Perioperative Medications Associated with Delayed Recovery from Anaesthesia: A Two-Decade Pharmacovigilance Study Based on the FAERS

Perioperative Medications Associated with Delayed Recovery from Anaesthesia: A Two-Decade Pharmacovigilance Study Based on the FAERS | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Perioperative Medications Associated with Delayed Recovery from Anaesthesia: A Two-Decade Pharmacovigilance Study Based on the FAERS Bo Gu, Bing Lv, Yuan Hu, Kehan Li, Liuli Xu, Ji Zheng, Qianying Li, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7332537/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Drug-induced delayed recovery from anaesthesia (DRA) represents a serious postoperative adverse drug reaction characterized by prolonged unconsciousness or respiratory depression following the cessation of anaesthetic agents. Objective: To systematically identify drugs significantly associated with DRA using the U.S. FDA Adverse Event Reporting System (FAERS). Methods: Pharmacovigilance disproportionality analysis was conducted with FAERS data (2003–2024), applying the Reporting Odds Ratio (ROR) to quantify drug-event associations. Results: A total of 1,831 reports related to DRA were included for disproportionality analysis, yielding 1,239 significant signals. The strong associations were observed for thiamylal (n = 4, ROR = 1273.21; 95% CI: 465.82–3480.02), sevoflurane (n = 111, ROR = 887.24; 95% CI: 715.31–1100.49), methohexital (n = 4, ROR = 715.20; 95% CI: 264.09–1936.83), remifentanil (n = 49, ROR = 584.70; 95% CI: 433.77–788.15), rocuronium (n = 86, ROR = 553.14; 95% CI: 436.93–700.25), desflurane (n = 15, ROR = 524.97; 95% CI: 312.45–882.04), isoflurane (n = 15, ROR = 473.59; 95% CI: 281.99–795.36), propofol (n = 171, ROR = 460.29; 95% CI: 380.80–556.37), and succinylcholine (n = 20, ROR = 287.47; 95% CI: 183.27–450.91). In our results, only midazolam (n = 57, ROR = 120.62; 95% CI: 91.37–159.25) and remifentanil (n = 49, ROR = 584.70; 95% CI: 433.77–788.15) were mentioned in FDA labeling as associated with delayed recovery, while the others were not. Conclusions: This pharmacovigilance analysis identified multiple agents with strong associations with DRA. Most lacked corresponding warnings in official drug labeling, underscoring the need for improved risk communication. Pharmacovigilance Disproportionality Analysis adverse Event Opioids Delayed Recovery from Anaesthesia Anaesthesia 1. Introduction Delayed recovery from anaesthesia (DRA), or delayed emergence, refers to the failure to regain consciousness, responsiveness, or spontaneous respiration within 30–60 minutes after discontinuation of anaesthetic drugs [ 1 ]. Although relatively uncommon, DRA can lead to delayed extubation, prolonged postanesthesia care unit stay, increased monitoring needs, and serious complications such as aspiration or respiratory depression. While its overall incidence is low (approximately 1.38–2.6%) [ 2 , 3 ], its clinical relevance is increasingly recognized in the context of enhanced recovery after surgery. DRA arises from disruptions in both pharmacodynamic and neurophysiological pathways [ 1 ]. Anaesthetic agents act by enhancing gamma-aminobutyric acid type A inhibition, antagonizing N-methyl-D-aspartate receptors, or impairing thalamocortical connectivity—mechanisms that suppress the organized cortical activity required for consciousness [ 4 ]. Importantly, emergence is not a passive drug clearance process but an active neurobiological transition that depends on reactivation of key arousal circuits, including the thalamus, basal forebrain, and the orexinergic system in the hypothalamus [ 5 – 7 ]. Pharmacologic factors may delay this process by sustaining receptor occupancy, disrupting gamma and alpha oscillatory coherence, or interfering with neuromodulatory loops essential for restoring cortical network synchrony [ 4 , 8 , 9 ]. Thus, precise modulation of drug–brain interactions offers the most actionable approach for preventing DRA [ 1 , 6 ]. While case reports have linked certain drugs to DRA [ 10 , 11 ], large-scale pharmacovigilance studies focusing specifically on DRA remain limited. To address this gap, we conducted a disproportionality analysis based on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to systematically identify drug-specific signals associated with DRA. Given the pharmacological diversity of the implicated agents [ 4 ], these findings may support more individualized perioperative drug selection, potentially improving recovery safety. 2. Methods 2.1. Data source This pharmacovigilance analysis was retrospectively conducted using data from the FAERS, a spontaneous reporting database that collects post-marketing safety information on pharmaceuticals and biologics ( https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html ). The FAERS database includes voluntarily submitted reports from healthcare professionals, consumers, and manufacturers, offering extensive data on patient demographics, suspected drugs, indications, and clinical outcomes. For data retrieval and processing, we employed the OpenVigil 2.1 platform ( http://h2876314.stratoserver.net:8080/OV2/search/ ), an open-access pharmacovigilance tool designed to support signal detection through cleaning, mining, and statistical analysis of FAERS records. Maintained by Böhm et al., OpenVigil 2.1 currently hosts structured data from the fourth quarter of 2003 to the fourth quarter of 2024. In total, 13,237,811 AE reports were included. 2.2. Definition of AEs and drugs The Medical Dictionary for Regulatory Activities (MedDRA, version 25.1), developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, is a standardized medical terminology system widely employed in AE reporting, pharmacovigilance, and the standardized coding and communication of clinical trial data. MedDRA is organized into a five-level hierarchical structure, among which the Preferred Term (PT) level is most commonly used for coding AEs. In this study, we selected the PT “delayed recovery from anaesthesia” (MedDRA code: 10012206) as the query term within the OpenVigil 2.1 platform, where the AE category was set to PT level for data retrieval. The extracted records were used for downstream pharmacovigilance analysis. Since some reports in the database utilized brand names instead of generic names, we mapped all drug names to their corresponding generic forms using DrugBank. Erroneously reported or ambiguous drug names were manually reviewed and excluded to ensure data integrity. 2.3. Statistical analysis We analyzed demographic characteristics for each individual AE report of “delayed recovery from anaesthesia.” The variables assessed included patient sex, age, reporting country (top five), and the occurrence of serious adverse events (SAEs). SAEs were defined as reports involving any of the following outcomes: death, disability, hospitalization (initial or prolonged), life-threatening conditions, or medical intervention to prevent permanent impairment or damage. Disproportionality analysis is a widely applied statistical method in pharmacovigilance, aiming to detect potential safety signals between specific drugs and AEs from spontaneous reporting systems such as FAERS, VigiBase, and EudraVigilance. The most commonly used metric in this context is the Reporting Odds Ratio (ROR), which compares the odds of reporting a particular AE for a given drug against the odds for all other drugs in the database (ROR = [a/c] / [b/d]). Although ROR does not establish causality, a value significantly greater than 1—often judged against predefined thresholds—serves as a valuable indicator of a disproportionately high reporting frequency, warranting further evaluation and hypothesis generation. The detailed formula and signal detection thresholds for ROR are presented in Table 1 . Table 1 summary of algorithms used for signal detection. Algorithms Equation Criteria ROR ROR=(a*d)/(b*c) RORL = EXP((LN(ROR)-1.96*SQRT((1/a)+(1/b)+(1/c)+(1/d)))) RORU = EXP((LN(ROR) + 1.96*SQRT((1/a)+(1/b)+(1/c)+(1/d)))) lower limit of 95% CI > 1, a ≥ 3 3. Results 3.1. Descriptive analysis A total of 2,430 AE reports related to DRA were identified from the fourth quarter of 2003 to the fourth quarter of 2024. Most reports involved female patients (n = 1,436, 59.1%), followed by males (n = 835, 34.4%), with sex unspecified in 6.5% of cases. The majority of patients were aged 61–80 years (n = 1,002, 41.2%), while 18.1% were aged 41–60 years, 11.1% were 19–40, and 9.4% were ≤ 18 years; age was not reported in 16.5% of cases. Over half of the reports indicated hospitalization (n = 1,302, 53.6%) as a SAE. Other SAEs included life-threatening events (8.1%), disability (4.3%), death (3.0%), and interventions to prevent permanent damage (4.7%). Reports originated predominantly from the United States (39.6%), Japan (16.4%), the United Kingdom (6.1%), France (5.8%), and China (2.4%) (Table 2 ). Table 2 Baseline characteristics of adverse event reports related to delayed recovery from anaesthesia in the FAERS database. Characteristics Case Number (n) Case Proportion (%) Total 2,430 - Gender Male 835 34.4 Female 1,436 59.1 Unknown 159 6.5 Age (years) ≤ 18 229 9.4 19–40 270 11.1 41–60 440 18.1 61–80 1,002 41.2 ≥ 81 89 3.7 Unknown 400 16.5 Serious Outcomes Hospitalization 1,302 53.6 Life-threatening 196 8.1 Disability 105 4.3 Death 74 3.0 Required Intervention (Permanent damage prevention) 113 4.7 Reported countries (top 5) United States 963 39.6 Japan 398 16.4 United Kingdom 149 6.1 France 140 5.8 China 59 2.4 3.2. Disproportionality analysis After excluding invalid or incomplete entries, a total of 1,831 reports related to DRA were included for disproportionality analysis. Based on the predefined threshold, 1,239 drug-AE pairs showed significant signals. The top 50 drugs with the highest ROR values are presented in Table 3 . The strong associations were observed for thiamylal (n = 4, ROR = 1273.21; 95% CI: 465.82–3480.02), sevoflurane (n = 111, ROR = 887.24; 95% CI: 715.31–1100.49), methohexital (n = 4, ROR = 715.20; 95% CI: 264.09–1936.83), remifentanil (n = 49, ROR = 584.70; 95% CI: 433.77–788.15), rocuronium (n = 86, ROR = 553.14; 95% CI: 436.93–700.25), desflurane (n = 15, ROR = 524.97; 95% CI: 312.45–882.04), isoflurane (n = 15, ROR = 473.59; 95% CI: 281.99–795.36), propofol (n = 171, ROR = 460.29; 95% CI: 380.80–556.37), and succinylcholine (n = 20, ROR = 287.47; 95% CI: 183.27–450.91). Table 3 Top 50 drugs for