Risk of Falls Associated with Benzodiazepine Hypnotics Use in Elderly Inpatients:A Case-Crossover Study

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This study aimed to analyse the risk of falls associated with benzodiazepine hypnotic drugs use in elderly inpatients. Methods We used a case-crossover design to investigate hospitalized fall patients who were older than 60 years and had taken benzodiazepine hypnotic medication from January 1st,2021 to December 31st,2023.We defined the day before the fall event as the case day (day 1) and days 2–8 before the fall event as the control days.The multivariate analysis result was reported as an odds ratio (OR) with 95% confidence interval (CI). Results In 70 eligible patients, the total case day was 70 days and the control days was244.Hypnotic drugs revealed a positive association with fall events (odds ratio [OR]: 1.836, 95%confidence interval [CI] = 1.029–3.275, p = 0.040). Among them, benzodiazepine receptor agonists (odds ratio [OR]:1.824, 95%confidence interval [CI] = 1.007–1.303, p = 0.047), and alprazolam (odds ratio [OR]: 1.937, 95%confidence interval [CI] = 1.021–3.673, p = 0.043), showed a positive association with fall events. Conclusion This study confirmed that the occurrence of falls in hospitalized elderly patients aged older than 60 years was clearly associated with the use of benzodiazepine hypnotics. Fall prevention plans should be developed and implemented for olderly inpatients taking hypnotic drugs. fall events elderly inpatient hypnotic drug benzodiazepine alprazolam nursing Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 INTRODUCTION Fall incidents and fall-related injuries, particularly among older adults, are a a highly prevalent problem. It has attracted global attention due to its impact on patients, families and socioeconomy[ 1 – 3 ]. Hospitalized elderly patients or older adults in a long-term care facility had a higher fall events than those living in the community [ 4 ]. Fall events of inpatients were also the most common adverse events reported in the hospital[ 5 , 6 ], about 2% of inpatients experiencing fall incidents during hospitalization[ 7 ]. Among hospitalized patients, fall incidents may lead to increased mortality and morbidity, longer hospital stays, additional treatment and higher rates from discharge to long-term care facilities compared to those without fall incidents [ 5 , 6 ]. Approximately 20–58% of adults over age 65 years suffer from the effects of insomnia and this proportion increases with increasing age[ 8 ] .Sleep disorders significantly reduce the quality of life, mobility and health level of the elderly, and increase the risk of falls[ 9 , 10 ]. In elderly hospitalized patients, the incidence of sleep disorders is higher due to changes in the environment and the influence of the disease. The hypnotic drugs are widely used. Sedative hypnotics have their side effects, such as daytime sleepiness, vertigo, and motor disorders[ 11 ], and various abnormal behaviors, such as appetite changes associated with sleep, night-walking, and memory loss after drug treatment[ 12 ]. The side effects of hypnotics have also led to an increased fall incidents [ 13 ]. Case-crossover design is an epidemiological approach used to study the instantaneous effects of transient exposure on rare acute diseases[ 14 ]. This study aimed to analyse the effect of hypnotic medication use on the occurrence of falling events in elderly inpatients through a case-crossover design. This study design includes the number of control days and case days of the same patient, and the exposure information includes the type of hypnotics, the total use time, for comparison. In addition, we further analyzed the association of fall events with other fall risk-increasing drugs (FRIDs). MATERIALS AND METHODS Case Source This is a investigative study conducted in Shunde Hospital of Southern Medical University (Foshan City, Guangdong Province, China). It is a general hospital with 1800 beds and capable of third-level medical treatment. Refer to the International Classification of Diseases (ICD−10), a fall incident is defined as a sudden, non-autonomous, unintentional posture change, which falls on the ground or lower plane[ 15 ].Personal data of the fall patients,including the hospitalization identification number, age, gender, fall time,was extracted from the reporting platform submitted by nurses who found the patients who had fallen.Then the patient's inpatient department,medical diagnosises, medication administration information were derived from the hospital medical record system. Study Design Following the case crossover design[ 14 ], we defined control days and case days for analysis. The day before the fall event as the case day (day 1), days 2 to 8 prior to the fall event (day 2- day8) as the control day group (Fig. 1). If the patient was hospitalized with multiple falls, only the first fall event was used. The days of drug use before hospitalization were not included. Delusion Assessment To avoid a bias in drug selection in the fall risk assessment, elderly patients with delusion and conscious confusion possibility were excluded from this study. A rapid diagnostic protocol (4AT) was adopted as the hospital criteria[ 16 ], which includes 4 dimensions: alertness, the 4-item Abbreviated Mental Test, attention, acute change and fluctuating course. When scored 4, we judged it false or psychiatric. 4AT is easy to use, and applicable for various clinical settings. The assessment was performed by the nurse. Patient Selection The electronic database records of the patients with fall incidents between January 1st, 2021 and December 31st, 2023 were reviewed. Among them, patients those aged less than 60years, without the control days during hospitalization, those with delirium on either the case day or the control days, or those who died during the hospitalization, were excluded (Fig. 2 ). Data analysis and statistical methods The patients’ general characteristics data were analyzed as the frequency, percentage, mean, and standard deviation. In this study we used a case–crossover design to analyze the effects of hypnotics, multivariable conditional logistic regression model was used to assess the association between the hypnotic drug use and the fall risk, as well as other fall risk increasing drugs (FRID) such as anti-psychotics, anti-depressants, anti-epileptic, opioid analgesics, anti-hypertensives, and diuretics.We performed the analysis using the SPSS 27.0 statistical software. The multivariate analysis result was reported as an odds ratio (OR) and 95%confidence interval (CI). Statistical significance was defined as a p < 0.05. Ethics Approval The studies protocol was conducted in accordance with the provision of the Declaration of Helsinki (2013 edition). This retrospective study process had no intervention and therefore need not obtain informed consent from the patients. Data were presented in a manner that was impossible to identify patients. This study has been approved by the Medical Ethics Committee of Shunde Hospital, Southern Medical University. RESULTS Patient Characteristics As shown in Fig. 2 , 146 inpatients had fall events during the study stage,76 patients were removed due to the exclusion criteria, and 70 patients were enrolled. The mean age of patients was 74.87 years-old (S.D.:7.59, range:60-92years).45.7% of the enrolled patients were aged 70–79 years (n = 32) (Fig. 3 A). Gender distribution was 35 cases for both men and women (50% each). Falls were reported from 23 departments (Fig. 3 B), the most prevalent departments were hepatobiliary surgery and neurosurgery (both were 9.79%, n = 9), followed by neurology (7.61%, n = 7) and Hematology (6.52%, n = 6). The