Markoulina Berger-Gryllaki

Albuterol delivery in an in vitro pediatric ventilator lung model: comparison of jet, ultrasonic, and mesh nebulizers.

Objective: To determine the influence of nebulizer types and nebulization modes on bronchodilator delivery in a mechanically ventilated pediatric lung model. Design: In vitro, laboratory study. Setting: Research laboratory of a university hospital. Interventions: Using albuterol as a marker, three nebulizer types (jet nebulizer, ultrasonic nebulizer, and vibrating-mesh nebulizer) were tested in three nebulization modes in a nonhumidified bench model mimicking the ventilatory pattern of a 10-kg infant. The amounts of albuterol deposited on the inspiratory filters (inhaled drug) at the end of the endotracheal tube, on the expiratory filters, and remaining in the nebulizers or in the ventilator circuit were determined. Particle size distribution of the nebulizers was also measured. Measurements and Main Results: The inhaled drug was 2.8% ± 0.5% for the jet nebulizer, 10.5% ± 2.3% for the ultrasonic nebulizer, and 5.4% ± 2.7% for the vibrating-mesh nebulizer in intermittent nebulization during the inspiratory phase (p < 0.01). The most efficient nebulizer was the vibrating-mesh nebulizer in continuous nebulization (13.3% ± 4.6%, p < 0.01). Depending on the nebulizers, a variable but important part of albuterol was observed as remaining in the nebulizers (jet and ultrasonic nebulizers), or being expired or lost in the ventilator circuit (all nebulizers). Only small particles (range 2.39–2.70 µm) reached the end of the endotracheal tube. Conclusions: Important differences between nebulizer types and nebulization modes were seen for albuterol deposition at the end of the endotracheal tube in an in vitro pediatric ventilator–lung model. New aerosol devices, such as ultrasonic and vibrating-mesh nebulizers, were more efficient than the jet nebulizer.

Development and Validation of an HPLC Method for the Simultaneous Monitoring of Bromazepam and Omeprazole

Abstract Bromazepam and omeprazole are frequently administered to hospitalized patients to decrease anxiety and prevent stress ulcers, respectively. In patients under enteral nutrition, these drugs are administered via a nasogastric feeding tube. However, this mode of administration renders their bioavailability highly variable, and calls for their therapeutic monitoring. Given the absence of published data on the compared bioavailability of the two drugs given orally or via a nasogastric feeding tube, we have developed a high performance liquid chromatography method with UV detection (HPLC‐UV) suitable for their simultaneous monitoring in human plasma. The method involves solid phase extraction of 2 mL plasma samples. Linearity was demonstrated in a concentration range of 5–100 ng/mL and 20–2000 ng/mL for bromazepam and omeprazole, respectively. The lower limit of quantification was 5 ng/mL and 20 mg/mL for bromazepam and omeprazole, respectively. The method proved its worth in the simultaneous monitoring of bromazepam and omeprazole administered to healthy volunteers.

A highly sensitive LC–tandem MS assay for the measurement in plasma and in urine of salbutamol administered by nebulization during mechanical ventilation in healthy volunteers

The new-generation nebulizers are commonly used for the administration of salbutamol in mechanically ventilated patients. The different modes of administration and new devices have not been compared. We developed a liquid chromatography-tandem mass spectrometry method for the determination of concentrations as low as 0.05 ng/mL of salbutamol, corresponding to the desired plasma concentration after inhalation. Salbutamol quantification was performed by reverse-phase HPLC. Analyte quantification was performed by electrospray ionization-triple quadrupole mass spectrometry using selected reaction monitoring detection ESI in the positive mode. The method was validated over concentrations ranging from 0.05 to 100 ng/mL in plasma and from 0.18 to 135 ng/mL in urine. The method is precise, with mean inter-day coefficient of variation (CV%) within 3.1-8.3% in plasma and 1.3-3.9% in urine, as well as accurate. The proposed method was found to reach the required sensitivity for the evaluation of different nebulizers as well as nebulization modes. The present assay was applied to examine whether salbutamol urine levels, normalized with the creatinine levels, correlated with the plasma concentrations. A suitable, convenient and noninvasive method of monitoring patients receiving salbutamol by mechanical ventilation could be implemented.

