Effects of the implementation of the dynamic silver code in the emergency department.

BACKGROUND: Older persons accessing the Emergency Department (ED) spend more time and are at increased risk of poor outcomes. The Dynamic Silver Code (DSC), based on administrative data, predicts mortality of 75+ subjects visiting the ED. OBJECTIVE: To evaluate the effects of the implementation of the DSC in the ED. METHODS: A pre-post comparison was conducted in the ED of a community hospital in Florence, Italy before and after the DSC was fully implemented. In the post-DSC phase, a clinical decision tree was applied: patients at low-mild risk (DSC class I and II) were assigned to Internal Medicine, those at moderate risk (class III) to Geriatrics, and those at high risk (class IV) required geriatric consultation before assignment. Outcome measures were ED length of stay (LOS) and, in patients admitted to Geriatrics, weight of the Diagnosis Related Groups (DRG), hospital LOS, and mortality. RESULTS: 7,270 patients were enrolled in the pre-DSC and 4,725 in the post-DSC phase. ED LOS decreased from a median of 380 [206, 958] in the pre-DSC to 318 [178, 655] min in the post-DSC period (p<0.001). Class III represented the largest share of admissions to Geriatrics in the post-DSC period (57.7 % vs. 38.3 %; p<0.001). In patients admitted to Geriatrics, hospital LOS decreased by one day (p = 0.006) between the two study periods, with greater DRG weight and comparable mortality. CONCLUSIONS: Application of the DSC seemed to ease patient flow and to reduce LOS of older patients in the ED and increased appropriateness of admissions to Geriatrics.

Estimating Prognosis and Frailty in Persons Aged ≥75 Years in the Emergency Department: Further Validation of Dynamic Silver Code.

OBJECTIVES: To assess concurrent validity of the Dynamic Silver Code (DSC), a tool based on administrative data that predicts prognosis in older adults accessing the emergency department (ED), in terms of association with markers of poor functional and cognitive status. DESIGN: Cross-sectional. SETTING AND PARTICIPANTS: Data were obtained in the AIDEA study, which enrolled a cohort of ≥75-year-old patients, accessing the ED of 2 hospitals in Florence, Italy. METHODS: The DSC score and classes (I to IV, corresponding to an increasing risk of death) were obtained from administrative data. Information on health and functional status prior to ED access were collected from face-to-face, direct, or proxy interviews. The 4AT test was administered to screen for possible delirium. Bivariate comparisons of the prevalence of each functional and cognitive marker across 4 DSC classes were performed. Multinomial logistic regression was used to assess the multivariable risk of being in II, III, or IV DSC class vs I. RESULTS: Among 3358 participants (mean age 83 years, men 44%), 32.9%, 30.3%, 19.5%, and 17.2% were in DSC class I, II, III, and IV. Preadmission abnormal functional and cognitive conditions, and delirium in the ED, were increasingly more common from DSC class I through IV (P < .001). In particular, the prevalence of total inability to walk increased from 2.9% (class I) to 23.4% (class IV). In multivariable analyses, this was the strongest predictor of being in progressively worse DSC classes, whereas feeling of exhaustion, reporting of serious falls, weight loss, and severe memory loss or diagnosis of dementia gave some contribution. CONCLUSIONS AND IMPLICATIONS: The ability of the DSC to predict survival in older persons appears to rely on its prevailing association with markers of functional impairment. These results may support clinical use of the tool.

Efficacy, Practicality, and Safety of Inhaled Methoxyflurane in Elderly Patients with Acute Trauma Pain: Subgroup Analysis of a Randomized, Controlled, Multicenter, Open-Label Trial (MEDITA).

PURPOSE: Acute trauma pain management in the elderly population is a challenge. Inhaled methoxyflurane represents a promising treatment option; however, data in the elderly population are limited. PATIENTS AND METHODS: Subgroup, post hoc analysis including 69 patients aged ≥65 years from a randomized, active-controlled, open-label study in the emergency setting. Key inclusion criterion was moderate-to-severe pain (Numerical Rating Scale [NRS] score ≥ 4]) secondary to trauma in a single limb. Patients received inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1 g or ketoprofen 100 mg for moderate pain [NRS 4-6] and IV morphine 0.1mg/kg for severe pain [NRS ≥7]). The primary endpoint was the overall change in visual analog scale (VAS) pain intensity from randomization to the next 3, 5, and 10 min. Secondary endpoints included time to onset of pain relief (TOPR), efficacy up to 30 min, judgment of operators and patients, and safety. RESULTS: Pain reduction over time was similar in both groups. Median TOPR was shorter for methoxyflurane (9 min; 95% CI: 7.8, 10.2 min) than SAT (15 min; 95% CI: 10.2, 19.8 min). In terms of treatment satisfaction, patients and operators rated treatment efficacy and practicality, respectively, as "Excellent" or "Very good" 5.7 times and 3.4 times more frequently than SAT. A similar rate of adverse events (methoxyflurane: 6 events; SAT: 7 events) was recorded, all non-serious. No clinically significant changes in vital signs parameters were observed, and methoxyflurane did not result in cases of bradycardia or hypotension. CONCLUSION: In elderly patients with trauma pain, inhaled methoxyflurane shows similar pain relief and safety compared to SAT, offering advantages in terms of onset of effect and user's satisfaction. Although this analysis presents some methodological limitations, it provides the first specific evidence of the use of inhaled methoxyflurane in the elderly population. TRIAL REGISTRATION: EudraCT number: 2017-001565-25; Clinicaltrials.gov identifier NCT03585374.

