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Objective Dobutamine is an inotropic agent given to patients with low cardiac output or undergoing cardiac surgery in intensive care units. Routine clinical care protocols recommend a target dilution concentration of 10 mg/mL dobutamine from the 250 mg/20 mL commercial solution. This study aimed to assess the 1-year stability of ready-to-use 10 mg/mL diluted dobutamine solutions. Two types of 50 mL conditioning, polypropylene (PP) syringes or cyclic-oleofin-copolymer (COC) vials and two diluents (5% dextrose (D5W) and normal saline (NS)) were tested. Methods Reversed-phase liquid chromatography coupled with an ultraviolet detection stability-indicating method was developed for dobutamine and validated according to selectivity, linearity, sensitivity, accuracy and precision. Chemical stability was considered to have been maintained if the measured concentrations were >90% of the initial concentration with no colour change. Physical stability was assessed through sterility tests, pH and osmolality monitoring, and subvisible particle counting. Containers were stored at −20±5°C, +5±3°C and +25±2°C with 60%±5% relative humidity in a dark, closed environment. Results According to this study, the physicochemical stability of 10 mg/mL dobutamine solutions prepared with D5W or NS is constant throughout a 365-day period when stored in COC vials, at all the aforementioned temperatures, whereas solutions in PP syringes required a refrigerated temperature and should not be administered after 21 days or 3 months when prepared with D5W or NS, respectively, or after 1 month at ambient temperature whatever the diluent. Conclusion Our results argue in favour of adopting the compounding of ready-to-use 10 mg/mL dobutamine solutions in COC vials in centralised intravenous additive services.

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.

OBJECTIVES: The objectives were to compare clinical pharmacist interventions between two care groups: COVID-19-positive and COVID-19-negative patients, and to identify drugs that require particular attention, especially those involved in COVID-19 management. METHODS: A prospective cohort study was conducted on patients with positive and negative COVID-19 statuses admitted to Lille University Hospital over 1 month. Pharmaceutical analysis instigated interventions to rectify drug-related errors. For each pharmaceutical intervention (PI), the anatomical therapeutic chemical classification of the drug and the outcome of such an intervention were specified. RESULTS: The study included 438 patients. Prescription analysis led to 188 PIs performed on 118 patients (64 COVID-19-positive patients and 54 COVID-19-negative patients). Most drug-related problems were incorrect dosage representing 36.7% (69/188) of all interventions: 27.9% (29/104) for the COVID-19-positive group and 47.6% (40/84) for the COVID-19-negative group. The most frequent PI in 34% (64/188) of cases was terminating a drug: 27.9% (29/104) for the COVID-19-positive group and 47.6% (40/84) for the COVID-19-negative group. The main drug classes involved were antithrombotic agents (20.7%, 39/188), antibacterials for systemic use (13.8%, 26/188) and drugs for gastric acid-related disorders (6.4%, 12/188). Study population was limited to a single centre over 1 month. CONCLUSION: No difference in PI was noted between the two groups. The presence of pharmacists led to a reduction in drug-related prescription problems, especially for antithrombotic and antibacterial drugs for both groups. Clinical pharmacy commitment in such a pandemic is therefore important.

Medication non-adherence (NA) after allogeneic hematopoietic cell transplantation (allo-HCT) can lead to serious complications. This study assesses NA in French adult and pediatric recipients and identifies factors associated with NA. In accordance with the EMERGE and STROBE guidelines, a cross sectional multicentric survey was conducted. We used a self-reported questionnaire that was adapted to adults and pediatrics and that could provide a picture of all three phases of medication adherence: initiation, implementation, persistence. We enrolled 242 patients, 203 adults (mean age: 51 years old, 50.7% male) and 39 children (mean age: 9 years old, 56.4% female). Reported NA was estimated at about 75% in both populations, adults and pediatrics. In adults, the univariate analysis showed that patients less than 50 years old (P = 0.041), (i) treated with cyclosporine (P = 0.02), (ii) treated with valacyclovir/acyclovir (P = 0.016), and (iii) experiencing side effects (P = 0.009), were significantly more non-adherent. In multivariate analysis, only recipient age was significantly associated to NA (P = 0.05). The limited size of the pediatric population did not allow us to draw any statistical conclusion about this population. To the best of our knowledge, this is the first study in France on NA in allo-HCT recipients. Our results highlight the age factor as the only factor related to NA. Further studies are needed to confirm our observations and refine results in pediatric populations, currently most at risk of medication NA.

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.

Purpose Midazolam is a benzodiazepine derivative commonly used in intensive care units to control sedation. Its use requires dilution of a 5-mg/mL commercial solution to a target concentration of 1 mg/mL. A study was conducted to evaluate the stability of diluted ready-to-use 1-mg/mL midazolam solutions over 365 days when stored in cyclic olefin copolymer vials or polypropylene syringes. Methods A specific stability-indicating high-performance liquid chromatography coupled with UV detection method was developed for midazolam hydrochloride and validated for selectivity, linearity, sensitivity, precision, and accuracy. Three storage conditions were tested: –20°C ± 5°C, 5°C ± 3°C, and 25°C ± 2°C at 60% ± 5% relative humidity. Half of the vials were stored upside down to test for the absence of interaction between midazolam and the stopper. Particle contamination, sterility, and pH were assessed. Results The limit of stability was set at 90% of the initial concentration. After 1 year’s storage at –20°C and 5°C, concentrations remained superior to 90% under all storage conditions. At 25°C, stability was maintained up to day 90 in syringes (mean [SD], 92.71% [1.43%]) and to day 180 in upright and upside-down vials (92.12% [0.15%] and 91.57% [0.15%], respectively). No degradation products were apparent, no variations in pH values were detected, and containers retained their sterility and conformity with regard to any specific contamination during the study. Conclusion The evaluated 1-mg/mL midazolam solution was stable over a 1-year period when stored at a refrigerated (5°C) or frozen (–20°C) temperature in both vials and syringes; with storage at 25°C, the stability duration was lower. The preparation of ready-to-use midazolam solutions by a hospital pharmacy is compatible with clinical practice and could help to decrease risks inherent in dilution in care units.

An important amount of cytotoxic drug may accumulate in the workplace following the breakage of a vial containing an anticancer drug. Thanks to the monthly monitoring of the surface contamination in our compounding unit, a strong increase of cyclophosphamide contamination was highlighted in the storage area following the breakage of the vial, despite application of the emergency procedure. This study presents an analysis of chemical decontamination in the context of massive contamination. Samples were taken on the floor and on the caster of a storage shelf where the vial broke. The residual contamination was measured with a liquid chromatography–mass spectrometry/mass spectrometry method. An admixture of 10−2 M sodium dodecyl sulfate and 70% isopropanol (SDS/IPA 8:2) was selected as the decontamination solution. High amounts of cyclophosphamide were retrieved. The initial contamination on the floor was over 20 ng/cm2. Three decontaminations with SDS/IPA were carried out at Day 61, Day 68, and Day 71. The amount of cyclophosphamide decreased to 0.45 ng/cm2 at D134. However, high values were still measured on the caster despite successive decontaminations, with a maximal value of 19.78 ng/cm2 observed at Day 106. Continuous monitoring in our unit led us to highlight the inefficiency of our emergency procedure to eliminate high cyclophosphamide contamination. The procedure involving the SDS/IPA admixture was more efficient on the floor compared to the caster, which is a different surface type and porosity. This work highlights the importance of improving the procedures of incident management using contamination monitoring and repeated decontamination procedures adapted to different contaminants and surfaces.

