Frequency, Characteristics, and Preventability of Adverse Drug Reactions in Perioperative Neurosurgery: Analysis Over 11 Years

Frequency, Characteristics, and Preventability of Adverse Drug Reactions in Perioperative Neurosurgery: Analysis Over 11 Years | 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 Frequency, Characteristics, and Preventability of Adverse Drug Reactions in Perioperative Neurosurgery: Analysis Over 11 Years Daina Kashiwazaki, Takahiro Tomita, Emiko Hori, Naoki Akioka, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2707715/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 May, 2024 Read the published version in World Neurosurgery → Version 1 posted You are reading this latest preprint version Abstract Introduction : Despite the importance of adverse drug reactions (ADRs), little is known about their role in perioperative neurosurgery. This study aimed to determine the prevalence of ADRs in perioperative neurosurgery in the past 11 years and clarify the characteristics, severity, preventability, and risk factors of ADRs. Methods : Data for all patients who underwent neurosurgical procedures over an 11-year period were analyzed. During the study period, 3648 surgical procedures were performed for 2695 patients, including 1440 males and 1255 females. The average age was 57.3 ± 22.7 years(range, 0-100). Demographic and clinical information documented included sex, age, body mass index, medical history, allergic history, diagnosis, surgical method, suspected drugs, concomitant medications, and drug details. Multivariate logistic regression analyses were performed to identify independent parameters that were correlated with ADRs. Results : In total, 467 ADRs (18.3% ADRs/all neurosurgical procedures) were experienced by 401 patients. Anticonvulsants were associated with the highest number of ADRs (16.0%), followed by antibiotics (14.7%). Patients with ADRs were older than patients without ADRs (P < 0.01). The total number of drugs in patients with ADRs was 8.8 ± 3.6, compared to 5.2 ± 2.4 for patients without ADRs (P < 0.01). There were no significant differences in sex, allergic history, severe renal dysfunction (eGFR < 30 ml/min/1.73 m2), hypertension, diabetes, urgency of surgery, and type of surgery. Multivariate analysis showed that a high total number of drugs (odds = 3.2; 95%CI 1.9–5.1) and older age (odds = 2.1; 95%CI 1.3–3.8) were independent risk factors for ADRs in perioperative neurosurgery. Conclusion : The frequency of suspected and severe ADRs was higher than expected. Polypharmacy and older age were independent risk factors for ADRs in perioperative neurosurgery. To decrease ADRs during perioperative neurosurgery, polypharmacy must be discouraged, especially among older adult patients. Adverse drug events Perioperative neurosurgery Preventability Authors contributions Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Key Points 1 The overall rate of ADRs was 18.3%. Furthermore, 11.3% were likely definitely preventable. 2 ADRs with anticonvulsants as the most common. ADRs were correlated with polypharmacy and age. Introduction According to the World Health Organization (WHO), adverse drug reactions (ADR) are unintended, harmful reactions detected in patients after the use of drugs for prophylaxis, diagnosis, or treatment of disease at recommended doses [ 1 ]. ADRs contribute significantly to morbidity and extended hospital stays, which can be a life-threatening problem in perioperative neurosurgery, even if the surgical procedure itself was successfully performed. ADRs to medications remain an obstacle in achieving optimal surgical outcomes in the management of perioperative neurosurgery. Despite the importance of ADRs, little is known about ADRs in perioperative neurosurgery. Therefore, the aims of the present study were to determine the prevalence of ADRs in perioperative neurosurgery in the past 11 years and clarify the characteristics, severity, preventability, and risk factors of ADRs. Additionally, we analyzed the drugs most frequently suspected to cause ADRs during perioperative neurosurgery. To minimize the consequences of ADRs, it is necessary to elucidate the distinctive features of ADRs in perioperative neurosurgery for their early identification and prevention. Patients And Methods Ethical This study was a posthoc analysis of a prospective database of morbidity and mortality events in our institution. This study was approved by the Institutional Review Board of our institution. Informed consent was obtained using an opt-out method on our institutional website. In accordance with the ethical standards of the institutional research committees, this non-invasive study did not require formal consent. Instead, the outline of the study was open to the public on our institutional homepage and provided an opportunity for patients and their guardians to decline inclusion in the research. Setting Our institution is a 612-bed general hospital. The Department of Neurosurgery at our hospital is the largest neurosurgical unit in our prefecture. Our main therapeutic targets include brain tumors, cerebrovascular disease, endovascular therapy, spinal, trauma, surgery for pediatrics, and functional neurosurgery. Digital subtraction angiography and endovascular treatments are performed in our department by certified neurosurgeons. Patient and data acquisition In this study, data for all patients who underwent neurosurgical procedures stored within our department over an 11-year period (April 2012 to June 2022) were analyzed. During the study period, 3648 surgical procedures were performed for 2695 patients (1440 males and 1255 females). The average age was 57.3 ± 22.7 years(range, 0-100 years). Procedures performed included: 1043 (28.6%) endovascular, 791 (21.7%) vascular surgical procedures, 761 (20.9%) surgeries for brain tumors, 319 (8.7%) surgical shunt or drainage, 261 (7.2%) trauma surgeries, and 473 (12.9%) others. Demographic and clinical information relevant to ADRs in perioperative neurosurgery was documented, including sex, age, body mass index, medical history, allergic history, diagnosis, surgical method, suspected drugs, concomitant medications, and drug details. All drugs were assessed, including drugs for therapy, prophylaxis, and examination, including