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Background: Diabetes overtreatment is a frequent and severe issue in multimorbid older patients with type 2 diabetes (T2D). Objective: This study aimed at assessing the association between diabetes overtreatment and 1-year functional decline, hospitalisation and mortality in older inpatients with multimorbidity and polypharmacy. Methods: Ancillary study of the European multicentre OPERAM project on multimorbid patients aged ≥70 years with T2D and glucose-lowering treatment (GLT). Diabetes overtreatment was defined according to the 2019 Endocrine Society guideline using HbA1c target range individualised according to the patient's overall health status and the use of GLT with a high risk of hypoglycaemia. Multivariable regressions were used to assess the association between diabetes overtreatment and the three outcomes. Results: Among the 490 patients with T2D on GLT (median age: 78 years; 38% female), 168 (34.3%) had diabetes overtreatment. In patients with diabetes overtreatment as compared with those not overtreated, there was no difference in functional decline (29.3% vs 38.0%, P = 0.088) nor hospitalisation rates (107.3 vs 125.8/100 p-y, P = 0.115) but there was a higher mortality rate (32.8 vs 21.4/100 p-y, P = 0.033). In multivariable analyses, diabetes overtreatment was not associated with functional decline nor hospitalisation (hazard ratio, HR [95%CI]: 0.80 [0.63; 1.02]) but was associated with a higher mortality rate (HR [95%CI]: 1.64 [1.06; 2.52]). Conclusions: Diabetes overtreatment was associated with a higher mortality rate but not with hospitalisation or functional decline. Interventional studies should be undertaken to test the effect of de-intensifying GLT on clinical outcomes in overtreated patients.

Chemotherapy doses are usually prescribed on the basis of body surface area but dose banding is emerging as an efficient alternative. Dose banding presents the possibility of in-advance preparation in a Centralized Intravenous Admixture Service. To evaluate the long-term stability of 5-fluorouracil at banded doses (700 mg and 800 mg) in polyolefin bags. Ten polyolefin bags were prepared under aseptic conditions and stored at 23 ± 2°C for 24 days. Five of them were composed of 14 mL 5-fluorocuracil (700 g) in 100 mL 0.9% sodium chloride solution and the five other of 16 mL 5-fluorouracil (800 mg) in 100 mL 0.9% sodium chloride solution. At defined times, physical stability parameters were assessed: optical densities, pH measurements, visual and microscopical inspections. Solutions concentrations were measured using high-performance liquid chromatography coupled with a photodiode array detector. No change was observed on pH and optical density measurements during the study period. Visual and microscopical inspections remained free of colour change, precipitate, microagregate or crystal. The concentrations of 5-Fluorouracil in 800 mg bags remained stable for 24 days while the concentration in 700 mg bags showed a stability of at least 17 days. Five-fluorouracil at banded doses of 700 and 800 mg in polyolefin bags is physicochemically stable for at least 17 days at 23 ± 2°C. These results support the possibility of in advance centralised preparation.

Background : In a retrospective study in 4 Belgian hospitals, we showed that the use of linezolid (LZD) was larger and the rate of adverse drug reactions (ADRs) higher (especially anemia and thrombocytopenia) than described in the summary of product characteristics (1). Associated risk factors for ADRs were long treatment duration, renal impairment at the treatment initiation, and presence of comorbidities (evaluated by the Charlson index (2)). Moreover, literature suggests that trough levels (Cmin) > 9 mg/L increase the risk of hematological toxicity (HT) [...].

We identified factors associated with healthcare costs and health-related quality of life (HRQoL) of multimorbid older adults with polypharmacy. Using data from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid older people) trial, we described the magnitude and composition of healthcare costs, and time trends of HRQoL, during 1-year after an acute-care hospitalization. We performed a cluster analysis to identify groups with different cost and HRQoL trends. Using multilevel models, we also identified factors associated with costs and HRQoL. Two months after hospitalization monthly mean costs peaked (CHF 7'124) and HRQoL was highest (0.67). They both decreased thereafter. Age, falls, and comorbidities were associated with higher 1-year costs. Being female and housebound were negatively associated with HRQoL, while moderate alcohol consumption had a positive association. Being independent in daily activities was associated with lower costs and higher HRQoL. Although only some identified potential influences on costs and HRQoL are modifiable, our observations support the importance of prevention before health deterioration in older people with multimorbid illness and associated polypharmacy.

Gemcitabine is an analogue of cytidine arabinoside, used alone or in combination chemotherapy to treat various type of cancer. The dose-banding of gemcitabine provides the opportunity to anticipate the preparation of this anticancer drug on condition of carrying out stability studies. The aim of this study is to develop and validate a stability-indicating ultra-high-performance Liquid Chromatography (UHPLC) method for measuring the concentration of gemcitabine and to evaluate its stability at standardised rounded doses in polyolefin bags. The UHPLC with photodiode array (PDA) detector method was developed and validated (linearity, precision, accuracy, limits of detection and quantification, robustness and degradation test). Thirty polyolefin bags of gemcitabine (1600 mg/292 ml (n = 10), 1800 mg/297 ml (n = 10) and 2000 mg/303 ml (n = 10)) were prepared under aseptic conditions and stored at 5 ± 3 °C and 23 ± 2 °C for 49 days. Physical stability tests were periodically performed: visual and microscopic inspection and optical densities. The chemical stability was evaluated through pH monitoring and chromatographic assays. The results confirm the stability of Gemcitabine at selected standardised rounded doses of 1600 mg, 1800 mg and 2000 mg in NaCl 0.9% polyolefin bags for at least 49 days at 5 ± 3 °C and 23 ± 2 °C, allowing in-advance preparation.

