Damien Lannoy

Impact of multiaccess infusion devices on in vitro drug delivery during multi-infusion therapy.

BACKGROUND: Multiaccess infusion sets allow multiple simultaneous infusions but may induce interference in drug delivery resulting from large variations in the delivery rate of potent drugs. In this study, we sought to understand the influence of multiaccess infusion device properties (dead space volume and antireflux valve [ARV]) on drug delivery during multi-infusion therapy. METHODS: Infusion sets differing in length, dead space volume, and presence of an ARV were assessed. Three drugs were infused simultaneously through different access points, and their concentrations were obtained using UV spectrophotometric analysis of the effluent. Different infusion configurations were compared by assessing (1) the amount of drug delivered to the patient per unit of time, (2) the mean amount of drug delivered to the patient per unit of time during the steady-state infusion (mass flow rate plateau), and (3) flow change efficiency calculated from the ratio of the area under the experimental instant mass flow rate curve to the area corresponding to theoretical instant mass flow rate curve. RESULTS: Infusion sets with lower dead space volumes offered significantly higher flow change efficiency (53.0% ± 15.4% with a dead space volume equal to 0.046 mL 5 min after the start of infusion) than infusion sets with higher dead space volume (5.6% ± 8.2% with a dead space volume equal to 6.16 mL), whatever the flow rate changes. Even in case of large dead space volumes, the presence of an ARV significantly increased the mass flow rate plateau (from 92.4% to 99.3% of the theoretical plateau without and with the presence of an ARV, respectively). CONCLUSIONS: Multi-infusion therapy induces perturbation in drug delivery. These perturbations (lag time, backflow, and bolus) could be reduced by using infusion sets including very low dead space volume and an ARV.

Infusion set characteristics such as antireflux valve and dead-space volume affect drug delivery: an experimental study designed to enhance infusion sets.

BACKGROUND: The ability of an infusion set to deliver a specific amount of drug to the patient can be directly related to the presence of an antireflux valve and dead-space volume. In this study we quantified separately the impact of these 2 components on drug delivery. METHODS: Various infusion sets were assessed differing in length, in dead-space volume, and with or without an antireflux valve. Noradrenalin was infused with a syringe pump simultaneously with a carrier flow. Effluent drug concentration was measured using ultraviolet spectrophotometry. Flow change efficiency (FCE) was calculated from the ratio of the area under the experimental mass flow rate curve to the area under the theoretical instantaneous mass flow rate curve. RESULTS: The FCE for infusion sets with or without antireflux valves were significantly different 10 to 15 minutes after the start of an infusion at flow rates of 7 mL/h for noradrenalin and 35 mL/h to 70 mL/h for the carrier fluid. They were not different with a carrier flow of 115 mL/h. DISCUSSION: These findings suggest that antireflux valves have a significant impact on FCE when the ratio of drug flow rate to carrier fluid flow rate is high. Infusion sets with very low dead-space volume connectors yield better FCE. There is a nonlinear relationship between dead-space volume and FCE 5 to 10 minutes after the onset of drug infusion. CONCLUSION: Care providers must consider dead-space volume and the presence of an antireflux valve when choosing their infusion sets.

The impact on drug mass flow rate of interrupting and resuming carrier fluid flow: an in vitro study on a very low dead-space volume infusion set.