signal strength of delayed recovery from anaesthesia. Drug name Number of reports ROR (95% CI) Package insert suggests risk thiamylal 4 1273.21 (465.82-3480.02) N sevoflurane 111 887.24 (715.31-1100.49) N methohexital 4 715.20 (264.09-1936.83) N remifentanil 49 584.70 (433.77-788.15) Y rocuronium 86 553.14 (436.93-700.25) N desflurane 15 524.97 (312.45-882.04) N isoflurane 15 473.59 (281.99-795.36) N propofol 171 460.29 (380.80-556.37) N levobupivacaine 6 428.88 (190.55–965.30) N remifentanil hydrochloride 3 376.98 (120.25-1181.85) Y lornoxicam 3 370.54 (118.21-1161.50) N succinylcholine 20 287.47 (183.27-450.91) N flumazenil 5 286.27 (118.08-694.07) N vecuronium 11 273.50 (149.97-498.77) N ropivacaine 24 236.98 (156.89-357.96) N cisatracurium besylate 8 229.62 (113.83-463.21) N sugammadex 9 200.11 (103.22-387.96) N nitrous oxide 7 179.49 (84.89-379.51) N neostigmine 4 174.75 (65.11-468.98) N sugammadex sodium 3 159.09 (50.96-496.65) N sufentanil 16 146.68 (88.97-241.82) N articaine + epinephrine 4 142.68 (53.19-382.71) N esmolol 3 141.44 (45.32–441.40) N etomidate 4 131.95 (49.20-353.88) N dexmedetomidine 12 122.01 (68.69-216.71) N midazolam 57 120.62 (91.37-159.25) Y articaine 5 98.26 (40.64-237.56) N thiopental 4 96.38 (35.96-258.33) N mepivacaine 3 92.83 (29.77-289.42) N bupivacaine 25 62.43 (41.71–93.47) N imipramine 6 54.50 (24.34-122.05) N ketamine 11 51.48 (28.29–93.68) N fluvoxamine 8 47.37 (23.53–95.36) N urapidil 3 43.00 (13.81-133.94) N fentanyl 102 39.35 (31.58–49.03) N cyclizine 3 37.63 (12.08-117.19) N biperiden 6 33.39 (14.91–74.75) N nicardipine 3 29.49 (9.47–91.82) N phenylephrine 7 28.80 (13.65–60.77) N cefazolin 6 28.77 (12.85–64.40) N fentanyl-100 3 22.12 (7.11–68.88) N sotalol 6 18.67 (8.34–41.78) N nusinersen 6 18.64 (8.33–41.73) N lidocaine 24 18.17 (12.04–27.40) N glycopyrrolate 4 15.86 (5.92–42.44) N epinephrine 17 15.61 (9.62–25.34) N granisetron 3 15.36 (4.93–47.81) N atropine 5 13.66 (5.66–32.97) N zonisamide 4 13.05 (4.88–34.94) N posaconazole 3 11.67 (3.75–36.33) N ROR, Reporting Odds Ratio; CI, Confidence Interval. In our results, only midazolam (n = 57, ROR = 120.62; 95% CI: 91.37–159.25) and remifentanil (n = 49, ROR = 584.70; 95% CI: 433.77–788.15) were mentioned in FDA labeling as associated with delayed recovery, while the others were not. It is noteworthy that several agents—despite showing positive disproportionality signals—are pharmacologically implausible as causes of delayed emergence. For instance, neostigmine, sugammadex, and sugammadex sodium. Therefore, these agents were not included in the main results or discussion but were retained in Table 3 for completeness. 4. Discussion To date, this study represents the most comprehensive pharmacovigilance analysis of AEs related to DRA, encompassing over two decades of data. More than half of the reported cases (53.6%) required hospitalization, underscoring the clinical and operational burden imposed by DRA. In addition, patients aged over 60 years accounted for nearly half of all reports (44.9%), consistent with findings from Zhang et al. [ 2 ] and Bayable et al. [ 3 ] who also identified advanced age as a significant risk factor for DRA. This age-related vulnerability may be attributed to neurocognitive decline and increased pharmacodynamic sensitivity to commonly perioperative medications. These findings highlight the importance of age-adjusted anaesthetic and sedative dosing strategies in mitigating the risk of DRA among older adults. Most DRA reports originated from the U.S. and Japan, likely due to regulatory differences and stronger pharmacovigilance engagement [ 12 ]. The predominance of female cases (59.1%) aligns with previous findings and may involve both higher reporting tendency and sex-specific pharmacodynamic sensitivity [ 1 ]. Hormonal modulation and metabolic differences may also affect anesthetic clearance [ 6 ]. Considering both the observed female predominance in DRA reports and established sex-related pharmacological differences, perioperative medication strategies may benefit from sex-sensitive risk assessment and tailored dosing in female patients. Among inhalational anesthetics, sevoflurane (ROR = 887.24, n = 111), desflurane (ROR = 524.97, n = 15), and isoflurane (ROR = 473.59, n = 15) exhibited strong disproportionality signals. In contrast, nitrous oxide (ROR = 63.19, n = 6) showed substantially lower signal intensity and fewer reports. Sevoflurane generated the largest report count and the highest ROR, a finding that matches its dominant clinical use worldwide [ 13 ] and well-documented suppression of cortico-striato-thalamo-cortical and γ-band networks that govern arousal [ 14 , 15 ]. Desflurane, despite faster emergence in controlled trials, still showed a strong signal; retrospective data indicate that specific subgroups (e.g., obstructive airway disease) can experience markedly prolonged extubation [ 16 ], and its recent decline in use for environmental reasons [ 13 ] may inflate ROR by reducing the denominator. Isoflurane, used far less often, produced only 15 reports yet retained a high ROR; experimental work links it to sleep-state rebound and residual cortical dys-connectivity [ 17 ], supporting biological plausibility. By contrast, nitrous oxide exhibited much lower signal strength, likely due to its pharmacokinetic profile and effect on cortical dynamics: while high‑dose N₂O can transiently induce large‑amplitude slow‑δ EEG activity, this effect is limited to 2–12 minutes only—insufficient to disrupt arousal circuitry significantly, and its rapid pulmonary elimination minimizes tissue accumulation [ 18 ]. Collectively, these disparities suggest that both pharmacodynamic mechanisms and exposure patterns shape our disproportionality results. Among intravenous anesthetics, thiamylal (ROR = 1273.21; n = 4) and methohexital (ROR = 715.20; n = 4), both thiobarbiturates, exhibited the highest disproportionality signals despite their minimal report counts. These agents represent classic intravenous induction anesthetics that have been largely supplanted by newer drugs due to safety and pharmacokinetic advantages; they now retain specific utility only in select scenarios such as status epilepticus and electroconvulsive therapy [ 19 ]. This “spike-like” pattern likely reflects their extremely limited contemporary clinical use, resulting in a very small exposure denominator. Pharmacokinetic studies have shown that thiobarbiturates possess high lipophilicity and long context-sensitive half-lives; when peripheral tissues become saturated, back-redistribution to the central nervous system may occur, potentially prolonging hypnotic effects and contributing to DRA [ 1 ]. Propofol (ROR = 460.29; n = 171) accounted for the largest number of DRA reports. This is likely attributed to its dominant use in induction and maintenance of general anesthesia, as well as its known cardiovascular depressant effects. Although propofol is typically associated with rapid emergence, recent studies have demonstrated that in elderly patients, delayed redistribution from adipose tissue and age-related reductions in hepatic clearance may impair postoperative neurocognitive recovery [ 20 ]. Moreover, intraoperative hypotension—a common consequence of propofol use—has been independently associated with delayed emergence (AOR 3.37; 95% CI: 2.93–9.41) [ 3 ]. In contrast, etomidate (ROR = 132.60; n = 9), though less frequently used due to concerns over adrenal suppression, is often preferred in hemodynamically unstable patients for its cardiovascular stability [ 21 ]. Midazolam (ROR = 120.62; n = 57) yielded the low disproportionality signal among agents analyzed; however, its mechanistic plausibility remains substantial. As a short-acting benzodiazepine primarily metabolized by cytochrome P450 3A4 (CYP3A4), midazolam exhibits high susceptibility to drug–drug interactions and impaired hepatic clearance. Co-administration with potent CYP3A4 inhibitors—such as posaconazole—has been shown to increase midazolam exposure by over sixfold and prolong its elimination half-life from 3 to 10 hours [ 22 ]. In cirrhotic patients, reduced metabolic capacity further extends psychomotor impairment [ 23 ]. Moreover, active glucuronide metabolites may accumulate in renal dysfunction, contributing to delayed sedation offset [ 24 ]. Neurophysiologically, midazolam disrupts cortical effective connectivity, potentially prolonging arousal latency beyond pharmacokinetic elimination [ 25 ]. Clinical data indicate that midazolam use independently predicts delayed emergence in outpatient settings [ 26 ]. These findings support risk-adjusted use of midazolam, with dose reduction in older adults and avoidance of CYP3A4 inhibitors to mitigate DRA risk. Opioid analgesics have been consistently associated with DRA. In our study, strong disproportionality signals were observed for remifentanil ( ROR = 584.70, n = 49), sufentanil ( ROR = 146.69, n = 16), and fentanyl ( ROR = 39.35, n = 102), supporting their association with DRA. Remifentanil is an ultra-short-acting opioid with organ-independent metabolism, and its FDA label explicitly lists “prolonged emergence from anesthesia” as a potential adverse reaction. High intraoperative doses or insufficient postoperative analgesia may trigger opioid-induced hyperalgesia and tolerance, necessitating additional sedation and delaying recovery [ 27 ]. In contrast, sufentanil is mainly used in deep anesthesia contexts such as neurosurgery, where delayed emergence is expected and less frequently reported. Although sufentanil has been shown to prolong extubation by 3–5 minutes, its overall exposure is limited [ 28 ]. Fentanyl, despite widespread use, showed a diluted signal due to a large exposure base. While DRA is not listed in its labeling, delayed respiratory depression 2–6 hours postoperatively has been reported following high-dose cardiac anesthesia, likely due to redistribution from adipose tissue [ 29 ], which may overlap with or contribute to DRA. Residual neuromuscular blockade remains prevalent, affecting 30–40% of adults in contemporary practice despite modern monitoring and reversal strategies [ 30 , 31 ]. Among NMBAs, rocuronium (ROR = 553.14; n = 86) exhibited the strongest signal for DRA, followed by succinylcholine (ROR = 287.47; n = 20) and vecuronium (ROR = 273.50; n = 11). Mechanistically, incomplete restoration of diaphragm and upper-airway muscle strength limits ventilation, causing hypercapnia and retarding elimination of