In vitro compatibility of various cardioactive drugs during simulated Y-site administration

Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in ICUs. A study was undertaken to evaluate the physicochemical compatibility of five common associations of cardioactive drugs: dopamine (DA)–norepinephrine (NE); dobutamine (DU)–NE; amiodarone (AM)–DU–NE; DU–sodium nitroprusside (NI)±sodium thiosulfate (THIO); and NI–THIO. Methods The drugs were diluted in the usual manner performed in the ICU. Their compatibility was verified by visual inspection of the different mixtures in glass tubes and by chemical assays and pH determination of the mixtures collected during in vitro simulated Y-site administration (solutions prepared in syringes placed on syringe pumps and connected to a Swan–Ganz catheter). Solutions were considered to be compatible in the absence of any visual change in the solution and of any significant variation in pH value and drug concentration at each time of the study. Results DA–NE, DU–NE, DU–NI (±THIO) and NI–THIO associations were compatible over 24 h in the tested proportion ranges, with the proviso that NI was protected from light. In addition, it was observed that AM, DU and NE were compatible but, in the dynamic simulation, AM reached the expected concentration only after 4 h. Conclusions When combined, the cardioactive amines were stable over 24 h. AM was compatible with DU and NE, but with a latency period owing to its adsorption on the heparin-coated Swan–Ganz catheter. Mixtures involving NI were compatible provided that NI was supplied in amber syringes or protected with aluminum foil.

Stability of prostaglandin E1 solutions stored in polypropylene syringes for continuous intravenous administration to newborns

Objective We aimed to monitor the physicochemical stability of prostaglandin E1 (PGE1) 1.5 and 15 µg/mL in 10% dextrose stored in polypropylene syringes. Methods We developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method to detect and quantify levels of PGE1. Method selectivity was performed with a mixture of PGE1 and its degradation products. Forced degradation tests were performed to determine which degradation products were most likely to form. PGE1 injection solutions in 10% dextrose were stored in unprotected and shielded-from-light polypropylene syringes in a climatic chamber. Samples were taken immediately after preparation (T0) and after 24, 48, 72 and 168 hours for analysis. PGE1 solutions were considered stable if ≥90.0% of the initial concentration was retained. Results The LC-HRMS method was validated in the range of 0.086-0.200µg/mL PGE1 with trueness values between 98.2% and 100.3%, and repeatability and intermediate precision values of <2.2%and <4.7%, respectively. The quantification and detection limits of the method were 0.086 and 0.026µg/mL, respectively. PGE1 and its degradation products were resolved chromatographically. PGE1 injection solutions were≥90.0%stable after 48hours in unprotected from light (UPL) syringes. The solutions remained clear without precipitation, colour or pH modification and subvisible particles within the permitted levels. Prostaglandin A1 was the sole degradation product observed. Conclusions A LC-HRMS method to evaluate PGE1 stability in a 10% dextrose was developed and validated. PGE1 1.5 and 15µg/mL in 10% dextrose solution are stable for 48hours when stored at 30ºC in UPL polypropylene syringes.

PS-009 Impact of syringe type on ph variation of drug solutions stored for intravenous continuous infusion

Background In hospital, continuous intravenous drug administration to patients for 24 hours is common. In some wards, such as intensive care units, these infusions may be kept beyond 24 hours. Purpose We aimed to assess pH variation of morphine 10 and 100 µg/mL and 10% dextrose solutions stored in three types of 50 mL polypropylene syringes for 72 hours. Material and methods Three solutions: (A) 10 µg/mL morphine and (B) 100 µg/mL morphine in water for injection, and C) 10% dextrose were prepared and divided in triplicate in two types of syringes: (1) polypropylene syringes unprotected from light (UPLS) and (2) light shielded polypropylene syringes (LSS). LSS came from two different companies, manufacturer 1 (LSS-1) and manufacturer 2 (LSS-2). Syringes were stored in a climatic chamber (daylight, 30±2°C, RH 65±5%) over the full duration of the study. The pH of solutions in UPLS, LSS-1 and LSS-2 was measured at T0, 24 hours and 72 hours. At each point time, the pH of each syringe was performed in triplicate. Results The pH of the 10% dextrose solution varied from T0 to T72: UPLS, 4.05±0.01 to 4.10±0.20; LSS-1, 4.23±0.08 to 6.12±0.08; and LSS-2, 4.09±0.02 to 4.14±0.02 (p<0.05). The pH of 10 µg/mL morphine in water for injection varied from T0 to T72: UPLS, 4.02±0.05 to 4.08±0.02; LSS-1, 4.12±0.04 to 4.82±0.07; and LSS-2, 3.93±0.05 to 3.98±0.01 (p<0.05). The pH of 100 µg/mL morphine in water for injection varied from T0 to T72: UPLS, 3.90±0.02 to 3.98±0.05; LSS-1, 3.98±0.04 to 5.56±0.11; and LSS-2, 3.95±0.01 to 3.99±0.02 (p<0.05). Conclusion The pH of identical drug solutions varied depending on the type of syringe in which they are stored. The pH values of solutions stored in LSS-1 were modified more than in UPLS and LSS-2. This phenomenon could be a serious problem in unbuffered solutions of drugs which are stable only in a defined range of pH, administered continuously over several days. No conflict of interest

