Background: Sevoflurane has anti-inflammatory proprieties and short lasting effects making it of interest for procedural sedation in critically ill patients. We evaluated the pharmacokinetics of sevoflurane and metabolites in severely ill burn patients and controls. The secondary objective was to assess potential kidney injury. Methods: Prospective interventional study in a burn and a surgical intensive care unit; 24 mechanically ventilated critically ill patients (12 burns, 12 controls) were included. The sevoflurane was administered with an expired fraction target of 2% during short-term procedural sedation. Plasma concentrations of sevoflurane, hexafluoroisopropanolol (HFIP) and free fluoride ions were recorded at different times. Kinetic Pro (Wgroupe, France) was used for pharmacokinetic analysis. Kidney injury was assessed with neutrophil gelatinase-associated lipocalin (NGAL). Results: The mean total burn surface area was 36 +/- 11%. The average plasma concentration of sevoflurane was 70.4 + 37.5 mg.L-1 in burns and 57.2 +/- 28.1 mg.L-1 in controls at the end of the procedure (P = 0.58). The volume of distribution was higher (46.8 +/- 7.2 vs 22.2 +/- 2.50 L, P < 0.001), and the drug half-life longer in burns (1.19 +/- 0.28 h vs 0.65 +/- 0.04 h, P < 0.0001). Free metabolite HFIP was higher in burns. Plasma fluoride was not different between burns and controls. NGAL did not rise after procedures. Conclusion: We observed an increased volume of distribution, slower elimination rate, and altered metabolism of sevoflurane in burn patients compared to controls. Repeated use for procedural sedation in burn patients needs further evaluation. No renal toxicity was detected. (C) 2018 Societe francaise d'anesthesie et de reanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Water-soluble vitamins are often included simultaneously in pharmaceutical formulations as food complements or in parenteral nutrition mixtures. Given their sensitivity to heat, light or pH variations, it is important to study their stability using validated stability indicating methods. We thus aimed to validate a liquid chromatography (LC) stability-indicating method for the simultaneous quantification of 5 water-soluble vitamins.

Background: Medical devices (MDs) in polyvinyl chloride (PVC) are not a well-known source of exposure to plasticizers, in particular during pregnancy. Because of its toxicity, the di-(2-ethylhexyl) phthalate (DEHP) has been replaced by other plasticizers such as di (isononyl)-cyclohexane-1,2-dicarboxilic acid (DINCH), tri-octyltrimellitate (TOTM) and di-(isononyl) phthalate (DiNP). Our study aimed to quantify the plasticizers (DEHP and alternative plasticizers) contained in PVC medical devices used for hospitalised pregnant women and to describe which these MDs had been used (type, number, duration of exposure).Methods: The plasticizers contained in the MDs used for daily care in the Obstetrics Department of a French University Hospital were extracted from PVC (after contact with a chloroform solution), identified and quantified by gas-chromatography-mass-spectrometry analysis. A total of 168 pregnant women hospitalised in the Obstetrics Department with at least one catheter were included in the observational study. The median number of MDs containing plasticizers used and the daily duration of exposure to the MDs were compared in three groups of pregnant women: "Pathology group" (women hospitalised for an obstetric disorder who did not give birth during this hospitalisation; n = 52), " Pathology and delivery group" (hospitalised for an obstetric disorder and who gave birth during this stay; n = 23) and " Delivery group" (admitted for planned or spontaneous delivery without obstetric disorder; n = 93).Results: DiNP, TOTM and DINCH were the predominant plasticizers contained in the MDs at an amount of 29 to 36 g per 100 g of PVC. Women in the " Pathology group" (preterm labour or other pathology) were exposed to a median number of two MDs containing TOTM and one MD containing DiNP, fewer than those in the " Pathology and delivery group" (p < 0.05). Women in the " Pathology group" had a median exposure of 3.4 h/day to MDs containing DiNP and 8.2 h/day to MDs containing TOTM, longer than those in the " Delivery group" (p < 0.01).Conclusions: Our study shows that the medical management of pregnant women in a hospital setting entails exposure to MDs containing alternative plasticizers (DiNP, TOTM and DINCH).