Role of Inhaled Methoxyflurane in the Management of Acute Trauma Pain.

Adequate treatment of trauma pain is an integral part of the management of trauma patients, not just for ethical reasons but also because undertreated pain can lead to increased morbidities and worse long-term outcomes. Trauma pain management presents challenges in the pre-hospital setting, particularly in adverse or hostile environments as well as in busy emergency departments (EDs). Inhaled methoxyflurane, administered at analgesic doses via a disposable inhaler, has recently become available in Europe for the emergency treatment of moderate to severe pain in conscious adult trauma patients. A growing body of evidence demonstrates that inhaled methoxyflurane is well tolerated and effective in providing a rapid onset of analgesia. In this paper, we discuss the rationale for methoxyflurane use in trauma pain management, data from clinical trials recently conducted in Europe, its efficacy and safety profile compared to current standard treatments, its place in therapy and organizational impact. We conclude that inhaled methoxyflurane represents an effective treatment option in the different settings where trauma patients require rapid and flexible pain resolution, with potential organizational advantages.

Inhaled Methoxyflurane versus Intravenous Morphine for Severe Trauma Pain in the Emergency Setting: Subgroup Analysis of MEDITA, a Multicenter, Randomized, Controlled, Open-Label Trial.

PURPOSE: Opioid analgesics remain the cornerstone of treatment for severe trauma pain in the emergency setting, but there are barriers to their use. This post hoc analysis of a previously reported trial (MEDITA) investigated the efficacy and safety of low-dose methoxyflurane versus intravenous (IV) morphine for severe trauma pain. PATIENTS AND METHODS: MEDITA was a Phase IIIb, randomized, active-controlled, parallel-group, open-label study in Italian pre-hospital units and emergency departments (EudraCT: 2017-001565-25; NCT03585374). Adult patients (N=272) with moderate-to-severe trauma pain (score ≥4 on the Numerical Rating Scale [NRS]) were randomized 1:1 to inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1g or ketoprofen 100mg for moderate pain [NRS 4-6] and IV morphine 0.1mg/kg for severe pain [NRS ≥7]). Analyses were performed for the severe pain subgroup. The primary efficacy variable was the overall change from baseline in visual analog scale (VAS) pain intensity at 3, 5 and 10min post-randomization. Non-inferiority of methoxyflurane versus morphine was concluded if the upper 95% confidence interval (CI) for the treatment difference was <1; superiority was concluded if the upper 95% CI was <0. RESULTS: Ninety-three patients (methoxyflurane: 49; SAT: 44) were included in the severe pain intention-to-treat population. The reduction in VAS pain intensity over the first 10min was superior for methoxyflurane versus morphine (adjusted mean treatment difference: -5.54mm; 95% CI: -10.49, -0.59mm; p=0.029). Median time to onset of pain relief was 9min for methoxyflurane and 15min for morphine. Patients rated treatment efficacy and physicians rated treatment practicality "Excellent" or "Very good" for more methoxyflurane-treated patients (42.8% and 67.3%) than morphine-treated patients (18.1% and 22.8%). Adverse events, all non-serious, were reported in 20.4% of methoxyflurane-treated patients and in 4.8% of morphine-treated patients. CONCLUSION: Methoxyflurane provided superior short-term pain relief to IV morphine in patients with severe trauma pain and offers an effective non-narcotic treatment option.

Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA).

