Daniel Bourdeaux

Analysis of PVC plasticizers in medical devices and infused solutions by GC–MS

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.

Influence of Lipid Type on Bis (2-ethylhexyl)phthalate (DEHP) Leaching From Infusion Line Sets in Parenteral Nutrition

BACKGROUND Bis(2-ethylhexyl)phthalate (or DEHP) is widely used in polyvinyl chloride (PVC) tubings for its good plasticizing properties. Because it is not covalently bound to the plastic matrix, it is able to escape from PVC during the infusion of the lipid emulsions used in parenteral nutrition (PN). This creates a vector through which it can enter into contact with the patient via the nutrition admixtures infused. This study was designed to assess the potential role of the type of lipids used in PN admixtures on the quantity of DEHP leached out from PVC-based tubings. METHODS PVC-based infusion lines, 6 commercially available lipid emulsions, and their oil base components were left in direct contact, and the amount of DEHP leached was measured by liquid chromatography. RESULTS After a 24-hour exposure period, DEHP migration varied significantly (P = .0000152) according to lipid type. The olive oil-based emulsion Clinoleic leached the most DEHP (65.8 µg/mL intravenous fat emulsion), followed by the fish oil-based emulsion Omegaven (37.8 µg/mL). The soybean oil-based emulsions Intralipid, Medialipide, Lipidem, and Structolipid showed comparable performances, with DEHP leaching rates into the emulsion measured at 27.3, 27.8, 23.6, and 19.6 µg/mL, respectively. Results from the same experiments run on pure-form oils (soybean oil, olive oil, coconut oil, and cod liver oil) confirmed the influence of lipid type on DEHP leaching. CONCLUSION The major DEHP leaching caused by olive oil-based emulsions raises cause for concern because DEHP presents distinctive toxic effects, including an increased risk of cholestasis.

Simple assay of plasma sevoflurane and its metabolite hexafluoroisopropanol by headspace GC–MS

The anesthetic sevoflurane can now be delivered over periods of up to 48h using a newly developed medical system, the AnaConDa (anesthetic conserving device). Lack of pharmacokinetic data on sevoflurane and its main metabolite (hexafluoroisopropanol, HFIP) in this indication prompted us to develop a headspace GC-MS method to quantify the two substances. The only previously published method for assaying the two substances could not be adapted to our study since it uses expensive and rarely employed system components together with toxic carbon disulfide as a dilution solvent. The method developed is straightforward and uses the relatively non-toxic solvent undecane as dilution solvent and chloroform as internal standard. The method is linear for a concentration range of 1-150microg/ml, and presents high accuracy and precision. LOD and LOQ are 0.2 and 1microg/ml, with a short analysis time (7.6 min for a single analysis). The method was applied to determine the plasma levels of sevoflurane and HFIP in six patients under 48-h anesthetic sedation delivered via the AnaConDa system. Average sevoflurane and HFIP concentrations plateaued at 75 and 4microg/ml, respectively. Sevoflurane quickly tailed off after inhalation was stopped, and HFIP levels remained low.

Bilateral sternal infusion of ropivacaine and length of stay in ICU after cardiac surgery with increased respiratory risk: A randomised controlled trial

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).

Optimisation of thawing conditions for solutions of cefuroxime in pre-filled syringes for intracameral injection to avoid a concentration gradient

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°C and thawed at 15, 20 and 25°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°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°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°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.

Sevoflurane for procedural sedation in critically ill patients: A pharmacokinetic comparative study between burn and non-burn patients

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±37.5mg·L-1 in burns and 57.2±28.1mg·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±2.50L, P<0.001), and the drug half-life longer in burns (1.19±0.28h vs 0.65±0.04h, 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. TRIAL REGISTRY NUMBER ClinicalTrials.gov Identifier NCT02048683.

Rubber Coring of Injectable Medication Vial Stoppers: An Evaluation of Causal Factors

Abstract Purpose: 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. Methods: The factors studied were: nature of the rubber stopper; rubber stopper thickness, type of metal needle bevel used to pierce the stopper, and puncture technique. For each one of 16 different situations, 40 medication vial rubber stoppers were punctured, and the contents filtered. The filters were then examined under optical microscopy and particles present counted and measured. Results: The incidence of particle formation ranged from 0 % to 75 %, depending on the situation. Particle length was on average of 0.98±0.39 mm. The situation that gave the most particles (75 %; 30/40) was obtained when using a short bevelled needle, a 4 mm thick chlorobutyl vial stopper and with a puncture angle of 90°. Whilst a puncture technique reduced particle formation by more than 50 % for the most at risk situation, but without eliminating particle formation (residual formation of 22.5 %; 11/40), the use of a blunt bevelled needle totally eliminated the incidence of visible particle creation. The thickness of the rubber and the nature of the elastomer seemed to be linked to coring incidence, but in lesser proportions. Conclusion: Puncturing the stoppers using a technique with a 45° puncture angle reduced particle formation, but only the use of a blunt metal needle totally eliminated it.