contrast medium; however, chemotherapy and chemotherapy-related drugs for malignant brain tumors were excluded from this study. The study period was divided into three periods: the first (2012–2014), second (2015–2017), and third periods (2018–2022) and the frequency of ADRs during each period was analyzed. Assessment of severity and preventability of ADRs The severity of ADRs was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In this study, severe ADRs were defined as CTCAE grade 3–5. Preventability was assessed using the Schumock-Thornton algorithm modified by Schmiedl et al. [ 2 ]. The detailed aspects of preventability were as follows: inappropriate drug use (drug not indicated; exceeding treatment duration; previous ADR or drug allergy; inappropriate drug due to age, body weight, comorbidities, contraindication), inappropriate dose (inappropriate dose due to age, body weight, comorbidities, insufficient dose adjustment of renally excreted drugs), relevant drug-drug interactions, missing ADR prevention (drug-related, non-drug-related), and others (non-adherence, self-medication). At least one of the above aspects was required for the ADE to be considered potentially preventable. Statistical analyses Continuous data are expressed as mean ± SDs. Data were compared between the two groups using Mann–Whitney U tests and χ2 tests, as appropriate. Multivariate logistic regression analyses were performed to identify independent parameters that were significantly correlated with ADRs in perioperative neurosurgery. Statistical significance was set at P < 0.05. Results Overall data and ADR risk factors in perioperative neurosurgery A total of 467 ADRs (18.3% ADRs/all neurosurgical procedures) were encountered by 401 patients (Fig. 1 a). The number of ADRs associated with each pharmacological drug class is summarized in Fig. 1 b. Anticonvulsants were associated with the highest number of ADRs (16.0%), followed by antibiotics (14.7%). Patients with ADRs were older than patients without (65.8 ± 17.8 years and 52.0 ± 24.1 years, respectively (P < 0.01). The total number of drugs used by patients with ADRs was significantly higher than in patients without ADRs (8.8 ± 3.6 vs 5.2 ± 2.4) (P < 0.01). There were no significant differences in sex, allergy history, severe renal dysfunction (eGFR < 30 ml/min/1.73 m 2 ), history of hypertension, history of diabetes, urgency of surgery, or type of surgery. Multivariate analysis indicated that a high total number of drugs (odds = 3.2; 95%CI 1.9–5.1) and older age (odds = 2.1; 95%CI 1.3–3.8) were independent risk factors for ADRs in perioperative neurosurgery ( Table 1) . The relationship between age and total number of drugs were showed in Fig. 2 . ADR severity and preventability ADR severity as assessed by CTCAE indicated that of 667 ADRs, the distribution of severity was as follows: grade 1, 329 (49.3%); grade 2, 230 (34.6%); grade 3, 79 (11.8%); grade 4, 28 (4.2%); and grade 5 one (0.1%) ( Fig. 1 c ) . Therefore, 108 ADRs (16.1%) were classified as severe. Anticonvulsant drugs were associated with the highest number of severe ADRs (n = 23, 21.3%), followed by antibiotic drugs (n = 21, 19.4%), and iodinated contrast medium (n = 15, 13.9%) ( Fig. 1 d ) . The most frequent severe ADRs were skin disorders, followed by hepatobiliary disorders, and blood and lymphatic system disorders. Detailed severe ADRs are shown in Fig. 3 . During the study period, 552 morbidity events were collected from morbidity and mortality conferences, including surgical technical issues, critical events, and human error, which were classified as CTCAE grades 3–5 in perioperative neurosurgery. Therefore, severe ADRs accounted for 20.7% of all morbidity events in CTCAE grades 3–5 ( Fig. 4 a ) . Preventability of ADRs as assessed by the modified Schumock-Thornton algorithm revealed that 75 ADRs (11.3%) were classified as definitely preventable, 167 ADRs (25.0%) were classified as probable preventable, and 425 ADRs (63.7%) were not preventable ( Fig. 4 b ). Seventy-five ADRs classified as definitely preventable included 35 ADRs categorized as inappropriate drugs, 22 ADRs categorized into inappropriate doses, 12 ADRs drug–drug interactions, and 6 ADRs categorized into others. An illustrated case judged as definitely preventable ADR is presented in Fig. 5 . ADRs and causative drug by time period The frequencies of ADRs and severe ADRs did not differ significantly among the three study periods (P = 0.23 and P = 0.45, respectively) ( Fig. 4 c and d). Major changes were made in anticonvulsants during the study period. Phenytoin was used more frequently in the first than second and third periods, as newly developed Lacosamide and Levetiracetam were commonly used in the second and third periods ( Fig. 6 ) . The proportion of ADRs caused by anticonvulsants did not differ significantly between groups. However, the frequency of severe ADRs caused by anticonvulsants significantly decreased over the three study periods (P < 0.01) ( Fig. 7 a ) . This improvement was achieved by newly developed anticonvulsants. The most common causative drug for severe ADRs among the anticonvulsants documented in this study was phenytoin ( Fig. 7 b ). Discussion This study focused on the frequency, characteristics, and preventability of ADRs during perioperative neurosurgery. The observed frequency of suspected ADRs was 18.3%, and 16.1% of ADRs were classified as severe. These results provide the first evidence of the frequency of ADRs in perioperative neurosurgery over 11 years. Further, severe ADRs accounted for approximately 20% of all morbidity events. Severe ADRs decreased for some drugs, such as anticonvulsants, due to the development of new drugs; however, the frequencies of ADRs and severe ADRs in the present study remain alarming. Studies in various settings have revealed that antimicrobial drugs cause the greatest number of ADRs[ 2 – 6 ]. However, the pharmacological drug class implicated in causing the highest number of ADRs (16.0%) was anticonvulsants, one of the most frequently prescribed classes of drugs, specifically in perioperative neurosurgery. It is important that neurosurgeons are aware of the characteristics of these drugs. To decrease ADRs in perioperative neurosurgery These findings clearly suggest that