Objectives Norepinephrine is a vasopressor frequently administered after dilution to treat hypotension and shocks in intensive care units. The stability of norepinephrine is known to be highly sensitive to storage conditions. Moreover, medication errors linked to the dilution step are frequent and may be deleterious for critically-ill patients, especially in intensive care units. This study aimed to evaluate the stability of ready-to-use diluted norepinephrine solutions prepared at two target concentrations (0.2 and 0.5 mg/mL), according to the summary of product characteristics, and stored for 365 days in two containers: AT-closed cyclic olefin copolymer vials, and polypropylene syringes. Methods A fast reversed-phase liquid chromatography method coupled with an ultra-violet detector was developed to assess the chemical stability of norepinephrine solutions. Validation was conducted according to the linearity of the calibration ranges, selectivity, sensitivity, accuracy and precision. Dosage, sub-visible particle contamination, pH monitoring and sterility assays were performed. Chemical stability was maintained if the measured concentration respected the lower limit of 90% of the initial concentration. Containers were stored at −20±5°C, +5±3°C and +25±2°C with 60±5% relative humidity in a dark closed enclosure. Results Stability was successfully maintained for every concentration and container tested when stored at −20±5°C and +5±3°C. In these storage conditions, particle contamination, pH monitoring and sterility assay respected the required criteria. Chemical degradation and colouring of solutions appeared before the end of the 1 year study period for most norepinephrine solutions stored at room temperature. Conclusions Ready-to-use solutions containing 0.2 and 0.5 mg/mL norepinephrine in polypropylene syringes or cyclic olefin copolymer vials must be stored at refrigerated or frozen temperatures to obtain acceptable 1 year shelf-stability. Exposure to higher temperatures significantly decreases shelf-stability. Our study protocol for compounding polypropylene syringes and cyclic olefin copolymer vials containing norepinephrine is adapted to implementation in centralised intravenous additive services.

International audience; Owing to their ease of use, glucose meters are frequently used in research and medicine. However, little is known of whether other non-glucose molecules, besides vitamin C, interfere with glucometry. Therefore, we sought to determine whether other antioxidants might behave like vitamin C in causing falsely elevated blood glucose levels, potentially exposing patients to glycemic mismanagement by being administered harmful doses of glucose-lowering drugs. To determine whether various antioxidants can be detected by seven commercial glucose meters, human blood samples were spiked with various antioxidants ex vivo and their effect on the glucose results were assessed by Parkes error grid analysis. Several of the glucose meters demonstrated a positive bias in the glucose measurement of blood samples spiked with vitamin C, N-acetylcysteine, and glutathione. With the most interference-sensitive glucose meter, non-blood solutions of 1 mmol/L N-acetylcysteine, glutathione, cysteine, vitamin C, dihydrolipoate, and dithiothreitol mimicked the results seen on that glucose meter for 0.7, 1.0, 1.2, 2.6, 3.7 and 5.5 mmol/L glucose solutions, respectively. Glucose meter users should be alerted that some of these devices might produce spurious glucose results not only in patients on vitamin C therapy but also in those being administered other antioxidants. As discussed herein, the clinical relevance of the data is immediate in view of the current use of antioxidant therapies for disorders such as the metabolic syndrome, diabetes, cardiovascular diseases, and coronavirus disease 2019.

Background The preparation of many drugs intended for parenteral administration is centralized in the pharmacy of healthcare institutions. However, no data are available describing the range of drugs with centralized preparation. The objective was to establish a profile of centralization practices for the preparation of non-hazardous drug doses in the pharmacy departments of Quebec healthcare institutions. Methods For this cross-sectional descriptive study, an e-mail survey was distributed in March 2017 to the directors of the pharmacy departments of Quebec healthcare institutions. Respondents were asked to estimate the percentage of parenteral drug doses that were prepared centrally in the pharmacy, the name of each drug prepared this way, the criteria used to select drugs for central preparation, and the barriers to centralizing preparation of drug doses. Only descriptive statistical analyses were performed. Results Of the 30 directors of pharmacy departments invited to participate, 27 (90 %) responded, representing a total of 40 Quebec healthcare facilities. Overall, 232 individual drugs were centrally prepared in one or more of these facilities, for an overall median of 22 drugs per facility (min: 1, max: 101). Conclusions This is the first survey in Quebec and indeed all of Canada to identify the many medications that are centrally prepared in hospital pharmacies. The survey showed that the selection of drugs for central preparation differed widely across facilities. It would be desirable for pharmacy departments in this province to collaborate on standardizing practices for central preparations.

Resume Objectifs Evaluer les connaissances et perceptions des pharmaciens et internes en pharmacie hospitaliere en France et au Quebec a propos des indicateurs de notoriete appliques en pharmacie. Identifier les determinants associes a ces connaissances. Methodes Il s’agit d’une etude descriptive transversale. Un questionnaire anonyme de 17 questions a ete elabore, publie sur le site de SurveyMonkey ( www.SurveyMonkey.com , SurveyMonkey, Portland, OR, EUA) et diffuse du 19 mars au 9 avril 2018. La proportion de repondants au Quebec et en France a ete comparee a l’aide d’un test de Chi2. Une valeur de p inferieure a 0,05 est consideree statistiquement significative. Resultats Un total de 899 pharmaciens et 147 internes a ete contacte par courriel. Le sondage a ete complete par 401 repondants (301-Quebec-taux de participation de 42 % ; 100-France-30 %). Globalement, 26 % (106/401) des repondants (67/301 au Quebec c. 39/100 France) ont declare avoir des connaissances ou de bonnes connaissances sur les indicateurs. Ces donnees sont corroborees par de nombreux autres resultats. Conclusion Une faible proportion de pharmaciens et internes en pharmacie hospitaliere connaissent les indicateurs de notoriete. Une bonne connaissance des indicateurs est notamment associee au fait d’exercer en France, dans un etablissement de sante universitaire ou de detenir des fonctions universitaires, d’avoir une experience professionnelle superieure a 10 ans, d’etre implique dans un projet de recherche, d’effectuer une veille electronique ou d’avoir un profil en ligne sur un moteur de recherche/base de donnees. Il apparait necessaire de mieux former les pharmaciens/internes en pharmacie sur les indicateurs de notoriete.

Although considerable efforts have been made over the last 40 years, occupational exposure to antineoplastic drugs is still a daily concern, since eradicating such contamination from workplaces seems unattainable. Considerable data are currently available on the risks associated with their use at work. Hospital facilities are often cleaned with marketed antimicrobials whose chemical decontamination efficacy certainly differs but remains unknown. To keep compounding facilities sterile, alcohol-based solutions are frequently used but with very limited efficiency. It would be particularly useful if a decontamination method could be added to the means already available so that all conventional antineoplastic drug contamination could be removed. Several degradation methods or desorption methods have previously been experimented, with varying success. They have never been compared or discussed in terms either of efficiency or usability. This review aims to analyse and discuss the results of each degradation or decontamination procedure and to compare them. This should facilitate selection of the method to be implemented in daily practice.

Neonatal hyperglycaemia is frequent and requires insulin therapy. To resolve the difficulties encountered by paediatricians in stabilising glycaemia, the preparation and administration of insulin aspart were assessed and optimised. After high-performance liquid chromatography (HPLC-UV) assessment of insulin aspart preparations made according to the old protocol, a new protocol was drawn up. Dosage reliability of solutions prepared by paediatric nurses was evaluated by HPLC-UV. This new protocol was also tested in a Y-infusion situation and the need to saturate infusion tubes assessed. Wide deviations in insulin aspart concentrations were found between theoretical concentrations and preparations made according to the old protocol. Glycated insulin aspart was found in the majority of these preparations. The new protocol significantly reduced the variability of data and relative deviations around the target value. It also eliminated the formation of glycated insulin even in the case of co-infusion of parenteral nutrition and confirmed the need to saturate infusion tubes.Conclusion: The revision of the insulin therapy protocol reduced the variability of insulin concentration in preparations and avoided the administration of glycated derivatives potentially toxic for neonates. What is Known: • Insulin preparation in NICUs is a risky task because it is a two-step preparation • Diluted in dextrose, insulin aspart is unstable, with formation of potentially toxic glycated derivatives What is New: • This work proposes a new insulin therapy protocol validated by HPLC-UV for NICU allowing suppression of the formation of glycated insulin, to significantly reduce deviations from theoretical concentrations and to limit adsorption phenomena • This protocol is validated in case of co-infusion of parenteral nutrition.