Background Identifying patients at high risk of drug-related hospital admission (DRA) may help to efficiently target preventive interventions. We developed a score to predict DRAs in older patients with multimorbidity and polypharmacy. Methods We used participants from the multicenter European OPERAM trial (“Optimising PharmacothERapy in the Mutlimorbid Elderly”). We assessed the association between easily identifiable a priori predictors and 1-year DRAs by univariable logistic regression. Variables with p<0.20 were taken forward to backward regression. We retained all variables with p<0.05 in the model. We assessed the C-statistic, calibration (observed/predicted proportions), and overall accuracy (scaled Brier score, <0.25 indicating a useful model) of the score, and internally validated it by tenfold cross-validation. Results Within 1 year, 435/1,879 (23.2%) patients (mean age 79.4 years) had a DRA. The score included 7 variables: previous hospitalizations, non-elective admission, hypertension, cirrhosis with portal hypertension, chronic kidney disease, diuretic, corticosteroid. The C-statistic was 0.64 (95% CI 0.61-0.67). Patients with <1 point had a 12.4% predicted and observed risk of DRA, while those with >3 points had a 40.4% predicted and 38.9% observed risk of DRA. Scaled Brier score was 0.05. Calibration showed adequate match between predicted and observed proportions. Conclusion Comorbidities related to drug metabolism, specific medications, non-elective admission, and a history of hospitalization, were associated with a higher risk of DRA. Awareness of these associations and the score we developed may help identifying short before discharge patients most likely to benefit from preventive interventions.

Background: Benzodiazepine receptor agonist (BZRA) use is highly prevalent in hospitalised older people although these drugs are associated with numerous and serious adverse events. Deprescribing can reduce risks associated with chronic BZRA use. The aim of this study was to measure the prevalence of, and factors associated with, BZRA depre‑ scribing in acute geriatric units. Methods: During a one-year period, this multicentre retrospective study included patients aged ≥70 years, hospital‑ ised in acute geriatric units, and using ≥1 BZRA on admission. BZRA deprescribing at discharge was defned as: ≥25% decrease in lorazepam-equivalent admission dose; discontinuation of all BZRAs; or cessation of a rescue prescription at discharge. BZRA cessation was defned as discontinuation of all BZRAs at discharge. We identifed social, medical, geriatric and medication factors associated with BZRA deprescribing using logistic regression. Results: In total, 561 patients were included (mean age: 85.3±5.9 years, 70% of women). BZRA deprescribing occurred in 240 (42.8%), including 85 with BZRA cessation (15.2%). Deprescribing occurred more frequently in patients with a BZRA-related adverse event on admission or during hospital stay (odds ratio (OR) 4.5; 95% confdence interval [2.6; 7.9]), with an antidepressant (1.6 [1.1; 2.4]) and a higher lorazepam-equivalent dosage on admission (OR 1.2 [1; 1.4]), and less frequently in patients with antipsychotic drug (OR 0.5 [0.3; 0.8]). BZRA cessation was more likely in patients with a BZRA-related adverse event (OR 2.2 [1.2; 4.3]) and a lower lorazepam-equivalent dosage on admission (OR 0.5 [0.3; 0.6]). Conclusions: During hospitalisation in the acute geriatric units of our hospital, BZRA deprescribing occurred in 42.8% of the patients. Identifcation of an BZRA-related adverse event by the treating physician appears to be a major factor: this reactive deprescribing accounted for 74% of cases in our study. Further prospective studies are needed

A patient-centred approach to medicines optimisation is considered essential. The OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people (OPERAM) trial evaluated the effectiveness of medication review with shared decision-making (SDM) in older people with multimorbidity. Beyond evaluating the clinical effectiveness, exploring the patient experience facilitates a better understanding of contextual factors and mechanisms affecting medication review effectiveness. To explore experiences of hospital-initiated medication changes in older people with multimorbidity. We conducted a multicentre mixed-methods study, embedded in the OPERAM trial, combining semi-structured interviews and the Beliefs about Medicines Questionnaire (BMQ) with a purposive sample of 48 patients (70-94 years) from four European countries. Interviews were analysed using the Framework approach. Trial implementation data on SDM were collected and the 9-item SDM questionnaire was conducted with 17 clinicians. Patients generally displayed positive attitudes towards medication review, yet emphasised the importance of long-term, trusting relationships such as with their general practitioners for medication review. Many patients reported a lack of information and communication about medication changes and predominantly experienced paternalistic decision-making. Patients' beliefs that 'doctors know best', 'blind trust', having limited opportunities for questions, use of jargon terms by clinicians, 'feeling too ill', dismissive clinicians, etc highlight the powerlessness some patients felt during hospitalisation, all representing barriers to SDM. Conversely, involvement of companions, health literacy, empathetic and trusting patient-doctor relationships, facilitated SDM. Paradoxical to patients' experiential accounts, clinicians reported high levels of SDM. The BMQ showed that most patients had high necessity and low concern beliefs about medicines. Beliefs about medicines, ex