polypharmacy and older age are independent risk factors for ADRs in perioperative neurosurgery, as supported by previous evidence. Polypharmacy has been associated with an increased risk of drug-drug interactions and ADRs [ 7 – 10 ]. This calls for attention to the prescription of medications by providing only the necessary medications and avoiding overuse of multiple medications in perioperative neurosurgery, especially if anticonvulsants or antibiotics are used, which may lead to a higher prevalence of ADRs. Neurosurgeons should be aware that polypharmacy is important in perioperative neurosurgery, as it is associated with several adverse outcomes, such as an increased risk of drug-drug interactions, hospitalizations, and mortality. Our findings indicated that older age was also an important factor for ADRs during perioperative neurosurgery. Patients in this study often had age-related comorbidities that increased their risk of ADRs. Marusic et al. pointed out that older patients are particularly vulnerable to ADRs owing to polypharmacy for chronic diseases and physiological changes in this population, such as reduced gastrointestinal motility, gastric blood flow, impaired repair mechanisms, and lower mucosal protection [ 11 ]. Further, older patients clearly had polypharmacy in this study; therefore, polypharmacy should be discouraged for older patients in particular. The preventability of ADRs in perioperative neurosurgery The results of this study suggest that definitely preventable (11.3%) or probable (25.0%) preventable ADRs still occur in perioperative neurosurgery; therefore, a large proportion (36.3%) of these ADRs could potentially be prevented. This proportion is higher than expected. The identified preventability aspects may draw attention to possible safety problems in perioperative neurosurgery pharmacotherapy. One strength of this study is that this is the first long-term study to report ADRs after perioperative neurosurgery. A limitation of this study is that it was single-center and conducted in a university hospital serving referred patients with complex diseases and more comorbidities, which may make it difficult to generalize the findings to a larger population. Conclusions In conclusion, the frequency of suspected ADRs in the present study was 18.3%. Severe ADRs account for approximately 20% of all perioperative neurosurgery morbidity events. Polypharmacy and older age are independent risk factors for ADRs in perioperative neurosurgery. To decrease ADRs during perioperative neurosurgery, polypharmacy must be discouraged. Declarations We confirmed this manuscript complies with all instructions to authors. The final manuscript was approved by all authors Authors contributions Daina Kashiwazaki; Draft MS, Design of the work, Acquisition of data: Statistics Takahiro Tomita; Acquisition of data Emiko Hori; Acquisition of data Naoki Akioka; Acquisition of data Takuya Akai: Acquisition of data Satoshi Kuroda: Interpretation of data Revising works critically for important intellectual content This manuscript has not been published elsewhere and is not under consideration by another journal This study was a posthoc analysis of a prospective database of morbidity and mortality events in our institution. This study was approved by the Institutional Review Board of our institution. Informed consent was obtained using an opt-out method on our institutional website. In accordance with the ethical standards of the institutional research committees, this non-invasive study did not require formal consent. Instead, the outline of the study was open to the public on our institutional homepage and provided an opportunity for patients and their guardians to decline inclusion in the research. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. We used STROBE check list. References Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356:1255-125910.1016/S0140-6736(00)02799-9. Schmiedl S, Rottenkolber M, Szymanski J, et al. Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients. Expert Opin Drug Saf. 2018;17:125-13710.1080/14740338.2018.1415322. Iftikhar S, Sarwar MR, Saqib A, Sarfraz M. Causality and preventability assessment of adverse drug reactions and adverse drug events of antibiotics among hospitalized patients: A multicenter, cross-sectional study in Lahore, Pakistan. PLoS One. 2018;13:e019945610.1371/journal.pone.0199456. Patidar D, Rajput MS, Nirmal NP, Savitri W. Implementation and evaluation of adverse drug reaction monitoring system in a tertiary care teaching hospital in Mumbai, India. Interdiscip Toxicol. 2013;6:41-4610.2478/intox-2013-0008. Rosli R, Dali AF, Aziz NA, Ming LC, Manan MM. Reported Adverse Drug Reactions in Infants: A Nationwide Analysis in Malaysia. Front Pharmacol. 2017;8:3010.3389/fphar.2017.00030. Salvo F, Miroddi M, Alibrandi A, et al. Attitudes and opinion about adverse drug events of women living in a city of south Italy. Pharmacology. 2013;91:173-17710.1159/000346737. Delara M, Murray L, Jafari B, et al. Prevalence and factors associated with polypharmacy: a systematic review and Meta-analysis. BMC Geriatr. 2022;22:60110.1186/s12877-022-03279-x. Nguyen JK, Fouts MM, Kotabe SE, Lo E. Polypharmacy as a risk factor for adverse drug reactions in geriatric nursing home residents. Am J Geriatr Pharmacother. 2006;4:36-4110.1016/j.amjopharm.2006.03.002. Wolf U, Baust H, Neef R, Steinke T. Individual Pharmacotherapy Management (IPM)-IV: Optimized Usage of Approved Antimicrobials Addressing Under-Recognized Adverse Drug Reactions and Drug-Drug Interactions in Polypharmacy. Antibiotics (Basel). 2022;1110.3390/antibiotics11101381. Ye L, Yang-Huang J, Franse CB, et al. Factors associated with polypharmacy and the high risk of medication-related problems among older community-dwelling adults in European countries: a longitudinal study. BMC Geriatr. 