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Summary— The use of clozapine, an unique antipsychotic drug, raises the real problem of drug-induced polymorphonuclear neutrophil cytoxicity. Clozapine prescription has been restricted due to a 1–2% incidence of drug-induced agranulocytosis. The exact mechanism of this adverse effect is not yet known. The myeloperoxidase-hydrogen peroxide system could play a key role in the initiation of agranulocytosis. Therefore, we have investigated the clozapine effects on hydrogen peroxide and hypochlorous acid, evaluated the peroxidase-mediated metabolism of clozapine by mass spectrometry analysis because myeloperoxidase uses hydrogen peroxide and chloride producing hypochlorous acid in its chlorination cycle, and thus could oxidise clozapine in its peroxidation cycle. First, evidence for inhibition of hypochlorous acid production and scavenging of hydrogen peroxide by clozapine were demonstrated in vitro, in different cell-free and cellular systems. Results are consistent with an inhibition of the myeloperoxidase chlorination cycle when clozapine is oxidised in the peroxidation cycle. Secondly, ion-spray mass spectrometry analysis allowed us to confirm clozapine oxidation by the myeloperoxidase system. Actually, clozapine N-oxide with a m/z at 343 was formed. It could be the final step of the metabolisation of clozapine via two successive univalent oxidations mediated by peroxidase. We suggest that generation of a free cation radical, CLZo+, was the initial step. CLZo+ is a very reactive species and may play an important role in the onset of agranulocytosis either by direct toxicity or via an immunological mechanism. However, this assumption does not exclude the possible role of other metabolic ways involving, in particular, N-desmethylclozapine.

Background Adverse drug reactions on skin affect approximately 2% of patients. Skin and drug challenge tests were performed in the dermatology department to assess these reactions and pharmacy-compounded drugs were tested through patches, pricks and intradermal (IDR) tests. Purpose To assess the incidence of positive allergic reactions in tested patients and to define the culprit drugs and their potential allergic role in these reactions. Materials and Methods The study was conducted between 2007 and 2010 on patients from our hospital. We collected information on the characteristics of the adverse drug reaction on skin, the drugs tested, the tests performed and their results. Results In the period studied, 220 patients referred by other practitioners (from the hospital or from ambulatory practitioners) for serious cutaneous reactions were tested and 3225 preparations were performed by the pharmacy. 92 patients had an immediate reaction to the drug and 128 had a non-immediate reaction. 64 (29%) patients developed a positive response: 48 (75%) through skin tests (patch, prick and IDR) and 16 (25%) through a Drug Challenge Test (DCT). The drugs most often involved in the positive tests were anti-infectious drugs (46%), paracetamol (16%) and iodinated contrast media (10%). Conclusions The percentage of positive tests in this cohort agrees with the data found in the literature (3–76%). The large difference is due to the variability in patient recruitment. However, it is difficult to compare these data because the preparation and interpretation of the tests are not standardised. Allergology tests still improve the care of patients as with negative skin tests and DPTs many patients were able to continue with their treatment. Manufacturing tests by the pharmacy standardise preparation conditions within the hospital and reduce cross contamination and microbial contamination. 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 Sildenafil, a phosphodiesterase V inhibitor, is used in paediatrics to treat pulmonary arterial hypertension. However no paediatric formulation was available until a recent launch announced a powder for oral suspension. Purpose To determine the stability of sildenafil capsules for paediatric dilutions. A HPLC assay has been developed for this purpose. Materials and Methods The sildenafil dosing method, developed from a previously published method1, is a reverse phase HPLC with UV detection at 240 nm. The column is a C18, the mobile phase composition is acetonitrile/ammonium acetate 0.2 M (50/50) with a flow set at 1 mL/min. Linearity and precision cheques (repeatability and intermediate precision) have been performed to validate the method. Capsules of 1 mg, 5 mg and 10 mg (of sildenafil base) were prepared with sildenafil citrate and corn starch. Samples wer kept at ambient temperature in transparent blister packs sealed with aluminium foil. Uniformity of mass was verified at D0. The visual appearance of the capsules, sildenafil concentrations and chromatographic profiles were checked at D0, D7, D14, D21, D35, D42, D56 and D70. Results The method was linear up to 150 mg/mL. Repeatability and intermediate precision were demonstrated (SD Conclusions The method has been validated and used in a stability study which demonstrated the stability of sildenafil capsules up to ten weeks under the storage conditions studied. These results led us to apply a shelf life of eight weeks to sildenafil capsules. Reference Daragmeh N. et al , Determination of sildenafil citrate and related substances in the commercial products and tablet dosage form using HPLC. J Pharm Biomed Anal . 2001;25:483–492 No conflict of interest.