Inappropriate polypharmacy has been linked with adverse outcomes in older, multimorbid adults. OPERAM is a European cluster-randomized trial aimed at testing the effect of a structured pharmacotherapy optimization intervention on preventable drug-related hospital admissions in multimorbid adults with polypharmacy aged 70 years or older. Clinical results of the trial showed a pattern of reduced drug-related hospital admissions, but without statistical significance. In this study we assessed the cost-effectiveness of the pharmacotherapy optimisation intervention. We performed a pre-planned within-trial cost-effectiveness analysis (CEA) of the OPERAM intervention, from a healthcare system perspective. All data were collected within the trial apart from unit costs. QALYs were computed by applying the crosswalk German valuation algorithm to EQ-5D-5L-based quality of life data. Considering the clustered structure of the data and between-country heterogeneity, we applied Generalized Structural Equation Models (GSEMs) on a multiple imputed sample to estimate costs and QALYs. We also performed analyses by country and subgroup analyses by patient and morbidity characteristics. Trial-wide, the intervention was numerically dominant, with a potential cost-saving of CHF 3'588 (95% confidence interval (CI): -7'716; 540) and gain of 0.025 QALYs (CI: -0.002; 0.052) per patient. Robustness analyses confirmed the validity of the GSEM model. Subgroup analyses suggested stronger effects in people at higher risk. We observed a pattern towards dominance, potentially resulting from an accumulation of multiple small positive intervention effects. Our methodological approaches may inform other CEAs of multi-country, cluster-randomized trials facing presence of missing values and heterogeneity between centres/countries.

BACKGROUND AND AIM Clonidine is frequently combined to opioids for the management of chronic pain. The aim of this study was to evaluate the physical stability of this combination at high and low concentrations in polypropylene syringes at 5±3°C and at 22±3°C. METHODS Five syringes with low concentration of clonidine (0.003 mg/mL) and morphine hydrochloride (0.417 mg/mL) and five syringes with high concentration of clonidine (0.032 mg/mL)and morphine hydrochloride (4.286 mg/mL) were evaluated. The turbidity, the pH and the crystal formation were controlled after the production and until 72h post-production. RESULTS No changes in color or appearance of opacity or turbidity were observed. Spectrophotometric measurements (at 350, 410 and 550 nm) and pH were not affected. The microscopic analysis did not detect any aggregate or crystal formation. DISCUSSION AND CONCLUSION The mixture of clonidine and morphine hydrochloride at low and high concentrations is physically stable for at least 72 hours post-production at 5±3°C and at 22±3°C. These results paved the way for a subsequent chemical stability study.

Most patients present for catheter ablation of atrial fibrillation (CAAF) with residual or full effect of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). In daily practice, it has been observed that the activated clotting time (ACT) was actually poorly sensitive to the effect of DOACs and that patients on DOACs required more unfractionated heparin (UFH) to achieve the ACT target of 300 s during the procedure, leading some authors to worry about potential overdosing. Conversely, we hypothesize that these higher doses of UFH are necessary to achieve adequate hemostasis during CAAF regardless of the residual effect of DOACs. During CAAF, thrombosis is promoted mainly by the presence of thrombogenic sheaths and catheters in the bloodstream. Preclinical data suggest that only high doses of DOACs are able to mitigate catheter-induced thrombin generation, whereas low dose UFH already do so. In addition, the effect of UFH seems to be lower in patients on DOACs, compared to patients on VKAs, explaining part of the differences observed in heparin requirements. Clinical studies could not identify increased bleeding risk in patients on DOACs compared to those on VKAs despite similar efficacy during CAAF procedures. Moreover, targeting a lower ACT was associated with an increased periprocedural thrombotic risk for both DOAC and VKA patients. Therefore, the low sensitivity of the ACT to the residual effect of DOACs should not be a major concern in its use in the interventional cardiology laboratory.

Death rattle, which could often be associated with a pulmonary fluid overload, occurs in 25% to 90% of dying patients. The co-administration of scopolamine (anticholinergic drug)and bumetanide (loop diuretic) could be considered in order to avoid unnecessary fluid overload at end-stage of life. The objective of this study was to investigate the physical and chemical stabilities of the admixture bumetanide and scopolamine in order to prepare them in advance by a centralized intravenous additive service in-hospital pharmacy. The stability of the lowest (LOW)concentration was evaluated on five polypropylene syringes containing the admixture bumetanide (Burinex, 2 mg/4 mL) and scopolamine (0.25 mg/mL) at 41.67 µg/mL and 5.21 µg/mL. The highest (HIGH) concentration with 125 µg/mL of bumetanide and 31.25 µg/mL of sc opolamine was evaluated on five polypropylene syringes. Ali syringes were stored for 18 days at 5°C ± 3°C. Periodic samples were visually and microscopically examined to observe any particle appearance or color change.The pH and absorbance at 3 wavelengths (350 nm, 410 nm, and 550 nm) were monitored. The concentrations were measured by ultra-high-performance liquid chromatography-photodiode array detection, using a newly developed method.During the 18 days of test, there was no change in color or appearance of opacity, turbidity, or precipitation, and the pH remained stable. Mean concentrations of bumetanide and scopolamine at LOW and HIGH concentrations after 18 days remained statistically unchanged. The lower limits of the 95% confidence intervals of molecules at LOW and HIGH concentrations remained higher than a 90% threshold of concentration thus considering the mixture chemically stable. Degradation rates of bumetanide and scopolamine content at LOW and HIGH concentration should not exceed a maximum of 0.70% every 10 days. This study was the first one to show that the admixture of bumetanide and scopolamine is physically and chemically stable at two conce

Background The Screening Tool of Older Persons’ Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) instrument is used to evaluate the appropriateness of medication in older people. STOPP/START criteria have been converted into software algorithms and implemented in a clinical decision support system (CDSS) to facilitate their use in clinical practice. Objective Our objective was to determine the frequency of CDSS-generated STOPP/START signals and their subsequent acceptance by a pharmacotherapy team in a hospital setting. Design and Methods Hospitalised older patients with polypharmacy and multimorbidity allocated to the intervention arm of the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial underwent a CDSS-assisted structured medication review in four European hospitals. We evaluated the frequency of CDSS-generated STOPP/START signals and the subsequent acceptance of these signals by a trained pharmacotherapy team consisting of a physician and pharmacist after evaluation of clinical applicability to the individual patient, prior to discussing pharmacotherapy optimisation recommendations with the patient and attending physicians. Multivariate linear regression analysis was used to investigate potential patient-related (e.g. age, number of co-morbidities and medications) and setting-related (e.g. ward type, country of inclusion) determinants for acceptance of STOPP and START signals.