National audience; PurposeDrug protocols in intensive care units may require the concomitant administration of many drugs as patients’ venous accesses are often limited. A major challenge for clinicians is to limit the risk of simultaneously infusing incompatible drugs. Incompatibilities can lead to the formation of particles and inactivation of drugs, whose consequences on the body have already been indicated. Our objective was to assess current strategies to counter the risk of incompatible infusions and control the resulting clinical consequences.MethodsThis review was independently conducted by three investigators in respect of the PRISMA statement. Three online databases were consulted. Full-text articles, notes, or letters written in English or French, published or in press between the 1990s and the end of February 2020, with clinical study design, were eligible. Parameters of interest were mainly number and size of particles, and a number of observed/avoided incompatibilities.ResultsAll in all, 382 articles were screened, 17 meeting all the acceptance criteria. The strategies outlined and assessed were filtration, the use of multi-lumen devices, the purging of infusion lines, incompatibility tables and databases, and the use of standard operating procedures.ConclusionAlthough many strategies have been developed in recent years to address drug incompatibility risks, clinical data is still lacking. All studies with in vitro design were excluded although some current innovative strategies, like niosomes, should be considered and studied by means of clinical data in the future.

Background: Parenteral nutrition (PN) is a complex medium in which added insulin can become unstable. The aim of this study is, therefore, to evaluate the stability of insulin in PN and to identify influencing factors. Methods: A total of 20 IU/L of regular insulin was added to PN in either glass or Ethylene Vinyl Acetate (EVA) containers. A 24 h stability study was performed via an electrochemiluminescence immunoassay in different media: A ternary PN admixture, separate compartments of the PN bag and a binary admixture. This study was repeated in the absence of zinc, with the addition of serum albumin or tween and with pH adjustment (3.6 or 6.3). Insulin concentration at t time was expressed as a percentage of the initial insulin concentration. Analysis of covariance (ANCOVA) was applied to determine the factors that influence insulin stability. Results: In all PN admixtures, the insulin concentration ratio decreased, stabilising at a 60% and then plateauing after 6 h. At pH 3.6, the ratio was above 90%, while at pH 6.3 it decreased, except in the amino acid solution. ANCOVA (r2 = 0.68, p = 0.01) identified dextrose and pH as significant factors influencing insulin stability. Conclusion: A low pH level seems to stabilise insulin in PN admixtures. The influence of dextrose content suggests that insulin glycation may influence stability.

The characterization of drug-drug interactions (DDIs) may require the use of several different tools, such as the thesaurus issued by our national health agency (i.e., ANSM), the metabolic pathways table from the Geneva University Hospital (GUH), and DDI-Predictor (DDI-P). We sought to (i) compare the three tools’ respective abilities to detect DDIs in routine clinical practice and (ii) measure the pharmacist intervention rate (PIR) and physician acceptance rate (PAR) associated with the use of DDI-P. The three tools’ respective DDI detection rates (in %) were measured. The PIRs and PARs were compared by using the area under the curve ratio given by DDI-P (RAUC) and applying a chi-squared test. The DDI detection rates differed significantly: 40.0%, 76.5%, and 85.2% for ANSM, GUH and DDI-P, respectively (p &lt, 0.0001). The PIR differed significantly according to the DDI-P’s RAUC: 90.0%, 44.2% and 75.0% for RAUC ≤ 0.5, RAUC 0.5–2 and RAUC &gt, 2, respectively (p &lt, 0.001). The overall PAR was 85.1% and did not appear to depend on the RAUC category (p = 0.729). Our results showed that more pharmacist interventions were issued when details of the strength of the DDI were available. The three tools can be used in a complementary manner, with a view to refining medication adjustments.

At admission, unintentional medication discrepancies (UMDs) can occur and may led to severe adverse events. Some of them are preventable through medication reconciliation (MR). As MR is a time-consuming activity, a better identification of high-risk patients of UMDs is mandatory. The objective was to identify risk factors associated with UMDs at admission in an internal medicine department. This prospective observational study was conducted from April 2017 to June 2019. At admission, inpatients had MR to obtain a complete list of home medications. This list was compared to prescriptions made at admission. All discrepancies were classified as intentional or UMDs. Univariate and multivariate analyses to identify the risk factors associated with UMDs were performed. MR was performed on 1157 patients (70.1 ± 16.8 years old); 550 MR (47.5%) contained at least one UMD. More than half of the UMDs (n = 892, 65.6%) corresponded to drug omission. The univariate analysis showed that age (> 60 years old), “living at home”, medication preparation not performed by patient, medication-intake difficulties, number of sources consulted, MR duration, presence of a high-risk drug and the number of home medications were associated with UMDs. In the multivariate analysis, adjusted on the number of sources consulted, independent risk factors were “living at home” and the number of home medications. At admission to an internal medicine department, UMDs were frequent and associated with “living at home” and poly-medication. Our findings might help physicians to identify high-risk patients of UMDs since their admission.

The dataset displays the pharmacokinetics data obtained from the TRACES pilot study. The nine patients included were undergoing haemorrhagic caesarean section (blood loss > 800 mL) and receiving a single i.v dose of tranexamic acid (0.5, 1 or 2 g over 1 min). The dataset gathers the tranexamic acid blood and urinary concentrations. With these first elements, a pharmacokinetic compartment model was built as described in Gilliot et al. and the individual pharmacokinetic parameters were estimated. In parallel, the patients anthropometric, biological, and clinical characteristics were collected. The correlation between the patient data and the estimated individual pharmacokinetic parameters were tested. The correlation tests revealed that the dose, the height, the body weight, and the ideal bodyweight had and impact on the volume of distribution of tranexamic acid. According to these results, these latter covariates were explored using a multi-regression analysis in Gilliot et al.

Background Patients undergoing chemotherapeutic treatment are currently treated by a concomittent infusion of alizapride and ondansetron. To optimise the procedure and to ensure patients’ safety, the admixture could be prepared in advance by the Centralized Intravenous Additive Service (CIVAS) provided that the stability of the mixture has been proven beforhand to reduce nausea and vomiting. Aim of the study: to evaluate the long-term stability of an admixture of alizapride 0.926 mg/l and ondansetron 0.074 mg/ml in 0.9% sodium chloride polyolefin bags stored at 5 ± 3°C. Material and methods Five polyolefin bags containing 100 ml sodium chloride 0.9% added with 4 ml alizapride (100 mg) and 4 ml ondansetron (8 mg) were prepared in aseptic conditions and stored at 5 ± 3°C for 56 days. Periodically, physical stability tests were performed including: pH measurements, optical density measurements at 350, 410 and 550 nm to track turbidity appearance, visual and microscopical inspections to detect colour changes, precipitation, microaggregates or crystals. The concentrations of the solutions were measured by High Performance Liquid Chromatography coupled with an UV detector. Results There was no change in pH and optical densities during the study period. Visual and microscopical inspections didn’t show any change of colour neither precipitation, microaggregate or crystal. The alizapride and ondansetron concentrations remained stable over the study. Conclusion The admixture of alizapride and ondansetron in 0.9% sodium chloride solution polyolefin bags is physicochemically stable up to 56 days at 5 ± 3°C. These results support the possibility of preparing the solutions in advance by a CIVAS.