coexistence disease of the selected patients are shown in Table 2 . The highest proportion was hypertension (29.35%, n = 27), followed by congestive heart failure (28.26%, n = 26) and pulmonary disease (23.91%, n = 22). The total numbers of case days were 70, and 244 for the control days,severally (Table 3 ). Then,hypnotics were use 24 days (34.9%) in case days and 54days (22.13%) in control days, benzodiazepine were administrated in 22 days (34.29%) in case days and 49 days (20.08%) in control days,non-benzodiazepine (Zolpidem) was prescribed for 5days (7.14%) in case days and 10 days(2.87%)in control days . In terms of the total days and proportion of drugs, hypnotic drugs, including benzodiazepine receptor agonists, zolpidem, anti-hypertensives and diuretics,were administrated more in the case day than in the control days. But, anti-psychotics,anti-depressants, opioid analgesics and anti-epileptics were prescribed less in the case days than in the control days (Table 3 ),comparatively. As the component of the hypnotherapy medication, Alprazolam, Gabapentin, Clonazepam, Zolpidem, Estazolam, and Olanzapine were administrated in 37,13,10,10,7,6 sum patient days in the control days and 18,2,6,3,1,3 sum patient days in the case days (Fig. 4 ). Table 1 Distribution of Inpatient Departments for Falling Patients in-patient departments %(n) Hepatobiliary Surgery 9.78(9) Department of Neurosurgery 9.78(9) Department of Neurology 7.61(7) Hematology Medicine 6.52(6) Respiratory Medicine 5.43(5) Urology Surgery 5.43(5) Nephrology 5.43(5) Gastrointestinal Surgery 5.43(5) Department of Rehabilitation Medicine 5.43(5) Rheumatology and lmmunology Department 4.35(4) General Practice 4.35(4) Division of Endocrinology and Metabolic Diseases 4.35(4) Digestive System Department 4.35(4) Internal Medicine-Cardiovascular Department 4.35(4) Spine Surgery 3.26(3) Traumatic Joint Surgery 2.17(2) Oncology Department 2.17(2) Gynaecology 2.17(2) Department of Sensory Disorders 1.09(1) Dermatology 1.09(1) Breast Surgery 1.09(1) Emergency Medicine 1.09(1) Ophthalmology 1.09(1) Thoracic Surgery 1.09(1) Geriatric Department 1.09(1) Variable values are described as percentage (%) and frequency ( n ) Table 2 Major Coexistence Diseases of thw Enrolled Patients Coexistence Diseases %(n) Hypertensions Stage 3 29.35(27) Congestive heart failure 28.26(26) Lung Disease 23.91(22) Cerebrovascular accident 19.57(18) Cancer 17.39(16) Fracture 14.13(13) Diabetes mellitus with peripheral vascular disease 13.04(12) Immunology Disease 11.96(11) Renal disease 9.78(9) Variable values are described as percentage (%) and frequency ( n ) Table 3 Total Days of the Drugs Use in the Case and the Control Days Drug classification Total control days n = 244 Total case days n = 70 Sum days n = 314 Hypnotics 22.13(54) 34.29(24) 24.84(78) Hypnotics drug classes Benzodiazepine receptor agonists 20.08(49) 30.43(22) 22.61(71) Zolpidem 2.87(10) 7.14(5) 4.78(15) Anti-depressants 9.84(24) 5.71(4) 8.92(28) Anti-psychotics 2.87(7) 4.29(3) 3.18(10) Opioid analgesics 12.30(30) 10.0(7) 11.78(37) Anti-epileptics 12.71(31) 10.0(7) 12.10(38) Diurectics 46.72(114) 31.42(22) 43.31(136) Anti-hypertensives 47.95(117) 41.42(29) 46.50(146) Variable values are described as percentage (%) and frequency ( n ) As the component of the hypnotherapy medication, alprazolam, gabapentin, clonazepam, zolpidem, estazolam, and olanzapine were administrated in 37,13,10,7, 6 total days in the control days and 18,2,6,5,1, 3 total days in the case days (Fig. 4 ). Associations between hypnotic drugs and Falls Conditional logistic regression analysis revealed a positive association between the risk of falls and the use of hypnotic (odds ratio [OR]:1.836; 95% confidence interval [CI] = 1.029–3.275, p = 0.040, p < 0.05).The association between diuretics and fall risk was also statistically significant (odds ratio [OR]:1.913,95%confidence interval [CI] = 1.089–3.362, p = 0.024, p < 0.05). In contrast, neither anti-depressants (odds ratio [OR]:: 1.8000, 95% confidence interval [CI] = 0.603–5.373, P = 0.292), anti-psychotic drugs (odds ratio [OR] : 0.660, 95%confidence interval [CI] = 0.166–2.620, P = 0.554), opioid analgesic medication (odds ratio [OR] : 1.262, 95% confidence interval [CI] = 0.529–3.010, p = 0.600), Anti-epileptics(odds ratio [OR] :1.310, 95%confidence interval [CI] = 0.550–3.117, p = 0.542), nor anti-hypertensives(odds ratio [OR] : 1.302, 95%confidence interval [CI] = 0.761–2.230, p = 0.336) showed statistically significant association with fall incidents (Fig. 5). Figure5 above shows the odds ratio (OR) and 95% confidence interval (CI) for the predictive risk factorof fall events for use of hypnotic drugs or Fall Risk Increasing Drugs (FRIDs) as indicated. Open circle symbols indicate statistically significant association with fall events ( p < 0.05), and open square symbols indicate statistically insignificant association with fall events ( p ≥ 0.05) by multivariate conditional logistic regression analyses. By classification of hypnotic drugs, furthermore, benzodiazepine receptor agonists (odds ratio [OR]:1.824, 95%confidence interval [CI]: 1.007–1.303, p = 0.047) and alprazolam(odds ratio [OR]:1.937, 95%confidence interval [CI] = 1.021–3.673, p = 0.043, and meanwhile, diurectics (odds ratio [OR]:1.252, 95%confidence interval [CI] = 1.253–3.024, p = 0.036) they showed statistically significant association with fall risk. However, neither Zolpidem༈odds ratio [OR]:1.061,95%confidence interval [CI] = 0.284–3.966, p = 0.934), Anti-depressants(odds ratio [OR]:1.810,95%confidence interval [CI] = 0.606-5.373I, p = 0.293), Anti-psychotics (odds ratio [OR]:0.663, 95%confidence interval [CI] = 0.166–2.681,p = 0.561) ,Opioid analgesics(odds ratio [OR]:1.373, 95%confidence interval [CI] = 0.556–3.231, p = 0.714),Anti-epileptics(odds ratio [OR]:1.012,95%confidence interval [CI] = 0.562–3.233, p = 0.661),nor anti-hypertensives (odds ratio [OR]:1.024, 95%confidence interval [CI] = 0.853–2.469, p = 0.493) showed statistically significant association with fall events (Fig. 6). Figure6 above show the odds ratio (OR) and 95% confidence interval (CI) for the prediction of fall risks by use of each hypnotic drug (benzodiazepine receptor agonists, Alprazolam or Zolpidem) or Fall Risk Increasing Drugs (FRIDs) as indicated. Open circle symbols indicate statistically significant association with fall incidents ( p < 0.05), and open square symbols indicate statistically insignificant association with fall incidents ( p ≥ 0.05) by multivariate conditional logistic regression analyses. Continue medication days of hypnotics The days of hypnotic Continue medication during the case and control time are shown in Fig. 7 . Three patients in the benzodiazepine receptor agonist group were treated for 8 consecutive days, and 15 patients experienced falls within 3 days of dosing. The other group using Zolpidem, 4 patients had a fall event within 3 days of administration. These evidences indicate a relatively high incidence of falls within the first 3 days of hypnotic use in older patients. DISCUSSION This study analyzed the association between fall risk and the use of benzodiazepine receptor agonists, non-benzodiazepine and other Fall Risk Increasing Drugs (FRIDs) between the use of hypnotic drugs and fall risk, by a case-crossover study, showing a statistically significant association between the use of benzodiazepine receptor agonists diuretics and fall events. Sleep disorders and taking hypnotic medication can increase the risk of falls [ 9 , 10 , 17 ]. Older adults with sleep disorders and taking sedative-hypnotic drugs have a higher risk of falls than those without sleep problems. Benzodiazepines, also known as GABA A receptor agonist,[ 18 ] benzodiazepine