Background When pharmacy staff is not available, nurses used to prepare diluted busulfan solution from commercial vials just before administration because of its low stability. Doing this without protection may cause occupational exposure to this cytotoxic drug. Purpose To devise a new protocol and perform a preliminary evaluation. Materials and Methods Literature and technical studies were performed to choose the best devices. Nurses and physicians performed a clinical evaluation using a 5-item satisfaction form. Results Medical devices containing polycarbonate must be avoided because of the interaction with N,N-dimethylacetamide used as an excipient. The new protocol consists of an individual kit with the commercial solution packed in a syringe, an infusion bag with the exact volume of diluent and a closed system transfer device (CSTD). Nurses just have to dilute the solution into the bag under a laminar air-flow hood using the CSTD. Although 2-part syringe methods were found in the literature, 3-part syringes with limited contact between the elastomeric tip and busulfan solution (reference 62.8426, Codan) were chosen because leaks were observed with the 2-part syringes during the technical study. PhaSeal devices: Injector to close the syringes and a Connector-Luer for infusion bags were selected as CSTDs. All these devices are polycarbonate free. 7 new kits were prepared for a period of 8 days without contact. The results of the evaluation show that nurses and physicians (n = 14) were overall dissatisfied by the previous protocol (neither good nor bad: 35.7%, bad: 21.4% and very bad: 35.7%) while the majority preferred the new one (very satisfied: 28.6%, satisfied: 42.9%, neither good nor bad 7.14%, no response: 21.4%). Overall nurses and physicians answered that new modalities limit the risk of dose errors (93%) and occupational exposure (86%). Conclusions Implementing this procedure has improved handling practise with good satisfaction. No conflict of interest.

Background New ENLock standard connectors (between the administration tube/enteral feeding catheter-EFC) and ENPlus (between nutrition bag/administration tube) are designed to administer enteral nutrition (EN) safely and avoid unsafe connexions. These connectors will coexist for a while with devices not equipped with them. Compatibility data will be necessary to ensure they are used safely. Purpose In vitro tests to evaluate the compatibility between devices with and without these connectors. Materials and Methods The evaluation focused on 12 EFC references from 6 suppliers, 4 nutrition bags from 4 suppliers and one administration tube with an ENLock connexion at both extremities (Nutricia). Following the NF-EN-1615 and 1618 norms, five tests were performed in triplicate on each reference. (1) A leak test required eosin solution and simulated pressure of 50 kPa for 2 min in the connectors. Leaks were revealed by spots on philtre paper. (2) An EFC connector deformability test was performed by measuring the inner and outer diameter with callipers after one connexion/disconnection a day for 30 days. (3–4) Two penetration tests, ENLock/EFC and ENPlus/bag, were performed using a dynamometer, exerting a linear force and measuring the maximum force for connexion. (5) An EFC connexion resistance test was performed using a dynamometer exerting a linear traction and measuring the maximum force for disconnection. Results No leaks were detected. The changes in the EFC connector internal and external diameters tested were respectively up to 30% and 6%. The tube connexion force to the EFC ranged from 37.8 N to 216.2 N and to the bag from 14.6 N to 20.1 N. Two suppliers’ bags could not be connected to the ENPlus device. The tube disconnection force to the EFC ranged from 3.2 N to 44.8 N (limit value: 15 N). Conclusions Important differences exist between suppliers. Some feeding lines don’t meet the specific EN norms for these devices particularly as regards the maximum disconnection force so their use with incompatible devices can be risky. No conflict of interest.

Clozapine is an antipsychotic drug with few extra-pyramidal motor side-effects, used to treat schizophrenia which is resistant to classical neuroleptic therapy. This report shows that norclozapine but not clozapine-N-oxide has the same D2 receptor affinity as clozapine. Assay results suggest a bimodal distribution which may be explained by CYP1A2 polymorphism. Extensive metabolizers could produce other active metabolites, probably other hydroxy-clozapine derivatives.