The use of long-term taurolidine locks (LTTL) seems to be effective in preventing catheter-related blood stream infections (CRBSI), especially in patients on home parenteral nutrition (HPN). This work targets the cost-effectiveness of LTTL in a cohort of adult HPN patients.A monocentric mirror-image design study was conducted in our referral centre among long-term HPN patients experiencing recurrent CRBSI. From 7th January 2011, LTTL were started after the third CRBSI episode within 12 months. CRBSI data was prospectively collected until 7th January 2013, in the same way as it had retrospectively been done before initiating LTTL. A cost-effective analysis was conducted to estimate the incremental costs and effects on CRBSI with LTTL. The efficacy of LTTL on CRBSI rate was assessed over 1000 days of catheter use.A total of 31,100 catheter days were analysed in 37 patients (median [interquartile range (IQR)]) aged 58 [42-68] years. The mean ± SD proven CRBSI rate was 3.18 ± 3.51 per 1000 catheter days before the introduction of LTTL and 0.39 ± 1.50 per 1000 catheter days after its introduction (p 0.0001). Considering both proven and probable CRBSI requiring hospital management, LTTL reduced by (mean [bootstrap CI 95%]) -2.63 [-3.26 to -2.06] infections per patient (from 2.89 [2.31 to 3.49] before to 0.26 [0.13 to 0.41] after) as well as incremental costs by -7 258 [-10 450 to -4 016] € (from 11 176 [8 004 to 14 968] € before to 3 918 [2 390 to 5 445] € after).Implementing LTTL to prevent recurrent CRBSI is cost-effective by dramatically decreasing their incidence.

Objectives: Home-Based Hospital (HBH) services concern patients of all ages suffering from conditions requiring technical care, close clinical monitoring, or hospital treatments that would normally...

In 2019, we celebrated the 40th anniversary of the famous article published by Falck et al , dealing with the mutagenicity of the urine of nurses who were in daily contact with conventional antineoplastic drugs.1 Since the publication of this article, highlighting the hazard of handling such drugs, extensive literature has flowed, in order to: All this knowledge has raised our level of vigilance on this issue and encouraged us to upgrade our practices constantly. Scientific data have been obtained through technological advances and in many different operating conditions, the latter making it difficult to define a fair protection level. Moreover, a lack of relevant clinical references and toxicological values has led to a continuous exploration for protective measures. Forty years after the first report of … Correspondence to Dr Nicolas Simon, GRITA Grp Rech Formes Injectables, LILLE Cedex 59006, France; nicolas.simon{at}univ-lille.fr

Insulin aspart (Novorapid) is a rapid-acting insulin analog that is maintained in hexameric form by phenolic preservatives (phenol and metacresol) and stabilized by insulin-zinc complex. According to the manufacturers, insulin can be independently diluted either in 5% dextrose solution (D5%) or 0.9% sodium chloride solution. In reality, in most clinical units, such as the neonatal intensive care unit (NICU), insulin aspart is more frequently diluted in D5% than in saline solution due to sodium restriction. However, injectable dextrose solutions contain glucose degradation products (1) that are capable of binding proteins—like insulin—through a glycation phenomenon. Therefore, dilution of Novorapid in D5% would be more likely to cause glycated insulin and may raise a worrisome problem in terms of insulin stability. The objective of this study was to investigate the stability of insulin aspart diluted in D5% at both adult and neonate therapeutic concentrations in order to ensure its appropriateness in the preparation of insulin aspart. To address this issue, insulin aspart diluted in D5% was assayed by a stability-indicating method using high-performance liquid chromatography (HPLC) coupled with an ultraviolet (UV) detector. The nature of the formed product was determined by HPLC coupled with a mass spectrometer. The effect of …

Background : In previous studies, the choice of doses of tranexamic acid was empirically defined as no pharmacokinetic study had been conducted in haemorrhagic caesarean section. Objective : The objective was to build a pharmacokinetic model in patients receiving a single 0.5, 1 or 2 g intravenous bolus. Method : A preliminary monocentric open study was performed in the Lille centre. Blood samples and one urinary sample were collected in the 6 hours following the injection. Nine patients were included. Tranexamic acid concentration was measured using liquid chromatography system coupled with tandem mass spectrometry. We used Monolix 2019R1 for population pharmacokinetic modelling. A structural model was constructed followed by the investigation of potential covariates. Results : Data were best described with a two-compartment model with a double first-order elimination from the central compartment. The model was improved when the variable ideal weight per dose was affected as a covariate for the apparent volume of distribution. Assuming a dose of 1 g and a height of 160 cm, the pharmacokinetic parameters were estimated at 10.26 L.h−1 for total clearance, 11.5 L for the volume of the central compartment, 15.8 L for the volume of the second compartment, a diffusional clearance of 30.36 L.h−1 , and a urinary excretion fraction of 25.8%. Conclusions : The population pharmacokinetic model of tranexamic acid in haemorrhagic caesarean section was successfully established in our tiny sample of patients. The results of this preliminary TRACES pharmacokinetic study suggested that elimination of tranexamic acid is partially non urinary in contrast with healthy patients.

Resume Introduction Le patient greffe renal est expose a un risque accru de iatrogenie medicamenteuse (IM). Le but de l’etude est de mesurer l’impact des interventions du pharmacien clinicien sur l’IM evitable. Materiel et methode Les cas d’IM ont ete recueillis sur 3 periodes : sans intervention, avec conciliation medicamenteuse (CM) d’entree, et avec une CM d’entree et entretien pharmaceutique de sortie. Les cas d’IM ont ete classes selon leur nature, leur gravite et leur evitabilite. Resultats Les patients inclus etaient majoritairement des hommes, d’environ 55 ans, en stade 3 d’IRC, greffes depuis moins de 3 mois ou depuis plus d’un an, avec des facteurs de risque cardiovasculaire, une nephropathie polykystique et en moyenne 9 medicaments/jour. Vingt pour cent des cas d’IM etaient evitables et majoritairement graves. A la periode 1, 27,7 % des patients presentaient au moins un cas d’IM, 21,3 % a la periode 2, et 17,4 % a la periode 3 (p = 0,03). Cent dix patients ont eu une CM a l’entree avec en moyenne 0,6 divergence non intentionnelle/patient. Elle portait surtout sur des oublis de medicament (81 %) et concernait des medicaments des voies digestives et metaboliques (24,5 %), du systeme cardiovasculaire (23 %) et du systeme nerveux (23 %). Soixante-huit entretiens pharmaceutiques de sortie ont ete realises, revelant des pratiques d’automedication. Conclusion Notre etude montre qu’une CM d’entree associee a un entretien pharmaceutique de sortie pourrait etre benefique pour reduire l’IM chez le patient greffe renal. Il serait licite d’envisager une etude specifique pour conforter ces resultats.

Resume Objectifs Il est reconnu que la manipulation de medicaments conditionnes en ampoules de verre peut generer des particules lors de l’ouverture de l’ampoule. L’utilisation d’aiguilles filtrantes lors du prelevement de medicaments conditionnes en ampoules de verre est recommandee par plusieurs auteurs pour diminuer la contamination particuliere. L’objectif principal est d’etablir un etat des lieux entourant l’utilisation des aiguilles filtrantes et la perception des pharmaciens au Quebec et en France. Methodes Il s’agit d’une etude descriptive transversale. Un questionnaire a ete envoye a tous les etablissements de sante au Quebec (n = 30) et une selection d’hopitaux en France (n = 100). Les repondants etaient invites a repondre a un questionnaire incluant la presence de politiques et procedures sur l’utilisation des aiguilles filtrantes ainsi que le recours a ces dispositifs et leurs modalites d’utilisation a la pharmacie et dans les services. Resultats Au total, 27 repondants quebecois (taux de reponse : 90 %) et 41 repondants francais (taux de reponse : 41 %) ont participe a notre enquete. Au Quebec, tous les questionnaires exploitables sauf un (42/43) rapportent un recours aux aiguilles filtrantes de cinq microns a la pharmacie contre 28 % des repondants dans les unites de soins. En France, cette pratique est quasiment ignoree. Conclusions Des actions doivent etre envisagees pour statuer sur l’utilisation des aiguilles filtrantes notamment des etudes pour confirmer les consequences de la presence de ces particules sur un modele animal, des discussions avec les autorites reglementaires afin de clarifier la situation, encourager les fabricants a utiliser le conditionnement en flacons.