mechanism is related to GABA (γ -aminobutyric acid) [ 19 ]. GABA is an important CNS inhibitory neurotransmitter benzodiazepine agents when occupying benzodiazepine receptors. formation of the benzodiazepine – chlorideion channel macromolecular complexes, increase the open frequency of the chloride channels, increase of receptor affinity to GABA, enhanced the effect of GABA. Thus, producing pharmacological effects such as sedative-hypnotic, anxiolytic, anticonvulsant, and central muscle relaxants. Adverse reactions such as drowsiness, dizziness, cognitive impaired motor disorder and delayed reaction time. These lead to increased risk of falls. The results of several systematic evaluation and meta-analysis studies [ 20 , 21 ], use of benzodiazepines is associated with a higher risk of falls in older patients, the highest risk of falls within 2 weeks of initiation, But after stratifying the population and the medical environment, heterogeneity still exists. Non-benzodiazepines, also called z-drugs, such as zolpidem, exert sedative-hypnotic effects by selectively agonizing the α subunit on γ -aminobutyric acid receptor A, which is somewhat similar to benzodiazepines. But zolpidem is more selectivity for the A1 subunit, which may initially explain the differences in its effects on sleep structure and lower incidence of adverse events[ 22 ]. The peak plasma concentration (Tmax) of zolpidem-IR occurs in the range of 45 to 60 min, with a terminal elimination half-life (t ½) equivalent to 2.4h. Zolpidem can overcome the disadvantages of benzodiazepines, including confounding dependence and abuse, safer and better than benzodiazepines[ 23 ] .The study results show that the association between z-drug and falls not statistically significant, fall rate is significantly lower than benzodiazepines. Ensrud[ 24 ] found that Z-drug will increase the risk of fall in elderly inpatients due to different research results, the doctor should still consider the risk of falling when choosing the drug. The use of off-label psychotropic medication for insomnia is prevalent in adult [ 5 ]. Among the elderly, antidepressants, antihistamines, antipsychotics, anticonvulsants (gabapentin), and herbal remedies are the regularly prescribed[ 25 ]. This study compared antidepressants, antipsychotics, opioid analgesics and antiepileptics with no statistically significant association with fall risk. Fall incidents in the elderly is the result of multiple factors, and the clinical evidence of pharmacogenetic risk still needs to accumulate. The more common diuretics used in this study were loop diuretics. Loop diuretics are the only diuretic significantly associated with an increased risk of fall[ 20 ]. A meta-analysis of pharmacological subgroups of loop diuretics showed a significant association between loop diuretics and an increased risk of fall[ 26 – 28 ]. It plays a diuretic role at the same time, patients can lose a lot of body fluids and sodium and potassium electrolytes in a short time, drowsiness, fatigue, dizziness, standing, walking instability and postural hypotension and fall. Compared with other diuretics, loop diuretics have rapid and powerful diuretic effects, causing faster changes in extracellular fluid, which could explain its association with fall risk[ 29 ]. The elderly who take diuretics for a long time should pay attention to the detection of electrolytes, try to use the toilet, do not use the squatting toilet and pay attention to the assistance of patients when frequent toilet, try not to take hypnotic drugs at the same time, to avoid fall incidents during and after the toilet. CONCLUSION This study confirmed that the occurrence of falls in hospitalized elderly patients aged older than 60 years was clearly associated with the use of benzodiazepine hypnotics. Fall prevention plans, including education and notification, medication arrangement, side effect identification, should be developed and implemented for olderly inpatients taking hypnotic drugs. Declarations Author Contribution All authors contributed to the study conception and design，Write the content in charge.Author Qiongfang Chen: contributed to the study design ，data statistical and analysis,paper check.Author Cuina Zhong: contributed to background review and data export.Author Xiaojie Zhang: contributed to data collection and sort outAuthor Taoni Ou: contributed to writing statical tables and chartsAuthor Yuli Huang: contributed to medical analysis of fall patients，revising the manuscriptAuthor Jingcheng He: contributed to pharmacy data discuss and analysis References A GD. 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Shunde","correspondingAuthor":false,"prefix":"","firstName":"Xiaojie","middleName":"","lastName":"Zhang","suffix":""},{"id":339358587,"identity":"eccc92a6-d89e-4437-bbda-060f6525d0ca","order_by":2,"name":"Cuina Zhong","email":"","orcid":"","institution":"Southern Medical University (The First People’s Hospital of Shunde","correspondingAuthor":false,"prefix":"","firstName":"Cuina","middleName":"","lastName":"Zhong","suffix":""},{"id":339358588,"identity":"bcf359d2-ea11-4060-b9e9-7c3a64c91851","order_by":3,"name":"Taoni Ou","email":"","orcid":"","institution":"Southern Medical University, The First People’s Hospital of Shunde","correspondingAuthor":false,"prefix":"","firstName":"Taoni","middleName":"","lastName":"Ou","suffix":""},{"id":339358589,"identity":"3c34a80e-6f4b-4ff9-94e7-3f1ec103d204","order_by":4,"name":"Yuli Huang","email":"","orcid":"","institution":"Southern Medical University, The First People’s Hospital of Shunde","correspondingAuthor":false,"prefix":"","firstName":"Yuli","middleName":"","lastName":"Huang","suffix":""},{"id":339358590,"identity":"3d7bf06d-982d-4eb5-a6b2-6393e0160319","order_by":5,"name":"Jingcheng He","email":"","orcid":"","institution":"Southern Medical University, The First People’s Hospital of Shunde","correspondingAuthor":false,"prefix":"","firstName":"Jingcheng","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2024-08-11 05:23:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4893823/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4893823/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66329102,"identity":"5ccdfae7-f48e-4348-bfb9-f680f7af636c","added_by":"auto","created_at":"2024-10-10 13:10:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20610,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of the case days and control days\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/051afdaf75d9fbcb9e8fcc9b.jpg"},{"id":66329549,"identity":"0317c139-5778-4187-9c94-a6a8d1b8047d","added_by":"auto","created_at":"2024-10-10 13:18:40","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":41976,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatients flow chart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/73b0176cb1d459536b853de7.jpg"},{"id":66329108,"identity":"bc8ef556-5570-4eec-a8b2-aee9e38c0883","added_by":"auto","created_at":"2024-10-10 13:10:41","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":31944,"visible":true,"origin":"","legend":"\u003cp\u003eEnrolled Patients `Age and Gender Distribution Are Shown in block A and block B\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/688707f7bbba41f7d04512f3.jpg"},{"id":66329104,"identity":"98c52e92-6ecb-4b02-aeb4-83803e3f2236","added_by":"auto","created_at":"2024-10-10 13:10:40","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":43534,"visible":true,"origin":"","legend":"\u003cp\u003eThe total number of patients administered on case and control days by hypnotic component drugs as indicated.