BACKGROUND The continuous bilateral infusion of a local anaesthetic solution around the sternotomy wound (bilateral sternal) is an innovative technique for reducing pain after sternotomy. OBJECTIVE To assess the effects of the technique on the need for intensive care in cardiac patients at increased risk of respiratory complications. DESIGN Randomised, observer-blind controlled trial. SETTING Single centre, French University Hospital. PATIENTS In total, 120 adults scheduled for open-heart surgery, with one of the following conditions: age more than 75 years, BMI >30 kg m−2, chronic obstructive pulmonary disease, active smoking habit. INTERVENTION Either a bilateral sternal infusion of 0.2% ropivacaine (3 ml h−1 through each catheter; ‘intervention’ group), or standardised care only (‘control’ group). Analgesia was provided with paracetamol and self-administered intravenous morphine. MAIN OUTCOME MEASURES The length of time to readiness for discharge from ICU, blindly assessed by a committee of experts. RESULTS No effect was found between groups for the primary outcome (P = 0.680, intention to treat); the median values were 42.4 and 37.7 h, respectively for the control and intervention groups (P = 0.873). Similar nonsignificant trends were noted for other postoperative delays. Significant effects favouring the intervention were noted for dynamic pain, patient satisfaction, occurrence of nausea and vomiting, occurrence of delirium or mental confusion and occurrence of pulmonary complications. In 12 patients, although no symptoms actually occurred, the total ropivacaine plasma level exceeded the lowest value for which neurological symptoms have been observed in healthy volunteers. CONCLUSION Because of a small size effect, and despite significant analgesic effects, this strategy failed to reduce the time spent in ICU. TRIAL REGISTRATION EudraCT (N°: 2012-005225-69); ClinicalTrials.gov (NCT01828788).

A wide variety of medical devices (MDs) used in hospitals are made of flexible plasticized polyvinylchloride (PVC). Different plasticizers are present in variable amounts in the PVC matrix of the devices and can leach out into the infused solutions and may enter into contact with the patients. The ARMED1 project aims to assess the migration of these plasticizers from medical devices and therefore the level of exposure in patients. For the first task of the project, eight methods were developed to directly detect and quantify the plasticizers in the PVC matrix of the MDs. We compared the overall performances of the analytical methods using standardized and validated criteria in order to provide the scientific community with the guidance and the technical specifications of each method for the intended application. We have shown that routine rapid screening could be performed directly on the MDs using the FTIR technique, with cost-effective analyses. LC techniques may also be used, but with limits and only with individual quantification of the main plasticizers expected in the PVC matrix. GC techniques, especially GC-MS, are both more specific and more sensitive than other techniques. NMR is a robust and specific technique to precisely discriminate all plasticizers in a MD but is limited by its cost and its low ability to detect and quantify plasticizer contamination, e.g. by DEHP. All these results have been confirmed by a real test, called the " blind test " carried out on 10 MD samples.

Coring of a medication vial’s rubber stopper has been reported as a major cause of visible particle presence in injectable preparations. In this study, we investigated and quantified visible particle formation caused by coring associated with four potential causal factors.

In 2008, di-(2-ethylhexyl) phthalate (DEHP), was categorized as CMR 1B under the CLP regulations and its use in PVC medical devices (MD) was called into question by the European authorities. This resulted in the commercialization of PVC MDs plasticized with the DEHP alternative plasticizers tri-octyl trimellitate (TOTM), di-(2-ethylhexyl) terephthalate (DEHT), di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di-isononyl phthalate (DINP), di-(2-ethylhexy) adipate (DEHA), and Acetyl tri-n-butyl citrate (ATBC). The data available on the migration of these plasticizers from the MDs are too limited to ensure their safe use. We therefore developed a versatile GC-MS method to identify and quantify both these newly used plasticizers and DEHP in MDs and to assess their migration abilities in simulant solution. The use of cubic calibration curves and the optimization of the analytical method by an experimental plan allowed us to lower the limit of plasticizer quantification. It also allowed wide calibration curves to be established that were adapted to this quantification in MDs during migration tests, irrespective of the amount present, and while maintaining good precision and accuracy. We then tested the developed method on 32 PVC MDs used in our hospital and evaluated the plasticizer release from a PVC MD into a simulant solution during a 24h migration test. The results showed a predominance of TOTM in PVC MDs accompanied by DEHP (<0.1% w/w), DEHT, and sometimes DEHA. The migration tests showed a difference in the migration ability between the plasticizers and a non-linear kinetic release.

