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Risk of hospitalisation associated with benzodiazepines and z-drugs in Italy: a nationwide multicentre study in emergency departments

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Benzodiazepines (BZD) and z-drugs (ZD) are a widely prescribed group of medicines. They are often used inappropriately, and this is associated with adverse events (AEs), which may cause emergency department (ED) visits. The present study aimed to describe the characteristics of BZD and ZD related AEs leading to emergency department (ED) visit and hospitalisation in Italy, considering their plasma half-life. Ninety-two Italian EDs were monitored between 2007 and 2018. Rates of ED visit and hospitalisation were calculated. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation. Univariate linear regression was performed to evaluate the ROR of hospitalisation according the plasma half-life of the suspected agents. A total of 3203 AE reports were collected. Overall, multivariate logistic regression showed that the risk of hospitalisation was higher for prazepam (3.26 [1.31–8.11]), flurazepam (1.62 [1.15–2.27]), and lorazepam (1.36 [1.15–1.61]). In the elderly, this risk was higher for prazepam (3.98 [1.03–15.3]), and lorazepam (1.58 [1.19–2.11]). Parenteral and rectal formulations were associated with a lower risk of hospitalisation compared to oral formulations. Our findings underlined the dangers in the use of BZD and ZD in Italy, particularly in women and older adults. ED clinicians must always take into account that the higher risk in terms of hospitalisation related to the use of BZD and ZD can be observed in patients treated with oral formulations, in those exposed to more than one sedative-hypnotics, and in patients exposed to compounds with intermediate or long plasma half-life.

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Members of the MEREAFaPS Study group who provided patient data for this study: Maria Luisa Aiezza (Naples), Alessandra Bettiol (Florence), Daria Bettoni (Brescia), Corrado Blandizzi (Pisa), Roberto Bonaiuti (Florence), Valentina Borsi (Florence), Annalisa Capuano (Naples), Errica Cecchi (Prato), Irma Convertino (Pisa), Giada Crescioli (Florence), Martina Del Lungo (Florence), Cristina Di Mauro (Naples), Gabriella Farina (Milan), Sara Ferraro (Pisa), Annamaria Fucile (Naples), Elena Galfrascoli (Milan), Elisabetta Geninatti (Turin), Linda Giovannetti (Florence), Luca Leonardi (Pisa), Rosa Liccardo (Naples), Niccolò Lombardi (Florence), Anna Marra (Ferrara), Eleonora Marrazzo (Turin), Giovanna Monina (Gallarate), Alessandro Mugelli (Florence), Silvia Pagani (Vimercate), Maria Parrilli (Florence), Concetta Rafaniello (Naples), Francesco Rossi (Naples), Marco Rossi (Siena), Stefania Rostan (Naples), Marco Ruocco (Vimercate), Marita Sironi (Vimercate), Giulia Spada (Vimercate), Liberata Sportiello (Naples), Marco Tuccori (Pisa), Alfredo Vannacci (Florence), Mauro Venegoni (Vimercate), Giuditta Violetta Vighi (Vimercate), Giuseppe Danilo Vighi (Vimercate).

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Appendix 1

Cases of death

A 92-year-old patients, affected by cognitive impairment and cerebral vasculopathy, presented to ED in coma due to an overdose of zolpidem, quetiapine, trazodone, and promazine. The patient was hospitalised and hydrated, but remained unresponsive to any stimuli. She died two days after ED admission. The causality assessment was consistent with a “possible” relationship between the event and the suspected drugs, including zolpidem.

A 85-years-old woman with a previous history of acute myocardial infarction, rhabdomyolysis and multiple organ dysfunction, presented to the ED with a decreased oxygen saturation (56%) and respiratory arrest. In addition to her usual therapy, the patient had taken several drops of delorazepam for anxiety, developing respiratory arrest during the same day. ED clinicians administered flumazenil, hydroxyethyl starch, physiological solution and proceeded with ventilation. The patient died the following day. The causality assessment was consistent with a “possible” relationship between the event and the suspected drug delorazepam.

A 84-year-old woman with an history if atrial fibrillation and aneurysm of the thoracic aorta treated with warfarin, digoxin and furosemide/spironolactone, presented the ED because of drowsiness due to triazolam abuse. Drowsiness resolved in few hours and the patient was discharged from the hospital without any pharmacological intervention. Two day after discharge, the patient committed suicide. The causality assessment was consistent with a “possible” relationship between the event and the suspected drug triazolam.

A 75-year-old woman affected by atrial fibrillation, hearth failure, dyslipidemia, and depression, presented ED with dyspnoea. She abused of diazepam that was previously prescribed for anxiety. During ED visit, clinicians administered flumazenil with an immediate improvement of clinical conditions. Few hours later, although clinicians tried to perform an intubation, the patient developed a respiratory arrest and died. The causality assessment was consistent with a “possible” relationship between the event and the suspected drug diazepam.

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Lombardi, N., Bettiol, A., Crescioli, G. et al. Risk of hospitalisation associated with benzodiazepines and z-drugs in Italy: a nationwide multicentre study in emergency departments. Intern Emerg Med 15, 1291–1302 (2020).

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