inhaled anesthetics—an indirect pathway to DRA [ 32 ]. Pharmacokinetic heterogeneity modulates risk: rocuronium relies on hepatic/biliary excretion—prolonging action in hepatic or renal dysfunction [ 33 ]. Objective quantitative monitoring and timely pharmacologic reversal (e.g., sugammadex or neostigmine) remain the cornerstone of prevention [ 34 ]. In this study, psychotropic agents such as imipramine (ROR = 54.50; n = 6) and fluvoxamine (ROR = 47.37; n = 8) showed comparatively lower signal strengths and fewer reports. However, their potential contribution to DRA should not be overlooked, particularly in patients receiving long-term maintenance therapy. These agents may delay emergence from anesthesia via central nervous system depression, cytochrome P450-mediated metabolic inhibition, enhanced sedation, or synergistic suppression [ 35 ]. However, due to risks of relapse and withdrawal, discontinuation should be carefully evaluated. Hemodynamic agents such as urapidil (ROR = 43.00; n = 3) may influence cerebral perfusion; intraoperative hypotension and reduced brain oxygenation have been proposed as contributing factors to DRA, particularly in older or high-risk patients [ 3 ]. Horiuchi T et al. identified cefazolin as one of the most frequent triggers of perioperative anaphylactic reactions in a large multicentre study in Japan, with resultant hypotension and cerebral hypoperfusion potentially contributing to delayed emergence [ 36 ]. Sloan PA further demonstrated that clindamycin and gentamicin can significantly enhance the neuromuscular blockade induced by agents like rocuronium, thereby delaying the recovery of spontaneous ventilation and consciousness [ 37 ]. However, in our analysis, only two antimicrobial agents—cefazolin (ROR = 28.77; n = 6) and posaconazole (ROR = 11.67; n = 3)—showed significant disproportionality signals. Given their relatively low signal strength and reporting frequency, and in light of Zhang et al.’s findings that antibiotics contributed to DRA in less than 1 per 1,000 cases [ 2 ], we consider that antimicrobial agents alone may not be a major driver of DRA unless accompanied by other risk factors such as advanced age, impaired metabolism, or concurrent sedative or neuromuscular blocking agents. Among the top-signal agents, including thiamylal, methohexital, and sevoflurane, many showed high RORs in association with DRA, yet lacked corresponding warnings for DRA in their FDA-approved labeling. Traditional short-acting barbiturates such as thiamylal and methohexital have been largely replaced by newer agents, resulting in limited contemporary safety surveillance. Similarly, the perceived safety of sevoflurane may obscure its potential to delay recovery in older adults. The high ROR signals identified in this study, despite the absence of corresponding warnings in labeling, highlight the need for further validation and periodic label reassessment. Preoperative evaluation should incorporate a checklist of drugs associated with DRA, and intraoperative monitoring should include objective measures of brain function to ensure timely recovery. This study is subject to several limitations inherent in spontaneous reporting systems like FAERS. First, underreporting and reporting bias may influence the representativeness of the data, and the absence of denominator data precludes accurate incidence estimation. Second, causal relationships cannot be established due to the observational nature of the data. Third, the MedDRA term “delayed recovery from anaesthesia” lacks standardized diagnostic criteria, which may lead to heterogeneity in reporting. Lastly, confounding factors such as comorbidities, anesthetic depth, or intraoperative events were not available for adjustment, which may affect signal interpretation. 5. Conclusion This pharmacovigilance study highlights that multiple perioperative drugs, including anesthetics, psychotropics, and opioids, are associated with disproportionality signals for DRA. Notably, for the vast majority of these agents, DRA is not listed as an adverse reaction in their official product labeling. Clinicians should be aware of these potential risks when managing perioperative medications. Further prospective studies are warranted to validate these associations and guide safer perioperative pharmacologic strategies. Abbreviations AE – Adverse Event CI – Confidence Interval DRA – Delayed Recovery from Anaesthesia FAERS – FDA Adverse Event Reporting System MedDRA – Medical Dictionary for Regulatory Activities NMBA – Neuromuscular Blocking Agent PT – Preferred Term ROR – Reporting Odds Ratio SAE – Serious Adverse Event SRS – Spontaneous Reporting System CYP3A4 – Cytochrome P450 3A4 Declarations Availability of data and materials The dataset supporting the conclusions of this study is available in the FAERS repository, accessible at [https://open.fda.gov/data/faers/]. Consent for publication Not applicable. Funding None. Competing interests The authors declare that they have no competing interests. Acknowledgements Declared none. Ethics approval and consent to participate Not applicable. Human and Animal Rights No animals/human participants were used. Author Contributions Bo Gu contributed significantly to the design and execution of the study, conducted the initial data analysis, and drafted the preliminary version of the manuscript. Bing Lv was responsible for data collection and analysis, provided critical revisions to the methodology, and participated in manuscript revisions. As the corresponding author, Jia Tang oversaw the overall concept and design of the research, led the interpretation and analysis of the data, authored and reviewed the final manuscript, ensuring the integrity and accuracy of the work. Jia Tang managed all communications related to the publication of this study. All authors have read and agreed to the published version of the manuscript. References Misal US, Joshi SA, Shaikh MM. Delayed recovery from anesthesia: A postgraduate educational review. Anesth Essays Res 20160501;10:164–72. https://doi.org/10.4103/0259-1162.165506. Zhang Q, Xu F, Xuan D, et al. 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Longer time to extubation after general anesthesia with desflurane in patients with obstructive respiratory dysfunction: a retrospective study. JA Clin Rep 2021;7:40. https://doi.org/10.1186/s40981-021-00443-x. Maheshwari K, Ahuja S, Mascha EJ, et al. Effect of sevoflurane versus isoflurane on emergence time and postanesthesia care unit length of stay: an alternating intervention trial. Anesth Analg 2020;130:360–6. https://doi.org/10.1213/ANE.0000000000004093. Pavone KJ, Akeju O, Sampson AL, et al. Nitrous oxide-induced slow and delta oscillations. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 2016;127:556–64. https://doi.org/10.1016/j.clinph.2015.06.001. Millischer V, Pramhas S, Wiedermann I, et al. Comparison of etomidate and methohexital as anesthetic agents for continuation and maintenance electroconvulsive therapy: A retrospective analysis of seizure quality and safety. J Affect Disord 2023;330:33–9. https://doi.org/10.1016/j.jad.2023.02.085. Li T, Han W, Yang X, et al. Effects of different injection rates of propofol on postoperative cognition in elderly patients undergoing laparoscopic inguinal hernia repair. Drug Des Devel Ther 2023;17:1741–52. https://doi.org/10.2147/DDDT.S407905. Tekwani KL, Watts HF, Sweis RT, et al. A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective, randomized study. Ann Emerg Med 2010;56:481–9. https://doi.org/10.1016/j.annemergmed.2010.05.034. G K, A M, L M, et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther 2009;31. https://doi.org/10.1016/j.clinthera.2009.02.022. MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986;27:190–5. https://doi.org/10.1136/gut.27.2.190. Bauer TM, Ritz R, Haberthür C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet Lond Engl 1995;346:145–7. https://doi.org/10.1016/s0140-6736(95)91209-6. F F, M M, S S, et al. Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proc Natl Acad Sci U S A 2010;107. https://doi.org/10.1073/pnas.0913008107. S M, Y T, H H, et al. Midazolam is associated with delay in recovery and agitation after ambulatory general anesthesia for dental treatment in patients with disabilities: a retrospective cohort study. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg 2012;70. https://doi.org/10.1016/j.joms.2012.01.004. Santonocito C, Noto A, Crimi C, et al. Remifentanil-induced postoperative hyperalgesia: current perspectives on mechanisms and therapeutic strategies. Local Reg Anesth 2018;11:15–23. https://doi.org/10.2147/LRA.S143618. Cuiabano IS, Naves RP, Diehl RB de A. Comparison of the recovery profile of sufentanil and remifentanil in total intravenous anesthesia: a systematic review and meta-analysis of randomized controlled trials. Braz J Anesthesiol Elsevier 2025;75:844558. https://doi.org/10.1016/j.bjane.2024.844558. Lehot JJ. Delayed respiratory depression following fentanyl anesthesia for cardiac surgery. Crit Care Med 1989;17:299–300. https://doi.org/10.1097/00003246-198903000-00023. Bijkerk V, Krijtenburg P, Verweijen T, et al. Residual neuromuscular block in the postanaesthesia care unit: a single-centre prospective observational study and systematic review. Br J Anaesth 2025;134:350–7. https://doi.org/10.1016/j.bja.2024.07.043. Blum FE, Locke AR, Nathan N, et al. Residual neuromuscular block remains a safety concern for perioperative healthcare professionals: a comprehensive review. J Clin Med 2024;13:861. https://doi.org/10.3390/jcm13030861. Murphy GS, Szokol JW, Marymont JH, et al. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg 2008;107:130–7. https://doi.org/10.1213/ane.0b013e31816d1268. Kisor DF, Schmith VD, Wargin WA, et al. Importance of the organ-independent elimination of cisatracurium. Anesth Analg 1996;83:1065–71. https://doi.org/10.1097/00000539-199611000-00029. Thilen SR, Weigel WA, Todd MM, et al. 2023 american society of anesthesiologists practice guidelines for monitoring and antagonism of neuromuscular blockade: a report by the american society of anesthesiologists task force on neuromuscular blockade. Anesthesiology 2023;138:13–41. https://doi.org/10.1097/ALN.0000000000004379. Harbell MW, Dumitrascu C, Bettini L, et al. Anesthetic considerations for patients on psychotropic drug therapies. Neurol Int 2021;13:640–58. https://doi.org/10.3390/neurolint13040062. Horiuchi T, Takazawa T, Orihara M, et al. Drug-induced anaphylaxis during general anesthesia in 14 tertiary hospitals in japan: A retrospective, multicenter, observational study. J Anesth 2021;35:154–60. https://doi.org/10.1007/s00540-020-02886-5. Pa S, M R. Prolongation of rapacuronium neuromuscular blockade by clindamycin and magnesium. Anesth Analg 2002;94. https://doi.org/10.1097/00000539-200201000-00023. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-7332537","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":498783386,"identity":"ac041aa4-19f6-403d-b07a-9abc63c4da70","order_by":0,"name":"Bo Gu","email":"","orcid":"","institution":"The Central People’s Hospital of Siping City","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Gu","suffix":""},{"id":498783387,"identity":"982dc814-5139-47f1-b822-5a0d7ab8fd86","order_by":1,"name":"Bing Lv","email":"","orcid":"","institution":"The First Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Lv","suffix":""},{"id":498783388,"identity":"a3612a7b-bdff-4ffc-8118-d1f4c2f0852d","order_by":2,"name":"Yuan Hu","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Hu","suffix":""},{"id":498783389,"identity":"4ac577e0-03ce-4dfa-b907-529f93012c18","order_by":3,"name":"Kehan Li","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kehan","middleName":"","lastName":"Li","suffix":""},{"id":498783390,"identity":"1bfad09c-f192-452d-a09c-1fcd1d8c5559","order_by":4,"name":"Liuli Xu","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Liuli","middleName":"","lastName":"Xu","suffix":""},{"id":498783391,"identity":"2159066d-bf12-45b3-b5d6-9f88b4dfdd9b","order_by":5,"name":"Ji Zheng","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ji","middleName":"","lastName":"Zheng","suffix":""},{"id":498783392,"identity":"66b69947-ccd6-4ee9-aff2-8ab0e5a4d024","order_by":6,"name":"Qianying Li","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qianying","middleName":"","lastName":"Li","suffix":""},{"id":498783393,"identity":"486ba4e8-c530-4b47-882f-603fc6ec83af","order_by":7,"name":"Jia Tang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIie3PMQrCMBSA4UggXZ66RpT2CkKgCF7GLnWJNxCXQpysq6DewclZCWbS3cGt0EEchEJHsenm0sZNMP+QEMhH8hCy2X4x2hB6A9KODvrYMyZui6qRPoIBQURvzEW8Xz5XK7x1JBKY3gKBztn9Oh0AcuRpV0Uam+OcgUoDgRf7IVfFxyAMr1UE00B0gcjilcuecVIQCn4lISV5acJTxl8GBDRpCskI4jiZCANCC9LZxtIlVPl4ElMgdbN4q3FKH7kEbxklGc9nbtuRqpJ8zlWuptd1+PnNbZvNZvuf3lmSQ3mh/oH0AAAAAElFTkSuQmCC","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jia","middleName":"","lastName":"Tang","suffix":""}],"badges":[],"createdAt":"2025-08-09 08:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7332537/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7332537/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95540116,"identity":"b585967f-dfff-44fa-9996-c3cb4ff84612","added_by":"auto","created_at":"2025-11-10 11:23:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":821123,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7332537/v1/4e6111e6-165b-4216-a087-cfd436cf68bf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Perioperative Medications Associated with Delayed Recovery from Anaesthesia: A Two-Decade Pharmacovigilance Study Based on the FAERS","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDelayed recovery from anaesthesia (DRA), or delayed emergence, refers to the failure to regain consciousness, responsiveness, or spontaneous respiration within 30\u0026ndash;60 minutes after discontinuation of anaesthetic drugs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although relatively uncommon, DRA can lead to delayed extubation, prolonged postanesthesia care unit stay, increased monitoring needs, and serious complications such as aspiration or respiratory depression. While its overall incidence is low (approximately 1.38\u0026ndash;2.6%) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], its clinical relevance is increasingly recognized in the context of enhanced recovery after surgery.\u003c/p\u003e\u003cp\u003eDRA arises from disruptions in both pharmacodynamic and neurophysiological pathways [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Anaesthetic agents act by enhancing gamma-aminobutyric acid type A inhibition, antagonizing N-methyl-D-aspartate receptors, or impairing thalamocortical connectivity\u0026mdash;mechanisms that suppress the organized cortical activity required for consciousness [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Importantly, emergence is not a passive drug clearance process but an active neurobiological transition that depends on reactivation of key arousal circuits, including the thalamus, basal forebrain, and the orexinergic system in the hypothalamus [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Pharmacologic factors may delay this process by sustaining receptor occupancy, disrupting gamma and alpha oscillatory coherence, or interfering with neuromodulatory loops essential for restoring cortical network synchrony [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Thus, precise modulation of drug\u0026ndash;brain interactions offers the most actionable approach for preventing DRA [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWhile case reports have linked certain drugs to DRA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], large-scale pharmacovigilance studies focusing specifically on DRA remain limited. To address this gap, we conducted a disproportionality analysis based on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to systematically identify drug-specific signals associated with DRA. Given the pharmacological diversity of the implicated agents [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], these findings may support more individualized perioperative drug selection, potentially improving recovery safety.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Data source\u003c/h2\u003e\u003cp\u003eThis pharmacovigilance analysis was retrospectively conducted using data from the FAERS, a spontaneous reporting database that collects post-marketing safety information on pharmaceuticals and biologics (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\u003c/span\u003e\u003cspan address=\"https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The FAERS database includes voluntarily submitted reports from healthcare professionals, consumers, and manufacturers, offering extensive data on patient demographics, suspected drugs, indications, and clinical outcomes. For data retrieval and processing, we employed the OpenVigil 2.1 platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://h2876314.stratoserver.net:8080/OV2/search/\u003c/span\u003e\u003cspan address=\"http://h2876314.stratoserver.net:8080/OV2/search/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), an open-access pharmacovigilance tool designed to support signal detection through cleaning, mining, and statistical analysis of FAERS records. Maintained by B\u0026ouml;hm et al., OpenVigil 2.1 currently hosts structured data from the fourth quarter of 2003 to the fourth quarter of 2024. In total, 13,237,811 AE reports were included.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Definition of AEs and drugs\u003c/h2\u003e\u003cp\u003eThe Medical Dictionary for Regulatory Activities (MedDRA, version 25.1), developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, is a standardized medical terminology system widely employed in AE reporting, pharmacovigilance, and the standardized coding and communication of clinical trial data. MedDRA is organized into a five-level hierarchical structure, among which the Preferred Term (PT) level is most commonly used for coding AEs.\u003c/p\u003e\u003cp\u003eIn this study, we selected the PT \u0026ldquo;delayed recovery from anaesthesia\u0026rdquo; (MedDRA code: 10012206) as the query term within the OpenVigil 2.1 platform, where the AE category was set to PT level for data retrieval. The extracted records were used for downstream pharmacovigilance analysis. Since some reports in the database utilized brand names instead of generic names, we mapped all drug names to their corresponding generic forms using DrugBank. Erroneously reported or ambiguous drug names were manually reviewed and excluded to ensure data integrity.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e\u003cp\u003eWe analyzed demographic characteristics for each individual AE report of \u0026ldquo;delayed recovery from anaesthesia.\u0026rdquo; The variables assessed included patient sex, age, reporting country (top five), and the occurrence of serious adverse events (SAEs). SAEs were defined as reports involving any of the following outcomes: death, disability, hospitalization (initial or prolonged), life-threatening conditions, or medical intervention to prevent permanent impairment or damage.\u003c/p\u003e\u003cp\u003eDisproportionality analysis is a widely applied statistical method in pharmacovigilance, aiming to detect potential safety signals between specific drugs and AEs from spontaneous reporting systems such as FAERS, VigiBase, and EudraVigilance. The most commonly used metric in this context is the Reporting Odds Ratio (ROR), which compares the odds of reporting a particular AE for a given drug against the odds for all other drugs in the database (ROR = [a/c] / [b/d]). Although ROR does not establish causality, a value significantly greater than 1\u0026mdash;often judged against predefined thresholds\u0026mdash;serves as a valuable indicator of a disproportionately high reporting frequency, warranting further evaluation and hypothesis generation. The detailed formula and signal detection thresholds for ROR are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003esummary of algorithms used for signal detection.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlgorithms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEquation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCriteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eROR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eROR=(a*d)/(b*c)\u003c/p\u003e\u003cp\u003eRORL\u0026thinsp;=\u0026thinsp;EXP((LN(ROR)-1.96*SQRT((1/a)+(1/b)+(1/c)+(1/d))))\u003c/p\u003e\u003cp\u003eRORU\u0026thinsp;=\u0026thinsp;EXP((LN(ROR)\u0026thinsp;+\u0026thinsp;1.96*SQRT((1/a)+(1/b)+(1/c)+(1/d))))\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elower limit of 95% CI\u0026thinsp;\u0026gt;\u0026thinsp;1, a\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Descriptive analysis\u003c/h2\u003e\u003cp\u003eA total of 2,430 AE reports related to DRA were identified from the fourth quarter of 2003 to the fourth quarter of 2024. Most reports involved female patients (n\u0026thinsp;=\u0026thinsp;1,436, 59.1%), followed by males (n\u0026thinsp;=\u0026thinsp;835, 34.4%), with sex unspecified in 6.5% of cases. The majority of patients were aged 61\u0026ndash;80 years (n\u0026thinsp;=\u0026thinsp;1,002, 41.2%), while 18.1% were aged 41\u0026ndash;60 years, 11.1% were 19\u0026ndash;40, and 9.4% were \u0026le;\u0026thinsp;18 years; age was not reported in 16.5% of cases.