No abstract available

Many strategies aimed at deprescribing benzodiazepine receptor agonists (BZRA) in older adults have already been evaluated with various success rates. There is so far no consensus on which strategy components increase deprescribing the most. Yet, despite an unfavourable benefit-to-risk ratio, BZRA use among older adults remains high. We systematically reviewed barriers and enablers for BZRA deprescribing in older adults. Two reviewers independently screened records identified from five electronic databases-Medline, Embase, PsycINFO, CINAHL and the Cochrane library-and published before October 2020. They searched for grey literature using Google Scholar. Qualitative and quantitative records reporting data on the attitudes of older adults, caregivers and healthcare providers towards BZRA deprescribing were included. Populations at the end of life or with specific psychiatric illness, except for dementia, were excluded. The two reviewers independently assessed the quality of the included studies using the mixed-methods appraisal tool. Barriers and enablers were identified and then coded into domains of the theoretical domains framework (TDF) using a combination of deductive and inductive qualitative analysis. The most relevant TDF domains for BZRA deprescribing were then identified. Twenty-three studies were included 13 quantitative, 8 qualitative and 2 mixed-method studies. The points of view of older adults, general practitioners and nurses were reported in 19, 9 and 3 records, respectively. We identified barriers and enablers in the majority of TDF domains and in two additional themes: "patient characteristics" and "BZRA prescribing patterns". Overall, the most relevant TDF domains were "beliefs about capabilities", "beliefs about consequences", "environmental context and resources", "intention", "goals", "social influences", "memory, attention and decision processes". Perceived barriers and enablers within domains differed across settings and across stakeholders. T

Purpose: Successful deprescribing requires understanding the attitudes of older adults and caregivers towards this process. This study aimed to capture these attitudes in four French-speaking countries and to investigate associated factors. Methods A multicenter cross-sectional study was conducted by administrating the French version of the revised Patients’ Attitudes Towards Deprescribing (rPATD) questionnaire in Belgium, Canada, France, and Switzerland. Community-dwelling or nursing home older adults ≥ 65 years taking ≥ 1 prescribed medications and caregivers of older adults with similar characteristics were included. Multivariate logistic regressions were carried out to examine factors associated with willingness to deprescribe. Results: A total of 367 older adults (79.3 ± 8.7 years, 63% community-dwelling, 54% ≥ 5 medications) and 255 unrelated caregivers (64.4 ± 12.6 years) of care recipients (83.4 ± 7.9 years, 52% community-dwelling, 69% ≥ 5 medications) answered the questionnaire. Among them, 87.5% older adults and 75.6% caregivers would be willing to stop medications if the physician said it was possible. Reluctance to stop a medication taken for a long time was expressed by 46% of both older adults and caregivers. A low score for the factor “concerns about stopping” (older adults: aOR: 0.21; 95% CI: 0.07–0.59), and a high score for the factor “involvement” (older adults: aOR: 2.66; 95% CI: 1.01–7.07; caregivers: aOR: 11.28; 95% CI: 1.48–85.91) were associated with willingness to deprescribe. Conclusions: A significant proportion of older adults and caregivers of French-speaking countries are open to deprescribing. Despite this apparent willingness, deprescribing conversations in clinical practice remains marginal, emphasizing the importance of optimizing the integration of existing tools such as rPATD.

Introduction Multimorbidity and polypharmacy are risk factors for drug-related hospital admissions (DRAs) in the ageing population. DRAs caused by medication errors (MEs) are considered potentially preventable. The STOPP/START criteria were developed to detect potential MEs in older people. Objective The aim of this study was to assess the detectability of MEs with a STOPP/START-based in-hospital medication review in older people with polypharmacy and multimorbidity prior to a potentially preventable DRA. Methods Hospitalised older patients (n = 963) with polypharmacy and multimorbidity from the intervention arm of the OPERAM trial received a STOPP/START-based in-hospital medication review by a pharmacotherapy team. Readmissions within 1 year after the in-hospital medication review were adjudicated for drug-relatedness. A retrospective assessment was performed to determine whether MEs identified at the first DRA were detectable during the in-hospital medication review. Results In total, 84 of 963 OPERAM intervention patients (8.7%) were readmitted with a potentially preventable DRA, of which 72 patients (n = 77 MEs) were eligible for analysis. About half (48%, n = 37/77) of the MEs were not present during the in-hospital medication review and therefore were not detectable at that time. The pharmacotherapy team recommended a change in medication regimen in 50% (n = 20/40) of present MEs, which corresponds to 26% (n = 20/77) of the total identified MEs at readmission. However, these recommendations were not implemented. Conclusion MEs identified at readmission were not addressed by a prior single in-hospital medication review because either these MEs occurred after the medication review (~50%), or no recommendation was given during the medication review (~25%), or the recommendation was not implemented (~25%). Future research should focus on optimisation of the timing and frequency of medication review and the implementation of proposed medication recommendations.