Medical devices (MDs) for infusion and enteral and parenteral nutrition are essentially made of plasticized polyvinyl chloride (PVC). The first step in assessing patient exposure to these plasticizers, as well as ensuring that the MDs are free from di(2-ethylhexyl) phthalate (DEHP), consists of identifying and quantifying the plasticizers present and, consequently, determining which ones are likely to migrate into the patient's body. We compared three different extraction methods using 0.1 g of plasticized PVC: Soxhlet extraction in diethyl ether and ethyl acetate, polymer dissolution, and room temperature extraction in different solvents. It was found that simple room temperature chloroform extraction under optimized conditions (30 min, 50 mL) gave the best separation of plasticizers from the PVC matrix, with extraction yields ranging from 92 to 100% for all plasticizers. This result was confirmed by supplemented Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR) and gravimetric analyses. The technique was used on eight marketed medical devices and showed that they contained different amounts of plasticizers, ranging from 25 to 36% of the PVC weight. These yields, associated with the individual physicochemical properties of each plasticizer, highlight the need for further migration studies.

Les experts du Scenihr [1] ont mis en évidence que l’ECMO (oxygénation membranaire extracorporelle) fait partie des situations à haut risque d’exposition au DEHP. Le DEHP est un plastifiant présent dans le PVC et reconnu comme toxique. Les laboratoires ont ainsi limité la quantité de DEHP dans les dispositifs médicaux et l’on remplacé par d’autres plastifiants dont le TOTM. L’objectif de cette étude consiste à étudier le relargage des plastifiants du circuit en fonction des débits et des contraintes mécaniques et de le comparer à la dose limite d’exposition (DNEL). Un modèle d’ECMO a été réalisé à 2 débits (1,5 et 5,5 L/min) et comparé à une situation statique pendant 6 jours. Un mélange d’éthanol absolu/eau (50/50 v/v) a été utilisé comme simulant du sang, selon les données de la littérature [2]. Des prélèvements de simulant ont été réalisés quotidiennement pour une analyse des plastifiants par chromatographie en phase gazeuse couplée à la spectrométrie de masse (CG-SM). Les concentrations obtenues en mg/L ont été extrapolées en mg/kg/j pour être comparées aux derived no effect level (DNEL). La composition en plastifiants des circuits et des accessoires a également été étudiée. Enfin, une expérience de clampage a été réalisée, afin d’évaluer le relargage potentiel de cette contrainte. Les différents plastifiants retrouvés dans le simulant après contact avec les tubulures d’ECMO sont les suivants : le DEHP, le TOTM, le DEHT et le DEHA. La composition initiale en plastifiants du circuit et de la poche d’amorçage est présentée dans le Tableau 1. Le TOTM, plastifiant majoritaire, migre peu dans le simulant et les doses d’exposition du patient sont inférieures à la DNEL (Fig. 1). Le DEHP quant à lui présente des doses d’exposition supérieures à la DNEL malgré une faible présence dans le circuit. Le DEHT et le DEHA sont présents à l’état de traces dans le simulant. Le débit n’impacte pas le relargage des plastifiants de même que le clampage (p > 0,05). Cette étude montre la présence majoritaire d’un nouveau plastifiant alternatif au DEHP, le TOTM, dans ces circuits d’ECMO. Le relargage du TOTM est faible, d’où un risque d’exposition acceptable. Les taux de DEHP retrouvé dépassent la DNEL. Ceci peut s’expliquer par la présence de DEHP en grande quantité dans la poche d’amorçage. Le remplacement du DEHP par le TOTM dans le circuit a permis de limiter l’exposition à un composé toxique (CMR1B). L’utilisation d’une poche sans PVC permettrait d’éliminer le DEHP et donc de sécuriser l’ensemble du circuit. Enfin, ces résultats démontrent l’absence d’influence des hauts débits et des contraintes mécaniques sur le relargage des plastifiants.