Resume Introduction L’evolution de la place du patient dans sa prise en charge implique qu’il ait acces a une information claire, complete et comprehensible. Le niveau de connaissance des patients et la qualite du transfert de l’information fournie par le chirurgien ne sont pas connus avec precision aussi nous avons mene une etude prospective observationnelle afin d’evaluer : (1) le niveau de connaissance des patients au cours de leur prise en charge, (2) la qualite du transfert d’information, (3) le besoin en information, (4) les facteurs influencant le niveau de connaissance. Hypothese Le niveau de connaissance des patients evolue au cours de leur parcours medical. Patients et methodes Nous avons mene une etude monocentrique prospective, entre janvier 2014 et mars 2015 en consultation et durant l’hospitalisation de 63 patients ayant beneficie d’une arthroplastie de hanche (n = 36) ou de genou (n = 27). Un meme observateur assistait a toutes les consultations et consignait les donnees transmises par le chirurgien. Les patients completaient un auto-questionnaire a l’issue de la consultation (T1), a leur entree dans le service (T2) et a leur sortie apres l’arthroplastie (T3). Le niveau de connaissance et le besoin d’information des patients etaient apprecies a l’aide de scores semi-quantitatifs et le transfert d’information en analysant la concordance entre les informations donnees par le chirurgien et les reponses des patients. Resultats Le score moyen de connaissance global etait de 17,22 ± 6,33 sur 42 a T1 et progressait au cours de la prise en charge : score superieur a T3 (19,44 ± 6,89) vs T1. La connaissance des complications etait superieure a T1 vs T3 (2,67 ± 1,98 vs 2,19 ± 1,91 ; p Discussion L’originalite de notre etude etait d’apprecier l’evolution des connaissances des patients au cours de leur prise en charge revelant un niveau de connaissance relativement bas et tres variable selon le sujet et le moment de la prise en charge. Cette etude montre la necessite d’informer le patient tout au long de sa prise en charge sans negliger la sortie, moment ou la demande d’information etait la plus forte. Niveau de preuve Niveau IV, etude prospective observationnelle sans groupe temoin.

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 LBPs.

Resume Introduction Les tensions d’approvisionnements sont devenues le quotidien d’un pharmacien hospitalier avec une activite chronophage. Une procedure a ete mise en place afin que l’information soit captee, verifiee, analysee et transmise a tous les professionnels de sante. Materiels et methodes Une etude retrospective sur 95 semaines a permis d’analyser les ruptures qu’a connues notre hopital, notamment sur leur nombre, duree, classe anatomique, therapeutique, chimique (ATC), fiabilite de l’information, medicament princeps ou generique, a reserve hospitaliere (RH) ou non, et la substitution envisagee. Resultats Deux cents specialites se sont retrouvees en ruptures dont 46 en RH, 72 % etaient des princeps avec une duree mediane de 7 semaines. Sur les 226 ruptures recensees, 43 % sont annoncees avec une date de retour a la normale. La fiabilite de ces informations etait conforme a 55 %. La substitution represente 49 % des solutions et 23 % pour l’achat pour compte. Le temps consacre a la gestion des ruptures est estime a 12–20 h par semaine. Discussion-conclusion En creant un arbre decisionnel selon le niveau de complexite des ruptures, la cellule approvisionnement a pu homogeneiser leur traitement et ainsi apporter des reponses rapides et adaptees. La communication a tous les professionnels de sante d’un bulletin d’information hebdomadaire est l’etape finale du processus. Le groupement d’achat et le DP-Ruptures (dossier pharmaceutique) sont des elements importants quant au relais de l’information et a leur fiabilite.

Resume Objectifs Il existe plusieurs questionnaires publies pour evaluer l’adhesion medicamenteuse dans la polyarthrite rhumatoide, mais aucun consensus sur un questionnaire recommande. L’objectif de ce travail etait de comparer les 2 questionnaires les plus utilises : le Morisky-Green (MG) et le Compliance Questionnaire of Rheumatology (CQR). Methodes Il s’agit d’une etude prospective, menee de janvier a juillet 2013. Les patients inclus devaient venir en consultation et avoir un traitement de fond a domicile. Trois autoquestionnaires ont ete soumis aux patients : le MG, le CQR et un questionnaire interne visant a rechercher les facteurs susceptibles d’influencer l’adhesion. Resultats Cent sept patients ont ete inclus de facon consecutive (sex-ratio homme/femme : 0,27 ; âge moyen : 57 ans ; anciennete moyenne de la maladie : 17 ans ; DAS moyen : 2,52). Une bonne adhesion a ete recensee chez 35 % des patients avec le MG contre 62 % avec le CQR. Les taux different en fonction des voies d’administration, revelant un taux toujours inferieur avec le MG. Trente pour cent des patients ont des niveaux d’adhesion discordants selon le questionnaire utilise. Les facteurs impactant l’adhesion ressortent plus nombreux avec le CQR qu’avec le MG, car il explore davantage de facettes de l’adhesion, notamment la relation patient/medecin, inexistante dans le MG, et bien connue comme ayant une influence positive. Conclusion Notre etude de comparaison conduit a preferer le CQR pour une analyse fine des comportements d’adhesion, permettant une identification rapide et precoce des patients a risque.

The objective of this study was to evaluate five commercial ready-to-use transdermal vehicles (Phytobase®, Lipovan®, Pentravan®, Pentravan® Plus and Pluronic Lecithin Organogel (PLO)), for the compounding of three antiemetic drugs (ondansetron, dexamethasone and aprepitant) and their administration in combination to treat chemotherapy-induced nausea and vomiting (CINV) at the hospital. Drugs were individually formulated in these vehicles and in mixture in Pentravan® Plus using different penetration enhancers. Quality control of the forms has demonstrated that formulation process was mastered and convenient for the hospital (time required: 20min). Diffusion experiments through synthetic membranes and pig ear epidermis performed using Franz-type diffusion cells, have shown that the release and permeation process were greater for ondansetron than for dexamethasone and aprepitant, with a release step not limiting. As permeation of aprepitant was too low, it was discarded of the study. When ondansetron and dexamethasone were compounded in combination in Pentravan® Plus, the most efficient vehicle, a permeation decrease was observed. Finally, the use of tween 20 instead of EtOH as chemical enhancer has led to 2-fold factor increase in the flux of dexamethasone, resulting in fluxes convenient for transdermal administration of ondansetron to a child, but insufficient for an adult and for dexamethasone.