BACKGROUND: The revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire allows capture of the beliefs and attitudes of older adults and caregivers towards deprescribing. OBJECTIVES: To translate and validate the rPATD questionnaire into French. METHODS: The French rPATD was translated using forward-backward translation. Psychometric properties were evaluated in both older adults ≥65 years living in the community or in institutions and who were taking at least one chronic medication and in caregivers of older adults with similar characteristics. Participants were recruited in four French-speaking countries (Belgium, Canada, France and Switzerland). Face and content validity were assessed during the translation process. Construct validity (exploratory factor analysis (EFA)) and internal consistency (Cronbach's alpha) were investigated in questionnaires without missing data. Test-retest reliability was evaluated using intra-class correlation coefficient (ICC) in a sample of participants. RESULTS: In total, 320 questionnaires from older adults and 215 questionnaires from caregivers were included to evaluate construct validity and internal consistency. EFA extracted four factors in the older adults' and caregivers' versions of the questionnaire consistent with the English rPATD. The extracted factors related to the perceived burden of medication taking, the beliefs in appropriateness of medications, concerns about stopping medications and the level of involvement in making decisions and of knowledge of medications. Internal consistency was satisfactory for three factors for both versions (Cronbach's alpha >0.70), with lower internal consistency in the concerns about stopping factor. Test-retest reliability was overall good for all factors in the caregivers' version (ICC > 0.75) while for the older adults' version, moderate (ICC range: 0.75-0.50) to good ICC values were found. CONCLUSIONS: The French rPATD presents globally good psychometric properties and

Purpose Polypharmacy, medication errors and adverse drug events are frequent among nursing home residents. Errors can occur at any step of the medication use process. We aimed to review interventions aiming at optimization of any step of medication use in nursing homes. Methods We narratively reviewed quantitative as well as qualitative studies, observational and experimental studies that described interventions, their effects as well as barriers and enablers to implementation. We prioritized recent studies with relevant findings for the European setting. Results Many interventions led to improvements in medication use. However, because of outcome heterogeneity, comparison between interventions was difficult. Prescribing was the most studied aspect of medication use. At the micro-level, medication review, multidisciplinary work, and more recently, patient-centered care components dominated. At the macro-level, guidelines and legislation, mainly for specific medication classes (e.g., antipsychotics) were employed. Utilization of technology also helped improve medication administration. Several barriers and enablers were reported, at individual, organizational, and system levels. Conclusion Overall, existing interventions are effective in optimizing medication use. However there is a need for further European well-designed and large-scale evaluations of under-researched intervention components (e.g., health information technology, patient-centered approaches), specific medication classes (e.g., antithrombotic agents), and interventions targeting medication use aspects other than prescribing (e.g., monitoring). Further development and uptake of core outcome sets is required. Finally, qualitative studies on barriers and enablers for intervention implementation would enable theory-driven intervention design.

The physico-chemical stability of an injectable preparation (IV) is conditioned by different parameters. A collaboration between the pharmacy, the chemistry laboratory and the statisticians of the scientific support unit was established in 1996, in order to carry out long-term chemical stability studies of commonly used IVs and to be able to take charge of their preparation in pharmacy. In 24 years of activity, the Drug Stability Research Group (DSRG) tested 39 IV at different concentration and temperature of storage. The DSRG has organized an annual symposium since 2015. The theme of the 2019 edition was devoted to the robotization of injectable reconstitution operations, focused on their impact on the workplace and the existing equipment.

Management of chemotherapies is a strategic issue for european healthcare. Dose-banding enables to reduce waiting time of patients in day care units and drug wastage. The aim of this study was to assess the stability of 5-Fluorouracile (5-FU) at standardised rounded doses of 4 and 5 g in MyFuser® portable infusion pump for in-advance preparation. Ten MyFuser® (4 and 5 gr 5-FU added to NaCl 0.9%) were prepared under aseptic conditions and stored at room temperature (23 ± 2 °C) for 28 days then at 30 °C for three days. Physical stability tests were periodically performed: visual and microscopic inspection, pH measurements and optical densities. The concentration of solutions was measured by High Performance Liquid Chromatography/UV detector. Results confirm the stability of 5-FU at selected SRD of 4 g and 5 g with NaCl 0.9% in MyFuser® for at least 28 days at room temperature and three days at 30 °C, allowing in-advance preparation.

In Belgium, linezolid is indicated for pneumonia and skin and soft tissue infections, but is more broadly used, due to its oral bioavailability and activity against multiresistant organisms. This could increase the risk of adverse drug reactions (ADR), notably hematological disorders (anemia, thrombocytopenia), neuropathy, or lactic acidosis. We analyzed linezolid clinical use in relationship with occurrence of ADR in Belgian hospitals and highlighted risk factors associated with the development of thrombocytopenia. A retrospective analysis of electronic medical records and laboratory tests of adult patients treated with linezolid in four Belgian hospitals in 2016 allowed the collection of ADR for 248 linezolid treatments. Only 19.7% of indications were in-label. ADR included 43 thrombocytopenia, 17 anemia, 4 neuropathies, and 4 increases in lactatemia. In a multi-variate analysis, risk factors of thrombocytopenia were a treatment duration > 10 days, a glomerular filtration rate < 60 mL/min, and a Charlson index ≥ 4. Off-label use of linezolid is frequent in Belgium, and ADR more frequent than reported in the summary of product characteristics, but not statistically associated with any indication. This high prevalence of ADR could be related to a high proportion of patients presenting risk factors in our population, highlighting the importance of detecting them prospectively