2022;22:84110.1186/s12877-022-03536-z. Marusic S, Sicaja M, Obreli Neto PR, Franic M, Marinovic I, Bacic-Vrca V. Adverse drug reactions in elderly patients following discharge from an internal medicine clinic. Int J Clin Pharmacol Ther. 2014;52:906-91310.5414/CP202041. Table 1 Table 1 is available in the Supplementary Files section. Supplementary Files STROBEchecklistv4combinedPlosMedicine.pdf Table1.docx Cite Share Download PDF Status: Published Journal Publication published 31 May, 2024 Read the published version in World Neurosurgery → 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2707715","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":187577323,"identity":"e7095c10-c2b8-4168-bf84-f29055f2ced9","order_by":0,"name":"Daina Kashiwazaki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYDACHiBm/Cchx8/AwAYTSyCghRlIsNkYSzaQqCUtccMBhBb8QN7n/MHbPDyHGTffSH724EMFgzzQhc8e4NNieLaZ2XKGxGFmsxtp5oYzzjAYzmxgSDfAq6WfmU3ig8FhNrMbCWbSvG0MCQYHGNIkCGpJSDjMYzwj/RtxWuR5m4G2HEiTMJDIIdIWA57DxpYzG2wMJM68KZOccUbCcGYzAb/I9yQ+vM3bIFHf356+TeJDhY08P3tP2gO8thxgYIA4QyABRALZzDxp+HQwyDfAtPAfgImxH8OrZRSMglEwCkYcAAAjVUPqwwKS7wAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-9249-1382","institution":"Toyama University - Sugitani Campus: Toyama Daigaku - Sugitani Campus","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Daina","middleName":"","lastName":"Kashiwazaki","suffix":""},{"id":187577324,"identity":"20bf074f-c7a1-41ab-b9e1-d361684c7494","order_by":1,"name":"Takahiro Tomita","email":"","orcid":"","institution":"Toyama Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Tomita","suffix":""},{"id":187577325,"identity":"2883a8dd-53b0-46bd-aff1-0a9849523a37","order_by":2,"name":"Emiko Hori","email":"","orcid":"","institution":"Toyama Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Emiko","middleName":"","lastName":"Hori","suffix":""},{"id":187577326,"identity":"5e49c60d-b036-4744-b3cc-578eef061ba3","order_by":3,"name":"Naoki Akioka","email":"","orcid":"","institution":"Toyama Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Naoki","middleName":"","lastName":"Akioka","suffix":""},{"id":187577327,"identity":"acf1bf7d-3d5b-44a9-90c2-a3cc69a74fc2","order_by":4,"name":"Takuya Akai","email":"","orcid":"","institution":"Toyama Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Akai","suffix":""},{"id":187577328,"identity":"b212d516-89ae-4e43-9deb-413e5f0ca83c","order_by":5,"name":"Satoshi Kuroda","email":"","orcid":"","institution":"Toyama Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Kuroda","suffix":""}],"badges":[],"createdAt":"2023-03-18 10:37:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2707715/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2707715/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1016/j.wneu.2024.06.136","type":"published","date":"2024-06-01T00:30:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":35123778,"identity":"c2d7a092-e135-4e1f-98a9-dd773b3b0ffa","added_by":"auto","created_at":"2023-03-31 21:31:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":97739,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea) \u003c/strong\u003eA total of 467 ADRs (18.3%) were observed during the study period \u003cstrong\u003eb) \u003c/strong\u003enumber of ADRs associated with pharmacological drugs classes \u003cstrong\u003ec)\u003c/strong\u003e Severity of ADRs 16.1% of all ADRs were classified into severe ADRs. \u003cstrong\u003ed) \u003c/strong\u003enumber of severe ADRs associated with pharmacological drugs classes.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/0346737826482f01f013ee30.png"},{"id":35124808,"identity":"3dd1c0ac-c18f-4a73-9667-0574b4e16301","added_by":"auto","created_at":"2023-03-31 21:39:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":23169,"visible":true,"origin":"","legend":"\u003cp\u003eBar graph showing the relationship between age and total number of drug used in perioperative neurosurgery.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/1b53c8c6070d00fc31487d96.png"},{"id":35123785,"identity":"8fa68c2d-27fa-42f8-aec2-4a3bc5492dfb","added_by":"auto","created_at":"2023-03-31 21:31:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":87971,"visible":true,"origin":"","legend":"\u003cp\u003eCircle chart showing the frequency and details of ADRs in perioperative neurosurgery. Skin disorder (25.0%) was the most frequent followed by hepatobiliary disorder (21.3%) and blood and lymphatic system disorder (17.6%).\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/319c0f5a47e27e747962a70f.png"},{"id":35124809,"identity":"12a1d6c6-5862-4e9d-bdf7-4407d35c696a","added_by":"auto","created_at":"2023-03-31 21:39:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":50895,"visible":true,"origin":"","legend":"\u003cp\u003eIn the three study periods, 552 morbidity events were collected from morbidity and mortality conferences, which classified into CTCAE grade 3-5 in perioperative neurosurgery \u003cstrong\u003ea)\u003c/strong\u003e Severe ADRs account for 20.7% of morbidity event in CTCAE grade 3-5 \u003cstrong\u003eb)\u003c/strong\u003e The preventability of ADRs showed 75 ADRs (11.3%) were classified into definitely preventable, 167 ADRs (25.0%) were classified into probable preventable, and 425 ADRs (63.7%) were not preventable. \u003cstrong\u003ec and d) \u003c/strong\u003eThe frequency of ADRs and severe ADRs did not differ significantly among 3 study periods (P=0.23 and P=0.45, respectively).\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/5191e6da1f678aac4cde397a.png"},{"id":35123779,"identity":"38517bc1-8d70-47e6-98c2-3eccdc8f9a7b","added_by":"auto","created_at":"2023-03-31 21:31:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":637931,"visible":true,"origin":"","legend":"\u003cp\u003eAn illustrative case of definitely preventable ADR: a 62 year old male with left hemiparesis came to our hospital. \u003cstrong\u003ea,b,) \u003c/strong\u003eMRI showed cerebral infarct and right ICA occlusion and 123I-IMP SPECT showed impaired CBF and CVR. Cerebral blood flow and cerebral vascular reserve were impaired. \u003cstrong\u003ec)\u003c/strong\u003eSTA-MCA bypass was performed. \u003cstrong\u003ed)\u003c/strong\u003e99mTc-PAO immediately after surgery showed hyperperfusion in right temporal lobe. Antihypertensive therapy was performed to prevent symptoms of hyperperfusion using continuous intravenous infusion of diltiazem hydrochloride. \u0026nbsp;An over-dose injection of diltiazem caused complete atrioventricular block and cardiogenic shock. \u003cstrong\u003ee)\u003c/strong\u003eImmediately, installation of a temporary pacemaker was performed. As the patient’s hemodynamics improved after cessation of diltiazem infusion, vasoactive support was no longer needed.