Purpose To assess the physico-chemical stability of Voriconazole Eye-Drops (VED), when stored frozen and refrigerated once thawed, in 3 containers: Amber glass with a Low-Density PolyEthylene (LDPE) eyedropper, and two types of LDPE bottles: one classical and one with an innovative insert that maintains sterility after opening (Novelia® from Nemera). Methods Three batches of 1% VED (10 mL) were aseptically compounded from marketed injectable voriconazole (Vfend®) diluted in sterile water for injection. VEDs were stored for three months at -20 °C in amber glass (n = 32), classical LDPE (n = 32) or innovative LDPE (n = 31) bottles. Stability-indicating (HPLC-UV-DAD) and chiral chromatography methods were developed. The stability study was conducted according to GERPAC-SFPC guidelines. At each study time, the following parameters were controlled: visual aspect, voriconazole concentration, pH and osmolality. In addition, non-visible particle count, sterility and absence of racemisation (impurity D – (2S,3R)-voriconazole) were assessed at the beginning and end of the study. Results are expressed as mean ± standard deviation. Statistical analyses were performed using non-parametric tests (α Results When stored frozen, concentration was between 95.2 ± 1.4% and 103.6 ± 1.3% of the initial concentration (C0) with no difference between the three containers (p = 0.564; non-significant). Fifteen days after thawing, concentration was between 97.1 ± 1.6% and 98.6 ± 0.8% of C0 with no difference between containers (p = 0.278 and 0.368 for VED thawed at room temperature and at 2–8 °C, respectively). pH remained stable between each time. Osmolality was slightly higher in glass (533.17 ± 8.93 mOsm/Kg) than in plastic containers (522.17±3.31mOsm/Kg, classical LDPE; 517.5 ± 12.42 mOsm/Kg, innovative LDPE) (p = 0.022). Sterility was preserved. Degradation product areas increased slightly but remained below the limit of quantification. Impurity D was never detected. Conclusion We have demonstrated that the ability of the innovative container Novelia® to maintain VED physicochemical and microbiological stability does not differ from that of amber glass and classical LDPE containers. Real life studies are required to find out if there is a potential difference between Novelia® and other containers in terms of sterility preservation.

Objectives Over the past 40 years, numerous actions have been undertaken to decrease the contamination of hospital facilities by intravenous conventional antineoplastic drugs (ICADs) such as centralizing compounding in pharmacies, using personal protective equipment, specific compounding, or infusion devices. As recently proposed in the monograph, an additional specific decontamination step must be envisaged. A recent literature review analysed and discussed the different solutions tested in terms of decontamination efficacy. This article aims to discuss the performance of these solutions in the framework of aseptic compounding. Methods The same dataset used in the previous literature review was reanalysed according to other parameters so as to select decontamination solutions: overall decontamination efficiency (EffQ), tested contaminants, and the risks of use in daily practice. Results Using an EffQ threshold of 90% resulted in discarding 26 out of the 59 solutions. Solutions were tested differently: 8 on 1 contaminant, 11 on 2 contaminants, and 14 solutions on between 3 and 11 contaminants. Three risks were identified to help make choices in routine practice: the mutagenicity of degradation products, the safety of operators and facilities, and respect for the aseptic environment. Conclusions From the results, performance is discussed according to specific situations: a one-time incident or the basic chemical contamination due to daily practice. Accordingly, the decontamination solution selected then required a risk analysis and an evaluation before implementing it in the daily practice of a compounding unit.

Resume La depletion dopaminergique de la voie nigro-striee est une des principales caracteristiques de la maladie de Parkinson (MP), qui pourrait etre amelioree par une restauration continue et focale des taux striataux de dopamine. L’administration orale intermittente de son precurseur la L-dopa n’arrive que partiellement a restaurer la transmission dopaminergique, a cause de ses caracteristiques pharmacologiques (demi-vie courte), qui engendre des complications motrices. L’administration continue intra-cerebro-ventriculaire de dopamine n’a jusqu’a present pas pu etre utilisee du fait de l’oxydation de la dopamine et d’une tachyphylaxie. Nous souhaitons developper une technique de stimulation dopaminergique continue par delivrance intra-cerebro-ventriculaire de dopamine anaerobie (A-dopamine, Brevet #WO2015173258 A1) proche du striatum dans 2 modeles de MP valides : souris intoxiquee au MPTP et rat intoxique de facon unilaterale a la 6-hydroxydopamine (6-OHDA). Sept jours d’administration continue d’A-dopamine par voie intra-cerebro-ventriculaire ont permis de restaurer les fonctions motrices de souris intoxiquees au MPTP, et ont induit une neuroprotection dose-dependante des neurones dopaminergiques nigro-stries, comparee a l’administration intra-cerebro-ventriculaire de dopamine aerobie (O-dopamine), ou a l’administration peripherique de L-dopa. Dans un modele de rat intoxique a la 6-OHDA, l’administration continue selon un rythme circadien d’A-dopamine a permis une restauration des fonctions motrices pendant 30 jours sans tachyphylaxie. Le traitement par A-dopamine n’a pas induit de dyskinesies chez l’animal, en comparaison avec l’administration peripherique de L-Dopa. L’administration continue d’A-dopamine par voie intra-cerebro-ventriculaire est efficace sur les symptomes moteurs de 2 modeles animaux valides de MP, avec un large index therapeutique et sans induire de dyskinesies ni de tachyphylaxie. Cette strategie pourrait constituer un nouveau traitement de la MP au stade des fluctuations motrices.

International audience; Chimeric Antigen Receptor T-cells (CART) belongs to a new class of medicine, Advanced Therapy Medicinal Product, such as define by the European Regulation 1394/2007, and more exactly to the category of gene therapy medicinal product. Their status of medicine, as well as genetically modified organisms, imposes a particular circuit at hospital while maintaining a way over the Hospital Pharmacy. The manipulation of genetically modified cells is not usual in pharmacy. It requires, besides the acquisition of new skills, a not insignificant reorganization of the teams and the rooms of the pharmacy as well as an adapted training of the staff. A good communication is essential between the various actors of the circuit. The hospital pharmacist plays a key role in the implementation of a circuit adapted to this new type of medicine. This article aims to identify the roles of the hospital pharmacist and more generally of the pharmacy in the management of CART. We shall detail the specificities of this type of medicine in every stage of the circuit and the adaptations necessary to realize to guarantee the quality and the safety of the treatment by CART. Beyond the implementation of the circuit in the hospital, the pharmacist has an important role to be played in the follow-up of the patients after administration in view of the complexity of the side effects and a certain role in the training of the teams to this new medicine.; Les lymphocytes T exprimant un Récepteur Chimérique à l’Antigène (CART) appartiennent à une nouvelle classe de médicaments, les médicaments de thérapies innovantes, tels que définis par le règlement Européen 1394/2007, et plus précisément à la catégorie des médicaments de thérapie génique. Leur statut de médicament ainsi que d’organismes génétiquement modifiés impose un circuit particulier à l’hôpital tout en maintenant un passage par la Pharmacie à Usage Intérieur du Centre Hospitalier. La manipulation de cellules génétiquement modifiées n’est pas habituelle en pharmacie. Elle nécessite, en plus de l’acquisition de nouvelles compétences, une réorganisation non négligeable des équipes et des locaux de la pharmacie ainsi qu’une formation adaptée du personnel. Une bonne communication est indispensable entre les différents intervenants du circuit. Le pharmacien hospitalier joue un rôle primordial dans la mise en place d’un circuit adapté à ce nouveau type de médicament. Le présent article a pour but d’identifier les rôles du pharmacien hospitalier et plus généralement de la pharmacie à usage intérieur dans la prise en charge des CART. Nous détaillerons les spécificités de ce type de médicament à chaque étape du circuit et les adaptations nécessaires à réaliser afin de garantir la qualité et la sécurité du traitement par CART. Au-delà de la mise en place du circuit au sein de l’hôpital, le pharmacien a un rôle important à jouer dans le suivi des patients après administration au vu de la complexité des effets secondaires et un rôle certain dans la formation des équipes à ce nouveau médicament.

Background: In neonatal intensive care units (NICUs), the simultaneous administration of drugs requires complex infusion methods. Such practices can increase the risk of drug incompatibilities resulting in the formation of a particulate load with possible clinical consequences. Methods: This paper evaluates strategies to reduce the particulate load of a protocol commonly used in NICUs with a potential medical incompatibility (vancomycin/cefepime combination). The protocol was reproduced in the laboratory and the infusion line directly connected to a dynamic particle counter to evaluate the particulate matter administered during infusion. A spectrophotometry UV assay of cefepime evaluated the impact of filters on the concentration of cefepime administered. Results: A significant difference was observed between the two infusion line configurations used in the NICU, with higher particulate load for cefepime infused via the emergency route. There was no change in particulate load in the absence of vancomycin. A filter on the emergency route significantly reduced this load without decreasing the cefepime concentration infused. Preparation of cefepime seemed to be a critical issue in the protocol as the solution initially contained a high level of particles. Conclusion: This study demonstrated the impact of a reconstitution method, drug dilution and choice of infusion line configuration on particulate load.