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/51f3ef858f2acd0b2ded17bd.jpg"},{"id":66329107,"identity":"c9ee548d-42ef-4959-ad32-02da11d6e00d","added_by":"auto","created_at":"2024-10-10 13:10:41","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":62356,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of fall events with use of hypnotic drugs\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/98071c01af8d3e9841436e73.jpg"},{"id":66329103,"identity":"351af9aa-b698-4681-aebc-4d6602ad0640","added_by":"auto","created_at":"2024-10-10 13:10:40","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":83082,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of fall events with use of each hypnotic drug component\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/68c2801e8f0e6e68ba8ba1e2.jpg"},{"id":66329550,"identity":"f09957c8-addc-4918-8cf2-ecfdecf32ca4","added_by":"auto","created_at":"2024-10-10 13:18:40","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":43563,"visible":true,"origin":"","legend":"\u003cp\u003eContinue medication days of hypnotics during the case and the control days of benzodiazepine receptor agonists (panel A), zolpidem (panel B) .\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/c3b705f487c4b1af74630350.jpg"},{"id":66329552,"identity":"6a19f5d5-2980-4e8a-895b-cf43ba17a16c","added_by":"auto","created_at":"2024-10-10 13:18:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":774614,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4893823/v1/03828e74-95dc-4a39-a5e3-ccded03c71e6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRisk of Falls Associated with Benzodiazepine Hypnotics Use in Elderly Inpatients:A Case-Crossover Study \u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eFall incidents and fall-related injuries, particularly among older adults, are a a highly prevalent problem. It has attracted global attention due to its impact on patients, families and socioeconomy[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Hospitalized elderly patients or older adults in a long-term care facility had a higher fall events than those living in the community\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Fall events of inpatients were also the most common adverse events reported in the hospital[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], about 2% of inpatients experiencing fall incidents during hospitalization[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Among hospitalized patients, fall incidents may lead to increased mortality and morbidity, longer hospital stays, additional treatment and higher rates from discharge to long-term care facilities compared to those without fall incidents [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eApproximately 20–58% of adults over age 65 years suffer from the effects of insomnia and this proportion increases with increasing age[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] .Sleep disorders significantly reduce the quality of life, mobility and health level of the elderly, and increase the risk of falls[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In elderly hospitalized patients, the incidence of sleep disorders is higher due to changes in the environment and the influence of the disease. The hypnotic drugs are widely used. Sedative hypnotics have their side effects, such as daytime sleepiness, vertigo, and motor disorders[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and various abnormal behaviors, such as appetite changes associated with sleep, night-walking, and memory loss after drug treatment[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The side effects of hypnotics have also led to an increased fall incidents [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCase-crossover design is an epidemiological approach used to study the instantaneous effects of transient exposure on rare acute diseases[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This study aimed to analyse the effect of hypnotic medication use on the occurrence of falling events in elderly inpatients through a case-crossover design. This study design includes the number of control days and case days of the same patient, and the exposure information includes the type of hypnotics, the total use time, for comparison. In addition, we further analyzed the association of fall events with other fall risk-increasing drugs (FRIDs).\u003c/p\u003e \u003cp\u003e\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e \u003cb\u003eCase Source\u003c/b\u003e This is a investigative study conducted in Shunde Hospital of Southern Medical University (Foshan City, Guangdong Province, China). It is a general hospital with 1800 beds and capable of third-level medical treatment. Refer to the International Classification of Diseases (ICD−10), a fall incident is defined as a sudden, non-autonomous, unintentional posture change, which falls on the ground or lower plane[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].Personal data of the fall patients,including the hospitalization identification number, age, gender, fall time,was extracted from the reporting platform submitted by nurses who found the patients who had fallen.Then the patient's inpatient department,medical diagnosises, medication administration information were derived from the hospital medical record system.\u003c/p\u003e\u003cp\u003e \u003cb\u003eStudy Design\u003c/b\u003e Following the case crossover design[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], we defined control days and case days for analysis. The day before the fall event as the case day (day 1), days 2 to 8 prior to the fall event (day 2- day8) as the control day group (Fig.\u0026nbsp;1). If the patient was hospitalized with multiple falls, only the first fall event was used. The days of drug use before hospitalization were not included.\u003c/p\u003e\u003cp\u003e \u003cb\u003eDelusion Assessment\u003c/b\u003e To avoid a bias in drug selection in the fall risk assessment, elderly patients with delusion and conscious confusion possibility were excluded from this study. A rapid diagnostic protocol (4AT) was adopted as the hospital criteria[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], which includes 4 dimensions: alertness, the 4-item Abbreviated Mental Test, attention, acute change and fluctuating course. When scored 4, we judged it false or psychiatric. 4AT is easy to use, and applicable for various clinical settings. The assessment was performed by the nurse.\u003c/p\u003e\u003cp\u003e \u003cb\u003ePatient Selection\u003c/b\u003e The electronic database records of the patients with fall incidents between January 1st, 2021 and December 31st, 2023 were reviewed. Among them, patients those aged less than 60years, without the control days during hospitalization, those with delirium on either the case day or the control days, or those who died during the hospitalization, were excluded (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e \u003cb\u003eData analysis and statistical methods\u003c/b\u003e The patients’ general characteristics data were analyzed as the frequency, percentage, mean, and standard deviation. In this study we used a case–crossover design to analyze the effects of hypnotics, multivariable conditional logistic regression model was used to assess the association between the hypnotic drug use and the fall risk, as well as other fall risk increasing drugs (FRID) such as anti-psychotics, anti-depressants, anti-epileptic, opioid analgesics, anti-hypertensives, and diuretics.We performed the analysis using the SPSS 27.0 statistical software. The multivariate analysis result was reported as an odds ratio (OR) and 95%confidence interval (CI). Statistical significance was defined as a p \u0026lt; 0.05.\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eEthics Approval\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e The studies protocol was conducted in accordance with the provision of the Declaration of Helsinki (2013 edition). This retrospective study process had no intervention and therefore need not obtain informed consent from the patients. Data were presented in a manner that was impossible to identify patients. This study has been approved by the Medical Ethics Committee of Shunde Hospital, Southern Medical University.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cb\u003ePatient Characteristics\u003c/b\u003e As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, 146 inpatients had fall events during the study stage,76 patients were removed due to the exclusion criteria, and 70 patients were enrolled. The mean age of patients was 74.87 years-old (S.D.:7.59, range:60-92years).45.7% of the enrolled patients were aged 70\u0026ndash;79 years (n\u0026thinsp;=\u0026thinsp;32) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Gender distribution was 35 cases for both men and women (50% each). Falls were reported from 23 departments (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eB), the most prevalent departments were hepatobiliary surgery and neurosurgery (both were 9.79%, n\u0026thinsp;=\u0026thinsp;9), followed by neurology (7.61%, n\u0026thinsp;=\u0026thinsp;7) and Hematology (6.52%, n\u0026thinsp;=\u0026thinsp;6).\u003c/p\u003e \u003cp\u003eThe coexistence disease of the selected patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The highest proportion was hypertension (29.35%, n\u0026thinsp;=\u0026thinsp;27), followed by congestive heart failure (28.26%, n\u0026thinsp;=\u0026thinsp;26) and pulmonary disease (23.91%, n\u0026thinsp;=\u0026thinsp;22).\u003c/p\u003e \u003cp\u003eThe total numbers of case days were 70, and 244 for the control days,severally (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Then,hypnotics were use 24 days (34.9%) in case days and 54days (22.13%) in control days, benzodiazepine were administrated in 22 days (34.29%) in case days and 49 days (20.08%) in control days,non-benzodiazepine (Zolpidem) was prescribed for 5days (7.14%) in case days and 10 days(2.87%)in control days .\u003c/p\u003e \u003cp\u003eIn terms of the total days and proportion of drugs, hypnotic drugs, including benzodiazepine receptor agonists, zolpidem, anti-hypertensives and diuretics,were administrated more in the case day than in the control days.\u003c/p\u003e \u003cp\u003eBut, anti-psychotics,anti-depressants, opioid analgesics and anti-epileptics were prescribed less in the case days than in the control days (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e),comparatively.\u003c/p\u003e \u003cp\u003eAs the component of the hypnotherapy medication, Alprazolam, Gabapentin, Clonazepam, Zolpidem, Estazolam, and Olanzapine were administrated in 37,13,10,10,7,6 sum patient days in the control days and 18,2,6,3,1,3 sum patient days in the case days (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\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\u003eDistribution of Inpatient Departments for Falling Patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ein-patient departments\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e%(n)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatobiliary Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.78(9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepartment of Neurosurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.78(9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepartment of Neurology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.61(7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematology Medicine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.52(6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory Medicine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.43(5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrology Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.43(5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.43(5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.43(5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepartment of Rehabilitation Medicine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.43(5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatology and lmmunology Department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.35(4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral Practice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.35(4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDivision of Endocrinology and Metabolic Diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.35(4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDigestive System Department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.35(4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInternal Medicine-Cardiovascular Department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.35(4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpine Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.26(3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTraumatic Joint Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.17(2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOncology Department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.17(2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGynaecology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.17(2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepartment of Sensory Disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDermatology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency Medicine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOphthalmology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThoracic Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeriatric Department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eVariable values are described as percentage (%) and frequency (\u003cem\u003en\u003c/em\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\u003eMajor Coexistence Diseases of thw Enrolled Patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoexistence Diseases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e%(n)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertensions Stage 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29.35(27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongestive heart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28.26(26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.91(22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebrovascular accident\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.57(18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17.39(16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFracture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.13(13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus with peripheral vascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.04(12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunology Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.96(11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.78(9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eVariable values are described as percentage (%) and frequency (\u003cem\u003en\u003c/em\u003e)\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\u003eTotal Days of the Drugs Use in the Case and the Control Days\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug classification\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal control days\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;244\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal case days\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;70\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSum days\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;314\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypnotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.13(54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34.29(24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.84(78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypnotics drug classes\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBenzodiazepine receptor agonists\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.08(49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30.43(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.61(71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZolpidem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.87(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.14(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.78(15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-depressants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.84(24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.71(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.92(28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-psychotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.87(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.29(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.18(10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpioid analgesics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.30(30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.0(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.78(37)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-epileptics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.71(31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.0(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.10(38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiurectics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46.72(114)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31.42(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43.31(136)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-hypertensives\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47.95(117)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41.42(29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46.50(146)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eVariable values are described as percentage (%) and frequency (\u003cem\u003en\u003c/em\u003e)\u003c/p\u003e \u003cp\u003eAs the component of the hypnotherapy medication, alprazolam, gabapentin, clonazepam, zolpidem, estazolam, and olanzapine were administrated in 37,13,10,7, 6 total days in the control days and 18,2,6,5,1, 3 total days in the case days (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eAssociations between hypnotic drugs and Falls\u003c/b\u003e \u003c/p\u003e \u003cp\u003eConditional logistic regression analysis revealed a positive association between the\u003c/p\u003e \u003cp\u003erisk of falls and the use of hypnotic (odds ratio [OR]:1.836; 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.029\u0026ndash;3.275, p\u0026thinsp;=\u0026thinsp;0.040, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).The association between diuretics and fall risk was also statistically significant (odds ratio [OR]:1.913,95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.089\u0026ndash;3.362, p\u0026thinsp;=\u0026thinsp;0.024, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In contrast, neither anti-depressants (odds ratio [OR]:: 1.8000, 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.603\u0026ndash;5.373, P\u0026thinsp;=\u0026thinsp;0.292), anti-psychotic drugs (odds ratio [OR] : 0.660, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.166\u0026ndash;2.620, P\u0026thinsp;=\u0026thinsp;0.554), opioid analgesic medication (odds ratio [OR] : 1.262, 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.529\u0026ndash;3.010, p\u0026thinsp;=\u0026thinsp;0.600), Anti-epileptics(odds ratio [OR] :1.310, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.550\u0026ndash;3.117, p\u0026thinsp;=\u0026thinsp;0.542), nor anti-hypertensives(odds ratio [OR] : 1.302, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.761\u0026ndash;2.230, p\u0026thinsp;=\u0026thinsp;0.336) showed statistically significant association with fall incidents (Fig.\u0026nbsp;5).\u003c/p\u003e \u003cp\u003eFigure5 above shows the odds ratio (OR) and 95% confidence interval (CI) for the predictive risk factorof fall events for use of hypnotic drugs or Fall Risk Increasing Drugs (FRIDs) as indicated. Open circle symbols indicate statistically significant association with fall events (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and open square symbols indicate statistically insignificant association with fall events (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026ge;\u0026thinsp;0.05) by multivariate conditional logistic regression analyses.\u003c/p\u003e \u003cp\u003eBy classification of hypnotic drugs, furthermore, benzodiazepine receptor agonists (odds ratio [OR]:1.824, 95%confidence interval [CI]: 1.007\u0026ndash;1.303, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047) and alprazolam(odds ratio [OR]:1.937, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.021\u0026ndash;3.673, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043, and meanwhile, diurectics (odds ratio [OR]:1.252, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.253\u0026ndash;3.024, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036) they showed statistically significant association with fall risk. However, neither Zolpidem༈odds ratio [OR]:1.061,95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.284\u0026ndash;3.966,\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.934), Anti-depressants(odds ratio [OR]:1.810,95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.606-5.373I, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.293), Anti-psychotics (odds ratio [OR]:0.663, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.166\u0026ndash;2.681,p\u0026thinsp;=\u0026thinsp;0.561) ,Opioid analgesics(odds ratio [OR]:1.373, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.556\u0026ndash;3.231,\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.714),Anti-epileptics(odds ratio [OR]:1.012,95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.562\u0026ndash;3.233, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.661),nor anti-hypertensives (odds ratio [OR]:1.024, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;0.853\u0026ndash;2.469, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.493) showed statistically significant association with fall events (Fig.\u0026nbsp;6).\u003c/p\u003e \u003cp\u003eFigure6 above show the odds ratio (OR) and 95% confidence interval (CI) for the prediction of fall risks by use of each hypnotic drug (benzodiazepine receptor agonists, Alprazolam or Zolpidem) or Fall Risk Increasing Drugs (FRIDs) as indicated. Open circle symbols indicate statistically significant association with fall incidents (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and open square symbols indicate statistically insignificant association with fall incidents (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026ge;\u0026thinsp;0.05) by multivariate conditional logistic regression analyses.\u003c/p\u003e \u003cp\u003e \u003cb\u003eContinue medication days of hypnotics\u003c/b\u003e The days of hypnotic Continue medication during the case and control time are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e7\u003c/span\u003e. Three patients in the benzodiazepine receptor agonist group were treated for 8 consecutive days, and 15 patients experienced falls within 3 days of dosing. The other group using Zolpidem, 4 patients had a fall event within 3 days of administration. These evidences indicate a relatively high incidence of falls within the first 3 days of hypnotic use in older patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study analyzed the association between fall risk and the use of benzodiazepine receptor agonists, non-benzodiazepine and other Fall Risk Increasing Drugs (FRIDs) between the use of hypnotic drugs and fall risk, by a case-crossover study, showing a statistically significant association between the use of benzodiazepine receptor agonists diuretics and fall events.\u003c/p\u003e \u003cp\u003eSleep disorders and taking hypnotic medication can increase the risk of falls [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Older adults with sleep disorders and taking sedative-hypnotic drugs have a higher risk of falls than those without sleep problems. Benzodiazepines, also known as GABA A receptor agonist,[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] benzodiazepine mechanism is related to GABA (γ -aminobutyric acid) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. GABA is an important CNS inhibitory neurotransmitter benzodiazepine agents when occupying benzodiazepine receptors. formation of the benzodiazepine – chlorideion channel macromolecular complexes, increase the open frequency of the chloride channels, increase of receptor affinity to GABA, enhanced the effect of GABA. Thus, producing pharmacological effects such as sedative-hypnotic, anxiolytic, anticonvulsant, and central muscle relaxants. Adverse reactions such as drowsiness, dizziness, cognitive impaired motor disorder and delayed reaction time. These lead to increased risk of falls. The results of several systematic evaluation and meta-analysis studies [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], use of benzodiazepines is associated with a higher risk of falls in older patients, the highest risk of falls within 2 weeks of initiation, But after stratifying the population and the medical environment, heterogeneity still exists.\u003c/p\u003e \u003cp\u003eNon-benzodiazepines, also called z-drugs, such as zolpidem, exert sedative-hypnotic effects by selectively agonizing the α subunit on γ -aminobutyric acid receptor A, which is somewhat similar to benzodiazepines. But zolpidem is more selectivity for the A1 subunit, which may initially explain the differences in its effects on sleep structure and lower incidence of adverse events[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The peak plasma concentration (Tmax) of zolpidem-IR occurs in the range of 45 to 60 min, with a terminal elimination half-life (t ½) equivalent to 2.4h. Zolpidem can overcome the disadvantages of benzodiazepines, including confounding dependence and abuse, safer and better than benzodiazepines[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] .The study results show that the association between z-drug and falls not statistically significant, fall rate is significantly lower than benzodiazepines. Ensrud[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] found that Z-drug will increase the risk of fall in elderly inpatients due to different research results, the doctor should still consider the risk of falling when choosing the drug.\u003c/p\u003e \u003cp\u003eThe use of off-label psychotropic medication for insomnia is prevalent in adult [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Among the elderly, antidepressants, antihistamines, antipsychotics, anticonvulsants (gabapentin), and herbal remedies are the regularly prescribed[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This study compared antidepressants, antipsychotics, opioid analgesics and antiepileptics with no statistically significant association with fall risk. Fall incidents in the elderly is the result of multiple factors, and the clinical evidence of pharmacogenetic risk still needs to accumulate.\u003c/p\u003e \u003cp\u003eThe more common diuretics used in this study were loop diuretics. Loop diuretics are the only diuretic significantly associated with an increased risk of fall[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A meta-analysis of pharmacological subgroups of loop diuretics showed a significant association between loop diuretics and an increased risk of fall[\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e–\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. It plays a diuretic role at the same time, patients can lose a lot of body fluids and sodium and potassium electrolytes in a short time, drowsiness, fatigue, dizziness, standing, walking instability and postural hypotension and fall. Compared with other diuretics, loop diuretics have rapid and powerful diuretic effects, causing faster changes in extracellular fluid, which could explain its association with fall risk[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The elderly who take diuretics for a long time should pay attention to the detection of electrolytes, try to use the toilet, do not use the squatting toilet and pay attention to the assistance of patients when frequent toilet, try not to take hypnotic drugs at the same time, to avoid fall incidents during and after the toilet.\u003c/p\u003e "},{"header":"CONCLUSION","content":"\u003cp\u003eThis study confirmed that the occurrence of falls in hospitalized elderly patients aged older than 60 years was clearly associated with the use of benzodiazepine hypnotics. Fall prevention plans, including education and notification, medication arrangement, side effect identification, should be developed and implemented for olderly inpatients taking hypnotic drugs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design，Write the content in charge.Author Qiongfang Chen: contributed to the study design ，data statistical and analysis,paper check.Author Cuina Zhong: contributed to background review and data export.Author Xiaojie Zhang: contributed to data collection and sort outAuthor Taoni Ou: contributed to writing statical tables and chartsAuthor Yuli Huang: contributed to medical analysis of fall patients，revising the manuscriptAuthor Jingcheng He: contributed to pharmacy data discuss and analysis\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eA GD. Prevention of Falls in Community-Dwelling Older Adults. N Engl J Med. 2020;382(8):734\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS FC, et al. Medical Costs of Fatal and Nonfatal Falls in Older Adults. J Am Geriatr Soc. 2018;66(4):693\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS, H., et al., Cost of falls in old age: a systematic review. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2010. 21(6): p. 891\u0026ndash;902.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilvana C, et al. Correlation between fall risk increasing drugs (FRIDs) and fall events at a rehabilitation hospital. Acta bio-medica: Atenei Parmensis. 2022;92(6):e2021397\u0026ndash;2021397.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM MI, et al. Inpatient fall prevention programs as a patient safety strategy: a systematic review. Ann Intern Med. 2013;158(5 Pt 2):390\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho MY, Jang SJ. Nurses' knowledge, attitude, and fall prevention practices at south Korean hospitals: a cross-sectional survey. BMC Nurs. 2020;19(1):108.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCenter Of Innovation On Disability And Rehabilitation, Research CINDRR, M.R.V.M. and, U.O. .F.M. Geriatric Research Education And Clinical Center GRECC, Preventing Falls in Hospitalized Patients. Clin Geriatr Med. 2019;35(2):273\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharon S, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin sleep medicine: JCSM : official publication Am Acad Sleep Med. 2008;4(5):487\u0026ndash;504.