C Marie, S Hamlaoui, L Bernard, D Bourdeaux, V Sautou, D Lémery, F Vendittelli, MP Sauvant-Rochat 2,4 Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France Clermont Université, Université d’Auvergne, EA 4681, PEPRADE, ClermontFerrand, France Clermont Université, Université d’Auvergne, EA 4676, C-Biosenss, Clermont-Ferrand, France Clermont Université, Université d’Auvergne, Faculté de Pharmacie, Département Santé Publique et Environnement, Clermont-Ferrand, France Contact: cmarie@chu-clermontferrand.fr Medical devices (MDs) can be a significant source of exposure to plasticizers, little known by health professionals. Di(2ethylhexyl)phthalate (DEHP) was the most commonly phthalate used as plasticizer into the polyvinyl chloride (PVC) MDs (infusion bags, tubing, catheter, etc.). As its toxicity is now recognized, it is substituted by other plasticizers such as [di(isononyl)-cyclohexane-1,2-dicarboxilic acid (DINCH), trioctyltrimellitate (TOTM), di-(2-ethylhexyl) terephthalate (DEHT), di-(isononyl) phthalate (DiNP), etc.]. To date, exposure of pregnant women to plasticizers of MDs is not studied. The aims of this study is to assess i) the proportion of pregnant women potentially exposed to plasticizers during hospitalization, and ii) the daily-exposure duration to plasticizers, depending on the reasons for hospitalization. In this cross-sectional study, 168 pregnant women hospitalized at the University Hospital of Clermont-Ferrand (52 in the group ‘‘Pathology’’ (‘‘Patho’’), 23 in the group ‘‘Pathology and delivery’’ (‘‘P&Deli’’) and 93 in the group ‘‘Delivery’’ (‘‘Deli’’)) were included. A PVC MD was used during hospitalization for 90% of the pregnant women. After analysis by GC-MS, DiNP, TOTM and DINCH were the main plasticizers of these MDs. The proportions of women exposed to DiNP, TOTM and DINCH were respectively 74%, 73% and 4%. For DiNP and TOTM, lower proportions in the group ‘‘Patho’’ was observed comparatively to the other two groups (p < 0.001). The women of the group ‘‘Patho’’ had statistically longer daily-exposure durations to DiNP (median: 3.4 hours/day) and to TOTM (8.2 hours/day) than those of the groups ‘‘Deli’’ (DiNP: 0.5 hours/ day; TOTM: 2.9 hours/day) (p < 0.01). Our study is the first to highlight the exposure of pregnant women to plasticizers incorporated into the MDs. In the Public Health context, further studies are needed to specify the migration and toxicity of these alternatives plasticizers. Key messages During pregnancy, women can be exposed to phthalates and alternatives plasticizers (DiNP, TOTM and DINCH) migrating from medical devices The duration exposure to plasticizers is linked to the reason for hospitalization, and the median exposure can reach 8.2 hours/day 8th European Public Health Conference: Parallel Sessions 193

To assess the stability of cisatracurium besilate solution stored at 5°C and 25°C.Cisatracurium solutions at 2, 5 and 0.1mg/mL in 0.9 % sodium chloride or 5 % glucose were exposed to 5°C and 25°C under 60 % relative humidity for seven days. The physicochemical stability was assessed at 24, 48hours and seven days with dosage of the active substance, detection of degradation products and a possible racemization, measuring pH, osmolality and turbidity, assessment of coloration, visible particles and invisible particles count.Cisatracurium besilate present good stability for 24hours at 5°C and 25°C for concentrations between 0.1 and 5mg/mL. Beyond 24hours, the solutions at 2 and 5mg/mL remained stable for seven days at 5°C. At 25°C, potentially toxic degradation products appear in solutions of 0.1mg/mL between 24 and 48hours. No racemization was detected, the drug remains in its active form cis.Cisatracurium solutions at 2 and 5mg/mL may be stored at 5°C or 25°C for seven days. It's advisable to keep the solutions in a dilution of 0.1mg/mL in 0.9 % sodium chloride or 5 % glucose in the refrigerator. No diluted solution should be stored at room temperature beyond 24hours.

BACKGROUND:Little is known regarding sevoflurane kinetics and toxicity during long-term sedation of intensive care unit (ICU) patients using the AnaConDa® system. The objective of the present study was to establish a pharmacokinetic description of 48-h sevoflurane administration, and to estimate plasma concentrations of metabolites.METHODS:Forty-eight hour sedation with sevoflurane vaporized via an AnaConDa® device, with an end-tidal concentration objective of 1.5% (v/v), was initiated in 12 non-obese patients who did not have hepatic or renal failure but who required sedation for more than 48 h in our ICU. Plasma sevoflurane, hexafluoroisopropanol, and fluoride concentrations were determined over this time period and pharmacokinetic analysis was performed.RESULTS:The mean plasma concentration of sevoflurane was 76 mg/L at 24 h and 70 mg/L at 48 h. Wash-out of plasma sevoflurane correlated with a rapid decrease in the mean end-tidal sevoflurane level. The mean free plasma fraction of hexafluoroisopropanol never exceeded 8 mg/mL. The mean fluoride concentration was 0.8 µmol/L on day 0, 51.7 µmol/L on day 1, and 68.1 µmol/L on day 2 (P<0.0001). The distribution volume was 53 L, the elimination constant 2.9 h-1, the transfer constant from compartment 1 to compartment 2 (K1-2) 1.2 h-1, the K2-1 0.26 h-1, the half-life of elimination 3.78 h, and the total clearance 156 L/h.CONCLUSION:Following 48 hours of sedation using sevoflurane inhalation administered using an AnaConDa® delivery device, sevoflurane washout was rapid. Plasma fluoride levels accumulated over the study period without apparent nephrotoxicity.