BACKGROUND: The repeated blackening of in-line filters has been observed during the infusion of parenteral nutrition 2-in-1 mixtures (binary parenteral nutrition [BPN]) delivered in a neonatal intensive care unit. This study aimed to examine the elemental content of precipitates isolated from infused BPN bags and determine the main physicochemical interactions occurring in these bags. MATERIALS AND METHODS: The infusion of BPN mixtures was simulated in vitro following hospital practices. Filter membranes were examined by scanning electron microscopy and energy dispersion spectroscopy (EDS). Amino acid (AA) profiles were obtained from BPN mixtures to determine the concentrations of each AA. RESULTS: Analyzed filter membranes revealed conglomerates of particles on filter surfaces. An EDS analysis generated spectra from isolated particles, identifying copper and sulfur as the major chemical elements. AA mean concentrations were relatively close to the expected value for each AA, except cysteine. Cysteine concentrations were very significantly lower than the expected values. CONCLUSION: A specific interaction was identified between 1 AA (cysteine) and a trace element (copper) in our BPN mixtures.

Resume Objectifs Verifier la conformite aux referentiels en vigueur et apprecier la facilite et le temps de mise melange des poches de nutrition parenterale compartimentees industrielles disponibles sur le marche francais en 2014. Materiels et methodes Trois tests in vitro ont ete effectues : mesure du volume extractible, tests de penetration et d’adhesion de la tubulure. Des manipulateurs evaluaient sur une echelle de Likert en 5 points les differentes etapes de remise en melange des poches. Les temps de lecture de la notice et de preparation de la poche etaient mesures. Resultats D’apres les tests in vitro, toutes les poches testees etaient conformes aux referentiels. Le test de manipulation a montre des disparites entre les gammes. Les deux gammes de poches bicompartimentees ont obtenu une appreciation generale similaire mais des temps de manipulation differents. Deux gammes de poches tricompartimentees (Olimel® et Kabiven®) pour administration par voie centrale presentaient une appreciation generale et un temps de manipulation differents. La gamme de poches tricompartimentees pour administration peripherique PeriOlimel® a recu de meilleures appreciations et un temps de manipulation inferieur aux deux autres elles-memes presentant des resultats similaires. Conclusion Les poches testees etaient conformes aux referentiels en termes de volume et de relation percuteur/cheminee. Le test de manipulation a objective des disparites de temps de manipulation et de facilite de remise en melange des poches.

Background Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation. Objectives We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD. Methods Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa. Results Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction. Conclusion Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.

Introduction Drug incompatibilities are a constant problem in hospital care units. The multiplication of drugs injected simultaneously during patient therapy increases the risk of incompatibilities and can have a significant clinical impact. The purpose of this research was to characterize and analyze various parameters inducing variability in particle counting using a dynamic particle counter. Materials and methods Observations were performed on two-ports manifolds with two incompatible drugs, thus creating a quantifiable particulate charge. We analyzed the number of different-sized particles measured during the experiment as well as their cumulative distribution. The parameters studied on particle count were: position of the infusion device, environmental vibrations and total flow rate. Results Significantly higher particle counts were observed when the infusion device was in a vertical position or disturbed by vibrations. Total flow rate significantly reduced the number of particles. Conclusion This study enabled us to identify several variation factors through dynamic particle counting. These factors should be taken into account to reduce variability in results.

International audience; Ibrutinib is an orally administered first-in-class irreversible Bruton's tyrosine kinase (BTK) covalent inhibitor for the treatment of patients with B-cell malignancies. Several isolated clinical observations reported its efficacy in central nervous system dissemination. Herein, we described the development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) procedure for the quantification of ibrutinib and its active metabolite PCI-45227 in cerebrospinal fluid (CSF). This is the first complete validated method for quantification of ibrutinib and PCI-45227 in CSF. The compounds were eluted on a Waters BEH C18 column (50.0 × 2.1 mm; 1.7 μm) using a gradient elution with a mobile phase composed of ammonium formate buffer 5 mM pH 3.2 and acetonitrile +0.1% formic acid with a flow rate of 400 μL·min-1. Two deuterated internal standards were used to obtain the most accurate quantification. The CSF samples were prepared by a simple and rapid dilution. The method was validated by testing the selectivity, response function, intra-day and inter-day precisions, trueness, limits of detection (LOD) and lower limits of quantification (LLOQ). The validation results proved that the methods were suitable to quantify ibrutinib and PCI-45227 in real biological CSF samples from 0.50 (ibrutinib) or 1.00 (PCI-45227) to 30.00 ng·mL-1. Furthermore, the developed method was adapted to allow the quantification of both compounds in plasma and the results were compared to those reported in literature. The plasmatic samples were treated by protein precipitation and the method was validated to quantify ibrutinib and PCI-45227 in real biological plasmatic samples from 5.00 to 491 ng·mL-1. Lastly, for both matrices, accuracy profiles were plotted from the trueness and precision results using a 20% α-risk (β = 80%) and the tolerance intervals were comprised within the acceptance limits fixed at ±25% for the LLOQ and ±15% for the other concentrations. Finally, these methods were successfully applied to quantify ibrutinib and PCI-45227 in real human CSF and plasma samples.

Objective The aim of this review is to analyse the clinical consequences of intravenous drug incompatibilities in critically ill patients, especially the incidence of organ dysfunctions and mortality. Methods A review of literature was conducted according to the PRISMA statement in June 2017, using Medline, ISI Web of Science and Clinicaltrials.gov. Data extraction Eligible studies were case reports and randomised controlled trials (RCTs) that assessed the effects of drug incompatibilities in critically ill patients on morbidity or mortality as primary or secondary outcomes, or adverse events. Two investigators independently reviewed the eligibility of the study from abstracts or manuscript data. Data synthesis Twelve articles met the selection criteria. The six articles reporting RCTs concern only four RCTs. RCTs were single-centre studies comparing infusion with or without filter. One of them included adult patients. The others included paediatric and neonatal intensive care unit patients. Primary endpoints were SIRS, organ failure, overall complication rate, bacteraemia, sepsis, phlebitis and length of stay. The results are mixed with one RCT reporting a reduction in SIRS, organ failure and overall complication rate, two studies in disagreement over the occurrence of sepsis and one study reporting no impact on length of hospital stay. The six articles on case reports show different drug incompatibility situations. They report pulmonary toxicity. Conclusion Little data is available on this topic. Infused particles may induce organ failure, in particular pulmonary toxicity and SIRS. Further studies are needed to establish a link between the level of exposure to drug incompatibilities and clinical implication.

International audience; BACKGROUND: Many patients who receive intravenous (i.v.) recombinant tissue-plasminogen activator (rt-PA) for acute cerebral ischemia were under angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) at stroke onset. ACE-Is and ARBs have neuroprotective properties in animal models.OBJECTIVE: To evaluate whether the 3-month outcome of patients treated with i.v. rt-PA for cerebral ischemia was influenced by on-going therapy with ACE-Is or ARBs.METHODS: This study was observational, conducted in two prospective registries of stroke patients treated with i.v. rt-PA. We evaluated outcomes with the modified Rankin scale and symptomatic intracranial hemorrhages (s-ICH) according to the ECASS2 criteria. We compared outcomes between patients with and without ACE-Is/ARBs according to the modified Rankin scale (mRS) at month 3, using logistic regression analyses adjusted on propensity scores, and propensity-matched analyses.RESULTS: Of 1803 patients, 455 (25.2%) were under ACE-Is (259), ARBs (188) or both (8). At 3 months, patients under ACE-Is or ARBs were more likely to have an mRS 0-1, but did not differ for mRS 0-2, s-ICH and death. After adjustment on propensity scores, the association between ACE-Is/ARBs and mRS 0-1 disappeared. The propensity-matched analysis, performed in 397 pairs of patients, found no difference in outcomes between patients with and without ACE-Is or ARBs.CONCLUSIONS: In patients treated by intravenous thrombolytic therapy for ischemic stroke, on-going treatment with ACE-Is or ARBs does not influence on outcomes after adjustment on baseline characteristics and propensity scores.