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS BG, C KA, L BD. Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64\u0026ndash;99 years. J Am Geriatr Soc. 2000;48(10):1234\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStone KL, Ensrud KE, Ancoli-Israel S. Sleep, insomnia and falls in elderly patients. Sleep Med. 2008;9(S1):S18\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzana U, et al. Side effects of treatment with benzodiazepines. Psychiatria Danubina. 2010;22(1):90\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitchell RJ, et al. Obesity and falls in older people: Mediating effects of disease, sedentary behavior, mood, pain and medication use. Arch Gerontol Geriatr. 2015;60(1):52\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasayoshi Z, et al. Hypnotics Use and Falls in Hospital Inpatients Stratified by Age. Global J Health Sci. 2016;9(4):148\u0026ndash;148.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalcolm M. Using Simulated Data to Assess Case-Crossover Designs for Studying Less Transient Effects of Drugs. Drug Saf. 2017;40(9):757\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO, et al. Fall definitions, faller classifications and outcomes used in falls research among people with multiple sclerosis: a systematic review. Disabil Rehabil. 2020;44(6):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarius M, et al. Delirium screening with 4AT in patients aged 65 years and older admitted to the Emergency Department with suspected sepsis: a prospective cohort study. Eur Geriatr Med. 2021;13(1):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eY AA, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc. 2005;53(6):955\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP LJ, A KD, C JT, Visualizing GABAA. Receptor Trafficking Dynamics with Fluorogenic Protein Labeling. Curr Protoc Neurosci. 2020;92(1):e97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInstitute Of Biochemistry And Molecular, Medicine UOBC. Department Of Molecular Neurosciences, The Benzodiazepine Binding Sites of GABA A Receptors. Trends Pharmacol Sci. 2018;39(7):659\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeppala LJ et al. Fall-Risk-Increasing Drugs: A Systematic Review and Meta-Analysis: II. Psychotropics. Journal of the American Medical Directors Association, 2018. 19(4): p. 371.e11-371.e17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ MS, et al. Medications as a Risk Factor for Fragility Hip Fractures: A Systematic Review and Meta-analysis. Calcif Tissue Int. 2020;107(1):1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonti JM, et al. Zolpidem\u0026rsquo;s use for insomnia. Asian J Psychiatry. 2017;25:79\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiroshan SA, et al. GPs' attitudes to benzodiazepine and 'Z-drug' prescribing: a barrier to implementation of evidence and guidance on hypnotics. Br J Gen practice: J Royal Coll Gen Practitioners. 2006;56(533):964\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eE EK, et al. Central nervous system active medications and risk for fractures in older women. Arch Intern Med. 2003;163(8):949\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR GC, Cyrus C, Avan AS. Prevalence and risk factors for falls in older men and women: The English Longitudinal Study of Ageing. Age Ageing. 2016;45(6):789\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eC HA, et al. Medication-related fall incidents in an older, ambulant population: the B-PROOF study. Drugs Aging. 2014;31(12):917\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS LL, et al. Loop diuretic use and rates of hip bone loss and risk of falls and fractures in older women. J Am Geriatr Soc. 2009;57(5):855\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL CM, et al. Greater daily defined dose of antihypertensive medication increases the risk of falls in older people\u0026ndash;a population-based study. J Am Geriatr Soc. 2014;62(8):1527\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD BS, et al. New loop diuretic prescriptions may be an acute risk factor for falls in the nursing home. Pharmacoepidemiol Drug Saf. 2012;21(5):560\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nursing","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurs","sideBox":"Learn more about [BMC Nursing](http://bmcnurs.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurs/default.aspx","title":"BMC Nursing","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"fall events, elderly inpatient, hypnotic drug, benzodiazepine, alprazolam, nursing","lastPublishedDoi":"10.21203/rs.3.rs-4893823/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4893823/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePreventing falls in patients is one of the most important concerns in hospitals. This study aimed to analyse the risk of falls associated with benzodiazepine hypnotic drugs use in elderly inpatients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe used a case-crossover design to investigate hospitalized fall patients who were older than 60 years and had taken benzodiazepine hypnotic medication from January 1st,2021 to December 31st,2023.We defined the day before the fall event as the case day (day 1) and days 2\u0026ndash;8 before the fall event as the control days.The multivariate analysis result was reported as an odds ratio (OR) with 95% confidence interval (CI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn 70 eligible patients, the total case day was 70 days and the control days was244.Hypnotic drugs revealed a positive association with fall events (odds ratio [OR]: 1.836, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.029\u0026ndash;3.275, p\u0026thinsp;=\u0026thinsp;0.040). Among them, benzodiazepine receptor agonists (odds ratio [OR]:1.824, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.007\u0026ndash;1.303, p\u0026thinsp;=\u0026thinsp;0.047), and alprazolam (odds ratio [OR]: 1.937, 95%confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.021\u0026ndash;3.673, p\u0026thinsp;=\u0026thinsp;0.043), showed a positive association with fall events.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study confirmed that the occurrence of falls in hospitalized elderly patients aged older than 60 years was clearly associated with the use of benzodiazepine hypnotics. Fall prevention plans should be developed and implemented for olderly inpatients taking hypnotic drugs.\u003c/p\u003e","manuscriptTitle":"Risk of Falls Associated with Benzodiazepine Hypnotics Use in Elderly Inpatients:A Case-Crossover Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-10 13:10:36","doi":"10.21203/rs.3.rs-4893823/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"checksComplete","content":"","date":"2024-08-12T19:23:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nursing","date":"2024-08-11T05:20:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nursing","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurs","sideBox":"Learn more about [BMC Nursing](http://bmcnurs.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurs/default.aspx","title":"BMC Nursing","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"01ca1fad-af50-4ae9-b1cb-cb229023a5d6","owner":[],"postedDate":"October 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-10-10T13:10:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-10 13:10:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4893823","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4893823","identity":"rs-4893823","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}