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.

Abstract 2726 Background. There is a need for improving conditioning regimens in poor risk Non Hodgkin Lymphoma (NHL) patients (pts) eligible for autologous stem cell transplantation (ASCT). Incorporating radioimmunotherapy in the conditioning is an option. Bexxar-BEAM does not appear to be superior to BEAM in relapsed Diffuse Large B –cell lymphoma (DLBCL). The benefic risk ratio of 90-yttrium ibritumomab tiuxetan (Zevalin) BEAM remains to be established. Aims and methods. We analyzed retrospectively the efficacy and the toxicity of Zevalin combined with BEAM chemotherapy (Z-BEAM) compared with BEAM alone followed by ASCT. From January 2000 to November 2004 (BEAM group) and from June 2005 to December 2011 (Z-BEAM group), 55 and 68 pts respectively were treated in 6 French centers (male n=78, female n=45). Zevalin was administered on day-14 prior to ASCT with standard dose of 0.4 mci/kg (n=32) or 0.3 mci/kg (n=36) chosen according to bone marrow reserve. The efficacy and toxicity were compared between the two groups. Results. The study included 123 pts (median age: 53 years old; range 21–69) with different histological subtypes (58 DLBCL, 19 Mantle cell lymphomas, 37 follicular lymphoma, 3 marginal zone lymphoma, 4 MALT lymphoma and 2 B-lymphocytic lymphoma). Fifty-four pts were treated in first line (20 in the Z-BEAM group and 34 in the BEAM group) and 69 pts in second line (Z-BEAM, n=48; BEAM, n=21). The median time to platelets engraftment (>20000/mm3) was 9 days and 10 days in the Z-BEAM and BEAM group respectively (p=0.334), and the median time to neutrophil engraftment (>500/mm3) was 11 days and 12 days respectively (P=0.117). Grade 3/4 infectious events were more frequent in the Z-BEAM group (80.9%) than in the BEAM group (56.4%), p=0.0001. Grade 3/4 mucositis were observed in 42.6% in the Z-BEAM group Vs 12.7% in the BEAM group (p60 y.o), histological subtype, first line treatment Vs second line, or IPI (0–1 Vs 2–3). In a subset analysis of the Z-BEAM group, female gender was associated with worse outcome; 3 years-OS was 69% (95%CI, 48–85%) in female and 93% (95%CI, 79–98%) in male (p=0.042); 3 years-PFS was 54% (95%CI, 34–73%) in female and 81% (95%CI, 65–91%) in male (p=0.032). Those results may be linked to a higher TRM, 23.1% Vs 0% (P=0.002), more respiratory complications 23.1% Vs 4.8 % ( P=0.047) and more admissions to intensive care unit 46,1% Vs 2 % (P< 0.0001) in female than in male group respectively. Conclusions. Z-BEAM is possibly as effective as BEAM alone as a conditioning regimen for ASCT with an increased toxicity. Surprisingly, our series report for the first time an increased toxicity and TRM in female. A longer follow up is needed to asses this results. Disclosures: No relevant conflicts of interest to declare.

PURPOSE/OBJECTIVES To assess the PCHIMX-1 (Doran International), a new sterile medical device intended by its manufacturer to improve the quality and safety of cytotoxic drug infusions, as well as its influence on manipulation times required for pharmacy technicians and nurses and its effect on infusion line outflow parameters. DESIGN PCHIMX-1 assemblies were compared to standard infusion sets. SETTING Pharmacy and oncology units of a French general hospital. METHODS Reference assemblies (an infusion bag connected to an infusion set) were compared to PCHIMX-1 assemblies (PCHIMX-1 connected to two bags and to an infusion set). Two assessments were performed: (a) comparison of the times of manipulation during both preparation and administration of 5-fluorouracil infusion bags (n = 40) and (b) effect of PCHIMX-1 on infusion quality. MAIN RESEARCH VARIABLES Manipulation times in the pharmacy (TP) and in the ward (TW) were measured, as well as flow rate and infusion efficiency. FINDINGS The results showed that TW was significantly increased, whereas TP was significantly decreased; total time was unchanged. Results also showed that PCHIMX-1 significantly changed infusion efficiency; flow rate was not affected. CONCLUSIONS PCHIMX-1 obliges pharmacy technicians and nurses to change their handling procedures. The device does not have any influence on infusion flow rate but considerably improves infusion quality by ensuring that the full quantity of medication prescribed is administered. IMPLICATIONS FOR NURSING PCHIMX-1 guarantees that the complete prescribed dose of chemotherapy is administered without any change in infusion quality and adheres to the latest recommendations concerning occupational exposure protection.