Objectives: We aimed to establish an explicit list of potentially clinically significant drug-drug interactions (DDIs) in people aged ≥65 years. Design: A preliminary list of potentially clinically significant DDIs was compiled, based on 154 DDIs identified from literature review. Subsequently, a 2-round online Delphi survey was undertaken with a multidisciplinary expert panel. A consensus meeting and a final round were conducted to validate the final DDI list and the scope of information provided. Setting and participants: Twenty nine experts, including geriatricians and clinical pharmacists from 8 European countries. Measures: For each DDI, in the first 2 rounds, experts were asked to score the severity of potential harm on a 5-point Likert-type scale. DDIs were directly included on the final list if the median score was 4 (major) or 5 (catastrophic). DDIs with a median score of 3 (moderate) were discussed at a consensus meeting and included if ≥75% of participants voted for inclusion in the final round. Results: Consensus was achieved on 66 potentially clinically significant DDIs (28 had a median score of 4/5 and 48 of 3 in the Delphi survey). Most concerned cardiovascular, antithrombotic, and central nervous system drugs. The final list includes information on the mechanism of interaction, harm, and management. Treatment modification is recommended for three-quarters of DDIs. Conclusion and implications: We validated a list of potentially clinically significant DDIs in older people, which can be used in clinical practice and education to support identification and management of DDIs or to assess prevalence in epidemiologic and intervention studies.

Hospital staff are a priority target group in the European COVID-19 vaccination strategy. Measuring the extent of COVID-19 vaccination hesitancy and understanding the reasons behind it are essential to be able to tailor effective communication campaigns. Using the Health Belief Model (HBM) as a theoretical framework, a survey was conducted among staff members of a Belgian three-site hospital center between 6 and 20 January 2021. Multivariable logistic ordinal regression was performed to assess determinants of the attitude towards COVID-19 vaccination. Reasons for and against COVID-19 vaccination and the need for information were explored among hesitant staff members. Among the respondents (N = 1132), 58% and 4.9% said that they would certainly and certainly not get vaccinated, respectively; 37.1% were hesitant, with different degrees of certainty. A positive attitude towards COVID-19 vaccination was associated with being older, being a physician, being vaccinated against seasonal flu, and with several HBM factors (including perceived benefits and cues to actions). Among hesitant staff, concerns about potential side effects and the impression that the vaccine was developed too quickly were the main reasons against COVID-19 vaccination. The key factors in the decision process were data on vaccine efficacy and safety, and knowing that vaccination went well in others. These data are helpful to further tailor the communication campaign and ensure sufficient vaccination coverage among hospital staff.

Objective: To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital. Design: Cluster randomised controlled trial. Setting: 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors. Participants: 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term). Intervention: Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person’s prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing. Main outcome measure: Primary outcome was first drug related hospital admission within 12 months. Results: 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug relate

The concomitant use of direct oral anticoagulants (DOAC) and strong P-gp and CYP3A4 inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels. We retrospectively identified hospitalized patients receiving simultaneously a DOAC and carbamazepine, phenobarbital, phenytoin or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady-state were included. DOAC peak or trough levels were compared to on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified. We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch). Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug-drug interaction.

Potentially toxic plasticizers are commonly added to polyvinyl chloride medical devices for transfusion in order to improve their flexibility and workability. As the plasticizers are not chemically bonded to the PVC, they can be released into labile blood products (LBPs) during storage. Ideally, LBPs would be used in laboratory studies of plasticizer migration from the medical device. However, short supply (i.e., limited stocks of human blood in collection centres) has prompted the development of specific simulants for each type of LBP in the evaluation of new transfusion devices. We performed a Delphi study with a multidisciplinary panel of 24 experts. In the first (qualitative) phase, the panel developed consensus definitions of the specification criteria to be met by each migration simulant. Next, we reviewed the literature on techniques for simulating the migration of plasticizers into LBPs. A questionnaire was elaborated and sent out to the experts, and the replies were synthesized in order to obtain a consensus. The qualitative study established specifications for each biological matrix (whole blood, red blood cell concentrate, plasma, and platelet concentrate) and defined the criteria required for a suitable LBP simulant. Ten criteria were suggested: physical and chemical characteristics, opacity, form, stability, composition, ability to mimic a particular clinical situation, ease and safety of use, a simulant-plastic interaction correlated with blood, and compatibility with analytical methods. The questionnaire data revealed a consensus on the use of natural products (such as pig's blood) to mimic the four LBPs. Opinions diverged with regard to synthetic products. However, an isotonic solution and a rheological property modifier were considered to be of value in the design of synthetic simulants. Consensus reached by the Delphi group could be used as a database for the development of simulants used to assess the migration of plasticizers from PVC bags into L

Background: Drug-drug interactions (DDIs) are highly prevalent in older patients but little is known about prevalence of DDIs over time. Our main objective was to assess changes in the prevalence and characteristics of drug-drug interactions (DDIs) during a one-year period after hospital admission in older people, and associated risk factors. Methods: We conducted a sub-study of the European OPERAM trial (OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people), which assessed the efects of a structured medication review (experimental arm) compared to usual care (control arm) on reducing drug-related hospital readmissions. All OPERAM patients (≥70 years, with multimorbidity and polypharmacy, hospitalized in four centers in Bern, Brussels, Cork and Utrecht between December 2016 and October 2018, followed over 1 year) who were alive at hospital discharge and had full medication data during the index hospitalization (at baseline i.e., enrolment at admission, and at discharge) were included. DDIs were assessed using an international consensus list of potentially clinically signifcant DDIs in older people. The point-prevalence of DDIs was evaluated at baseline, discharge, and at 2, 6 and 12months after hospitalization. Logistic regression models were performed to assess independent variables associated with changes in DDIs 2months after baseline. Results: Of the 1950 patients (median age 79 years) included, 1045 (54%) had at least one potentially clinically signifcant DDI at baseline; point-prevalence rates were 58, 57, 56 and 57% at discharge, and 2, 6 and 12months, respectively. The prevalence increased signifcantly from baseline to discharge (P<.001 [signifcant only in the control group]), then remained stable over time (P for trend .31). The fve most common DDIs –all pharmacodynamic in nature– accounted for 80% of all DDIs and involved drugs that afect potassium concentrations, centrally-acting drugs and antithrombotics. At 2months, DD