International audience; BACKGROUND: Patients are playing an increasingly large role in their own management and must therefore receive clear, complete, and comprehensible information. In the field of hip and knee arthroplasty, little is known about the level of patient knowledge and effectiveness of surgeon-to-patient information transfer. We therefore designed a prospective observational study with the objective of assessing four factors: patient knowledge during management, quality of information transfer, informational needs, and factors associated with the level of knowledge. HYPOTHESIS: The level of patient knowledge changes during the management process. PATIENTS AND METHODS: A prospective single-centre study was conducted between January 2014 and March 2015 during the outpatient visits and inpatient stays of 63 patients who underwent arthroplasty of the hip (n=36) or knee (n=27). A single observer attended all patient visits and recorded the information provided by the surgeon. Each patient completed a self-questionnaire after the outpatient visit (T1), at admission (T2), and at discharge after surgery (T3). Semi-quantitative scores were used to assess knowledge and informational needs. The effectiveness of information transfer was evaluated by comparing the information provided by the surgeon to the replies made by the patients. RESULTS: The mean overall knowledge score (on a 0-42 scale) increased from 17.22±6.33 at T1 to 19.44±6.89 at T3 (P=0.0028). In contrast, knowledge about complications was better at T1 than at T3 (2.67±1.98 vs. 2.19±1.91; P

Injecting intracameral cefuroxime has been found beneficial in reducing the risk of postoperative endophthalmitis but its use has been limited through a lack of approved marketing and of ready-to-use single-units as well as the problem of aseptic compounding.Our aim was to assess a new automated primary packaging system which should ensure a higher level of sterility, thanks to its closed, sterile, ready-to-use polymer vial called "Crystal® vial". The chemical stability of a 10 mg/mL cefuroxime solution was compared in 1 mL Crystal® vials and 1 mL Luer-lock polypropylene syringes (actual reference) to eliminate any potential and specific interactions with its cyclic olefin copolymer (COC) body and elastomer stopper.Cefuroxime solution was introduced into vials and syringes and stored at -20 °C, +5 °C and +25°C/60% Relative Humidity. Cefuroxime concentration and the relative amount of the main degradation product (descarbamoyl-cefuroxime) were both determined by an HPLC/UV method indicating stability. Solutions were considered steady if the concentration remained at over 90% of the initial value. In the adapted storage conditions, the evolution of osmolality, pH and sterility was assessed.Stability profiles were identical between vials and syringes in all storage and temperature conditions. The solution was stable (cefuroxime concentration, pH and osmolality) and still sterile for 365 days at -20°C. The concentration fell below 90% after 21 days at +5 °C and after 16 h at +25°C/60%s relative humidity.The COC and thermoplastic elastomer of the vials had no impact on the degradation process confirming its possible use for a ready-to-use cefuroxime solution single-unit dose.

International audience; Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo-SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context.A retrospective study was carried out on children hospitalized between 2007 and 2015 for allo-SCT with TBI-based myeloablative conditioning associated with cyclophosphamide (CY, 60 mg/kg/day × 2 days) or EP. The primary endpoint of the study was the occurrence of acute kidney injury (AKI). Additional endpoints were time to recovery for children with AKI, survival, and treatment-related mortality.Thirty-five patients were analyzed (CY: 22 vs. EP: 13). AKI occurred more frequently in the EP group than in the CY one (69% vs. 27%, adjusted odds ratio 6.0, 95% confidence interval [CI] [1.145; 31.445], P = 0.03). The median time to recovery was estimated at 3 days, 95% CI (2; 17), with CY and 11 days 95% CI (5; 18) with EP (adjusted hazard ratio of recovery for EP vs. CY 0.262, 95% CI [0.071; 0.969], P = 0.04). No significant difference was highlighted between the two treatments for survival or for treatment-related mortality.This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect.

PurposeThe aims of this study were to propose a simple methodology to assess the rinsing volume of syringe extension sets and to compare several marketed devices.MethodsA UV-spectrophotometry assay using quinine hydrochloride as drug substitute was developed. Quinine concentration ranged from 20 to 200 µg/ml. The assay was validated with the accuracy profile method and tested on five different assemblies (device+extension sets) with different dead-space volumes (1.28–2.80 ml) and at two different quinine concentrations (0.3 and 8.0 mg/ml). Rinsing was performed stepwise with water for injection until reaching an undetectable quinine concentration. After fitting the data with a Weibull model, assemblies were compared with an ANOVA performed on ranks (GraphPad, La Jolla, USA).ResultsThe within-day and between-day precision ranges were 0.39–0.81 and 0.48–0.84%, respectively. The lower limit of quantification was 4.26 µg/ml. The volume required to completely rinse the infusion line was different according to the initial drug concentration and to the device assessed: from 6 to 10 ml for a low quinine concentration and from 7 to 17 ml for a high quinine concentration.ConclusionThis study shows that a simple, cheap and easy-to-use methodology may be used to assess the rinsing volume of syringe extension sets. The rinsing volume is different according to the tested device.

The administration of several intravenous products on the same catheter is a very common situation in neonatology, where the stakes are high and the dangers sometimes unknown to clinicians. A large number of factors are involved in this administration, directly related to the installation of the infusion line. Moreover, the therapeutics used are often limited, and excluding classic “Marketing Authorization”. Some of these products may prove to be incompatible and thus lose their effectiveness, or even generate particles that are likely to be administered to the patient. We must be aware of these risks in order to optimize the prescription and administration of these intravenous products, especially as we treat fragile and immature patients. The aim of this work is to review the literature on the subject for the prescribers of neonatology units.

International audience; BACKGROUND: Despite the use of closed system drug transfer devices (CSTD), residual contamination from antineoplastic drugs is still detected inside isolators. The aim of this study was to compare the decontamination level obtained using a CSTD + standard cleaning procedure with a CSTD + standard cleaning procedure + specific decontamination procedure. METHODS AND FINDINGS: A comparative and prospective study was carried out in a newly opened compounding unit. Compounding was performed with a CSTD (BD-Phaseal, Becton-Dickinson). In the Control isolator (C), the cleaning process was completed daily with a standard biocide solution (AnioxysprayTM, Anios, France). In the Intervention isolator (I), weekly decontamination with a homemade admixture of sodium dodecyl sulfate 10-2 M/70% isopropanol (80/20, v/v) was added. Monitoring was performed via a validated LC-MS/MS method. Eight drugs (cyclophosphamide, cytarabine, dacarbazine, fluorouracile, gemcitabine, ifosfamide, irinotecan and methotrexate) were monitored daily over 14 consecutive weeks on three sites inside the isolators: gloves, workbench and window. Results are presented as the odds-ratio (OR) of contamination and as overall decontamination efficiency (EffQ, %). The proportion of EffQ ≥ 90% was assessed by a Fisher's exact test (p

The study of calcineurin inhibitor (CNI) blood level variability to evaluate adherence in transplantation has improved over the years. The aim of our study was to assess factors associated with this variability using the coefficient of variation (CV). A cross-sectional sample of kidney recipients grafted for more than 1 year was recruited. We recorded clinical data, data from a clinical pharmacist interview and from six questionnaires measuring adherence, satisfaction, behaviours, beliefs, perception of the illness and social vulnerability. A total of 408 recipients were enrolled (61.2% male, mean age 54) and divided into two groups: low variability CV