Medication errors can occur at any stage of the healthcare product circuit in the hospital and can lead to adverse events with potentially fatal consequences for patients Some actions can prevent the occurrence of these errors and optimize the use of drugs. This thesis brings together studies that led to secure the use of high-risk medications and the therapeutic strategies in high-risk patients.The safety of drug preparation was investigated in critical care services using two ways. First, the DrugLog® (Pharmacolog, Sweden), an automated quality control system for injectable drugs prepared in care units, was evaluated in a neonatal intensive care unit. It allows the rapid identification and quantification of drugs in solution. The calibration of the DrugLog® was performed in the laboratory. Robustness and clinical feasibility studies were conducted in the unit. Among the medications, 11 were calibrated out of 15 evaluated; during the clinical study, 9 medications were studied and 68,90% of the preparations met the quantitative acceptance limits. Technical limitations, detailed in the following work, led to the postponement of its routine use; however, several qualities make this system an innovative and interesting tool for qualifying care teams in simulation situations. The second way to secure the drug preparation step was to assess the possibility of centralizing the preparations within the hospital pharmacy. With this aim in view, we evaluated the long-term stability of ready-to-use injectable solutions. Four stability studies were performed on insulin aspartate diluted at 1 IU/mL, dobutamine at 10 mg/mL, noradrenaline at 0.2 and 0.5 mg/mL, and midazolam at 1 mg/mL. The physicochemical and microbiological stability was evaluated over 1 year in two types of packaging: polypropylene (PP) syringes, to prepare ready-to-use solutions, and cyclic olefin copolymer (COC) vials, whose properties are interesting for the storage of injectable drugs and for which the filling is automated. These studies showed that the use of COC vials allowed for better long-term stability than that conferred by PP syringes. Using a dedicated automated filling machine for these vials allows for a significant manufacturing yield and ensures preparation in a controlled aseptic environment. This work encourages the development of hospital mass production.The feasibility of optimizing the therapeutic regimen of a high-risk drug used in a critical situation was investigated through a particular case, tranexamic acid (TXA) for curative purposes in per partum hemorrhage. A single-center open-label pilot study and a double-blind randomized controlled multicenter study were performed as part of the TRACES (TRAnexamic acid in hemorrhagic CESarean section) trial. TXA was given as a single bolus in selected patients and blood and urine TXA concentrations were determined. Nonlinear parametric mixed-effect modeling was performed. The pharmacokinetic model of TXA was validated and covariates influencing the variability of the pharmacokinetic parameters were identified: the creatinine clearance and the total boy weight before pregnancy. This work led to the hypothesis of a double elimination of TXA by the central compartment which can be explained by leakage into the uterine hemorrhagic blood. The rapid decrease in plasmatic concentrations encourages to repeat dose of 1g TXA during the first hour if bleeding doesn't stop.; Les erreurs médicamenteuses peuvent survenir à chaque étape du circuit des produits de santé à l'hôpital, et engendrer des évènements indésirables dont les conséquences peuvent être fatales pour les patients. Des actions peuvent prévenir la survenue de ces erreur et optimiser l'usage des médicaments. Cette thèse rassemble des travaux dont la finalité était de sécuriser la thérapeutique en minimisant les situations à risque liées soit au médicament soit au patient lui-même.La sécurisation de la thérapeutique a été investiguée au niveau de la préparation des médicaments en services de soins critiques au travers de deux moyens de sécurisation. Le premier moyen est un automate de contrôle-qualité des médicaments injectables préparés en services de soins, le DrugLog® (Pharmacolog, Suède). La calibration de l'automate a été conduite en laboratoire et une étude de robustesse et de faisabilité clinique a été conduite dans un service de réanimation néonatale. Parmi les médicaments testés, 11/15 ont pu été calibrés. Au cours de l'étude clinique, 9 médicaments ont été étudiés et 68,90% des préparations étaient conformes aux limites d'acceptabilité quantitatives fixées. Des limites, détaillées dans le travail qui suit, ont conduit à sursoir son utilisation en routine ; cependant, plusieurs qualités font de cet automate un outil innovant et intéressant pour qualifier les équipes de soins en situations de simulation. Le second moyen pour sécuriser la préparation a été d'étudier la possibilité de centraliser les préparations au sein de la pharmacie à usage intérieur. La stabilité de ces solutions injectables prêtes à l'emploi a été étudiée ; quatre études de stabilité ont été conduites sur l'insuline asparte diluée à 1 UI/mL, la dobutamine à 10 mg/mL, la noradrénaline à 0,2 et 0,5 mg/mL, le midazolam à 1 mg/mL. La stabilité physico chimique et microbiologique a été évaluée sur 1 an dans deux conditionnements : des seringues en polypropylène (PP), dans le but de préparer des solutions prêtes à l'emploi, et des flacons en copolymère oléofine cyclique (COC), dont les propriétés sont intéressantes pour le stockage des médicaments injectables et pour lesquels le remplissage est automatisé. Ces études montraient que l'utilisation de flacons en COC permettait une stabilité sur le long terme, meilleure que celle conférée par les seringues en PP. L'utilisation d'un automate dédié pour le remplissage de ces flacons permet un rendement important de fabrication et assure une préparation dans un environnement aseptique contrôlé. Ces travaux encouragent le développement de la fabrication hospitalière en série.La sécurisation de la thérapeutique a également été étudiée pour connaître la possibilité d'optimiser le schéma thérapeutique d'un médicament à risque utilisé en situation critique. Cette sécurisation a été investiguée au travers d'un cas particulier, l'acide tranexamique (TXA) à visée curative dans l'hémorragie du per partum. Une étude pilote monocentrique ouverte et une étude multicentrique double aveugle randomisée et contrôlée ont été menées dans le cadre de l'essai TRACES (TRAnexamic acid in hemorrhagic CESarean section). Le TXA a été administré en bolus unique chez les patientes sélectionnées puis des dosages sanguins et urinaires ont été effectués. Une modélisation non linéaire à effet mixte paramétrique a été réalisée. Le modèle pharmacocinétique du TXA a pu être validé et des covariables influençant la variabilité des paramètres pharmacocinétiques ont été déterminées : la clairance à la créatinine et le poids réel avant grossesse. Ce travail a conduit à l'hypothèse d'une double élimination du TXA par le compartiment central qui peut être expliquée par une fuite dans le sang hémorragique utérin. La rapide diminution des concentrations plasmatiques encourage la répétition d'une dose de 1g en cas de poursuite du saignement au cours de la 1ère heure.

For the simultaneous administration of injectable drugs, the infusion line includes a main line with one or several derivative lines. The main line, which is directly connected to the catheter, is dedicated to hydration infusion or to maintain a permeable vein. Other medications will be added on the derivative lines.Intensive care unit patients frequently require lots of medications in the same time. Most of emergency drugs are substances with narrow therapeutic range. When concentrated solutions are employed, tiny mass flow rate disturbances can provoke clinical damages, such as haemodynamic instability. So, several parameters have been studied on simultaneous infusions: mass flow rate and syringes changeovers.The purpose of this work was to develop and optimize complex infusion line systems. An innovative infusion medical device has been evaluated in clinical trials and in vitro studies. The final objective was to design an optimized infusion line, which could be applied to ICUs.The whole medical devices used in ICUs was first listed. Then, noradrenaline has been used as the reference drug to study central venous catheter proximal line. A 0.5 mg/mL noradrenaline solution Y-infused with a saline (5mL/h) has been shown by clinical and in vitro data to be the best solution. Nevertheless, this conclusion was valid only with the use of a very low dead-space volume Y-extension set. Thanks to this device, syringe changeovers optimization is possible.The central venous catheter distal line has been studied in a second time through an open randomized controlled prospective clinical trial. Primary endpoint of the study was the impact of two different insulin infusion lines (Edelvaiss-Multiline 8, Doran International versus standard line) on glycaemic variability. Doran’s innovative device consists of an exten¬sion set with eight accesses connected to nine separated lumens in a single tube. This allows to dedicate an isolated way for insulin. With its use, a significant decrease of hypoglycaemia occurring in 1000h of infusion period was clinically demonstrated. Finally, all the data were synthetized to optimize an ICU multi-infusion line. The one, which has been designed for surgery and intensive care units, was tested on patients.To conclude, items responsible for mass flow rate disturbances have been identified: medical devices material, addition of appropriated valves, internal volume line minimization and use of automated infusion systems (as pumps). The ideal infusion line has to take into account all these parameters.; Au cours de l’administration simultanée de plusieurs médicaments injectables, sont utilisées une ligne principale de perfusion et une ou plusieurs ligne(s) en dérivation. La ligne principale est directement reliée au cathéter et permet l’administration des solutions utilisées pour l’apport hydro-électrolytique ou de maintenir une voie d’abord veineuse perméable. Les autres thérapeutiques vont être perfusées en dérivation de cette ligne principale. La prise en charge des patients relevant de soins intensifs et de réanimation nécessite une polymédication. Les traitements d’urgence impliquent majoritairement des médicaments à marge thérapeutique étroite. Lors de l’administration de médicaments en solutions concentrées, de faibles perturbations du débit d’administration peuvent engendrer de fortes perturbations cliniques et notamment, pour les médicaments vasoactifs, créer une instabilité hémodynamique. C’est pourquoi il est important d’étudier la problématique de la perfusion simultanée, de déterminer l’impact sur le débit massique des lignes de perfusion et la technique optimale des changements de seringues pour prévenir les variations intempestives du débit de perfusion. Ce mémoire présente un travail de développement et d’évaluation d’une démarche d’optimisation d’un système de perfusion complexe. Il consiste à étudier au travers d’évaluations in vitro et d’études cliniques la conception d’une ligne de perfusion en évaluant notamment un dispositif médical innovant afin de proposer, in fine, une solution applicable dans un service de soins intensifs. La première partie consiste à présenter l’ensemble des dispositifs médicaux de perfusion utilisés dans un département d’anesthésie-réanimation. La seconde partie s’intéresse à l’administration d’un médicament couramment perfusé sur la voie proximale: la noradrénaline. Les études in vitro, corroborées par des données cliniques, ont permis de montrer la supériorité de l’administration de noradrénaline à 0,5 mg/mL perfusée en Y avec une solution saline isotonique à débit fixe de 5 mL/h. Cette multiperfusion fait intervenir l’utilisation d’un prolongateur trois voies à faible volume résiduel, permettant d’optimiser les conditions de relais de seringues, connues comme étant à l’origine d’instabilités hémodynamiques chez les patients traités par catécholamines. Un programme hospitalier de recherche clinique interrégional est déposé dans le but d’établir des recommandations de perfusion des catécholamines.La troisième partie aborde l’administration des médicaments sur voie distale en sélectionnant l’insuline comme marqueur-médicament. Les résultats de cette étude clinique prospective randomisée contrôlée ont montré que l’utilisation d’un dispositif médical innovant, le dispositif Edelvaiss-Multiline 8 (Doran International) caractérisé par un tube multilumières à faible volume résiduel qui permet de dédier une voie à une seule thérapeutique, permettait de réduire significativement le temps passé en hypoglycémie pour 1000 heures de perfusion d’insuline au cours de perfusion continue d’insuline en soins intensifs périopératoires.Enfin, dans une dernière partie, les critères clés d’un montage optimisé de multiperfusion sont élaborés et sont mis en application dans un département d’anesthésie-réanimation dans le but d’optimiser et uniformiser la ligne de perfusion des patients. Ce travail a permis de valider les caractéristiques clés de la ligne de perfusion définis dans de précédentes études non cliniques : la nature du matériau des dispositifs médicaux utilisés, l’utilisation de valves appropriées, la minimisation des volumes internes des tubulures de perfusion, l’utilisation de systèmes de perfusion automatisés permettant de contrôler au mieux le débit d’administration des médicaments.