\u003e\n\u003cli\u003eWang M, Zhao X, Yin P, Bao X, Tang H, Kang X. Profile of Remimazolam in Anesthesiology: A Narrative Review of Clinical Research Progress. Drug Des Devel Ther. 2022. 16: 3431-3444.\u003c/li\u003e\n\u003cli\u003ePastis NJ, Yarmus LB, Schippers F, et al. Safety and Efficacy of Remimazolam Compared With Placebo and Midazolam for Moderate Sedation During Bronchoscopy. Chest. 2019. 155(1): 137-146.\u003c/li\u003e\n\u003cli\u003eChen S, Wang J, Xu X, et al. The efficacy and safety of remimazolam tosylate versus propofol in patients undergoing colonoscopy: a multicentered, randomized, positive-controlled, phase III clinical trial. Am J Transl Res. 2020. 12(8): 4594-4603.\u003c/li\u003e\n\u003cli\u003eChen SH, Yuan TM, Zhang J, et al. Remimazolam tosylate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial. J Gastroenterol Hepatol. 2021. 36(2): 474-481.\u003c/li\u003e\n\u003cli\u003eWatanabe T, Miyoshi H, Noda Y, et al. Effects of Remimazolam and Propofol on Ca(2+) Regulation by Ryanodine Receptor 1 with Malignant Hyperthermia Mutation. Biomed Res Int. 2021. 2021: 8845129.\u003c/li\u003e\n\u003cli\u003eUchiyama K, Sunaga H, Katori N, Uezono S. General anesthesia with remimazolam in a patient with clinically suspected malignant hyperthermia. JA Clin Rep. 2021. 7(1): 78.\u003c/li\u003e\n\u003cli\u003eMatsumoto T, Sakurai K, Takahashi K, Kawamoto S. Use of remimazolam in living donor liver transplantation: a case report. JA Clin Rep. 2022. 8(1): 65.\u003c/li\u003e\n\u003cli\u003eXin Y, Chu T, Wang J, Xu A. Sedative effect of remimazolam combined with alfentanil in colonoscopic polypectomy: a prospective, randomized, controlled clinical trial. BMC Anesthesiol. 2022. 22(1): 262.\u003c/li\u003e\n\u003cli\u003eHuang B, Li NP, Tan GK, Liang N. Effectiveness and safety of remimazolam combined with alfentanil in hysteroscopic examination: A prospective, randomized, single-blind trial. Medicine (Baltimore). 2024. 103(15): e37627.\u003c/li\u003e\n\u003cli\u003eFrassanito L, Sbaraglia F, Piersanti A, et al. Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review. J Clin Med. 2023. 12(12): 3869.\u003c/li\u003e\n\u003c/ol\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Malignant hyperthermia, Remimazolam, Pediatric anesthesia, RYR1 mutation, Deep sedation","lastPublishedDoi":"10.21203/rs.3.rs-6150816/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6150816/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMalignant hyperthermia (MH) is a life-threatening autosomal-dominant disorder caused by mutations in the ryanodine receptor 1 (RYR1) gene, leading to calcium dysregulation in skeletal muscle. Patients with genetically confirmed MH susceptibility must strictly avoid volatile anesthetics and succinylcholine. Intravenous deep sedation presents a viable alternative, yet evidence supporting remimazolam use in pediatric MH patients remains scarce.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eWe report the first case of a 1-year-old male patient with genetically confirmed MH susceptibility undergoing orchidopexy under remimazolam-alfentanil deep sedation combined with caudal block. The patient had no MH manifestations intraoperatively or postoperatively and recovered uneventfully.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case demonstrates the feasibility of remimazolam-based deep sedation in genetically confirmed pediatric MH patients, supporting its safety profile in this population. Further multicenter studies are needed to establish standardized protocols.\u003c/p\u003e","manuscriptTitle":"Successful Deep Sedation with Remimazolam and Alfentanil in a Child Susceptible to Malignant Hyperthermia: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-04 11:15:14","doi":"10.21203/rs.3.rs-6150816/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-08T06:06:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-04T07:40:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139386095572495931681312948666549853583","date":"2025-04-03T19:14:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-02T15:41:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"262121708977256801677679089278341202770","date":"2025-04-02T15:01:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-02T13:01:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"131874338848110242773242169333325981964","date":"2025-04-02T12:10:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-02T10:28:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-01T12:45:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Anesthesiology","date":"2025-03-30T16:56:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"82ac4704-8f88-43d4-b3f1-c7e15e17f933","owner":[],"postedDate":"April 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-28T16:00:21+00:00","versionOfRecord":{"articleIdentity":"rs-6150816","link":"https://doi.org/10.1186/s12871-025-03076-0","journal":{"identity":"bmc-anesthesiology","isVorOnly":false,"title":"BMC Anesthesiology"},"publishedOn":"2025-04-23 15:57:18","publishedOnDateReadable":"April 23rd, 2025"},"versionCreatedAt":"2025-04-04 11:15:14","video":"","vorDoi":"10.1186/s12871-025-03076-0","vorDoiUrl":"https://doi.org/10.1186/s12871-025-03076-0","workflowStages":[]},"version":"v1","identity":"rs-6150816","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6150816","identity":"rs-6150816","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}