Clonidine is an alpha-2 adrenoreceptor agonist and is frequently combined with opioids (ie, morphine hydrochloride (HCl)) for the management of chronic pain. In palliative care, the administration of clonidine and morphine HCl is recommended in case of tolerance effect. This study aimed to evaluate the physical and chemical stability of this admixture at high and low concentrations in 14 and 48 mL polypropylene syringes. The stability of a low concentration admixture of clonidine (Catapressan 0.15 mg/mL, Boehringer Ingelheim, Germany) and morphine (morphine HCl 40 mg/mL, Sterop, Belgium) at 0.003 and 0.417 mg/mL, respectively, was evaluated by using five polypropylene syringes of 48 mL. The high concentration admixture consisted of 0.032 mg/mL clonidine and 4.286 mg/mL morphine HCl and was evaluated by using five polypropylene syringes of 14 mL. All syringes were stored for 30 days at 5°C±3°C. Periodic samples were visually and microscopically examined to observe any particle appearance or colour change. pH and absorbance at three wavelengths (350, 410 and 550 nm) were monitored. The concentrations were measured by ultra-high performance liquid chromatography-photodiode array detection. During the 30 days, there was no change in colour or appearance of opacity, turbidity or precipitation, and pH remained stable. The low and high concentration admixtures were considered chemically stable since the lower limit of the 90% CI remained superior to 90% of the initial concentration. Concentration measurements showed that the degradation rate was less than 1% over 10 days for each component in both admixtures. The admixture of clonidine and morphine HCl at low and high concentrations in polypropylene syringes appeared to be physically and chemically stable throughout the study period of 30 days at 5°C±3°C. In conclusion, the admixture can be prepared in advance under aseptic conditions by a centralised intravenous additive service in the pharmacy department.

The objective of this review was to collect information and results about the method of the microwave freeze-thaw treatment of injectable drugs and whether the method can support the development of Centralized Intravenous Admixtures Services. A systematic review of the scientific literature about injectable drug stability studies was performed. The data are presented in a table, which describes the name of the drug, producer, final concentration, temperature and time of freezing storage, type of microwave oven, thawing power, method of dosage, and the results after treatment or final long-term storage at 5°C ± 3°C. From 1980 to 2021, 60 drugs were studied by the microwave freeze-thaw treatment, and the results were presented in 49 publications. Forty papers were presented by 8 teams (2 to 18 by team). The temperatures of freezing storage varied from -70°C to -10°C, the time storage from 4 hours to 12 months, and the thaw from low to full power. Drug concentrations were mainly determined by high-performance liquid chromatography. Most of the 59 drugs were stable during and after treatment. Only three teams tested the long-term stability after the microwave freeze-thaw treatment, the first for ganciclovir after 7 days, the second for ceftizoxime after 30 days, and the third for 20 drugs after 11 to 70 days. This review can help Centralized Intravenous Additive Services take charge of the productions of ready-to-use injectable drugs.

A literature review was conducted in 2019 on the reconstitution of intravenous drugs. The following methods were identified: manual, semi-automatic, and automatic. A classification was carried out in three categories: automatic syringes, peristaltic pumps, and compounding doses robots. Data concerning the robots described in the previous review and possible robots that have appeared in the meantime were collected. The robots have been classified into 2 categories: with or without arms. The objective of the present review focuses on an updated review of the availability of compounding robots for intravenous therapy that are currently on the market.

BACKGROUND AND OBJECTIVE: Infusion containing paracetamol, alizapride, ketorolac and tramadol is used after a general anaesthesia in order to limit pain, fever and nausea. Currently, these infusions are prepared according to demand in the anaesthesia unit, but the preparation in advance could improve quality of preparation and time management. The aim of this study was to investigate the long-term stability of this infusion in glass bottles at 5°C ± 3 °C. METHOD: Five bottles of infusion were stored at 5°C ± 3 °C for 60 days. A visual and microscope inspection were performed periodically to observe any particle appearance or colour change. pH and absorbance at three wavelengths were measured. The concentrations were measured by ultra-high performance liquid chromatography - diode array detection. RESULTS: Multiple verifications were performed during the first 35 days and no crystal, impurity or colour change were observed. At the next time point (42nd day), crystals were visible to the naked eye. pH and absorbance at 350 nm and 550 nm were stable. A slight increase in the absorbance at 410 nm was observed during the study, suggesting that a degradation product could be formed and absorb at this wavelength. The infusion was considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Concentration measurements demonstrated that ketorolac and alizapride remained stable in the infusion for 35 days. The stability of tramadol was 28 days. However, degradation of paracetamol was much faster given that concentration has fallen below 90% of the initial concentration after 7 days. CONCLUSION: Infusion of paracetamol, alizapride, ketorolac and tramadol remains stable for 7 days in glass bottles at 5°C ± 3 °C and could be prepared in advance with these storage conditions.

