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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.

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.

Vancomycin hydrochloride is an antibiotic belonging to the glycopeptide family and acts by inhibiting the synthesis of the peptidoglycan wall. This antibiotic is active against Gram-positive aerobic and anaerobic bacteria1 2 and is commonly used in hospitals to treat serious infections.3 4 Vancomycin has slow bactericidal time-dependent activity and can be administered by continuous or intermittent intravenous infusion. In France, administering vancomycin by continuous infusion over 24 hours is recommended.5 6 The Summary of Product Characteristics (SmPC) recommends reconstituting a 1 g vial with 20 mL of water for injection (WFI), then diluting it in 100 mL of saline solution. The amount of vancomycin to treat an adult infection is superior to 1 g and so the volume administered can be higher than 100 mL. This volume must be limited in children or in patients on water restriction, such as those suffering from hyponatraemia and cardiovascular diseases or are in intensive care.7 Some studies on vancomycin stability have already been performed. Solutions at 5 and 10 mg/mL were stable for 58 days at +4°C in 100 mL polyvinyl chloride (PVC) infusion bags with no specification with regard to protection from light.8 Vancomycin was stable at 5 mg/mL in PVC bags for 48 hours at +22°C without protection from light and for 7 days at +4°C with protection from light.9 Raverdy et al 10 examined the stability of vancomycin diluted in 5% dextrose at high concentration (83 mg/mL) and was stable for 72 hours at +37°C. However, none of these studies reflects real infusion conditions as vancomycin is usually administered at 30 mg/kg/day.11 12 In practice, clinical services infuse vancomycin into electric syringe pumps using 50 mL (for adults) or 20 mL (for children) syringes. No stability study has yet been performed for such concentrations, in 50 or 20 mL syringes, at room temperature, nor has the reconstitution procedure13 been …

Background Drug incompatibilities, such as precipitates, may contribute to the clinical deterioration of paediatric patients (sepsis), especially when infusing vancomycin and piperacillin (VAN/PIP). Drug concentration and infusion sets affect the overall particulate contamination of paediatric infusion protocols. Using multilumen infusion sets could prevent these incompatibilities. Purpose To define and assess a new way to infuse VAN/PIP during leukaemia treatment in paediatric patients, without any visible precipitate. Material and methods Two infusion sets were studied, which differed in design and drug dead-space volume (V): 1) a standard single lumen set with 2 four-port manifolds with extension lines (ref RPB4320, Cair LGL, France; V ∼ 12 mL) and 2) a 5-lumen infusion set (ML-5) (Edelvaiss-Multiline, Doran International, France; V ∼ 1 mL). Different vancomycin concentrations (VANc) were tested to infuse VAN/PIP simultaneously without any precipitate (optimised multidrug protocol). A dynamic particle count test was performed (N = 5) over 24 h to evaluate the overall particulate contamination of our standard (VANc = 42 mg/mL) and optimised (VANc = 4 mg/mL) protocols, using both standard and ML-5. We performed a t-test. Results No visible particles were detected on reducing VANc (4 mg/mL) instead of the standard dose (42 mg/mL). For the optimised multidrug protocol, using the ML-5 reduced the overall particulate contamination by 68%, compared to the standard infusion set (716,349 ± 89,322 vs. 251,980 ± 49,429; p = 0.002). The number of large particle sizes was significantly reduced when using the ML-5 ∼ 60% (p = 0.027) and 90% (p = 0.009) for particle sizes ≥10 and 25 µm, respectively. Conclusion This study demonstrated the large number of particles administered during parenteral multidrug infusion. This can be minimised through the choice of the drug concentration and/or the type of infusion set. Although this kind of contamination is invisible, further studies are required to evaluate its adverse clinical impact. References and/or acknowledgements No conflict of interest.

Background For several years, many infusion systems have been marketed for the administration of antineoplastic drugs (AD). Purpose To compare the ability of these devices to deliver the expected volume of antineoplastic drug in solution. Material and methods Seven infusion devices were assessed (see table 1) by simulated infusions with a radiotracer ( 99m TcO 4 − ) as drug substitute. The same activity (370 MBq) was diluted in 250 mL 0.9% NaCl bags. The evolution of the drug concentration at the egress of the infusion system was recorded continuously with a sodium iodine crystal detector. The area-under-curve of drug concentration according to time of both administration (AUC adm ) and rinsing (AUC rin ) steps were calculated using the linear trapezoidal rule after correcting for radioactivity decay. The rinsing volumes (V rin ), volumes required to get no more radioactivity, were measured in a graduated test tube. The values were compared using a Kruskall-Wallis test (p Results Despite the differences in dead-space volume, AUC adm were not significantly different (see table 1). The rinsing volumes were significantly different between the tested devices, ranging between 46.8 ± 5.7 mL and 92.2 ± 8.9 mL. Conclusion The rinsing conditions required to administer the same dose are really different between devices. The impact of good handling practice of these devices has to be assessed on the pharmacokinetic parameters. Reference Kontny NE, Boos J, Wurthwein G, et al . Minimization of the preanalytical error in pharmacokinetic analyses and therapeutic drug monitoring: focus on IV drug administration. Ther Drug Monit 2012;34:460–6 No conflict of interest.