Screening for physicochemical incompatibilities of intravenous drugs in intensive care units: the case of monobasic potassium phosphate and furosemide

Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in hospital settings. Having observed a drug precipitation during Y-site administration in our intensive care units, we undertook an investigation to find out its cause. Methods We conducted a literature search on the injectable drugs involved in the observed precipitates and undertook laboratory physicochemical incompatibility testing of potentially incompatible drug combinations not reported in the literature. Results Among the drugs tested, only furosemide with midazolam or with monobasic potassium phosphate was physically incompatible. The pH-dependent solubility of furosemide was the origin of the observed incompatibilities. Conclusions Monobasic potassium phosphate is not compatible with furosemide in the concentration range used in our intensive care unit and should not be administered together in the same intravenous line. Other drug formulations buffered to a low pH should not be administered with furosemide solutions either.

Visual compatibility of insulin aspart with intravenous drugs frequently used in ICU

Objective Insulin as continuous infusion is frequently used in critical care. Data on compatibilities are available for regular insulin but not for insulin aspart. The present study aimed at assessing the physical compatibility of insulin aspart with 47 drugs commonly used in intensive care units by simulated Y-site administration. Methods The physical compatibility of insulin aspart 1 IU/mL in sodium chloride 0.9% and in dextrose 5% was evaluated by visual inspection over a 24 h period. Tested drugs were diluted in the same solvents or tested without dilution, based on standard practices. Tests were conducted in duplicates. Results Insulin aspart was compatible over 24 h with 43 drugs over the 47 selected. Imipenem-cilastin, meropenem, esomeprazole and pantoprazole were compatible over a shorter period. Conclusions Of the 47 drugs tested, only four were not physically compatible over 24 h. Our data will allow a switch from regular insulin to insulin aspart if needed.

Physicochemical aspects of nebulisation: An in vitro comparison of three aerosal devices types

(± SD, n=5), *p<0.001 (vs MNb and MNa), **p<0.001 (vs MNb, MNa and UN), ***p<0.05 (vs before) Salbutamol output was 1.8 and 2.7 times higher with the UN and MN devices compared to the JN. Particle size was significantly higher with the MN. Temperature decreased during nebulisation when the MN and the JN were used, but it increased with the UN. Osmolality of the drug solution was stable during nebulisation with the MN but increased with the UN and the JN, indicating an evaporation of the solvent. The number of holes decreased significantly with the MNa after 2 months of use (Fig 7-8), which could result in a decreased quality of droplets. Results Therapeutic Procedures 87L / 162

Formulation optimization in a university hospital : The example of pediatric solutions of the ACE inhibitor captopril

Many major drugs are not available in pediatric form. As a result, hospital pharmacists are often requested to provide the medical staff with liquid formulations for individualized dosage and easy administration to newborn and young patients. Such in-house formulations must of course fulfil stringent criteria of purity and stability. This paper reports the development of a liquid solution of captopril for pediatric use. A specific HPLC-UV method was developed. A number of formulations described in the literature as affording one-month stability were examined and found wanting. A simple solution of the drug (1 mg/ml) in purified water containing 0.1% EDTA-Na proved chemically and microbiologically stable at room temperature for two years.