INTRODUCTION: Low-dose methoxyflurane, administered via a hand-held inhaler, has been used for short-term pain relief in emergency medicine in Australia and New Zealand for over 40 years, and was recently approved in Europe for the rapid relief of moderate-to-severe trauma-related pain in adults. There is currently a lack of data for methoxyflurane versus active comparators, therefore this trial will investigate the efficacy and safety of inhaled methoxyflurane compared with standard of care (SoC) in the treatment of acute trauma-related pain in pre-hospital and ED settings in Italy. METHODS: MEDITA (Methoxyflurane in Emergency Department in ITAly) is a Phase IIIb, prospective, randomised, active-controlled, parallel-group, open-label, multicentre trial. A total of 272 adult patients with moderate-to-severe pain [score ≥ 4 on the Numerical Rating Scale (NRS)] due to limb trauma will be randomised 1:1 to receive 3 mL methoxyflurane (self-administered by the patient via inhalation under supervision of a trained person) or medications that currently comprise the SoC in Italy [intravenous (IV) morphine for severe pain (NRS ≥ 7); IV paracetamol or ketoprofen for moderate pain (NRS 4-6)], administered as soon as possible after randomisation. PLANNED OUTCOMES: Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline (time of randomisation) and at intervals up to 30 min. Time of onset of pain relief as reported by the patient and use of rescue medication will be recorded. The patient will rate the efficacy and the healthcare professional will rate the practicality of study treatment at 30 min after randomisation using a 5-point Likert scale. Adverse events will be recorded until safety follow-up at 14 ± 2 days. Vital signs will be measured at baseline, 10 and 30 min. The primary aim is to demonstrate non-inferiority of methoxyflurane versus SoC for the change in VAS pain intensity from baseline (randomisation) to 3, 5 and 10 min. TRIAL REGISTRATION: EudraCT number: 2017-001565-25. Clinicaltrials.gov identifier: NCT03585374. FUNDING: Mundipharma Pharmaceuticals srl.

Analgesic Efficacy, Practicality and Safety of Inhaled Methoxyflurane Versus Standard Analgesic Treatment for Acute Trauma Pain in the Emergency Setting: A Randomised, Open-Label, Active-Controlled, Multicentre Trial in Italy (MEDITA).

INTRODUCTION: Inhaled low-dose methoxyflurane is approved in Europe for emergency relief of moderate-to-severe trauma-related pain in adults, but data versus active comparators are sparse. The phase IIIb Methoxyflurane in Emergency Department in ITAly (MEDITA) trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain. METHODS: This was a randomised, active-controlled, parallel-group, open-label trial conducted in 15 Italian emergency units. Adults with limb trauma and pain score ≥ 4 on numerical rating scale (NRS) were randomised 1:1 to inhaled methoxyflurane 3 mL or SAT [intravenously administered (IV) morphine 0.1 mg/kg for severe pain (NRS ≥ 7); IV paracetamol 1 g or IV ketoprofen 100 mg for moderate pain (NRS 4-6)]. The primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10 min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the treatment comparison (methoxyflurane-SAT) was less than 1 and less than 0, respectively. RESULTS: Between 8 February 2018 and 8 February 2019, 272 patients were randomised (136 per treatment group). A total of 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS 67 mm) were treated and analysed for efficacy and safety. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference - 5.94 mm; 95% CI - 8.83, - 3.06 mm), moderate pain (- 5.97 mm; 95% CI - 9.55, - 2.39 mm) and severe pain (- 5.54 mm; 95% CI - 10.49, - 0.59 mm). Median onset of pain relief was 9 min for methoxyflurane and 15 min for SAT. Practicality of methoxyflurane treatment was rated "Excellent", "Very Good" or "Good" by 90% of clinicians vs. 64% for SAT. Adverse events (all non-serious) were reported by 17% of methoxyflurane-treated patients and 3% of SAT-treated patients. CONCLUSION: Methoxyflurane provided superior pain relief to SAT in patients with moderate-to-severe trauma pain and may offer a simple, fast, effective non-opioid treatment option. TRIAL REGISTRATION: Trial registered with EudraCT (2017-001565-25) on 2 March 2018 and ClinicalTrials.gov (NCT03585374) on 13 July 2018. FUNDING: Mundipharma Pharmaceuticals S.r.l.

Differential recognition of a tyrosine-dependent signal in the basolateral and endocytic pathways of thyroid epithelial cells.

Trafficking of receptors is of crucial importance for the physiology of most exocrine and endocrine organs. It is not known yet if the same mechanisms are used for sorting in the exocytic and endocytic pathways in the different epithelial tissues. In this work, we have used a deletion mutant of the human neurotrophin receptor p75(hNTR) that is normally localized on the apical membrane when expressed in Madin-Darby canine kidney cells. This internal 57-amino acid deletion of the cytoplasmic tail leads to a relocation of the protein from the apical to the basolateral membrane and to rapid and efficient endocytosis. These events are mediated by a signal localized within 9 amino acids of the mutated cytoplasmic tail that is strictly dependent on a tyrosine residue (Tyr-308). We have analyzed the basolateral sorting efficiency and endocytic capacity of this signal in Fischer rat thyroid (FRT) cells, in which basolateral and endocytic determinants have not yet been identified. We found that this targeting signal can mediate efficient transport to the basolateral membrane also in FRT cells with similar tyrosine dependence as in MDCK cells. In contrast to MDCK cells, this Tyr-based signal was not able to mediate coated pits localization and endocytosis in FRT cells. These data represent the first characterization of basolateral/endocytic signals in thyroid epithelial cells. Furthermore, our results indicate that requirements for tyrosine-dependent basolateral sorting signals are conserved among cell lines from different tissues but that the recognition of the colinear endocytic signal is tissue specific.