BACKGROUND: Stopping and resuming carrier fluid flow can lead to potentially dangerous transient disturbances in drug mass flow rate. We compared the impact of 2 infusion sets, one with very low dead-space volume and the other with greater dead-space volume, on the amount of drug delivered during stop-and-go carrier fluid flows. METHODS: Two infusion sets, both with antireflux, connected to an angiocatheter and with dead-space volumes of 6.185 mL and 0.071 mL, respectively, were assessed. Two protocols were studied: carrier fluid flow of 90 mL/h associated with noradrenaline infused at 7 mL/h and carrier fluid flow of 350 mL/h with a noradrenaline infusion flow of 65 mL/h. During both protocols, the carrier fluid was stopped and resumed at the same rate 30 minutes later. Effluent noradrenaline concentration was measured using UV spectrophotometry. Flow change efficiency was calculated from the ratio of the area under the experimental mass flow rate curve to the area under the theoretical instantaneous mass flow rate curve. RESULTS: For both flow rate conditions, flow change efficiency was significantly different for the 2 infusion sets during the 10-minute period after stopping carrier fluid flow and the 10-minute period after restarting it. The major phenomena were sudden decreases in drug delivery after stopping carrier flow and sudden, temporary increases when it was resumed. The very low dead-space volume infusion set resulted in significant reduction in changes in drug delivery compared with the standard set, even at high flow rates. CONCLUSION: The use of a very low dead-space volume set attenuates disturbances in drug delivery caused by interrupting and resuming carrier fluid flow.

In Vitro Assessment of Interaction Between Amino Acids and Copper in Neonatal Parenteral Nutrition

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.

Technical evaluation of a new sterile medical device to improve anticancer chemotherapy administration.

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.

Stability of 10 mg/mL cefuroxime solution for intracameral injection in commonly used polypropylene syringes and new ready-to-use cyclic olefin copolymer sterile vials using the LC-UV stability-indicating method

Abstract Context: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Physicochemical and Microbiological Stability of a New Oral Clonidine Solution for Paediatric Use

Abstract Background As many drugs are unavailable for paediatric use, hospital pharmacies are often required to develop suitable formulations themselves. Clonidine is commonly used in paediatrics (in severe hypertension, in opiate withdrawal syndrome, in tics and Gilles de la Tourette syndrome or in anaesthetic premedication) but no appropriate formulation has been drawn up. The aims of this work were to develop an oral solution of clonidine dedicated to children and to assess its physicochemical and microbiological stability. Methods Formulation of an oral solution of clonidine hydrochloride suitable for neonates and paediatrics was developed using the active pharmaceutical ingredient (API), with as few excipients as possible and without any complex excipient vehicle. A stability study was made according to GERPAC-SFPC guidelines. At each point in time (D0, D1, D7, D15, D29, D60 and D90), visual aspect (limpidity), pH and osmolality were established. Clonidine concentration was quantified using a stability-indicating HPLC-UV-DAD method previously developed from a forced degradation study and validated according to SFSTP Pharma. Microbiological stability was also tested according to the European Pharmacopeia monograph with the best adapted method (by comparing membrane filtration and inclusion). Solutions were stored in amber glass bottles with an oral adapter for up to 3 months in two different conditions: 5 °C +/– 3 °C and at 25 °C +/– 2 °C with 60 % residual humidity (climatic chamber). Results The formulated oral solution is composed of API at a concentration of 10 µg/mL and of potassium sorbate (0.3 %), citric acid, potassium citrate (pH 5 buffer) and sodium saccharine (0.025 %). Forced degradation highlighted six degradation products and the method was validated in the acceptance limits of ± 5 %. On D29, the mean percentages of the initial clonidine concentrations (+/–standard deviation) were 92.95+/–1.28 % in the solution stored at 25 °C +/– 2 °C and 97.44+/–1.21 % when stored at 5 °C +/– 3 °C. On D90, means were respectively 81.82+/–0.41 % and 93.66+/–0.71 %. The visual aspect did not change. Physical parameters remained stable during the study: pH varied from 4.94 to 5.09 and osmolality from 82 to 92 mOsm/kg in the two conditions tested here. Membrane filtration appeared to be the more sensitive method. Whatever the storage conditions,<1 micro-organism/mL was identified (only environmental) with no detected E.coli. Conclusions This formulation is stable for at least 3 months at 5 °C +/– 3 °C in amber glass bottles and for one month when stored at room temperature. Microbiological stability was proven in accordance with the European Pharmacopeia.