\u003c/p\u003e\u003cp\u003eOver half of the reports indicated hospitalization (n\u0026thinsp;=\u0026thinsp;1,302, 53.6%) as a SAE. Other SAEs included life-threatening events (8.1%), disability (4.3%), death (3.0%), and interventions to prevent permanent damage (4.7%). Reports originated predominantly from the United States (39.6%), Japan (16.4%), the United Kingdom (6.1%), France (5.8%), and China (2.4%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics of adverse event reports related to delayed recovery from anaesthesia in the FAERS database.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCase Number (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase Proportion (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2,430\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e835\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1,436\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e159\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e229\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u0026ndash;40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e270\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e41\u0026ndash;60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e440\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e61\u0026ndash;80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1,002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e400\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerious Outcomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1,302\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLife-threatening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e196\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e105\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRequired Intervention (Permanent damage prevention)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReported countries (top 5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnited States\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e963\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e398\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnited Kingdom\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFrance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Disproportionality analysis\u003c/h2\u003e\u003cp\u003eAfter excluding invalid or incomplete entries, a total of 1,831 reports related to DRA were included for disproportionality analysis. Based on the predefined threshold, 1,239 drug-AE pairs showed significant signals. The top 50 drugs with the highest ROR values are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The strong associations were observed for thiamylal (n\u0026thinsp;=\u0026thinsp;4, ROR\u0026thinsp;=\u0026thinsp;1273.21; 95% CI: 465.82\u0026ndash;3480.02), sevoflurane (n\u0026thinsp;=\u0026thinsp;111, ROR\u0026thinsp;=\u0026thinsp;887.24; 95% CI: 715.31\u0026ndash;1100.49), methohexital (n\u0026thinsp;=\u0026thinsp;4, ROR\u0026thinsp;=\u0026thinsp;715.20; 95% CI: 264.09\u0026ndash;1936.83), remifentanil (n\u0026thinsp;=\u0026thinsp;49, ROR\u0026thinsp;=\u0026thinsp;584.70; 95% CI: 433.77\u0026ndash;788.15), rocuronium (n\u0026thinsp;=\u0026thinsp;86, ROR\u0026thinsp;=\u0026thinsp;553.14; 95% CI: 436.93\u0026ndash;700.25), desflurane (n\u0026thinsp;=\u0026thinsp;15, ROR\u0026thinsp;=\u0026thinsp;524.97; 95% CI: 312.45\u0026ndash;882.04), isoflurane (n\u0026thinsp;=\u0026thinsp;15, ROR\u0026thinsp;=\u0026thinsp;473.59; 95% CI: 281.99\u0026ndash;795.36), propofol (n\u0026thinsp;=\u0026thinsp;171, ROR\u0026thinsp;=\u0026thinsp;460.29; 95% CI: 380.80\u0026ndash;556.37), and succinylcholine (n\u0026thinsp;=\u0026thinsp;20, ROR\u0026thinsp;=\u0026thinsp;287.47; 95% CI: 183.27\u0026ndash;450.91).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTop 50 drugs for signal strength of delayed recovery from anaesthesia.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrug name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of reports\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eROR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePackage insert suggests risk\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ethiamylal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1273.21 (465.82-3480.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esevoflurane\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e111\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e887.24 (715.31-1100.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emethohexital\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e715.20 (264.09-1936.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eremifentanil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e584.70 (433.77-788.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003erocuronium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e553.14 (436.93-700.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003edesflurane\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e524.97 (312.45-882.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eisoflurane\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e473.59 (281.99-795.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epropofol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e460.29 (380.80-556.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003elevobupivacaine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e428.88 (190.55\u0026ndash;965.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eremifentanil hydrochloride\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e376.98 (120.25-1181.85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003elornoxicam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e370.54 (118.21-1161.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esuccinylcholine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e287.47 (183.27-450.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eflumazenil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e286.27 (118.08-694.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003evecuronium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e273.50 (149.97-498.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eropivacaine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e236.98 (156.89-357.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecisatracurium besylate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e229.62 (113.83-463.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esugammadex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e200.11 (103.22-387.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enitrous oxide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e179.49 (84.89-379.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eneostigmine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e174.75 (65.11-468.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esugammadex sodium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e159.09 (50.96-496.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esufentanil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e146.68 (88.97-241.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003earticaine\u0026thinsp;+\u0026thinsp;epinephrine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e142.68 (53.19-382.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eesmolol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e141.44 (45.32\u0026ndash;441.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eetomidate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e131.95 (49.20-353.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003edexmedetomidine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e122.01 (68.69-216.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emidazolam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e120.62 (91.37-159.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003earticaine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.26 (40.64-237.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ethiopental\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.38 (35.96-258.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emepivacaine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e92.83 (29.77-289.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ebupivacaine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62.43 (41.71\u0026ndash;93.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eimipramine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54.50 (24.34-122.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eketamine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51.48 (28.29\u0026ndash;93.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003efluvoxamine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e47.37 (23.53\u0026ndash;95.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eurapidil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.00 (13.81-133.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003efentanyl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e102\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39.35 (31.58\u0026ndash;49.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecyclizine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37.63 (12.08-117.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ebiperiden\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33.39 (14.91\u0026ndash;74.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enicardipine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.49 (9.47\u0026ndash;91.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ephenylephrine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.80 (13.65\u0026ndash;60.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecefazolin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.77 (12.85\u0026ndash;64.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003efentanyl-100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.12 (7.11\u0026ndash;68.