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/3a30ce56ae4df7e5128ecbae.png"},{"id":35125906,"identity":"040752e2-b618-4122-8f33-14c3de1bda58","added_by":"auto","created_at":"2023-03-31 21:47:38","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":26803,"visible":true,"origin":"","legend":"\u003cp\u003eDuring study period, major changes were made in anticonvulsants. Phenytoin use was most frequent in the first period, but it was decreased in second and third periods. Levetiracetam, Lacosamide, and Perampanel were newly developed and used in the second and third periods.\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/dd7ca45152497c942a4c8dcd.png"},{"id":35123783,"identity":"47ad7a50-8f45-42de-8d74-a0ab7a5708a0","added_by":"auto","created_at":"2023-03-31 21:31:38","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":56098,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea) \u003c/strong\u003eThe frequency of severe ADRs assessed by CTCAE grade caused by anticonvulsant were significant decreased among 3 study periods (P\u0026lt;0.01). \u0026nbsp;\u003cstrong\u003eb) \u003c/strong\u003eThe drug most frequently causative of severe ADRs among anticonvulsants documented in this study was Phenytoin.\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/815e3fe1f896c02435ec4d55.png"},{"id":59336421,"identity":"fdbe8044-a191-4f85-8df3-2c8f3d04af41","added_by":"auto","created_at":"2024-06-30 00:31:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1638613,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/55e62e67-f505-47e0-8b2c-2c7ec5dc7967.pdf"},{"id":35123786,"identity":"ee4f4776-0a28-45b5-b132-f49f80046323","added_by":"auto","created_at":"2023-03-31 21:31:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":145065,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklistv4combinedPlosMedicine.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/02d4cfed022fa0d3b588ef9e.pdf"},{"id":35123781,"identity":"09e728f7-cc74-45fc-ae87-eaf2ba38fe53","added_by":"auto","created_at":"2023-03-31 21:31:38","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18807,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2707715/v1/2b5266623776f2a52d94ddd7.docx"}],"financialInterests":"","formattedTitle":"Frequency, Characteristics, and Preventability of Adverse Drug Reactions in Perioperative Neurosurgery: Analysis Over 11 Years","fulltext":[{"header":"Key Points","content":"\u003cp\u003e1 The overall rate of ADRs was 18.3%. Furthermore, 11.3% were likely definitely preventable.\u003c/p\u003e\n\u003cp\u003e2 ADRs with anticonvulsants as the most common. ADRs were correlated with polypharmacy and age.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAccording to the World Health Organization (WHO), adverse drug reactions (ADR) are unintended, harmful reactions detected in patients after the use of drugs for prophylaxis, diagnosis, or treatment of disease at recommended doses [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. ADRs contribute significantly to morbidity and extended hospital stays, which can be a life-threatening problem in perioperative neurosurgery, even if the surgical procedure itself was successfully performed. ADRs to medications remain an obstacle in achieving optimal surgical outcomes in the management of perioperative neurosurgery. Despite the importance of ADRs, little is known about ADRs in perioperative neurosurgery. Therefore, the aims of the present study were to determine the prevalence of ADRs in perioperative neurosurgery in the past 11 years and clarify the characteristics, severity, preventability, and risk factors of ADRs. Additionally, we analyzed the drugs most frequently suspected to cause ADRs during perioperative neurosurgery. To minimize the consequences of ADRs, it is necessary to elucidate the distinctive features of ADRs in perioperative neurosurgery for their early identification and prevention.\u003c/p\u003e"},{"header":"Patients And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthical\u003c/h2\u003e \u003cp\u003eThis study was a posthoc analysis of a prospective database of morbidity and mortality events in our institution. This study was approved by the Institutional Review Board of our institution. Informed consent was obtained using an opt-out method on our institutional website. In accordance with the ethical standards of the institutional research committees, this non-invasive study did not require formal consent. Instead, the outline of the study was open to the public on our institutional homepage and provided an opportunity for patients and their guardians to decline inclusion in the research.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSetting\u003c/h2\u003e \u003cp\u003eOur institution is a 612-bed general hospital. The Department of Neurosurgery at our hospital is the largest neurosurgical unit in our prefecture. Our main therapeutic targets include brain tumors, cerebrovascular disease, endovascular therapy, spinal, trauma, surgery for pediatrics, and functional neurosurgery. Digital subtraction angiography and endovascular treatments are performed in our department by certified neurosurgeons.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatient and data acquisition\u003c/h2\u003e \u003cp\u003eIn this study, data for all patients who underwent neurosurgical procedures stored within our department over an 11-year period (April 2012 to June 2022) were analyzed. During the study period, 3648 surgical procedures were performed for 2695 patients (1440 males and 1255 females). The average age was 57.3\u0026thinsp;\u0026plusmn;\u0026thinsp;22.7 years(range, 0-100 years). Procedures performed included: 1043 (28.6%) endovascular, 791 (21.7%) vascular surgical procedures, 761 (20.9%) surgeries for brain tumors, 319 (8.7%) surgical shunt or drainage, 261 (7.2%) trauma surgeries, and 473 (12.9%) others. Demographic and clinical information relevant to ADRs in perioperative neurosurgery was documented, including sex, age, body mass index, medical history, allergic history, diagnosis, surgical method, suspected drugs, concomitant medications, and drug details. All drugs were assessed, including drugs for therapy, prophylaxis, and examination, including contrast medium; however, chemotherapy and chemotherapy-related drugs for malignant brain tumors were excluded from this study. The study period was divided into three periods: the first (2012\u0026ndash;2014), second (2015\u0026ndash;2017), and third periods (2018\u0026ndash;2022) and the frequency of ADRs during each period was analyzed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of severity and preventability of ADRs\u003c/h2\u003e \u003cp\u003eThe severity of ADRs was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In this study, severe ADRs were defined as CTCAE grade 3\u0026ndash;5. Preventability was assessed using the Schumock-Thornton algorithm modified by Schmiedl et al. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The detailed aspects of preventability were as follows: inappropriate drug use (drug not indicated; exceeding treatment duration; previous ADR or drug allergy; inappropriate drug due to age, body weight, comorbidities, contraindication), inappropriate dose (inappropriate dose due to age, body weight, comorbidities, insufficient dose adjustment of renally excreted drugs), relevant drug-drug interactions, missing ADR prevention (drug-related, non-drug-related), and others (non-adherence, self-medication). At least one of the above aspects was required for the ADE to be considered potentially preventable.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eContinuous data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SDs. Data were compared between the two groups using Mann\u0026ndash;Whitney U tests and χ2 tests, as appropriate. Multivariate logistic regression analyses were performed to identify independent parameters that were significantly correlated with ADRs in perioperative neurosurgery. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOverall data and ADR risk factors in perioperative neurosurgery\u003c/h2\u003e \u003cp\u003eA total of 467 ADRs (18.3% ADRs/all neurosurgical procedures) were encountered by 401 patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The number of ADRs associated with each pharmacological drug class is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb. Anticonvulsants were associated with the highest number of ADRs (16.0%), followed by antibiotics (14.7%). Patients with ADRs were older than patients without (65.8\u0026thinsp;\u0026plusmn;\u0026thinsp;17.8 years and 52.0\u0026thinsp;\u0026plusmn;\u0026thinsp;24.1 years, respectively (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The total number of drugs used by patients with ADRs was significantly higher than in patients without ADRs (8.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 vs 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). There were no significant differences in sex, allergy history, severe renal dysfunction (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e), history of hypertension, history of diabetes, urgency of surgery, or type of surgery. Multivariate analysis indicated that a high total number of drugs (odds\u0026thinsp;=\u0026thinsp;3.2; 95%CI 1.9\u0026ndash;5.1) and older age (odds\u0026thinsp;=\u0026thinsp;2.1; 95%CI 1.3\u0026ndash;3.8) were independent risk factors for ADRs in perioperative neurosurgery (\u003cb\u003eTable\u0026nbsp;1)\u003c/b\u003e. The relationship between age and total number of drugs were showed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eADR severity and preventability\u003c/h2\u003e \u003cp\u003eADR severity as assessed by CTCAE indicated that of 667 ADRs, the distribution of severity was as follows: grade 1, 329 (49.3%); grade 2, 230 (34.6%); grade 3, 79 (11.8%); grade 4, 28 (4.2%); and grade 5 one (0.1%) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec\u003cb\u003e)\u003c/b\u003e. Therefore, 108 ADRs (16.1%) were classified as severe. Anticonvulsant drugs were associated with the highest number of severe ADRs (n\u0026thinsp;=\u0026thinsp;23, 21.3%), followed by antibiotic drugs (n\u0026thinsp;=\u0026thinsp;21, 19.4%), and iodinated contrast medium (n\u0026thinsp;=\u0026thinsp;15, 13.9%) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed\u003cb\u003e)\u003c/b\u003e. The most frequent severe ADRs were skin disorders, followed by hepatobiliary disorders, and blood and lymphatic system disorders. Detailed severe ADRs are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. During the study period, 552 morbidity events were collected from morbidity and mortality conferences, including surgical technical issues, critical events, and human error, which were classified as CTCAE grades 3\u0026ndash;5 in perioperative neurosurgery. Therefore, severe ADRs accounted for 20.7% of all morbidity events in CTCAE grades 3\u0026ndash;5 \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003ePreventability of ADRs as assessed by the modified Schumock-Thornton algorithm revealed that 75 ADRs (11.3%) were classified as definitely preventable, 167 ADRs (25.0%) were classified as probable preventable, and 425 ADRs (63.7%) were not preventable \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb\u003cb\u003e).\u003c/b\u003e Seventy-five ADRs classified as definitely preventable included 35 ADRs categorized as inappropriate drugs, 22 ADRs categorized into inappropriate doses, 12 ADRs drug\u0026ndash;drug interactions, and 6 ADRs categorized into others.\u003c/p\u003e \u003cp\u003eAn illustrated case judged as definitely preventable ADR is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eADRs and causative drug by time period\u003c/h2\u003e \u003cp\u003eThe frequencies of ADRs and severe ADRs did not differ significantly among the three study periods (P\u0026thinsp;=\u0026thinsp;0.23 and P\u0026thinsp;=\u0026thinsp;0.45, respectively) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec \u003cb\u003eand d).