BACKGROUND: Serious adverse drug reactions have been associated with the underuse or the misuse of oral anticoagulant therapy. We systematically reviewed the impact of computerized clinical decision support systems (CDSS) on the prescribing of oral anticoagulants and we described CDSS features associated with success or failure. METHODS: We searched Medline, Embase, CENTRAL, CINHAL, and PsycINFO for studies that compared CDSS for the initiation or monitoring of oral anticoagulants with routine care. Two reviewers performed study selection, data collection, and risk-of-bias assessment. Disagreements were resolved with a third reviewer. Potentially important CDSS features, identified from previous literature, were evaluated. RESULTS: Sixteen studies were included in our qualitative synthesis. Most trials were performed in primary care (n = 7) or hospitals (n = 6) and included atrial fibrillation (AF) patients (n = 9). Recommendations mainly focused on anticoagulation underuse (n = 11) and warfarin-drug interactions (n = 5). Most CDSS were integrated in electronic records or prescribing and provided support automatically at the time and location of decision-making. Significant improvements in practitioner performance were found in 9 out of 16 studies, while clinical outcomes were poorly reported. CDSS features seemed slightly more common in studies that demonstrated improvement. CONCLUSIONS: CDSS might positively impact the use of oral anticoagulants in AF patients at high risk of stroke. The scope of CDSS should now evolve to assist prescribers in selecting the most appropriate and tailored medication. Efforts should nevertheless be made to improve the relevance of notifications and to address implementation outcomes.

BACKGROUND: Older patients are regularly exposed to multiple medication changes during a hospital stay and are more likely to experience problems understanding these changes. Medication counselling is often proposed as an important component of seamless care to ensure appropriate medication use after hospital discharge. OBJECTIVES: The purpose of this systematic review was to describe the components of medication counselling in older patients (aged ≥ 65 years) prior to hospital discharge and to review the effectiveness of such counselling on reported clinical outcomes. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology (PROSPERO CRD42019116036), a systematic search of MEDLINE, EMBASE and CINAHL was conducted. The QualSyst Assessment Tool was used to assess bias. The impact of medication counselling on different outcomes was described and stratified by intervention content. RESULTS: Twenty-nine studies were included. Fifteen different components of medication counselling were identified. Discussing the dose and dosage of patients' medications (19/29; 65.5%), providing a paper-based medication list (19/29; 65.5%) and explaining the indications of the prescribed medications (17/29; 58.6%) were the most frequently encountered components during the counselling session. Twelve different clinical outcomes were investigated in the 29 studies. A positive effect of medication counselling on medication adherence and medication knowledge was found more frequently, compared to its impact on hard outcomes such as hospital readmissions and mortality. Yet, evidence remains inconclusive regarding clinical benefit, owing to study design heterogeneity and different intervention components. Statistically significant results were more frequently observed when counselling was provided as part of a comprehensive intervention before discharge. CONCLUSIONS: Substantial heterogeneity between the included studies was found for the components

Medication harm is in the spotlight with the World Health Organization’s (WHO) Global Patient Safety challenge. Defined as “any negative patient outcome or injury related to a medication”, it is a costly problem for healthcare systems. Mortality, secondary to medication harm, is reported at 0.3% of all hospital patients. Recent local studies in two Australian hospitals linked medication harm to anticoagulants, insulin and antihypertensives, which is similar to findings from other health systems. [...]

BACKGROUND: Critically ill patients are at high risk of iatrogenic withdrawal syndrome (IWS), due to exposure to high doses or prolonged periods of opioids and benzodiazepines. PURPOSE: To examine pharmacological management strategies designed to prevent and/or treat IWS from opioids and/or benzodiazepines in critically ill neonates, children and adults. METHODS: We included non-randomised studies of interventions (NRSI) and randomised controlled trials (RCTs), reporting on interventions to prevent or manage IWS in critically ill neonatal, paediatric and adult patients. Database searching included: PubMed, CINAHL, Embase, Cochrane databases, TRIP, CMA Infobase and NICE evidence. Additional grey literature was examined. Study selection and data extraction were performed in duplicate. Data collected included: population, definition of opioid, benzodiazepine or mixed IWS, its assessment and management (drug or strategy, route of administration, dosage and titration), previous drug exposures and outcomes measures. Methodological quality assessment was performed by two independent reviewers using the Cochrane risk of bias tool for RCTs and the ROBINS-I tool for NRSI. A qualitative synthesis of the results is provided. For the subset of studies evaluating multifaceted protocolised care, we meta-analysed results for 4 outcomes and examined the quality of evidence using GRADE post hoc. RESULTS: Thirteen studies were eligible, including 10 NRSI and 3 RCTs; 11 of these included neonatal and paediatric patients exclusively. Eight studies evaluated multifaceted protocolised interventions, while 5 evaluated individual components of IWS management (e.g. clonidine or methadone at varying dosages, routes of administration and duration of tapering). IWS was measured using an appropriate tool in 6 studies. Ten studies reported upon occurrence of IWS, showing significant reductions (n = 4) or no differences (n = 6). Interventions failed to impact duration of mechanical ventilation, IC

Cette étude offre un aperçu de la pratique actuelle de l'administration des vaccins dans les États voisins ou comparables à la Belgique. Nous avons décrit un panorama hétérogène de systèmes de santé qui gèrent l'administration du vaccin de différentes manières. La littérature sur le thème du transfert des tâches vers l'administration de vaccins sans médecin suggère qu'il y a des pistes à explorer en termes de possibilités de communication et d'accessibilité pour les patients. Les informations que nous avons recueillies indiquent qu'il existe de nombreuses possibilités d'apprentissage trans-frontaliers dans ce domaine

Le mot "hôpital vient du latin hospitare (recevoir des hôtes) et est régi par la règle bénédictine qui veut que tous les hôtes doivent être reçus comme le Christ.

La stabilité physico-chimique d'une préparation injectable (IV) est conditionnée par différents paramètres. Une collaboration entre pharmacie, laboratoire de chimie et statisticiens de l'unité de support scientifique s'est installée en 1996, afin de réaliser des études de stabilité chimique à long terme d'IV couramment utilisés et de pouvoir prendre en charge leur préparation en pharmacie.