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esotalol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.67 (8.34\u0026ndash;41.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enusinersen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.64 (8.33\u0026ndash;41.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003elidocaine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.17 (12.04\u0026ndash;27.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eglycopyrrolate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.86 (5.92\u0026ndash;42.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eepinephrine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.61 (9.62\u0026ndash;25.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003egranisetron\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.36 (4.93\u0026ndash;47.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eatropine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.66 (5.66\u0026ndash;32.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ezonisamide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.05 (4.88\u0026ndash;34.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eposaconazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.67 (3.75\u0026ndash;36.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eROR, Reporting Odds Ratio; CI, Confidence Interval.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn our results, only midazolam (n\u0026thinsp;=\u0026thinsp;57, ROR\u0026thinsp;=\u0026thinsp;120.62; 95% CI: 91.37\u0026ndash;159.25) and remifentanil (n\u0026thinsp;=\u0026thinsp;49, ROR\u0026thinsp;=\u0026thinsp;584.70; 95% CI: 433.77\u0026ndash;788.15) were mentioned in FDA labeling as associated with delayed recovery, while the others were not. It is noteworthy that several agents\u0026mdash;despite showing positive disproportionality signals\u0026mdash;are pharmacologically implausible as causes of delayed emergence. For instance, neostigmine, sugammadex, and sugammadex sodium. Therefore, these agents were not included in the main results or discussion but were retained in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e for completeness.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eTo date, this study represents the most comprehensive pharmacovigilance analysis of AEs related to DRA, encompassing over two decades of data. More than half of the reported cases (53.6%) required hospitalization, underscoring the clinical and operational burden imposed by DRA. In addition, patients aged over 60 years accounted for nearly half of all reports (44.9%), consistent with findings from Zhang et al. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and Bayable et al. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] who also identified advanced age as a significant risk factor for DRA. This age-related vulnerability may be attributed to neurocognitive decline and increased pharmacodynamic sensitivity to commonly perioperative medications. These findings highlight the importance of age-adjusted anaesthetic and sedative dosing strategies in mitigating the risk of DRA among older adults.\u003c/p\u003e\u003cp\u003eMost DRA reports originated from the U.S. and Japan, likely due to regulatory differences and stronger pharmacovigilance engagement [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The predominance of female cases (59.1%) aligns with previous findings and may involve both higher reporting tendency and sex-specific pharmacodynamic sensitivity [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hormonal modulation and metabolic differences may also affect anesthetic clearance [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Considering both the observed female predominance in DRA reports and established sex-related pharmacological differences, perioperative medication strategies may benefit from sex-sensitive risk assessment and tailored dosing in female patients.\u003c/p\u003e\u003cp\u003eAmong inhalational anesthetics, sevoflurane (ROR\u0026thinsp;=\u0026thinsp;887.24, n\u0026thinsp;=\u0026thinsp;111), desflurane (ROR\u0026thinsp;=\u0026thinsp;524.97, n\u0026thinsp;=\u0026thinsp;15), and isoflurane (ROR\u0026thinsp;=\u0026thinsp;473.59, n\u0026thinsp;=\u0026thinsp;15) exhibited strong disproportionality signals. In contrast, nitrous oxide (ROR\u0026thinsp;=\u0026thinsp;63.19, n\u0026thinsp;=\u0026thinsp;6) showed substantially lower signal intensity and fewer reports. Sevoflurane generated the largest report count and the highest ROR, a finding that matches its dominant clinical use worldwide [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and well-documented suppression of cortico-striato-thalamo-cortical and γ-band networks that govern arousal [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Desflurane, despite faster emergence in controlled trials, still showed a strong signal; retrospective data indicate that specific subgroups (e.g., obstructive airway disease) can experience markedly prolonged extubation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and its recent decline in use for environmental reasons [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] may inflate ROR by reducing the denominator.\u003c/p\u003e\u003cp\u003eIsoflurane, used far less often, produced only 15 reports yet retained a high ROR; experimental work links it to sleep-state rebound and residual cortical dys-connectivity [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], supporting biological plausibility. By contrast, nitrous oxide exhibited much lower signal strength, likely due to its pharmacokinetic profile and effect on cortical dynamics: while high‑dose N₂O can transiently induce large‑amplitude slow‑δ EEG activity, this effect is limited to 2\u0026ndash;12 minutes only\u0026mdash;insufficient to disrupt arousal circuitry significantly, and its rapid pulmonary elimination minimizes tissue accumulation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Collectively, these disparities suggest that both pharmacodynamic mechanisms and exposure patterns shape our disproportionality results.\u003c/p\u003e\u003cp\u003eAmong intravenous anesthetics, thiamylal (ROR\u0026thinsp;=\u0026thinsp;1273.21; n\u0026thinsp;=\u0026thinsp;4) and methohexital (ROR\u0026thinsp;=\u0026thinsp;715.20; n\u0026thinsp;=\u0026thinsp;4), both thiobarbiturates, exhibited the highest disproportionality signals despite their minimal report counts. These agents represent classic intravenous induction anesthetics that have been largely supplanted by newer drugs due to safety and pharmacokinetic advantages; they now retain specific utility only in select scenarios such as status epilepticus and electroconvulsive therapy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This \u0026ldquo;spike-like\u0026rdquo; pattern likely reflects their extremely limited contemporary clinical use, resulting in a very small exposure denominator. Pharmacokinetic studies have shown that thiobarbiturates possess high lipophilicity and long context-sensitive half-lives; when peripheral tissues become saturated, back-redistribution to the central nervous system may occur, potentially prolonging hypnotic effects and contributing to DRA [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePropofol (ROR\u0026thinsp;=\u0026thinsp;460.29; n\u0026thinsp;=\u0026thinsp;171) accounted for the largest number of DRA reports. This is likely attributed to its dominant use in induction and maintenance of general anesthesia, as well as its known cardiovascular depressant effects. Although propofol is typically associated with rapid emergence, recent studies have demonstrated that in elderly patients, delayed redistribution from adipose tissue and age-related reductions in hepatic clearance may impair postoperative neurocognitive recovery [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, intraoperative hypotension\u0026mdash;a common consequence of propofol use\u0026mdash;has been independently associated with delayed emergence (AOR 3.37; 95% CI: 2.93\u0026ndash;9.41) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, etomidate (ROR\u0026thinsp;=\u0026thinsp;132.60; n\u0026thinsp;=\u0026thinsp;9), though less frequently used due to concerns over adrenal suppression, is often preferred in hemodynamically unstable patients for its cardiovascular stability [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMidazolam (ROR\u0026thinsp;=\u0026thinsp;120.62; n\u0026thinsp;=\u0026thinsp;57) yielded the low disproportionality signal among agents analyzed; however, its mechanistic plausibility remains substantial. As a short-acting benzodiazepine primarily metabolized by cytochrome P450 3A4 (CYP3A4), midazolam exhibits high susceptibility to drug\u0026ndash;drug interactions and impaired hepatic clearance. Co-administration with potent CYP3A4 inhibitors\u0026mdash;such as posaconazole\u0026mdash;has been shown to increase midazolam exposure by over sixfold and prolong its elimination half-life from 3 to 10 hours [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In cirrhotic patients, reduced metabolic capacity further extends psychomotor impairment [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Moreover, active glucuronide metabolites may accumulate in renal dysfunction, contributing to delayed sedation offset [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Neurophysiologically, midazolam disrupts cortical effective connectivity, potentially prolonging arousal latency beyond pharmacokinetic elimination [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Clinical data indicate that midazolam use independently predicts delayed emergence in outpatient settings [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These findings support risk-adjusted use of midazolam, with dose reduction in older adults and avoidance of CYP3A4 inhibitors to mitigate DRA risk.\u003c/p\u003e\u003cp\u003eOpioid analgesics have been consistently associated with DRA. In our study, strong disproportionality signals were observed for remifentanil ( ROR\u0026thinsp;=\u0026thinsp;584.70, n\u0026thinsp;=\u0026thinsp;49), sufentanil ( ROR\u0026thinsp;=\u0026thinsp;146.69, n\u0026thinsp;=\u0026thinsp;16), and fentanyl ( ROR\u0026thinsp;=\u0026thinsp;39.35, n\u0026thinsp;=\u0026thinsp;102), supporting their association with DRA. Remifentanil is an ultra-short-acting opioid with organ-independent metabolism, and its FDA label explicitly lists \u0026ldquo;prolonged emergence from anesthesia\u0026rdquo; as a potential adverse reaction. High intraoperative doses or insufficient postoperative analgesia may trigger opioid-induced hyperalgesia and tolerance, necessitating additional sedation and delaying recovery [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In contrast, sufentanil is mainly used in deep anesthesia contexts such as neurosurgery, where delayed emergence is expected and less frequently reported. Although sufentanil has been shown to prolong extubation by 3\u0026ndash;5 minutes, its overall exposure is limited [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Fentanyl, despite widespread use, showed a diluted signal due to a large exposure base. While DRA is not listed in its labeling, delayed respiratory depression 2\u0026ndash;6 hours postoperatively has been reported following high-dose cardiac anesthesia, likely due to redistribution from adipose tissue [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], which may overlap with or contribute to DRA.\u003c/p\u003e\u003cp\u003eResidual neuromuscular blockade remains prevalent, affecting 30\u0026ndash;40% of adults in contemporary practice despite modern monitoring and reversal strategies [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Among NMBAs, rocuronium (ROR\u0026thinsp;=\u0026thinsp;553.14; n\u0026thinsp;=\u0026thinsp;86) exhibited the strongest signal for DRA, followed by succinylcholine (ROR\u0026thinsp;=\u0026thinsp;287.47; n\u0026thinsp;=\u0026thinsp;20) and vecuronium (ROR\u0026thinsp;=\u0026thinsp;273.50; n\u0026thinsp;=\u0026thinsp;11). Mechanistically, incomplete restoration of diaphragm and upper-airway muscle strength limits ventilation, causing hypercapnia and retarding elimination of inhaled anesthetics\u0026mdash;an indirect pathway to DRA [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Pharmacokinetic heterogeneity modulates risk: rocuronium relies on hepatic/biliary excretion\u0026mdash;prolonging action in hepatic or renal dysfunction [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Objective quantitative monitoring and timely pharmacologic reversal (e.g., sugammadex or neostigmine) remain the cornerstone of prevention [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, psychotropic agents such as imipramine (ROR\u0026thinsp;=\u0026thinsp;54.50; n\u0026thinsp;=\u0026thinsp;6) and fluvoxamine (ROR\u0026thinsp;=\u0026thinsp;47.37; n\u0026thinsp;=\u0026thinsp;8) showed comparatively lower signal strengths and fewer reports. However, their potential contribution to DRA should not be overlooked, particularly in patients receiving long-term maintenance therapy. These agents may delay emergence from anesthesia via central nervous system depression, cytochrome P450-mediated metabolic inhibition, enhanced sedation, or synergistic suppression [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, due to risks of relapse and withdrawal, discontinuation should be carefully evaluated. Hemodynamic agents such as urapidil (ROR\u0026thinsp;=\u0026thinsp;43.00; n\u0026thinsp;=\u0026thinsp;3) may influence cerebral perfusion; intraoperative hypotension and reduced brain oxygenation have been proposed as contributing factors to DRA, particularly in older or high-risk patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHoriuchi T et al. identified cefazolin as one of the most frequent triggers of perioperative anaphylactic reactions in a large multicentre study in Japan, with resultant hypotension and cerebral hypoperfusion potentially contributing to delayed emergence [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Sloan PA further demonstrated that clindamycin and gentamicin can significantly enhance the neuromuscular blockade induced by agents like rocuronium, thereby delaying the recovery of spontaneous ventilation and consciousness [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. However, in our analysis, only two antimicrobial agents\u0026mdash;cefazolin (ROR\u0026thinsp;=\u0026thinsp;28.77; n\u0026thinsp;=\u0026thinsp;6) and posaconazole (ROR\u0026thinsp;=\u0026thinsp;11.67; n\u0026thinsp;=\u0026thinsp;3)\u0026mdash;showed significant disproportionality signals. Given their relatively low signal strength and reporting frequency, and in light of Zhang et al.\u0026rsquo;s findings that antibiotics contributed to DRA in less than 1 per 1,000 cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], we consider that antimicrobial agents alone may not be a major driver of DRA unless accompanied by other risk factors such as advanced age, impaired metabolism, or concurrent sedative or neuromuscular blocking agents.\u003c/p\u003e\u003cp\u003eAmong the top-signal agents, including thiamylal, methohexital, and sevoflurane, many showed high RORs in association with DRA, yet lacked corresponding warnings for DRA in their FDA-approved labeling. Traditional short-acting barbiturates such as thiamylal and methohexital have been largely replaced by newer agents, resulting in limited contemporary safety surveillance. Similarly, the perceived safety of sevoflurane may obscure its potential to delay recovery in older adults. The high ROR signals identified in this study, despite the absence of corresponding warnings in labeling, highlight the need for further validation and periodic label reassessment. Preoperative evaluation should incorporate a checklist of drugs associated with DRA, and intraoperative monitoring should include objective measures of brain function to ensure timely recovery.\u003c/p\u003e\u003cp\u003eThis study is subject to several limitations inherent in spontaneous reporting systems like FAERS. First, underreporting and reporting bias may influence the representativeness of the data, and the absence of denominator data precludes accurate incidence estimation. Second, causal relationships cannot be established due to the observational nature of the data. Third, the MedDRA term \u0026ldquo;delayed recovery from anaesthesia\u0026rdquo; lacks standardized diagnostic criteria, which may lead to heterogeneity in reporting. Lastly, confounding factors such as comorbidities, anesthetic depth, or intraoperative events were not available for adjustment, which may affect signal interpretation.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis pharmacovigilance study highlights that multiple perioperative drugs, including anesthetics, psychotropics, and opioids, are associated with disproportionality signals for DRA. Notably, for the vast majority of these agents, DRA is not listed as an adverse reaction in their official product labeling. Clinicians should be aware of these potential risks when managing perioperative medications. Further prospective studies are warranted to validate these associations and guide safer perioperative pharmacologic strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAE \u0026ndash; Adverse Event\u003c/p\u003e\n\u003cp\u003eCI \u0026ndash; Confidence Interval\u003c/p\u003e\n\u003cp\u003eDRA \u0026ndash; Delayed Recovery from Anaesthesia\u003c/p\u003e\n\u003cp\u003eFAERS \u0026ndash; FDA Adverse Event Reporting System\u003c/p\u003e\n\u003cp\u003eMedDRA \u0026ndash; Medical Dictionary for Regulatory Activities\u003c/p\u003e\n\u003cp\u003eNMBA \u0026ndash; Neuromuscular Blocking Agent\u003c/p\u003e\n\u003cp\u003ePT \u0026ndash; Preferred Term\u003c/p\u003e\n\u003cp\u003eROR \u0026ndash; Reporting Odds Ratio\u003c/p\u003e\n\u003cp\u003eSAE \u0026ndash; Serious Adverse Event\u003c/p\u003e\n\u003cp\u003eSRS \u0026ndash; Spontaneous Reporting System\u003c/p\u003e\n\u003cp\u003eCYP3A4 \u0026ndash; Cytochrome P450 3A4\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset supporting the conclusions of this study is available in the FAERS repository, accessible at [https://open.fda.gov/data/faers/].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\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\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeclared none.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman and Animal Rights\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo animals/human participants were used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBo Gu contributed significantly to the design and execution of the study, conducted the initial data analysis, and drafted the preliminary version of the manuscript. Bing Lv was responsible for data collection and analysis, provided critical revisions to the methodology, and participated in manuscript revisions. As the corresponding author, Jia Tang oversaw the overall concept and design of the research, led the interpretation and analysis of the data, authored and reviewed the final manuscript, ensuring the integrity and accuracy of the work. Jia Tang managed all communications related to the publication of this study. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMisal US, Joshi SA, Shaikh MM. Delayed recovery from anesthesia: A postgraduate educational review. Anesth Essays Res 20160501;10:164\u0026ndash;72. https://doi.org/10.4103/0259-1162.165506.\u003c/li\u003e\n\u003cli\u003eZhang Q, Xu F, Xuan D, et al. Risk factors for delayed recovery in postanesthesia care unit after surgery: a large and retrospective cohort study. Int J Surg 2023;109:1281\u0026ndash;90. https://doi.org/10.1097/JS9.0000000000000364.\u003c/li\u003e\n\u003cli\u003eBayable SD, Amberbir WD, Fetene MB. Delayed awakening and its associated factor following general anesthesia service, 2022: A cross-sectional study. Ann Med Surg 2023;85:4321\u0026ndash;8. https://doi.org/10.1097/MS9.0000000000001103.\u003c/li\u003e\n\u003cli\u003eZhou K, Hou Z-J, Jiang X-L, et al. Striatal neurones expressing D1 dopamine receptors modulate consciousness in sevoflurane but not propofol anaesthesia in mice. Br J Anaesth 2025;134:1105\u0026ndash;21. https://doi.org/10.1016/j.bja.2024.10.049.\u003c/li\u003e\n\u003cli\u003eKelz MB, Sun Y, Chen J, et al. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci U S A 2008;105:1309\u0026ndash;14. https://doi.org/10.1073/pnas.0707146105.\u003c/li\u003e\n\u003cli\u003eThomas E, Martin F, Pollard B. Delayed recovery of consciousness after general anaesthesia. BJA Educ 2020;20:173\u0026ndash;9. https://doi.org/10.1016/j.bjae.2020.01.007.\u003c/li\u003e\n\u003cli\u003eRan M, Wang Z, Yang H, et al. Orexin-1 receptor is involved in ageing-related delayed emergence from general anaesthesia in rats. Br J Anaesth 2018;121:1097\u0026ndash;104. https://doi.org/10.1016/j.bja.2018.05.073.