Background Polyvinyl chloride (PVC) infusion tubes are too widely used in our hospital. Even in intensive care units (ICU), PVC is commonly used although polyethylene (PE) is specifically recommended to limit container-content interactions. For example, insulin is used to achieve tight glucose control in ICU patients. Its adsorption on PVC is well known, but rarely considered in the choice of infusion device when nurses compose their infusion assemblies. Purpose This model of interaction was used as a tool, to educate nurses in the issue of choosing the right equipment and to illustrate the clinical impact of an unsuitable medical device in the administration of a drug. For this, we showed healthcare workers how the insulin concentration changed by comparing the infusion between two devices available in our hospital. Materials and methods ICU nurses prepared 40 mL insulin syringes (1 IU/mL) according to the ICU preparation protocol. The concentration was determined by UV-spectrophotometry at 4 points in the syringes to assess their homogeneity and dose accuracy. Then, PVC and PE syringe extension lines (SEL, L:150 cm, ID:1 mm) used in our hospital were evaluated. Firstly, each SEL was filled with 1 IU/mL insulin solution and closed with Luer-lock plugs. Measurements were achieved after 15 and 60 min of contact. Secondly, the insulin levels were measured at the egress of both SEL every 5 min over a 24 h time period at a flow rate of 2 mL/h. Results were expressed as a percentage of the theoretical value. All experiments were repeated 5 times. Statistical comparisons were performed with a Mann-Whitney test (p = 0.05). Results Eleven nurses prepared 48 insulin syringes with an average proportion of 100.6 ± 3.9% of the theoretical value in all points of the syringes. After 15 min of contact, the insulin levels dropped significantly in PVC SEL compared to PE SEL (46.2 ± 2.4% vs 98.4 ± 1.7%, p = 0.01, respectively). The level continued to drop at 60 min (30.1 ± 4.0% vs 96.0 ± 0.6%, p = 0.01, respectively). During infusion tests, the insulin concentration after a 24 h infusion was only 64.6 ± 2.0% using PVC SEL whereas it was maintained at 101.7 ± 0.8% with PE SEL (p = 0.01). Conclusions A paradoxical situation exists in the insulin infusion context. Although this interaction with PVC is well documented and confirmed by this study, ICUs still use it. This study allowed us to demonstrate that even if the preparation process is performed correctly and the concentration is homogeneous, PE SEL are really more suitable for insulin administration and must replace PVC SEL. The use of such a tool may help pharmacists in the ongoing education of nurses. Other drugs are being considered to enhance the study and to support our infusion training group. An evaluation of the impact of our training course on daily practice is planned. No conflict of interest.

Background Drug incompatibility is a problem when managing patients in intensive care units. Patients receive many drugs simultaneously but through limited venous accesses. The recent marketing of new multi-lumen infusion access device may open the way to preventing incompatibility. Purpose To evaluate the impact of multi-lumen infusion access devices connected to single-lumen central venous catheters on the occurrence of known drug incompatibilities through a controlled in vitro study. Materials and Methods Two infusion devices were studied: 1) a standard set with six-gang-manifolds and its extension line and 2) a multi-lumen infusion access device with nine lumens (Edelvaiss-Multiline, Doran International, France). Six drugs were selected: three basic drugs (furosemide, pantoprazole and amoxicillin/clavulanic acid) and three acid drugs (amiodarone, dobutamine and midazolam). Two, four or six drugs and an infusion vehicle (saline, Ringer’s or 5% glucose) were infused simultaneously. The infusion rate of the vehicle was initially set at 100 mL/h and decreased stepwise by 10 mL/h until precipitate formation occurred. Physical incompatibility was assessed by visual inspection and sub-visible particle count test as defined by the European Pharmacopeia according to the European Pharmacopeia. The lowest value of the vehicle infusion rate that satisfied the two tests was reported for each infusion set and for each drug combination. Results The use of multiline access devices contributed to preventing drug incompatibilities when simultaneously infusing two and four drugs. Indeed, infusion vehicle flow rate gains oscillated between 10 and 40 mL per hour, in more than 55% and 25% of cases, respectively for two and four drugs. When infusing six drugs simultaneously, no differences were identified. Conclusions Our main hypothesis is that fluid dynamics differ depending on the infusion device resulting in differences in the contact time between drugs. Under specified infusion conditions, the nine-lumen device prevents physical drug incompatibilities. No conflict of interest.

Background The drug manufacturing conditions in hospitals have become increasingly demanding and the use of a Controlled Atmosphere Area (CAA) in the preparation unit is now mandatory. Purpose To make an inventory of fixtures used for European aseptic manufacturing units; to compare the cost of CAA provided by isolators to CAA provided by Biological Safety Cabinets (BSCs) in order to determine the most economical scheme in hospital and to develop a model to estimate CAA design and operating costs. Materials and methods 43 hospitals were interviewed (21 French and 22 from four other European countries) by email, telephone and visits over 7 months. A form with 390 items was programmed in VBA (Visual Basic for Applications) to assist with replying. Hospitals were compared according to their location and their type of workstation: BSCII, BSCIII or UDF (Unidirectional Flow) (Group B) and Isolator (Group I). Statistics were generated using the Mann-Whitney test and Monte Carlo modelling. Results 21 hospitals responded (11 French and 10 foreign). All European preparation units were organised similarly except that in France, isolator use seems more common than in the rest of Europe (73% vs 30% respectively; p=0.0502). Each cost item was compared; only 2 were significantly different: the staff training cost/agent and the cost/m 2 of microbiological control were significantly higher in Group B than in Group I with 3,404 € and 1,731 €/agent respectively (p=0.0028) and 50.46 € and 2.68 €/m 2 respectively (p=0.0017). A synthesis costs program was drafted to calculate an estimate preparation cost. The preparation cost in Group B seemed higher than in Group I (41 € and 30 € respectively in study conditions) although this cost difference disappeared when the annual number of items prepared increased. Conclusions This pilot study provides data that could be used to optimise resources and save money. A further international study would enable significant results to be obtained.