Until 2010, diethylhexylphthalate (DEHP) was the plasticizer most commonly used to soften PVC medical devices (MDs), because of a good efficiency/cost ratio. In flexible plasticized PVC, phthalates are not chemically bound to PVC and they are released into the environment and thus may come into contact with patients. The European Directive 2007/47/CE, classified DEHP as a product with a toxicity risk and restricted its use in MDs. MD manufacturers were therefore forced to quickly find alternatives to DEHP to maintain the elasticity of PVC nutrition tubings, infusion sets and hemodialysis lines. Several replacement plasticizers, so-called “alternative to DEHP plasticizers” were incorporated into the MDs. Nowadays, the risk of exposure to these compounds for hospitalized patients, particularly in situations classified “at risk”, has not yet been evaluated, because migrations studies, providing sufficient exposure and human toxicity data have not been performed. To assess the risk to patients of DEHP plasticizer alternatives, reliable analytical methods must be first developed in order to generate data that supports clinical studies being conducted in this area. After a brief introduction of the characteristics and toxicity of the selected plasticizers used currently in MDs, this review outlines recently analytical methods available to determine and quantify these plasticizers in several matrices, allowing the evaluation of potential risk and so risk management.

Objectives. - To assess the stability of cisatracurium besilate solution stored at 5 degrees C and 25 degrees C.Materials and methods. - Cisatracurium solutions at 2, 5 and 0.1 mg/mL in 0.9 % sodium chloride or 5 % glucose were exposed to 5 degrees C and 25 degrees C under 60 % relative humidity for seven days. The physicochemical stability was assessed at 24, 48 hours and seven days with dosage of the active substance, detection of degradation products and a possible racemization, measuring pH, osmolality and turbidity, assessment of coloration, visible particles and invisible particles count.Results. - Cisatracurium besilate present good stability for 24 hours at 5 degrees C and 25 degrees C for concentrations between 0.1 and 5 mg/mL. Beyond 24 hours, the solutions at 2 and 5 mg/mL remained stable for seven days at 5 degrees C. At 25 degrees C, potentially toxic degradation products appear in solutions of 0.1 mg/mL between 24 and 48 hours. No racemization was detected, the drug remains in its active form cis.Conclusion. - Cisatracurium solutions at 2 and 5 mg/mL may be stored at 5 degrees C or 25 degrees C for seven days. It's advisable to keep the solutions in a dilution of 0.1 mg/mL in 0.9% sodium chloride or 5 % glucose in the refrigerator. No diluted solution should be stored at room temperature beyond 24 hours. (C) 2014 Societe francaise d'anesthesie et de reanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Study objective The intracameral injection of cefuroxime has shown its effectiveness in the prevention of endophthalmitis consecutive to cataract surgery. The solution is generally loaded into syringes that are deep frozen to ensure stability before use. However, a concentration gradient has been found inside the syringes after thawing. We set out to determine the optimal thawing conditions that would ensure homogeneity.Method Solutions of cefuroxime in pre-filled syringes were deep frozen at -20 degrees C and thawed at 15, 20 and 25 degrees C with or without homogenisation. Samples were taken from three segments of each syringe immediately after preparation and then 15, 30 and 60 min after removal from the freezer. Cefuroxime was assayed by high-performance liquid chromatography and temperature in the solution was monitored using a thermocouple. Measurement of pH, osmolality and particulate matter were also performed.Results Before thawing, the cefuroxime concentration is homogeneous in the syringes. After 15 min of thawing at 15, 20 and 25 degrees C without homogenisation, a steep concentration gradient is observed, with a variation in cefuroxime concentration of +/- 25-30% along the syringe. After 1 h of thawing, the concentration variations are narrower, about 15%. Manual homogenisation of the solutions gives a stable concentration after 15 min of thawing between 15 and 25 degrees C, but the solution takes fully 30 min to reach the ambient temperature. The solution of cefuroxime displays a pH, an osmolality and a particle count that were compatible with intracameral injection.Conclusions This study demonstrates the need to let syringes containing cefuroxime thaw out for 30 min between 15 and 25 degrees C and to homogenise the contents at least by inversion of the syringe before injecting into the patient. If this procedure is not followed, the patient may be exposed to overdosing or underdosing of cefuroxime according to whether the surgeon injects the first or the last 0.1 ml of the solution.