\u003c/li\u003e\n\u003cli\u003eLi D, Hambrecht-Wiedbusch VS, Mashour GA. Accelerated recovery of consciousness after general anesthesia is associated with increased functional brain connectivity in the high-gamma bandwidth. Front Syst Neurosci 2017;11:16. https://doi.org/10.3389/fnsys.2017.00016.\u003c/li\u003e\n\u003cli\u003eTakemori T, Oyama Y, Makino T, et al. Long-term delayed emergence after remimazolam-based general anesthesia: A case report. JA Clin Rep 2022;8:86. https://doi.org/10.1186/s40981-022-00576-7.\u003c/li\u003e\n\u003cli\u003eAl-Emam A. Butyryl-cholinesterase deficiency: A case report of delayed recovery after general anaesthesia. Toxicol Rep 2021;8:1226\u0026ndash;8. https://doi.org/10.1016/j.toxrep.2021.06.016.\u003c/li\u003e\n\u003cli\u003eLiu Y, Huang H. Clinical report of delayed recovery after general anaesthesia in elderly patients with cervical spine surgery: A case report. J Int Med Res 2022;50:3000605221134462. https://doi.org/10.1177/03000605221134462.\u003c/li\u003e\n\u003cli\u003eMatsuda S, Aoki K, Kawamata T, et al. Bias in spontaneous reporting of adverse drug reactions in japan. PLOS One 2015;10:e0126413. https://doi.org/10.1371/journal.pone.0126413.\u003c/li\u003e\n\u003cli\u003eWu H, Wang S, Dai F-B, et al. Research progress in the clinical application of inhaled anesthetic sevoflurane. Med Gas Res 2024;15:85\u0026ndash;92. https://doi.org/10.4103/mgr.MEDGASRES-D-23-00003.\u003c/li\u003e\n\u003cli\u003ePal D, Li D, Dean JG, et al. Level of consciousness is dissociable from electroencephalographic measures of cortical connectivity, slow oscillations, and complexity. J Neurosci Off J Soc Neurosci 2020;40:605\u0026ndash;18. https://doi.org/10.1523/JNEUROSCI.1910-19.2019.\u003c/li\u003e\n\u003cli\u003eDesowska A, Berde CB, Cornelissen L. Emerging functional connectivity patterns during sevoflurane anaesthesia in the developing human brain. Br J Anaesth 2023;130:e381\u0026ndash;90. https://doi.org/10.1016/j.bja.2022.05.033.\u003c/li\u003e\n\u003cli\u003eTakeyama E, Nakajima M, Nakanishi Y, et al. Longer time to extubation after general anesthesia with desflurane in patients with obstructive respiratory dysfunction: a retrospective study. JA Clin Rep 2021;7:40. https://doi.org/10.1186/s40981-021-00443-x.\u003c/li\u003e\n\u003cli\u003eMaheshwari K, Ahuja S, Mascha EJ, et al. Effect of sevoflurane versus isoflurane on emergence time and postanesthesia care unit length of stay: an alternating intervention trial. Anesth Analg 2020;130:360\u0026ndash;6. https://doi.org/10.1213/ANE.0000000000004093.\u003c/li\u003e\n\u003cli\u003ePavone KJ, Akeju O, Sampson AL, et al. Nitrous oxide-induced slow and delta oscillations. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 2016;127:556\u0026ndash;64. https://doi.org/10.1016/j.clinph.2015.06.001.\u003c/li\u003e\n\u003cli\u003eMillischer V, Pramhas S, Wiedermann I, et al. Comparison of etomidate and methohexital as anesthetic agents for continuation and maintenance electroconvulsive therapy: A retrospective analysis of seizure quality and safety. J Affect Disord 2023;330:33\u0026ndash;9. https://doi.org/10.1016/j.jad.2023.02.085.\u003c/li\u003e\n\u003cli\u003eLi T, Han W, Yang X, et al. Effects of different injection rates of propofol on postoperative cognition in elderly patients undergoing laparoscopic inguinal hernia repair. Drug Des Devel Ther 2023;17:1741\u0026ndash;52. https://doi.org/10.2147/DDDT.S407905.\u003c/li\u003e\n\u003cli\u003eTekwani KL, Watts HF, Sweis RT, et al. A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective, randomized study. Ann Emerg Med 2010;56:481\u0026ndash;9. https://doi.org/10.1016/j.annemergmed.2010.05.034.\u003c/li\u003e\n\u003cli\u003eG K, A M, L M, et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther 2009;31. https://doi.org/10.1016/j.clinthera.2009.02.022.\u003c/li\u003e\n\u003cli\u003eMacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986;27:190\u0026ndash;5. https://doi.org/10.1136/gut.27.2.190.\u003c/li\u003e\n\u003cli\u003eBauer TM, Ritz R, Haberth\u0026uuml;r C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet Lond Engl 1995;346:145\u0026ndash;7. https://doi.org/10.1016/s0140-6736(95)91209-6.\u003c/li\u003e\n\u003cli\u003eF F, M M, S S, et al. Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proc Natl Acad Sci U S A 2010;107. https://doi.org/10.1073/pnas.0913008107.\u003c/li\u003e\n\u003cli\u003eS M, Y T, H H, et al. Midazolam is associated with delay in recovery and agitation after ambulatory general anesthesia for dental treatment in patients with disabilities: a retrospective cohort study. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg 2012;70. https://doi.org/10.1016/j.joms.2012.01.004.\u003c/li\u003e\n\u003cli\u003eSantonocito C, Noto A, Crimi C, et al. Remifentanil-induced postoperative hyperalgesia: current perspectives on mechanisms and therapeutic strategies. Local Reg Anesth 2018;11:15\u0026ndash;23. https://doi.org/10.2147/LRA.S143618.\u003c/li\u003e\n\u003cli\u003eCuiabano IS, Naves RP, Diehl RB de A. Comparison of the recovery profile of sufentanil and remifentanil in total intravenous anesthesia: a systematic review and meta-analysis of randomized controlled trials. Braz J Anesthesiol Elsevier 2025;75:844558. https://doi.org/10.1016/j.bjane.2024.844558.\u003c/li\u003e\n\u003cli\u003eLehot JJ. Delayed respiratory depression following fentanyl anesthesia for cardiac surgery. Crit Care Med 1989;17:299\u0026ndash;300. https://doi.org/10.1097/00003246-198903000-00023.\u003c/li\u003e\n\u003cli\u003eBijkerk V, Krijtenburg P, Verweijen T, et al. Residual neuromuscular block in the postanaesthesia care unit: a single-centre prospective observational study and systematic review. Br J Anaesth 2025;134:350\u0026ndash;7. https://doi.org/10.1016/j.bja.2024.07.043.\u003c/li\u003e\n\u003cli\u003eBlum FE, Locke AR, Nathan N, et al. Residual neuromuscular block remains a safety concern for perioperative healthcare professionals: a comprehensive review. J Clin Med 2024;13:861. https://doi.org/10.3390/jcm13030861.\u003c/li\u003e\n\u003cli\u003eMurphy GS, Szokol JW, Marymont JH, et al. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg 2008;107:130\u0026ndash;7. https://doi.org/10.1213/ane.0b013e31816d1268.\u003c/li\u003e\n\u003cli\u003eKisor DF, Schmith VD, Wargin WA, et al. Importance of the organ-independent elimination of cisatracurium. Anesth Analg 1996;83:1065\u0026ndash;71. https://doi.org/10.1097/00000539-199611000-00029.\u003c/li\u003e\n\u003cli\u003eThilen SR, Weigel WA, Todd MM, et al. 2023 american society of anesthesiologists practice guidelines for monitoring and antagonism of neuromuscular blockade: a report by the american society of anesthesiologists task force on neuromuscular blockade. Anesthesiology 2023;138:13\u0026ndash;41. https://doi.org/10.1097/ALN.0000000000004379.\u003c/li\u003e\n\u003cli\u003eHarbell MW, Dumitrascu C, Bettini L, et al. Anesthetic considerations for patients on psychotropic drug therapies. Neurol Int 2021;13:640\u0026ndash;58. https://doi.org/10.3390/neurolint13040062.\u003c/li\u003e\n\u003cli\u003eHoriuchi T, Takazawa T, Orihara M, et al. Drug-induced anaphylaxis during general anesthesia in 14 tertiary hospitals in japan: A retrospective, multicenter, observational study. J Anesth 2021;35:154\u0026ndash;60. https://doi.org/10.1007/s00540-020-02886-5.\u003c/li\u003e\n\u003cli\u003ePa S, M R. Prolongation of rapacuronium neuromuscular blockade by clindamycin and magnesium. Anesth Analg 2002;94. https://doi.org/10.1097/00000539-200201000-00023.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pharmacovigilance, Disproportionality Analysis, adverse Event, Opioids, Delayed Recovery from Anaesthesia, Anaesthesia","lastPublishedDoi":"10.21203/rs.3.rs-7332537/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7332537/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eDrug-induced delayed recovery from anaesthesia (DRA) represents a serious postoperative adverse drug reaction characterized by prolonged unconsciousness or respiratory depression following the cessation of anaesthetic agents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo systematically identify drugs significantly associated with DRA using the U.S. FDA Adverse Event Reporting System (FAERS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003ePharmacovigilance disproportionality analysis was conducted with FAERS data (2003–2024), applying the Reporting Odds Ratio (ROR) to quantify drug-event associations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 1,831 reports related to DRA were included for disproportionality analysis, yielding 1,239 significant signals. The strong associations were observed for thiamylal (n = 4, ROR = 1273.21; 95% CI: 465.82–3480.02), sevoflurane (n = 111, ROR = 887.24; 95% CI: 715.31–1100.49), methohexital (n = 4, ROR = 715.20; 95% CI: 264.09–1936.83), remifentanil (n = 49, ROR = 584.70; 95% CI: 433.77–788.15), rocuronium (n = 86, ROR = 553.14; 95% CI: 436.93–700.25), desflurane (n = 15, ROR = 524.97; 95% CI: 312.45–882.04), isoflurane (n = 15, ROR = 473.59; 95% CI: 281.99–795.36), propofol (n = 171, ROR = 460.29; 95% CI: 380.80–556.37), and succinylcholine (n = 20, ROR = 287.47; 95% CI: 183.27–450.91). In our results, only midazolam (n = 57, ROR = 120.62; 95% CI: 91.37–159.25) and remifentanil (n = 49, ROR = 584.70; 95% CI: 433.77–788.15) were mentioned in FDA labeling as associated with delayed recovery, while the others were not.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003eThis pharmacovigilance analysis identified multiple agents with strong associations with DRA. Most lacked corresponding warnings in official drug labeling, underscoring the need for improved risk communication.\u003c/p\u003e","manuscriptTitle":"Perioperative Medications Associated with Delayed Recovery from Anaesthesia: A Two-Decade Pharmacovigilance Study Based on the FAERS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-12 09:40:50","doi":"10.21203/rs.3.rs-7332537/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"90d64f2a-bad8-4d26-8aa9-c06d82bc8326","owner":[],"postedDate":"August 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-10T11:23:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-12 09:40:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7332537","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7332537","identity":"rs-7332537","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}