ABSTRACT
Poly vinyl chloride (PVC) infusion equipment contains substantial amounts of the plasticiser di(2-ethylhexyl) phthalate (DEHP). We determined the amount of DEHP leached from Mediplus Dual TIVA(®) Infusion sets, into lipid and non-lipid infusates. Two propofol admixtures (Diprivan(®) 1%, Propoven(®) 1%), Intralipid(®) 10% and 0.9% saline were evaluated as infusates. Solutions were infused through TIVA sets at 12 ml.h(-1) for 6 h at 24, 32 and 37 °C. In addition, TIVA sets were filled with 2 ml infusates, sealed and incubated at 24 and 37 °C for 6 h. Di(2-ethylhexyl) phthalate was detected in all lipid infusates after dynamic infusion and static contact, and in 0.9% saline after dynamic infusion at 37 °C. At 32 and 37 °C, the quantity of di(2-ethylhexyl) phthalate leaching into the lipid infusates may exceed the recommended maximum exposure amount set by the European Union for DEHP of 20-48 µg.kg(-1) day(-1) if lipid based infusates are used for sedation or intravenous feeding of infants or neonates.
Subject(s)
Diethylhexyl Phthalate/chemistry , Equipment Contamination , Fat Emulsions, Intravenous/chemistry , Hot Temperature , Infusions, Intravenous/instrumentation , Polyvinyl Chloride/chemistry , Analysis of Variance , Chromatography , Drug Contamination , Emulsions/chemistry , Maximum Allowable Concentration , Phospholipids/chemistry , Plasticizers/chemistry , Propofol , Sodium Chloride , Soybean Oil/chemistry , TemperatureABSTRACT
Although well established in clinical practice, both propofol and midazolam have limitations. New hypnotics with different and potentially superior pharmacokinetics and pharmacodynamics are under development. These include the benzodiazepine receptor agonists CNS7056 and JM-1232 (-), the etomidate-based methoxycarbonyl-etomidate and carboetomidate, the propofol-related structures PF0713 and fospropofol, and THRX-918661/AZD3043. The basic pharmacology and the initial anaesthesia studies for each of these agents are reviewed. Several of the agents (CNS7056, THRX-918661/AZD3043, and fospropofol) have reached the stage of clinical trials. To be successful, novel compounds need to establish clear clinical advantages over existing agents and where possible the new agents are discussed in this context. Computer-controlled drug administration offers the ability to automatically implement infusion schemes too complex for manual use and the possibility of linking patient monitoring to administration to enhance patient safety.
Subject(s)
Anesthesia, Intravenous/trends , Anesthetics, Intravenous/pharmacology , Anesthesia, Intravenous/methods , Anesthetics, Intravenous/administration & dosage , Anesthetics, Intravenous/chemistry , Drug Delivery Systems , Etomidate/analogs & derivatives , Etomidate/pharmacology , GABA-A Receptor Agonists , HumansABSTRACT
BACKGROUND: As a result of its very low water solubility, propofol is generally presented as a lipid-based formulation with well-characterized limitations. METHODS: Propofol (99.7%) was added directly to an aqueous solution of poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide)copolymers (PVP-PLA) block copolymers and stirred in order to obtain a clear solution. This formulation was filtered sterile and then lyophilized to its solid form Propofol-PM (propofol polymeric micelle) which reconstitutes to a propofol 1%w/v (10 mg ml(-1)) clear aqueous solution of 30-60 nm propofol-containing micelles. Population pharmacokinetic data from whole blood and plasma were obtained by administering reconstituted Propofol-PM formulations and a 1% oil in water formulation, Diprivan to male Sprague-Dawley rats (n = 40) at a dose of 10 mg kg(-1). Preliminary recovery data were obtained from a further small study. RESULTS: The pharmacokinetics were best described using a two-compartment mamillary population model, which incorporated sample matrix (blood or plasma) and propofol formulation (Diprivan) or Propofol-PM) as covariates. Sample matrix was applied to all structural model parameters as a dichotomous covariate. An influence of propofol formulation was observed for all parameters (excluding distributional clearance) but only when plasma was used for propofol quantification. In this preliminary pharmacodynamic study, there was no statistically significant difference in the timing of the recovery endpoints between the Propofol-PM formulation and Diprivan groups. CONCLUSIONS: Propofol-PM formulations produce anaesthesia in rats. Whole blood pharmacokinetics of Propofol-PM did not differ from those observed with Diprivan.
Subject(s)
Anesthetics, Intravenous/blood , Propofol/blood , Anesthetics, Intravenous/chemistry , Anesthetics, Intravenous/pharmacokinetics , Animals , Chemistry, Pharmaceutical , Drug Evaluation, Preclinical/methods , Male , Micelles , Polystyrenes , Polyvinyls , Propofol/chemistry , Propofol/pharmacokinetics , Rats , Solubility , WaterABSTRACT
BACKGROUND: Sedation of critically ill children requiring artificial ventilation remains a therapeutic challenge due to large individual variation in drug effects and a paucity of knowledge of pharmacokinetics in this population. This study aimed to determine the pharmacokinetics of remifentanil in children requiring ventilation after cardiac surgery. METHODS: Twenty-six ventilated children aged 1 month to 9.25 yr (median 1.77 yr) who had undergone cardiac surgery were sedated with a fixed rate infusion of midazolam 50 microg kg(-1) h(-1) and a remifentanil infusion that was commenced at 0.8 microg kg(-1) min(-1) for a minimum of 60 min and subsequently decreased by 0.1 microg kg(-1) min(-1)every 20 min until the patient awoke. Arterial blood concentrations of remifentanil and midazolam were measured using high-performance liquid chromatography. Mixed-effects population models were fitted to the remifentanil concentration-time data. RESULTS: Satisfactory sedation was achieved in all patients as assessed by Comfort score during the initial maintenance and reduction phase of the remifentanil infusion. One patient was withdrawn from the study due to hypotension. Remifentanil pharmacokinetics were best described using a two-compartment allometric model. For a typical child with a body weight of 10.5 kg, clearance was 68.3 ml kg(-1) min(-1), intercompartmental clearance was 80 ml kg(-1) min(-1), the central compartment volume was 91.7 ml kg(-1), and the peripheral compartment volume was 141 ml kg(-1). CONCLUSIONS: A combination of remifentanil and midazolam provided satisfactory sedation for these patients. Owing to enhanced clearance rates, smaller (younger) children will require higher remifentanil infusion rates than larger (older) children and adults to achieve equivalent blood concentrations.
Subject(s)
Cardiac Surgical Procedures , Hypnotics and Sedatives/blood , Midazolam/blood , Piperidines/blood , Respiration, Artificial , Blood Specimen Collection/methods , Child , Child, Preschool , Chromatography, High Pressure Liquid/methods , Conscious Sedation/methods , Critical Care/methods , Electroencephalography/drug effects , Female , Humans , Infant , Male , Models, Biological , Postoperative Care/methods , RemifentanilABSTRACT
OBJECTIVE: To investigate the stability of epirubicin bladder instillation, prepared from two different epirubicin formulations, under refrigerated storage, transportation and clinical use conditions. METHOD: A sequential study design was used. Epirubicin instillation (1 mg/mL) in polypropylene syringes was sequential incubated for periods of 84 days at 8 degrees C followed by 2 h at 25 degrees C and 1 h at 37 degrees C, the latter two temperatures replicating transport and intravesical conditions, respectively. RESULTS: The instillation was both chemically and physically stable under those incubation conditions. The formulation of epirubicin used to prepare the instillation infusions did not affect stability.
