Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report

Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: 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 Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report Xiaolin Li, Yunpeng Jin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3194312/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 14 You are reading this latest preprint version Abstract Background: Zolpidem is a non-benzodiazepine hypnotics widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before. Case presentation: A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril valsartan sodium tablets 25 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started on zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no obvious change. The night before admission, the patient attempted suicide by overdose with 40 mg of zolpidem after an argument, which resulted in severe lethargy. At admission, his ECG revealed new-onset AF, so zolpidem was stopped immediately. 9 hours into admission, AFspontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that no AF was detected. Conclusions: Zolpidem is a frequent first choice of medication for insomnia. However, this case suggests zolpidem overdose could increase the risk of AF in patients with cardiomyopathy. Zolpidem could have caused AF via respiratory depression, which leads to acute atrial distension and hypercapnia. These acute transient arrhythmogenic changes during zolpidem overdose can increase vulnerability to AF in patient with pre-existing cardiomyopathy. Thus, the heart rhythm should be monitored when zolpidem is prescribed in patients with cardiomyopathy. case report zolpidem atrial fibrillation cardiomyopathy Duchenne muscular dystrophy Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Zolpidem is a non-benzodiazepine hypnotics widely used in pharmacological therapy of insomnia in adults [ 1 ]. It has adverse events including falls and subsequent fractures [ 2 , 3 ]; neuropsychological adverse effects such as parasomnias, amnesia, hallucinations, suicidality [ 4 , 5 ], and abuse, dependence, and withdrawal [ 6 ]. Arrhythmia is also a side effect of zolpidem, but rarely reported. There have been reports of zolpidem causing QT prolongation and provoking ventricular fibrillation [ 7 , 8 ]. However, atrial fibrillation (AF) as a side effect of zolpidem use has not been reported yet. Herein, we report a case of a 40-year-old man with Duchenne muscular dystrophy (DMD)-related cardiomyopathy who attempted suicide and developed new-onset AF after zolpidem overdose. Case presentation A 40-year-old man who attempted suicide by overdose with sleeping pills (zolpidem tartrate tablets, 40 mg) resulting in lethargy for 8 hours was admitted to our hospital. On presentation, his vital signs were as follows: blood pressure, 91/66 mmHg; irregular heart rate, 54 beats/min; and normal oxygen saturation. The timeline of the case is shown in Table 1 . The patient suffered from mild skeletal muscle weakness since the age of 15 years and was diagnosed with DMD by dystrophy gene analysis and based on his clinical manifestations. In the patient’s family, four men spanning three generations were also diagnosed with DMD (Fig. 1 ). Multiplex PCR analysis of the dystrophin gene from peripheral blood revealed a deletion of exons 45–49 (Fig. 2 ), which applies to all the family members (except for the patient's uncle [ I 1] for death). There is no involvement of family in this study. There was no other special discovery in the patient's past history, personal history and family history in addition to the above. Table 1 The timeline of the case. Date Episode Main symptoms Main examination Medication 2019-10-07 First Chest discomfort and fatigue after daily walks for 1 month. ECG and 24-hour Holter ECG revealed complete right bundle branch block, premature ventricular contractions. AF had never been observed via continuous monitoring during follow-up. Echocardiography revealed diffuse severe hypokinesis with an estimated ejection fraction of 22.7%, enlargement of the left atrium (58.0mm) and left ventricle (72.7mm), and mild mitral regurgitation. Start digoxin (0.125 mg/day), spironolactone (40 mg/day), furosemide (20 mg/day), bisoprolol (5mg/day), sacubitril valsartan sodium tablets (25 mg/day). 2020-09-18 Second Insomnia for 6 months. ECG revealed complete right bundle branch block, premature ventricular contractions. Start zolpidem tartrate tablets (10mg/day). 2020-10-04 Third Attempted suicide by overdose with sleeping pills (zolpidem tartrate tablets, 40mg) resulting in lethargy for 8 hours. On arrival ECG revealed new-onset AF with a heart rate of 54 beats/min. Echocardiography revealed diffuse severe hypokinesis with an estimated ejection fraction of 35%, enlargement of the left atrium (60.2mm) and left ventricle (73.0mm), and mild mitral regurgitation. Stop zolpidem tartrate tablets. Nine hours later ECG revealed complete right bundle branch block, premature ventricular contractions. He was insisted on medication and regular follow-up after discharge. No palpitations and insomnia. Till date ECG and 24-hour Holter ECG revealed complete right bundle branch block, premature ventricular contractions. No AF was detected. No drug dose adjusted. He became cautious toward sleeping pills. ECG: electrocardiogram; AF: atrial fibrillation. The patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month since the previous year. His electrocardiography (ECG) (Fig. 3 ) and 24-hour Holter ECG results revealed a complete right bundle branch block and premature ventricular contractions. Moreover, his ECG results revealed diffuse severe hypokinesis with an estimated ejection fraction of 22.7%, enlarged left atrium (58.0 mm) and left ventricle (72.7 mm), and mild mitral regurgitation. The patient regularly took oral medication including digoxin (0.125 mg/day), spironolactone (40 mg/day), furosemide (20 mg/day), bisoprolol (5 mg/day), sacubitril valsartan sodium tablets (25 mg/day). His symptoms improved after taking these medications. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before this hospital admission, the patient visited a sleep clinic and started on zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months. His ECG results revealed no obvious change. The night before admission, the patient attempted suicide by taking 40 mg zolpidem tartrate tablets after an argument, resulting in severe lethargy. At admission, his ECG revealed new-onset AF with a heart rate of 54 beats/min (Fig. 4 ) and diffuse severe hypokinesis with an estimated ejection fraction of 35%, enlargement of the left atrium (60.2 mm) and left ventricle (73.0 mm), and mild mitral regurgitation, roughly the same as before. Notable laboratory test values had no obvious dynamic change before and after admission: an elevated creatine kinase, 1059 U/L; creatine kinase-MB, 41.7 U/L; troponin-I, 0.82 ng/ml; and N-terminal pro B-type natriuretic peptide, 911.66 ng/L. Zolpidem was stopped immediately, heart rhythm was monitored on telemetry, and i.v. fluids were administered upon admission. The patient stabilized 9 hours after admission, and AF spontaneously terminated into normal sinus rhythm. The medication history was carefully confirmed from the patient and his family. His body mass index (BMI) was 23.9 kg/m 2 . Cognitive behavioral therapy was performed to improve his insomnia, and he was discharged 3 days after admission. According to the ECG monitor during the next few days and the 24-hour Holter ECG at 1-month follow-up, his heart rate maintained a sinus rhythm, and no AF was detected. Causality, severity, and preventability assessment of the adverse drug reaction (ADR) are shown in Table 2 . According to the Naranjo causality scale and World Health Organization Uppsala Monitoring Center (WHO-UMC) assessment scale, this ADR and zolpidem may be associated. The Hartwig’s severity scale score indicated a moderate severity level for the reaction (level 4b). The ADR may indeed have been preventable based on the modified Schoumock and Thornton scale [ 9 ]. Table 2 Causality, severity, and preventability assessment of the adverse drug reaction. Parameter Observation Naranjo causality scale Probable (7) WHO-UMC assessment scale Probable Hartwig’s severity scale Moderate, level 4b Severity of the reaction Hospitalization Outcome Recovered Predisposing factors Overdose Modified Schoumock and Thornton scale Preventable WHO-UMC: World Health Organization Uppsala Monitoring Center. All appropriate patient consent forms for images and other clinical information to be reported in the journal were obtained for this case report. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Discussion and conclusions Patients with DMD have evolving insomnia over their lifetimes [ 10 ]. It is common to identify DMD patients experiencing chronic insomnia who also suffer from other psychiatric comorbidities such as mood and anxiety disorders [ 11 ]. Certain medications can be used to augment nonpharmacologic interventions to manage insomnia. Non-benzodiazepine hypnotics, including zolpidem, are commonly prescribed by physicians [ 12 ]. Clinically, zolpidem is widely used in patients with insomnia, including DMD patients. However, DMD patients have a high risk of attempting suicide due to the possible coexistence of other psychiatric disorders, as in our patient. Nonpharmacologic treatment strategies are preferred for this situation. Zolpidem also causes arrhythmia. Two cases have suggested that zolpidem could contribute to a prolonged QTc and ventricular fibrillation. However, AF after zolpidem use has not been reported before. Over the past hundred years, AF is the arrhythmia that has been studied the most among all other heart rhythm disorders [ 13 ]. However, crucial questions regarding the formation and perpetuation of the disease remain unanswered. To the best of our knowledge, atrial fibrosis, inflammation, oxidative stress, aging, arterial hypertension, obesity, excessive alcohol use, diabetes mellitus, certain medications, obstructive sleep apnea (OSA), and genetic factors contribute to the development of AF [ 14 ]. Other causes such as electrolyte disorders, intracranial pressure elevation, hyperthyroidism, infection and hyperthermia have been ruled out in the present case. Results of the causality analysis of the new-onset AF are shown in Table 3 . Table 3 Causality analysis of the new-onset AF. Causes Observation Possibility Medication Zolpidem overdose Probable Digoxin Doubtful Spironolactone Doubtful Furosemide Doubtful Bisoprolol Doubtful Sacubitril valsartan sodium tablets Doubtful Atrial fibrosis, inflammation, and oxidative stress Cardiomyopathy: considered stable Possible Aging 40 years old Doubtful Arterial hypertension Denied Doubtful Obesity Not observed Doubtful Excessive alcohol use Denied Doubtful Diabetes mellitus Denied Doubtful Obstructive sleep apnea Not observed Doubtful Genetic factors No family history of AF Doubtful AF: atrial fibrillation. In this case, the underlying disease (DMD-related cardiomyopathy) and combined medication may increase the risk of AF. In the present case, cardiomyopathy was considered stable based on the consistent clinical manifestations and ECG and laboratory test results on admission. New-onset heart failure or any other types of arrhythmia had not been observed; AF had not been detected before. After stopping zolpidem, AF subsequently terminated spontaneously into normal sinus rhythm and did not recur. Therefore, the association between cardiomyopathy and new-onset AF remains unclear. The patient has been taking normal doses of digoxin, spironolactone, furosemide, bisoprolol, and sacubitril valsartan sodium tablets since 1 year before admission. Zolpidem was primarily suspected due to its overdose right before the new-onset AF; once withdrawn, the patient’s AF resolved. Therefore, the overdose on zolpidem is the most likely cause of AF based on the Naranjo causality scale and WHO-UMC assessment scale. Zolpidem could have caused AF via respiratory depression. DMD and insomnia are both commonly comorbid with OSA [ 15 , 16 ]. We are not sure if the patient has OSA, but certainly the high dose of zolpidem could have caused it because of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia [ 17 ]. Obstructed inspiration generates large negative intrathoracic pressure fluctuations, leads to acute atrial distension, shortens atrial refractoriness, slows conduction, and increases the occurrence of intraatrial conduction block in humans. These acute transient arrhythmogenic changes during apnea may contribute to the development of AF [ 18 ]. In addition, zolpidem can decrease central respiratory drive, increase upper airway resistance, decrease inspiratory flow, decrease carbon dioxide ventilatory response and increase blood carbon dioxide concentration [ 19 ]. Hypercapnia increases effective refractory period in action potentials and conduction in the atria which can increase vulnerability to AF in pre-existing atrial myopathy [ 20 ], which was very likely present in this case with atrial dilation. Several observational epidemiological studies have produced conflicting results on the relationship between hypnotics use and heart disease. A meta-analysis of observational epidemiological studies supported that zolpidem showed a decreased risk (− 29%) of developing or dying from heart disease, but benzodiazepines were associated with an increased risk (80%) of or mortality from heart disease [ 21 ]. Exposure to benzodiazepines was associated with increased cardiovascular mortality (HR: 1.65; 95% CI 1.39, 1.97) in a large population study with 85,353 women, but not when further adjusted for antidepressant use (HR: 1.15; 95% CI 0.94, 1.40), nor in the multivariable model (HR: 0.93; 95% CI 0.75, 1.16) [ 22 ]. Therefore, it is still unknown whether zolpidem could increase the risk of AF. In this case, it is of interest that only 40 mg zolpidem induced severe lethargy and new-onset AF, and this dose is generally not considered toxic. On the contrary, a study on the subjective effects of zolpidem showed that 20 mg was considered “pleasant” and gave a “high” despite zolpidem increased ratings of “sleepy” [ 23 ]. When given in a nightly dosage of up to 20 mg, zolpidem is generally well tolerated by patients with insomnia, only 5.2% of them resulted in lethargy [ 24 ]. Once the patient stabilized after admission, the patient and his family denied intake of other toxic substances. Because zolpidem is metabolized through cytochrome P450, while bisoprolol [ 25 ], digoxin [ 26 ], spironolactone [ 27 ], and furosemide [ 28 ] have the same metabolic pathway through cytochrome P450, co-application of these medications may result in impaired metabolism of affected compounds and elevate zolpidem plasma concentrations toward critical levels. The presence of cardiomyopathy that reduce the repolarization reserve is expected to precipitate AF during zolpidem treatment. Another thing worth mentioning is that the new-onset AF was accompanied by a slow ventricular rate. A rat study supported the fluctuation of heart rate would be attenuated with a higher dose of zolpidem [ 29 ]. As in this case, the slow ventricular rate of AF may also associated with the zolpidem overdose. The main limitation of this case report is the lack of toxicity analyses and recurrence of ADR with rechallenge, which would not be ethical. Patients with any cardiomyopathy have high risk of AF. We cannot completely rule out accidental detection of AF during admission in this case. This case suggests zolpidem overdose could increase the risk of AF in patients with cardiomyopathy based on both causality analysis and explainable mechanism. Thus, the heart rhythm should be monitored when zolpidem is prescribed in patients with cardiomyopathy. Further research is necessary to establish a definite causation link between zolpidem and AF. Abbreviations AF: atrial fibrillation; ECG: electrocardiogram; DMD: Duchenne muscular dystrophy; ADR: adverse drug reaction; WHO-UMC: World Health Organization Uppsala Monitoring Center; OSA: obstructive sleep apnea. Declarations Acknowledgments Not applicable. Authors’ contributions LXL wrote the report, performed the research and took the pictures. JYP wrote a part of the report and revised the report, and is the corresponding author. All authors read and approved the final version of the manuscript. Funding This study was funded by the Foundation of Zhejiang Provincial Education Department (Grant No. Y202146832 and Y202249328), Science and Technology program of Jinhua Science and Technology Bureau (Grant No. 2020-4-104), Science and Technology program of Yiwu Science and Technology Bureau (Grant No. 2020-3-059), Foundation of The fourth Affiliated Hospital Zhejiang University School of Medicine (Grant No. JG20230203). The funders had no role in the study design, data collection and analysis, the decision to publish or the preparation of the manuscript. Availability of data and materials The data underlying this article will be shared on reasonable request with the corresponding author. Ethics approval and consent to participate Ethical approval for the publication of this study was obtained from the Ethics Committee of The Fourth Affiliated Hospital of Zhejiang University School of Medicine. Informed consent was obtained from the patient included in the study. Consent for publication Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests. References Edinoff AN, Wu N, Ghaffar YT, Prejean R, et al. Zolpidem: Efficacy and Side Effects for Insomnia. Health Psychol Res. 2021;9(1):24927. 10.52965/001c.24927 . Westermeyer J, Carr TM. Zolpidem-Associated Consequences: An Updated Literature Review With Case Reports. J Nerv Ment Dis. 2020;208(1):28–32. 10.1097/NMD.0000000000001074 . Treves N, Perlman A, Kolenberg Geron L, Asaly A, et al. Z-drugs and risk for falls and fractures in older adults-a systematic review and meta-analysis. Age Ageing. 2018;47(2):201–8. 10.1093/ageing/afx167 . Stallman HM, Kohler M, White J. Medication induced sleepwalking: A systematic review. Sleep Med Rev. 2018;37:105–13. 10.1016/j.smrv.2017.01.005 . Schifano F, Chiappini S, Corkery JM, Guirguis A. An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions. Int J Neuropsychopharmacol. 2019;22(4):270–7. 10.1093/ijnp/pyz007 . Chiaro G, Castelnovo A, Bianco G, Maffei P, et al. Severe Chronic Abuse of Zolpidem in Refractory Insomnia. J Clin Sleep Med. 2018;14(7):1257–9. 10.5664/jcsm.7240 . Ahn HJ, Jeong WJ, Kim KJ, Kim SC, et al. Serial plasma and urine measurements of a patient with acute intoxication of zolpidem and flunitrazepam resulting in QT prolongation and ventricular tachycardia. Clin Toxicol (Phila). 2020;58(6):501–3. 10.1080/15563650.2019.1663206 . Suarez L, Kolla BP, Hall-Flavin D, Mansukhani MP. QTc Prolongation Secondary to Zolpidem Use. Prim Care Companion CNS Disord. 2020;22(2):19l02506. 10.4088/PCC.19l02506 . Jiang H, Lin Y, Ren W, Fang Z, et al. Adverse drug reactions and correlations with drug-drug interactions: A retrospective study of reports from 2011 to 2020. Front Pharmacol. 2022;13:923939. 10.3389/fphar.2022.923939 . MacKintosh EW, Chen ML, Benditt JO. Lifetime Care of Duchenne Muscular Dystrophy. Sleep Med Clin. 2020;15(4):485–95. 10.1016/j.jsmc.2020.08.011 . Duan D, Goemans N, Takeda S, Mercuri E, et al. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. 10.1038/s41572-021-00248-3 . Hu X, Jong GP, Wang L, Lin MC, et al. Hypnotics Use Is Associated with Elevated Incident Atrial Fibrillation: A Propensity-Score Matched Analysis of Cohort Study. J Pers Med. 2022;12(10):1645. 10.3390/jpm12101645 . Lau DH, Linz D, Sanders P. New Findings in Atrial Fibrillation Mechanisms. Card Electrophysiol Clin. 2019;11(4):563–71. 10.1016/j.ccep.2019.08.007 . Sagris M, Vardas EP, Theofilis P, Antonopoulos AS, et al. Atrial Fibrillation: Pathogenesis, Predisposing Factors, and Genetics. Int J Mol Sci. 2021;23(1):6. 10.3390/ijms23010006 . LoMauro A, D'Angelo MG, Aliverti A. Sleep Disordered Breathing in Duchenne Muscular Dystrophy. Curr Neurol Neurosci Rep. 2017;17(5):44. 10.1007/s11910-017-0750-1 . Ong JC, Crawford MR. Insomnia and Obstructive Sleep Apnea. Sleep Med Clin. 2013;8(3):389–98. 10.1016/j.jsmc.2013.04.004 . Carberry JC, Fisher LP, Grunstein RR, Gandevia SC, et al. Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem. Eur Respir J. 2017;50(6):1701344. 10.1183/13993003.01344-2017 . Linz D, McEvoy RD, Cowie MR, Somers VK, et al. Associations of Obstructive Sleep Apnea With Atrial Fibrillation and Continuous Positive Airway Pressure Treatment: A Review. JAMA Cardiol. 2018;3(6):532–40. 10.1001/jamacardio.2018.0095 . Stege G, Vos PJ, van den Elshout FJ, Richard Dekhuijzen PN, et al. Sleep, hypnotics and chronic obstructive pulmonary disease. Respir Med. 2008;102(6):801–14. 10.1016/j.rmed.2007.12.026 . Stevenson IH, Roberts-Thomson KC, Kistler PM, et al. Atrial electrophysiology is altered by acute hypercapnia but not hypoxemia: implications for promotion of atrial fibrillation in pulmonary disease and sleep apnea. Heart Rhythm. 2010;7(9):1263–70. 10.1016/j.hrthm.2010.03.020 . Kim YH, Kim HB, Kim DH, Kim JY, et al. Use of hypnotics and the risk of or mortality from heart disease: a meta-analysis of observational studies. Korean J Intern Med. 2018;33(4):727–36. 10.3904/kjim.2016.282 . Mesrine S, Gusto G, Clavel-Chapelon F, Boutron-Ruault MC, et al. Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years. Eur J Clin Pharmacol. 2018;74(11):1475–84. 10.1007/s00228-018-2515-4 . Licata SC, Mashhoon Y, Maclean RR, Lukas SE. Modest abuse-related subjective effects of zolpidem in drug-naive volunteers. Behav Pharmacol. 2011;22(2):160–6. 10.1097/FBP.0b013e328343d78a . Langtry HD, Benfield P, Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs. 1990;40(2):291–313. 10.2165/00003495-199040020-00008 . Horikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci. 1998;87(3):289–94. 10.1021/js970316d . Salphati L, Benet LZ. Metabolism of digoxin and digoxigenin digitoxosides in rat liver microsomes: involvement of cytochrome P4503A. Xenobiotica. 1999;29(2):171–85. 10.1080/004982599238722 . Garcia PJ, Mundaca H, Ugarte-Gil C, Leon P, et al. Randomized clinical trial to compare the efficacy of ivermectin versus placebo to negativize nasopharyngeal PCR in patients with early COVID-19 in Peru (SAINT-Peru): a structured summary of a study protocol for randomized controlled trial. Trials. 2021;22(1):262. 10.1186/s13063-021-05236-2 . Yang KH, Choi YH, Lee U, Lee JH, et al. Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism. J Pharm Pharmacol. 2009;61(1):47–54. 10.1211/jpp/61.01.0007 . Mailliet F, Galloux P, Poisson D. Comparative effects of melatonin, zolpidem and diazepam on sleep, body temperature, blood pressure and heart rate measured by radiotelemetry in Wistar rats. Psychopharmacology. 2001;156(4):417–26. 10.1007/s002130100769 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 12 Jun, 2024 Reviews received at journal 11 Jun, 2024 Reviews received at journal 26 May, 2024 Reviews received at journal 24 May, 2024 Reviewers agreed at journal 18 May, 2024 Reviewers agreed at journal 18 May, 2024 Reviewers agreed at journal 16 May, 2024 Reviewers agreed at journal 26 Sep, 2023 Reviewers agreed at journal 24 Sep, 2023 Reviewers invited by journal 20 Sep, 2023 Editor assigned by journal 19 Sep, 2023 Editor invited by journal 17 Aug, 2023 Submission checks completed at journal 17 Aug, 2023 First submitted to journal 22 Jul, 2023 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-3194312","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":226952908,"identity":"743e377b-b107-4d73-acd6-819497ea96e5","order_by":0,"name":"Xiaolin Li","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaolin","middleName":"","lastName":"Li","suffix":""},{"id":226952909,"identity":"80f972bd-d1ce-4c87-a49a-c6c9f8215893","order_by":1,"name":"Yunpeng Jin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYBACfmbG5gcJBjVyDAwHgFw2IrRItje3GXwoOGZMvBaDM8cbJGd8YE5sAHOJsmVGYoMxjwFb+vzGMwYMH8oOM/DPbsCvhV8iseExj4FMbmPDGQPGGecOM0jcOUCcLbnNDGcMmHnbDjMYSCQQ8MuNxAZpHgPmdDaQlr9EaTlzEOh9A+YEHpAWRmK0SLY3AgPZ4JjhDIZjBQd7zqXzSNwgoIWfmf3xg4Q/NfLyMw5vfPCjzFqOfwYBLQggcQAcmTzEqgfZ10CC4lEwCkbBKBhRAABip0YdJZPitgAAAABJRU5ErkJggg==","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yunpeng","middleName":"","lastName":"Jin","suffix":""}],"badges":[],"createdAt":"2023-07-22 10:44:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3194312/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3194312/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":41960198,"identity":"f68aac0c-eea4-4246-816a-919f31c9b284","added_by":"auto","created_at":"2023-08-22 21:13:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":104328,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree of the family with Duchenne muscular dystrophy genes. I = first generation, II = second generation, III = third generation, arrow = proband.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3194312/v1/d3a796bc2886b3c5a05facb0.png"},{"id":41959652,"identity":"06778d6f-be39-4731-b773-11d7dd0206dc","added_by":"auto","created_at":"2023-08-22 21:05:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":349428,"visible":true,"origin":"","legend":"\u003cp\u003eMultiplex PCR analysis of dystrophin gene from peripheral blood of the patient.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3194312/v1/2b17795c6b9ca10d1a4d24ad.png"},{"id":41959649,"identity":"39804f3c-3f92-475f-ba58-ed9740888b80","added_by":"auto","created_at":"2023-08-22 21:05:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":445492,"visible":true,"origin":"","legend":"\u003cp\u003eECG 1 year before this admission.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3194312/v1/0e6575b0872d95c1e2855665.png"},{"id":41959651,"identity":"af90e57b-4443-408f-b809-d95a8ebd399a","added_by":"auto","created_at":"2023-08-22 21:05:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":405551,"visible":true,"origin":"","legend":"\u003cp\u003eECG at admission.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3194312/v1/1c4f52f55fa15d70af3dcb88.png"},{"id":41961926,"identity":"dcd5f2ed-f239-426c-9869-32e8d1810afe","added_by":"auto","created_at":"2023-08-22 21:21:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1878532,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3194312/v1/e5b961e7-17cc-4288-9b05-ce3746be25e9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report","fulltext":[{"header":"Background","content":"\u003cp\u003eZolpidem is a non-benzodiazepine hypnotics widely used in pharmacological therapy of insomnia in adults [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. It has adverse events including falls and subsequent fractures [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]; neuropsychological adverse effects such as parasomnias, amnesia, hallucinations, suicidality [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e], and abuse, dependence, and withdrawal [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eArrhythmia is also a side effect of zolpidem, but rarely reported. There have been reports of zolpidem causing QT prolongation and provoking ventricular fibrillation [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, atrial fibrillation (AF) as a side effect of zolpidem use has not been reported yet. Herein, we report a case of a 40-year-old man with Duchenne muscular dystrophy (DMD)-related cardiomyopathy who attempted suicide and developed new-onset AF after zolpidem overdose.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 40-year-old man who attempted suicide by overdose with sleeping pills (zolpidem tartrate tablets, 40 mg) resulting in lethargy for 8 hours was admitted to our hospital. On presentation, his vital signs were as follows: blood pressure, 91/66 mmHg; irregular heart rate, 54 beats/min; and normal oxygen saturation. The timeline of the case is shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eThe patient suffered from mild skeletal muscle weakness since the age of 15 years and was diagnosed with DMD by dystrophy gene analysis and based on his clinical manifestations. In the patient\u0026rsquo;s family, four men spanning three generations were also diagnosed with DMD (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Multiplex PCR analysis of the dystrophin gene from peripheral blood revealed a deletion of exons 45\u0026ndash;49 (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), which applies to all the family members (except for the patient\u0026apos;s uncle [ I 1] for death). There is no involvement of family in this study. There was no other special discovery in the patient\u0026apos;s past history, personal history and family history in addition to the above.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe timeline of the case.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEpisode\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMain symptoms\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMain examination\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMedication\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2019-10-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChest discomfort and fatigue after daily walks for 1 month.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eECG and 24-hour Holter ECG revealed complete right bundle branch block, premature ventricular contractions. AF had never been observed via continuous monitoring during follow-up.\u003c/p\u003e\n \u003cp\u003eEchocardiography revealed diffuse severe hypokinesis with an estimated ejection fraction of 22.7%, enlargement of the left atrium (58.0mm) and left ventricle (72.7mm), and mild mitral regurgitation.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStart digoxin (0.125 mg/day), spironolactone (40 mg/day), furosemide (20 mg/day), bisoprolol (5mg/day), sacubitril valsartan sodium tablets (25 mg/day).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2020-09-18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsomnia for 6 months.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eECG revealed complete right bundle branch block, premature ventricular contractions.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStart zolpidem tartrate tablets (10mg/day).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e2020-10-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eThird\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAttempted suicide by overdose with sleeping pills (zolpidem tartrate tablets, 40mg) resulting in lethargy for 8 hours.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOn arrival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECG revealed new-onset AF with a heart rate of 54 beats/min.\u003c/p\u003e\n \u003cp\u003eEchocardiography revealed diffuse severe hypokinesis with an estimated ejection fraction of 35%, enlargement of the left atrium (60.2mm) and left ventricle (73.0mm), and mild mitral regurgitation.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStop zolpidem tartrate tablets.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNine hours later\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECG revealed complete right bundle branch block, premature ventricular contractions.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHe was insisted on medication and regular follow-up after discharge.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo palpitations and insomnia.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTill date\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECG and 24-hour Holter ECG revealed complete right bundle branch block, premature ventricular contractions. No AF was detected.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo drug dose adjusted. He became cautious toward sleeping pills.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eECG: electrocardiogram; AF: atrial fibrillation.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month since the previous year. His electrocardiography (ECG) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) and 24-hour Holter ECG results revealed a complete right bundle branch block and premature ventricular contractions. Moreover, his ECG results revealed diffuse severe hypokinesis with an estimated ejection fraction of 22.7%, enlarged left atrium (58.0 mm) and left ventricle (72.7 mm), and mild mitral regurgitation. The patient regularly took oral medication including digoxin (0.125 mg/day), spironolactone (40 mg/day), furosemide (20 mg/day), bisoprolol (5 mg/day), sacubitril valsartan sodium tablets (25 mg/day). His symptoms improved after taking these medications. AF had never been observed before this admission via continuous monitoring during follow-up.\u003c/p\u003e\n\u003cp\u003eSixteen days before this hospital admission, the patient visited a sleep clinic and started on zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months. His ECG results revealed no obvious change.\u003c/p\u003e\n\u003cp\u003eThe night before admission, the patient attempted suicide by taking 40 mg zolpidem tartrate tablets after an argument, resulting in severe lethargy. At admission, his ECG revealed new-onset AF with a heart rate of 54 beats/min (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e) and diffuse severe hypokinesis with an estimated ejection fraction of 35%, enlargement of the left atrium (60.2 mm) and left ventricle (73.0 mm), and mild mitral regurgitation, roughly the same as before. Notable laboratory test values had no obvious dynamic change before and after admission: an elevated creatine kinase, 1059 U/L; creatine kinase-MB, 41.7 U/L; troponin-I, 0.82 ng/ml; and N-terminal pro B-type natriuretic peptide, 911.66 ng/L. Zolpidem was stopped immediately, heart rhythm was monitored on telemetry, and i.v. fluids were administered upon admission. The patient stabilized 9 hours after admission, and AF spontaneously terminated into normal sinus rhythm. The medication history was carefully confirmed from the patient and his family. His body mass index (BMI) was 23.9 kg/m\u003csup\u003e2\u003c/sup\u003e. Cognitive behavioral therapy was performed to improve his insomnia, and he was discharged 3 days after admission. According to the ECG monitor during the next few days and the 24-hour Holter ECG at 1-month follow-up, his heart rate maintained a sinus rhythm, and no AF was detected.\u003c/p\u003e\n\u003cp\u003eCausality, severity, and preventability assessment of the adverse drug reaction (ADR) are shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. According to the Naranjo causality scale and World Health Organization Uppsala Monitoring Center (WHO-UMC) assessment scale, this ADR and zolpidem may be associated. The Hartwig\u0026rsquo;s severity scale score indicated a moderate severity level for the reaction (level 4b). The ADR may indeed have been preventable based on the modified Schoumock and Thornton scale [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCausality, severity, and preventability assessment of the adverse drug reaction.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eObservation\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNaranjo causality scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProbable (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWHO-UMC assessment scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHartwig\u0026rsquo;s severity scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModerate, level 4b\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSeverity of the reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHospitalization\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePredisposing factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOverdose\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModified Schoumock and Thornton scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePreventable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eWHO-UMC: World Health Organization Uppsala Monitoring Center.\u003c/p\u003e\n\u003cp\u003eAll appropriate patient consent forms for images and other clinical information to be reported in the journal were obtained for this case report. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\u003c/p\u003e"},{"header":"Discussion and conclusions","content":"\u003cp\u003ePatients with DMD have evolving insomnia over their lifetimes [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. It is common to identify DMD patients experiencing chronic insomnia who also suffer from other psychiatric comorbidities such as mood and anxiety disorders [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eCertain medications can be used to augment nonpharmacologic interventions to manage insomnia. Non-benzodiazepine hypnotics, including zolpidem, are commonly prescribed by physicians [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. Clinically, zolpidem is widely used in patients with insomnia, including DMD patients. However, DMD patients have a high risk of attempting suicide due to the possible coexistence of other psychiatric disorders, as in our patient. Nonpharmacologic treatment strategies are preferred for this situation.\u003c/p\u003e\n\u003cp\u003eZolpidem also causes arrhythmia. Two cases have suggested that zolpidem could contribute to a prolonged QTc and ventricular fibrillation. However, AF after zolpidem use has not been reported before.\u003c/p\u003e\n\u003cp\u003eOver the past hundred years, AF is the arrhythmia that has been studied the most among all other heart rhythm disorders [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, crucial questions regarding the formation and perpetuation of the disease remain unanswered. To the best of our knowledge, atrial fibrosis, inflammation, oxidative stress, aging, arterial hypertension, obesity, excessive alcohol use, diabetes mellitus, certain medications, obstructive sleep apnea (OSA), and genetic factors contribute to the development of AF [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. Other causes such as electrolyte disorders, intracranial pressure elevation, hyperthyroidism, infection and hyperthermia have been ruled out in the present case. Results of the causality analysis of the new-onset AF are shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCausality analysis of the new-onset AF.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCauses\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eObservation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePossibility\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003eMedication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZolpidem overdose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDigoxin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpironolactone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFurosemide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBisoprolol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSacubitril valsartan sodium tablets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAtrial fibrosis, inflammation, and oxidative stress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiomyopathy: considered stable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAging\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArterial hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDenied\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObesity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot observed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExcessive alcohol use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDenied\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDenied\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObstructive sleep apnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot observed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGenetic factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo family history of AF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAF: atrial fibrillation.\u003c/p\u003e\n\u003cp\u003eIn this case, the underlying disease (DMD-related cardiomyopathy) and combined medication may increase the risk of AF.\u003c/p\u003e\n\u003cp\u003eIn the present case, cardiomyopathy was considered stable based on the consistent clinical manifestations and ECG and laboratory test results on admission. New-onset heart failure or any other types of arrhythmia had not been observed; AF had not been detected before. After stopping zolpidem, AF subsequently terminated spontaneously into normal sinus rhythm and did not recur. Therefore, the association between cardiomyopathy and new-onset AF remains unclear.\u003c/p\u003e\n\u003cp\u003eThe patient has been taking normal doses of digoxin, spironolactone, furosemide, bisoprolol, and sacubitril valsartan sodium tablets since 1 year before admission. Zolpidem was primarily suspected due to its overdose right before the new-onset AF; once withdrawn, the patient\u0026rsquo;s AF resolved. Therefore, the overdose on zolpidem is the most likely cause of AF based on the Naranjo causality scale and WHO-UMC assessment scale.\u003c/p\u003e\n\u003cp\u003eZolpidem could have caused AF via respiratory depression. DMD and insomnia are both commonly comorbid with OSA [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. We are not sure if the patient has OSA, but certainly the high dose of zolpidem could have caused it because of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Obstructed inspiration generates large negative intrathoracic pressure fluctuations, leads to acute atrial distension, shortens atrial refractoriness, slows conduction, and increases the occurrence of intraatrial conduction block in humans. These acute transient arrhythmogenic changes during apnea may contribute to the development of AF [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition, zolpidem can decrease central respiratory drive, increase upper airway resistance, decrease inspiratory flow, decrease carbon dioxide ventilatory response and increase blood carbon dioxide concentration [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Hypercapnia increases effective refractory period in action potentials and conduction in the atria which can increase vulnerability to AF in pre-existing atrial myopathy [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e], which was very likely present in this case with atrial dilation.\u003c/p\u003e\n\u003cp\u003eSeveral observational epidemiological studies have produced conflicting results on the relationship between hypnotics use and heart disease. A meta-analysis of observational epidemiological studies supported that zolpidem showed a decreased risk (\u0026minus;\u0026thinsp;29%) of developing or dying from heart disease, but benzodiazepines were associated with an increased risk (80%) of or mortality from heart disease [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Exposure to benzodiazepines was associated with increased cardiovascular mortality (HR: 1.65; 95% CI 1.39, 1.97) in a large population study with 85,353 women, but not when further adjusted for antidepressant use (HR: 1.15; 95% CI 0.94, 1.40), nor in the multivariable model (HR: 0.93; 95% CI 0.75, 1.16) [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, it is still unknown whether zolpidem could increase the risk of AF.\u003c/p\u003e\n\u003cp\u003eIn this case, it is of interest that only 40 mg zolpidem induced severe lethargy and new-onset AF, and this dose is generally not considered toxic. On the contrary, a study on the subjective effects of zolpidem showed that 20 mg was considered \u0026ldquo;pleasant\u0026rdquo; and gave a \u0026ldquo;high\u0026rdquo; despite zolpidem increased ratings of \u0026ldquo;sleepy\u0026rdquo; [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. When given in a nightly dosage of up to 20 mg, zolpidem is generally well tolerated by patients with insomnia, only 5.2% of them resulted in lethargy [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. Once the patient stabilized after admission, the patient and his family denied intake of other toxic substances. Because zolpidem is metabolized through cytochrome P450, while bisoprolol [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], digoxin [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e], spironolactone [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], and furosemide [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] have the same metabolic pathway through cytochrome P450, co-application of these medications may result in impaired metabolism of affected compounds and elevate zolpidem plasma concentrations toward critical levels. The presence of cardiomyopathy that reduce the repolarization reserve is expected to precipitate AF during zolpidem treatment.\u003c/p\u003e\n\u003cp\u003eAnother thing worth mentioning is that the new-onset AF was accompanied by a slow ventricular rate. A rat study supported the fluctuation of heart rate would be attenuated with a higher dose of zolpidem [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. As in this case, the slow ventricular rate of AF may also associated with the zolpidem overdose.\u003c/p\u003e\n\u003cp\u003eThe main limitation of this case report is the lack of toxicity analyses and recurrence of ADR with rechallenge, which would not be ethical. Patients with any cardiomyopathy have high risk of AF. We cannot completely rule out accidental detection of AF during admission in this case.\u003c/p\u003e\n\u003cp\u003eThis case suggests zolpidem overdose could increase the risk of AF in patients with cardiomyopathy based on both causality analysis and explainable mechanism. Thus, the heart rhythm should be monitored when zolpidem is prescribed in patients with cardiomyopathy. Further research is necessary to establish a definite causation link between zolpidem and AF.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAF: atrial fibrillation; ECG: electrocardiogram; DMD: Duchenne muscular dystrophy; ADR: adverse drug reaction; WHO-UMC: World Health Organization Uppsala Monitoring Center; OSA: obstructive sleep apnea.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLXL wrote the report, performed the research and took the pictures. JYP wrote a part of the report and revised the report, and is the corresponding author. All authors read and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Foundation of Zhejiang Provincial Education Department (Grant No. Y202146832\u0026nbsp;and\u0026nbsp;Y202249328), Science and Technology program of Jinhua Science and Technology Bureau (Grant No. 2020-4-104), Science and Technology program of Yiwu Science and Technology Bureau (Grant No. 2020-3-059), Foundation of\u0026nbsp;The fourth Affiliated Hospital Zhejiang University School of Medicine\u0026nbsp;(Grant No.\u0026nbsp;JG20230203). The funders had no role in the study design, data collection and analysis, the decision to publish or the preparation of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data underlying this article will be shared on reasonable request with the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for the publication of this study was obtained from the Ethics Committee of The Fourth Affiliated Hospital of Zhejiang University School of Medicine. Informed consent was obtained from the patient included in the study.\u0026nbsp;\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 for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEdinoff AN, Wu N, Ghaffar YT, Prejean R, et al. Zolpidem: Efficacy and Side Effects for Insomnia. Health Psychol Res. 2021;9(1):24927. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.52965/001c.24927\u003c/span\u003e\u003cspan address=\"10.52965/001c.24927\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWestermeyer J, Carr TM. Zolpidem-Associated Consequences: An Updated Literature Review With Case Reports. J Nerv Ment Dis. 2020;208(1):28\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/NMD.0000000000001074\u003c/span\u003e\u003cspan address=\"10.1097/NMD.0000000000001074\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTreves N, Perlman A, Kolenberg Geron L, Asaly A, et al. Z-drugs and risk for falls and fractures in older adults-a systematic review and meta-analysis. Age Ageing. 2018;47(2):201\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ageing/afx167\u003c/span\u003e\u003cspan address=\"10.1093/ageing/afx167\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStallman HM, Kohler M, White J. Medication induced sleepwalking: A systematic review. Sleep Med Rev. 2018;37:105\u0026ndash;13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.smrv.2017.01.005\u003c/span\u003e\u003cspan address=\"10.1016/j.smrv.2017.01.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchifano F, Chiappini S, Corkery JM, Guirguis A. An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions. Int J Neuropsychopharmacol. 2019;22(4):270\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ijnp/pyz007\u003c/span\u003e\u003cspan address=\"10.1093/ijnp/pyz007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChiaro G, Castelnovo A, Bianco G, Maffei P, et al. Severe Chronic Abuse of Zolpidem in Refractory Insomnia. J Clin Sleep Med. 2018;14(7):1257\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5664/jcsm.7240\u003c/span\u003e\u003cspan address=\"10.5664/jcsm.7240\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhn HJ, Jeong WJ, Kim KJ, Kim SC, et al. Serial plasma and urine measurements of a patient with acute intoxication of zolpidem and flunitrazepam resulting in QT prolongation and ventricular tachycardia. Clin Toxicol (Phila). 2020;58(6):501\u0026ndash;3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/15563650.2019.1663206\u003c/span\u003e\u003cspan address=\"10.1080/15563650.2019.1663206\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuarez L, Kolla BP, Hall-Flavin D, Mansukhani MP. QTc Prolongation Secondary to Zolpidem Use. Prim Care Companion CNS Disord. 2020;22(2):19l02506. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4088/PCC.19l02506\u003c/span\u003e\u003cspan address=\"10.4088/PCC.19l02506\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang H, Lin Y, Ren W, Fang Z, et al. Adverse drug reactions and correlations with drug-drug interactions: A retrospective study of reports from 2011 to 2020. Front Pharmacol. 2022;13:923939. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fphar.2022.923939\u003c/span\u003e\u003cspan address=\"10.3389/fphar.2022.923939\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMacKintosh EW, Chen ML, Benditt JO. Lifetime Care of Duchenne Muscular Dystrophy. Sleep Med Clin. 2020;15(4):485\u0026ndash;95. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jsmc.2020.08.011\u003c/span\u003e\u003cspan address=\"10.1016/j.jsmc.2020.08.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuan D, Goemans N, Takeda S, Mercuri E, et al. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41572-021-00248-3\u003c/span\u003e\u003cspan address=\"10.1038/s41572-021-00248-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu X, Jong GP, Wang L, Lin MC, et al. Hypnotics Use Is Associated with Elevated Incident Atrial Fibrillation: A Propensity-Score Matched Analysis of Cohort Study. J Pers Med. 2022;12(10):1645. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jpm12101645\u003c/span\u003e\u003cspan address=\"10.3390/jpm12101645\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLau DH, Linz D, Sanders P. New Findings in Atrial Fibrillation Mechanisms. Card Electrophysiol Clin. 2019;11(4):563\u0026ndash;71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ccep.2019.08.007\u003c/span\u003e\u003cspan address=\"10.1016/j.ccep.2019.08.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSagris M, Vardas EP, Theofilis P, Antonopoulos AS, et al. Atrial Fibrillation: Pathogenesis, Predisposing Factors, and Genetics. Int J Mol Sci. 2021;23(1):6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ijms23010006\u003c/span\u003e\u003cspan address=\"10.3390/ijms23010006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoMauro A, D'Angelo MG, Aliverti A. Sleep Disordered Breathing in Duchenne Muscular Dystrophy. Curr Neurol Neurosci Rep. 2017;17(5):44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11910-017-0750-1\u003c/span\u003e\u003cspan address=\"10.1007/s11910-017-0750-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOng JC, Crawford MR. Insomnia and Obstructive Sleep Apnea. Sleep Med Clin. 2013;8(3):389\u0026ndash;98. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jsmc.2013.04.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jsmc.2013.04.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarberry JC, Fisher LP, Grunstein RR, Gandevia SC, et al. Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem. Eur Respir J. 2017;50(6):1701344. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1183/13993003.01344-2017\u003c/span\u003e\u003cspan address=\"10.1183/13993003.01344-2017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLinz D, McEvoy RD, Cowie MR, Somers VK, et al. Associations of Obstructive Sleep Apnea With Atrial Fibrillation and Continuous Positive Airway Pressure Treatment: A Review. JAMA Cardiol. 2018;3(6):532\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamacardio.2018.0095\u003c/span\u003e\u003cspan address=\"10.1001/jamacardio.2018.0095\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStege G, Vos PJ, van den Elshout FJ, Richard Dekhuijzen PN, et al. Sleep, hypnotics and chronic obstructive pulmonary disease. Respir Med. 2008;102(6):801\u0026ndash;14. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.rmed.2007.12.026\u003c/span\u003e\u003cspan address=\"10.1016/j.rmed.2007.12.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStevenson IH, Roberts-Thomson KC, Kistler PM, et al. Atrial electrophysiology is altered by acute hypercapnia but not hypoxemia: implications for promotion of atrial fibrillation in pulmonary disease and sleep apnea. Heart Rhythm. 2010;7(9):1263\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.hrthm.2010.03.020\u003c/span\u003e\u003cspan address=\"10.1016/j.hrthm.2010.03.020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim YH, Kim HB, Kim DH, Kim JY, et al. Use of hypnotics and the risk of or mortality from heart disease: a meta-analysis of observational studies. Korean J Intern Med. 2018;33(4):727\u0026ndash;36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3904/kjim.2016.282\u003c/span\u003e\u003cspan address=\"10.3904/kjim.2016.282\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMesrine S, Gusto G, Clavel-Chapelon F, Boutron-Ruault MC, et al. Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years. Eur J Clin Pharmacol. 2018;74(11):1475\u0026ndash;84. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00228-018-2515-4\u003c/span\u003e\u003cspan address=\"10.1007/s00228-018-2515-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLicata SC, Mashhoon Y, Maclean RR, Lukas SE. Modest abuse-related subjective effects of zolpidem in drug-naive volunteers. Behav Pharmacol. 2011;22(2):160\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/FBP.0b013e328343d78a\u003c/span\u003e\u003cspan address=\"10.1097/FBP.0b013e328343d78a\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLangtry HD, Benfield P, Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs. 1990;40(2):291\u0026ndash;313. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2165/00003495-199040020-00008\u003c/span\u003e\u003cspan address=\"10.2165/00003495-199040020-00008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci. 1998;87(3):289\u0026ndash;94. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1021/js970316d\u003c/span\u003e\u003cspan address=\"10.1021/js970316d\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalphati L, Benet LZ. Metabolism of digoxin and digoxigenin digitoxosides in rat liver microsomes: involvement of cytochrome P4503A. Xenobiotica. 1999;29(2):171\u0026ndash;85. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/004982599238722\u003c/span\u003e\u003cspan address=\"10.1080/004982599238722\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia PJ, Mundaca H, Ugarte-Gil C, Leon P, et al. Randomized clinical trial to compare the efficacy of ivermectin versus placebo to negativize nasopharyngeal PCR in patients with early COVID-19 in Peru (SAINT-Peru): a structured summary of a study protocol for randomized controlled trial. Trials. 2021;22(1):262. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13063-021-05236-2\u003c/span\u003e\u003cspan address=\"10.1186/s13063-021-05236-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang KH, Choi YH, Lee U, Lee JH, et al. Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism. J Pharm Pharmacol. 2009;61(1):47\u0026ndash;54. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1211/jpp/61.01.0007\u003c/span\u003e\u003cspan address=\"10.1211/jpp/61.01.0007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMailliet F, Galloux P, Poisson D. Comparative effects of melatonin, zolpidem and diazepam on sleep, body temperature, blood pressure and heart rate measured by radiotelemetry in Wistar rats. Psychopharmacology. 2001;156(4):417\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s002130100769\u003c/span\u003e\u003cspan address=\"10.1007/s002130100769\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\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-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"case report, zolpidem, atrial fibrillation, cardiomyopathy, Duchenne muscular dystrophy","lastPublishedDoi":"10.21203/rs.3.rs-3194312/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3194312/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eZolpidem is a non-benzodiazepine hypnotics widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril valsartan sodium tablets 25 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started on zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no obvious change. The night before admission, the patient attempted suicide by overdose with 40 mg of zolpidem after an argument, which resulted in severe lethargy. At admission, his ECG revealed new-onset AF, so zolpidem was stopped immediately. 9 hours into admission, AFspontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that no AF was detected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Zolpidem is a frequent first choice of medication for insomnia. However, this case suggests zolpidem overdose could increase the risk of AF in patients with cardiomyopathy. Zolpidem could have caused AF via respiratory depression, which leads to acute atrial distension and hypercapnia. These acute transient arrhythmogenic changes during zolpidem overdose can increase vulnerability to AF in patient with pre-existing cardiomyopathy. Thus, the heart rhythm should be monitored when zolpidem is prescribed in patients with cardiomyopathy.\u003c/p\u003e","manuscriptTitle":"Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-22 21:05:28","doi":"10.21203/rs.3.rs-3194312/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-12T21:14:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-11T17:43:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-26T07:36:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-24T05:14:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"99561563123388530087043669491442310462","date":"2024-05-18T23:21:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58051399584087084398123450202019527436","date":"2024-05-18T09:43:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306253056477198824430407335302297514019","date":"2024-05-17T01:47:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"484d8893-c5b7-4018-a0a6-aaee692e0b13","date":"2023-09-26T11:14:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9fc5bc99-2c53-4be1-834d-9f657d3fb08b","date":"2023-09-24T14:52:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-09-20T11:08:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-09-19T12:32:24+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-08-17T04:36:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-08-17T04:30:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2023-07-22T10:34:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b1c84bbd-2df1-486b-8465-6503dc984bb0","owner":[],"postedDate":"August 22nd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-26T17:51:09+00:00","versionOfRecord":[],"versionCreatedAt":"2023-08-22 21:05:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3194312","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3194312","identity":"rs-3194312","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}