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Altered mental status (AMS) describes an undifferentiated presentation of disorders of mentation. It represents a common problem for prehospital and hospital providers and may be found in 5% to 10% of patients admitted to the Emergency Department (ED). Psychomotor Agitation (PMA), a state of motor restlessness and mental tension associated with a variety of psychiatric conditions, is one of the most frequent manifestations of AMS. In this observational retrospective study we included all the patients who presented PMA, treated by the out-of-hospital Emergency Medical System (EMS), and transported to the ED of the University Hospital of Udine, Italy. The objectives were to determine the incidence of patients with PMA treated by EMS in the area of investigation, the evaluation of pharmacologically treated patients considering the most commonly administered drugs, the intubation rate, the fraction of inspired oxygen (FiO2) needs, the length of hospital stay (LOHS), the adverse drug reactions (ADRs), and the excited delirium syndrome (ExDS). From January 2017 to December 2018, 319 patients were enrolled. The prevalence of PMA was 2.5% and 0.5% were the cases of PMA managed by the EMS. The predominant drugs used for sedation were midazolam (19.75%) and ketamine (9.09%), alone or in association; patients with consistent PMA required more than one sedative. Statistically significant differences were found in FiO2 supplementation for ketamine-sedated psychiatric patients and midazolam-sedated psychiatric patients with chronic home therapy, in the LOHS >24 hours (h), with a longer stay in case of midazolam and ketamine use, and in LOHS and FiO2 supplementation due to polypharmacy administration with more than one sedative drug. PMA is a frequent and widespread phenomenon and in the prehospital setting requires rapid assessment and management. Therapeutical strategies with benzodiazepines, ketamine, and rarely associations of drugs are safe, do not increase hypoxia and intubation rate. [ABSTRACT FROM AUTHOR]