\u003c/b\u003e Major changes were made in anticonvulsants during the study period. Phenytoin was used more frequently in the first than second and third periods, as newly developed Lacosamide and Levetiracetam were commonly used in the second and third periods \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The proportion of ADRs caused by anticonvulsants did not differ significantly between groups. However, the frequency of severe ADRs caused by anticonvulsants significantly decreased over the three study periods (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea\u003cb\u003e)\u003c/b\u003e. This improvement was achieved by newly developed anticonvulsants. The most common causative drug for severe ADRs among the anticonvulsants documented in this study was phenytoin \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eb\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study focused on the frequency, characteristics, and preventability of ADRs during perioperative neurosurgery. The observed frequency of suspected ADRs was 18.3%, and 16.1% of ADRs were classified as severe. These results provide the first evidence of the frequency of ADRs in perioperative neurosurgery over 11 years. Further, severe ADRs accounted for approximately 20% of all morbidity events. Severe ADRs decreased for some drugs, such as anticonvulsants, due to the development of new drugs; however, the frequencies of ADRs and severe ADRs in the present study remain alarming.\u003c/p\u003e \u003cp\u003eStudies in various settings have revealed that antimicrobial drugs cause the greatest number of ADRs[\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, the pharmacological drug class implicated in causing the highest number of ADRs (16.0%) was anticonvulsants, one of the most frequently prescribed classes of drugs, specifically in perioperative neurosurgery. It is important that neurosurgeons are aware of the characteristics of these drugs.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTo decrease ADRs in perioperative neurosurgery\u003c/h2\u003e \u003cp\u003eThese findings clearly suggest that polypharmacy and older age are independent risk factors for ADRs in perioperative neurosurgery, as supported by previous evidence. Polypharmacy has been associated with an increased risk of drug-drug interactions and ADRs [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This calls for attention to the prescription of medications by providing only the necessary medications and avoiding overuse of multiple medications in perioperative neurosurgery, especially if anticonvulsants or antibiotics are used, which may lead to a higher prevalence of ADRs. Neurosurgeons should be aware that polypharmacy is important in perioperative neurosurgery, as it is associated with several adverse outcomes, such as an increased risk of drug-drug interactions, hospitalizations, and mortality.\u003c/p\u003e \u003cp\u003eOur findings indicated that older age was also an important factor for ADRs during perioperative neurosurgery. Patients in this study often had age-related comorbidities that increased their risk of ADRs. Marusic et al. pointed out that older patients are particularly vulnerable to ADRs owing to polypharmacy for chronic diseases and physiological changes in this population, such as reduced gastrointestinal motility, gastric blood flow, impaired repair mechanisms, and lower mucosal protection [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Further, older patients clearly had polypharmacy in this study; therefore, polypharmacy should be discouraged for older patients in particular.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eThe preventability of ADRs in perioperative neurosurgery\u003c/h2\u003e \u003cp\u003eThe results of this study suggest that definitely preventable (11.3%) or probable (25.0%) preventable ADRs still occur in perioperative neurosurgery; therefore, a large proportion (36.3%) of these ADRs could potentially be prevented. This proportion is higher than expected. The identified preventability aspects may draw attention to possible safety problems in perioperative neurosurgery pharmacotherapy.\u003c/p\u003e \u003cp\u003eOne strength of this study is that this is the first long-term study to report ADRs after perioperative neurosurgery. A limitation of this study is that it was single-center and conducted in a university hospital serving referred patients with complex diseases and more comorbidities, which may make it difficult to generalize the findings to a larger population.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, the frequency of suspected ADRs in the present study was 18.3%. Severe ADRs account for approximately 20% of all perioperative neurosurgery morbidity events. Polypharmacy and older age are independent risk factors for ADRs in perioperative neurosurgery. To decrease ADRs during perioperative neurosurgery, polypharmacy must be discouraged.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eWe confirmed this manuscript complies with all instructions to authors.\u003c/p\u003e\n\n\u003cp\u003eThe final manuscript was approved by all authors\u003c/p\u003e\n\u003cp\u003eAuthors contributions\u003c/p\u003e\n\u003cp\u003eDaina Kashiwazaki; Draft MS, Design of the work, Acquisition of data: Statistics\u003c/p\u003e\n\u003cp\u003eTakahiro Tomita; Acquisition of data\u003c/p\u003e\n\u003cp\u003eEmiko Hori; Acquisition of data\u003c/p\u003e\n\u003cp\u003eNaoki Akioka; Acquisition of data\u003c/p\u003e\n\u003cp\u003eTakuya Akai: Acquisition of data\u003c/p\u003e\n\u003cp\u003eSatoshi Kuroda: Interpretation of data Revising works critically for important intellectual content\u003c/p\u003e\n\n\u003cp\u003eThis manuscript has not been published elsewhere and is not under consideration by another journal\u003c/p\u003e\n\n\u003cp\u003eThis study was a posthoc analysis of a prospective database of morbidity and mortality events in our institution. This study was approved by the Institutional Review Board of our institution. Informed consent was obtained using an opt-out method on our institutional website. In accordance with the ethical standards of the institutional research committees, this non-invasive study did not require formal consent. Instead, the outline of the study was open to the public on our institutional homepage and provided an opportunity for patients and their guardians to decline inclusion in the research.\u003c/p\u003e\n\u003cp\u003eThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\n\u003cp\u003eWe used STROBE check list.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEdwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. \u003cem\u003eLancet. \u003c/em\u003e2000;356:1255-125910.1016/S0140-6736(00)02799-9.\u003c/li\u003e\n\u003cli\u003eSchmiedl S, Rottenkolber M, Szymanski J, et al. Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients. \u003cem\u003eExpert Opin Drug Saf. \u003c/em\u003e2018;17:125-13710.1080/14740338.2018.1415322.\u003c/li\u003e\n\u003cli\u003eIftikhar S, Sarwar MR, Saqib A, Sarfraz M. Causality and preventability assessment of adverse drug reactions and adverse drug events of antibiotics among hospitalized patients: A multicenter, cross-sectional study in Lahore, Pakistan. \u003cem\u003ePLoS One. \u003c/em\u003e2018;13:e019945610.1371/journal.pone.0199456.\u003c/li\u003e\n\u003cli\u003ePatidar D, Rajput MS, Nirmal NP, Savitri W. Implementation and evaluation of adverse drug reaction monitoring system in a tertiary care teaching hospital in Mumbai, India. \u003cem\u003eInterdiscip Toxicol. \u003c/em\u003e2013;6:41-4610.2478/intox-2013-0008.\u003c/li\u003e\n\u003cli\u003eRosli R, Dali AF, Aziz NA, Ming LC, Manan MM. Reported Adverse Drug Reactions in Infants: A Nationwide Analysis in Malaysia. \u003cem\u003eFront Pharmacol. \u003c/em\u003e2017;8:3010.3389/fphar.2017.00030.\u003c/li\u003e\n\u003cli\u003eSalvo F, Miroddi M, Alibrandi A, et al. Attitudes and opinion about adverse drug events of women living in a city of south Italy. \u003cem\u003ePharmacology. \u003c/em\u003e2013;91:173-17710.1159/000346737.\u003c/li\u003e\n\u003cli\u003eDelara M, Murray L, Jafari B, et al. Prevalence and factors associated with polypharmacy: a systematic review and Meta-analysis. \u003cem\u003eBMC Geriatr. \u003c/em\u003e2022;22:60110.1186/s12877-022-03279-x.\u003c/li\u003e\n\u003cli\u003eNguyen JK, Fouts MM, Kotabe SE, Lo E. Polypharmacy as a risk factor for adverse drug reactions in geriatric nursing home residents. \u003cem\u003eAm J Geriatr Pharmacother. \u003c/em\u003e2006;4:36-4110.1016/j.amjopharm.2006.03.002.\u003c/li\u003e\n\u003cli\u003eWolf U, Baust H, Neef R, Steinke T. Individual Pharmacotherapy Management (IPM)-IV: Optimized Usage of Approved Antimicrobials Addressing Under-Recognized Adverse Drug Reactions and Drug-Drug Interactions in Polypharmacy. \u003cem\u003eAntibiotics (Basel). \u003c/em\u003e2022;1110.3390/antibiotics11101381.\u003c/li\u003e\n\u003cli\u003eYe L, Yang-Huang J, Franse CB, et al. Factors associated with polypharmacy and the high risk of medication-related problems among older community-dwelling adults in European countries: a longitudinal study. \u003cem\u003eBMC Geriatr. \u003c/em\u003e2022;22:84110.1186/s12877-022-03536-z.\u003c/li\u003e\n\u003cli\u003eMarusic S, Sicaja M, Obreli Neto PR, Franic M, Marinovic I, Bacic-Vrca V. Adverse drug reactions in elderly patients following discharge from an internal medicine clinic. \u003cem\u003eInt J Clin Pharmacol Ther. \u003c/em\u003e2014;52:906-91310.5414/CP202041.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":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":"Adverse drug events, Perioperative neurosurgery, Preventability Authors contributions","lastPublishedDoi":"10.21203/rs.3.rs-2707715/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2707715/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e: Despite the importance of adverse drug reactions (ADRs), little is known about their role in perioperative neurosurgery. This study aimed to determine the prevalence of ADRs in perioperative neurosurgery in the past 11 years and clarify the characteristics, severity, preventability, and risk factors of ADRs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Data for all patients who underwent neurosurgical procedures over an 11-year period were analyzed. During the study period, 3648 surgical procedures were performed for 2695 patients, including 1440 males and 1255 females. The average age was 57.3 ± 22.7 years(range, 0-100). Demographic and clinical information documented included sex, age, body mass index, medical history, allergic history, diagnosis, surgical method, suspected drugs, concomitant medications, and drug details. Multivariate logistic regression analyses were performed to identify independent parameters that were correlated with ADRs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: In total, 467 ADRs (18.3% ADRs/all neurosurgical procedures) were experienced by 401 patients. Anticonvulsants were associated with the highest number of ADRs (16.0%), followed by antibiotics (14.7%). Patients with ADRs were older than patients without ADRs (P \u0026lt; 0.01). The total number of drugs in patients with ADRs was 8.8 ± 3.6, compared to 5.2 ± 2.4 for patients without ADRs (P \u0026lt; 0.01). There were no significant differences in sex, allergic history, severe renal dysfunction (eGFR \u0026lt; 30 ml/min/1.73 m2), hypertension, diabetes, urgency of surgery, and type of surgery. Multivariate analysis showed that a high total number of drugs (odds = 3.2; 95%CI 1.9–5.1) and older age (odds = 2.1; 95%CI 1.3–3.8) were independent risk factors for ADRs in perioperative neurosurgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The frequency of suspected and severe ADRs was higher than expected. Polypharmacy and older age were independent risk factors for ADRs in perioperative neurosurgery. To decrease ADRs during perioperative neurosurgery, polypharmacy must be discouraged, especially among older adult patients.\u003c/p\u003e","manuscriptTitle":"Frequency, Characteristics, and Preventability of Adverse Drug Reactions in Perioperative Neurosurgery: Analysis Over 11 Years","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-31 21:31:33","doi":"10.21203/rs.3.rs-2707715/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":"cb052bca-7d80-44c0-8354-6a1cc3015c5a","owner":[],"postedDate":"March 31st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-06-30T00:30:56+00:00","versionOfRecord":{"articleIdentity":"rs-2707715","link":"https://doi.org/10.1016/j.wneu.2024.06.136","journal":{"identity":"world-neurosurgery","isVorOnly":true,"title":"World Neurosurgery"},"publishedOn":"2024-06-01 00:30:56","publishedOnDateReadable":"June 1st, 2024"},"versionCreatedAt":"2023-03-31 21:31:33","video":"","vorDoi":"10.1016/j.wneu.2024.06.136","vorDoiUrl":"https://doi.org/10.1016/j.wneu.2024.06.136","workflowStages":[]},"version":"v1","identity":"rs-2707715","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2707715","identity":"rs-2707715","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}