A.E. Rigby-Jones

Pharmacokinetics of Propofol Infusions in Critically Ill Neonates, Infants, and Children in an Intensive Care Unit

Background Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children. Methods Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4–6 mg · kg−1 · h−1 of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography. Results A propofol infusion rate of 4 mg · kg−1 · h−1 achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml · kg−1 · min−1 and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery. Conclusions Propofol kinetics are altered in very small babies and in children recovering from cardiac surgery. Increased peripheral distribution volume and reduced metabolic clearance following surgery causes prolonged elimination.

New drugs and technologies, intravenous anaesthesia is on the move (again)

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.

Anaesthetic effects of propofol polymeric micelle: a novel water soluble propofol formulation

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.

Propofol and children--what we know and what we do not know.

The pharmacokinetics of propofol are relatively well described in the pediatric population. Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation. Pharmacodynamic data for propofol in children are scarcer, because of practical difficulties in data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. Keo half‐lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target‐controlled infusion pumps.

Electroencephalograph variables, drug concentrations and sedation scores in children emerging from propofol infusion anaesthesia

Background : Inadequate sedation or oversedation are common problems in Paediatric Intensive Care because of wide variations in drug response and the lack of objective tests for sedative depth. We undertook a pilot study to try to identify correlates of propofol drug concentration, electroencephalographic (EEG) variables and observed behaviour during a stepwise reduction in propofol infusion after paediatric cardiac surgery.

The effect of temperature on di(2-ethylhexyl) phthalate leaching from PVC infusion sets exposed to lipid emulsions.

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.

First human administration of MR04A3: a novel water-soluble nonbenzodiazepine sedative.

Background: JM-1232(–), (–)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta [f]isoindol-1(2H)-one, molecular formula, C24H27N3O2; molecular weight, 389.49, is a novel isoindoline water-soluble benzodiazepine receptor agonist with favorable anesthetic/sedative properties in animals. MR04A3 is a 1% aqueous presentation of JM-1232(–). Methods: In Step 1, healthy male volunteers received 10-min infusions of MR04A3, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg, with three MR04A3 subjects and one placebo subject per dose concentration. In Step 2, doses were 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, and 0.4 mg/kg over 1 min with six MR04A3 subjects and one placebo subject per dose concentration. Results: Hypnotic effects of MR04A3 were seen at all dose concentrations in Step 1 and at doses of 0.075 mg/kg or more in Step 2. Central nervous system effect was seen at all dose concentrations with larger doses of MR04A3 producing a deeper and longer reduction in bispectral index. Ramsay sedation scores were increased with higher doses causing sedation and then unresponsiveness. The adverse event profile of subjects receiving MR04A3 was similar to that of subjects given placebo except that some subjects receiving MR04A3 developed upper airway obstruction while sedated. This responded to simple maneuvers (i.e., chin lift). Changes in systolic arterial blood pressure and heart rate were minimal. Conclusions: MR04A3 is hypnotic in man with a satisfactory hemodynamic and safety profile.

Pharmacokinetics and pharmacodynamics--is there anything new?

The basic principles of pharmacokinetics (PK) and pharmacodynamics (PD) have been well understood for many years. An epic editorial in 1979 sets these out in a manner that remains relevant today [1], concluding: ‘‘the clinical anaesthetist may, if he has persisted this far, be forgiven for feeling the sources of variation are so legion that in the case of many drugs used in anaesthetic practice it is better to titrate dose against response than to attempt to predict the correct dose on theoretical groups. He is, of course, right . . . ’’. Why then bother with PK-PD and has our thinking moved forward? For PK to be useful we need intelligible information that clinicians use to adjust or understand their practice. Historically, drug disposition was described by half-lives (a, b ± c depending on whether a twoor threecompartment model is preferred). Dissonance between these numbers and clinical experience of recovery from drug effects stimulated the creation of new descriptors, e.g. decrement time [2], context sensitive half time [3] and mean effect time [4] (Table 1). The latter integrates the influence of PD and PK on time to recovery. Similarly, at the start of anaesthesia, time to peak effect [5] (Fig. 1) is exactly what it says it is.

Stability of intravesical epirubicin infusion: a sequential temperature study

Objective:  To investigate the stability of epirubicin bladder instillation, prepared from two different epirubicin formulations, under refrigerated storage, transportation and clinical use conditions.

First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial.

BackgroundOrg 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data.MethodsIn the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg.ResultsWithin the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter.ConclusionsOrg 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics.