Propofol is an intravenous agent used commonly for the induction and maintenance of anesthesia, procedural, and critical care sedation in children. The mechanisms of action on the central nervous system involve interactions at various neurotransmitter receptors, especially the gamma-aminobutyric acid A receptor. Approved for use in the USA by the Food and Drug Administration in 1989, its use for induction of anesthesia in children less than 3 years of age still remains off-label. Despite its wide use in pediatric anesthesia, there is conflicting literature about its safety and serious adverse effects in particular subsets of children. Particularly as children are not “little adults”, in this review, we emphasize
 the maturational aspects of propofol pharmacokinetics. Despite the myriad of propofol pharmacokinetic-pharmacodynamic studies and the ability to use allometrical scaling to smooth out differences due to size and age, there is no optimal model that can be used in target controlled infusion pumps for providing closed loop total intravenous anesthesia in children. As the commercial formulation of propofol is a nutrient-rich emulsion, the risk for bacterial contamination exists despite the Food and Drug Administration mandating addition of antimicrobial preservative, calling for manufacturers’ directions to discard open vials after 6 h. While propofol has advantages over inhalation anesthesia such as less postoperative nausea and emergence delirium in children, pain on injection remains a problem even with newer formulations. Propofol is known to depress mitochondrial function by its action as an uncoupling agent in oxidative phosphorylation. This has implications for children with mitochondrial diseases and the occurrence of propofol-related infusion syndrome, a rare but seriously life-threatening complication of propofol. At the time of this review, there is no direct evidence in humans for propofol-induced neurotoxicity to the infant brain; however, current concerns of neuroapoptosis in developing brains induced by propofol persist and continue to be a focus of research.

/pdf/propofol-a-review-of-its-role-in-pediatric-anesthesia-and-aq44w29sq4.pdf

Propofol: a review of its role in pediatric anesthesia and sedation

Background Pharmacokinetic (PK) and pharmacodynamic (PD) models are used in target-controlled-infusion (TCI) systems to determine the optimal drug administration to achieve a desired target concentration in a central or effect-site compartment. Our aim was to develop a PK–PD model for propofol that can predict the bispectral index (BIS) for a broad population, suitable for TCI applications. Methods Propofol PK data were obtained from 30 previously published studies, five of which also contained BIS observations. A PK–PD model was developed using NONMEM. Weight, age, post-menstrual age (PMA), height, sex, BMI, and presence/absence of concomitant anaesthetic drugs were explored as covariates. The predictive performance was measured across young children, children, adults, elderly, and high-BMI individuals, and in simulated TCI applications. Results Overall, 15 433 propofol concentration and 28 639 BIS observations from 1033 individuals (672 males and 361 females) were analysed. The age range was from 27 weeks PMA to 88 yr, and the weight range was 0.68–160 kg. The final model uses age, PMA, weight, height, sex, and presence/absence of concomitant anaesthetic drugs as covariates. A 35-yr-old, 170 cm, 70 kg male (without concomitant anaesthetic drugs) has a V1, V2, V3, CL, Q2, Q3, and ke0 of 6.28, 25.5, 273 litres, 1.79, 1.75, 1.11 litres min−1, and 0.146 min−1, respectively. The propofol TCI administration using the model matches well with recommendations for all age groups considered for both anaesthesia and sedation. Conclusions We developed a PK–PD model to predict the propofol concentrations and BIS for broad, diverse population. This should be useful for TCI in anaesthesia and sedation.

Pharmacokinetic–pharmacodynamic model for propofol for broad application in anaesthesia and sedation

Target-controlled infusions (TCIs) have been used in research and clinical practice for >2 decades Nonapproved TCI software systems have been used during the conduct of almost 600 peer-reviewed published studies involving large numbers of patients The first-generation pumps were first approved in 1996, and since then an estimated 25,000 units have been sold and used Second-generation pumps were first approved in 2003 During 2004 to 2013, >36,000 units were sold Currently, TCI systems are approved or available in at least 96 countries TCI systems are used to administer propofol and opioids for IV sedation and general anesthesia for millions of patients every year In countries where TCI systems are approved, nonapproved software is still commonly used in studies of the pharmacology of hypnotics and opioids, because research software offers greater flexibility than approved TCI systems Research software is also readily integrated into data management modules Although TCI is a part of established practice around the world, TCI devices have not received regulatory approval in the United States In the United States, TCI administration of propofol and opioids for sedation and anesthesia is only possible using research software in IRB-approved research studies

Target-Controlled Infusion : A Mature Technology

BACKGROUND: Pharmacokinetic (PK) models are used to predict drug concentrations for infusion regimens for intraoperative displays and to calculate infusion rates in target-controlled infusion systems. For propofol, the PK models available in the literature were mostly developed from particular patient groups or anesthetic techniques, and there is uncertainty of the accuracy of the models under differing patient and clinical conditions. Our goal was to determine a PK model with robust predictive performance for a wide range of patient groups and clinical conditions. METHODS: We aggregated and analyzed 21 previously published propofol datasets containing data from young children, children, adults, elderly, and obese individuals. A 3-compartmental allometric model was estimated with NONMEM software using weight, age, sex, and patient status as covariates. A predictive performance metric focused on intraoperative conditions was devised and used along with the Akaike information criteria to guide model development. RESULTS: The dataset contains 10,927 drug concentration observations from 660 individuals (age range 0.25-88 years; weight range 5.2-160 kg). The final model uses weight, age, sex, and patient versus healthy volunteer as covariates. Parameter estimates for a 35-year, 70-kg male patient were: 9.77, 29.0, 134 L, 1.53, 1.42, and 0.608 L/min for V1, V2, V3, CL, Q2, and Q3, respectively. Predictive performance is better than or similar to that of specialized models, even for the subpopulations on which those models were derived. CONCLUSIONS: We have developed a single propofol PK model that performed well for a wide range of patient groups and clinical conditions. Further prospective evaluation of the model is needed.

A General Purpose Pharmacokinetic Model for Propofol

Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted (target) drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. We also describe the launch of the current clinically available systems.

/pdf/the-history-of-target-controlled-infusion-1p0efp9aq5.pdf

The History of Target-Controlled Infusion

Background A prototype paediatric propofol target-controlled infusion (TCI) system, the ‘Paedfusor’ has been developed. This system incorporates a paediatric pharmacokinetic data set and algorithm specific for children in a Graseby 3500 anaesthesia syringe driver. In this study we have evaluated the accuracy of the Paedfusor TCI system in children who underwent either cardiac surgery or cardiac catheterization procedures. Methods Twenty-nine children aged 1–15 yr were investigated. General anaesthesia was provided using propofol administered by the Paedfusor system. Accuracy of the system was evaluated by obtaining up to 9 arterial samples for measurement of propofol concentration both during anaesthesia and in the recovery period. Measured arterial propofol concentrations were then compared with values calculated by the Paedfusor. Results The predictive indices of median performance error (MDPE), and median absolute performance error (MDAPE) of the Paedfusor system were found to be 4.1% and 9.7%, respectively and the median value for wobble was 8.3%. These values are much better than those found with the adult ‘Diprifusor’ system. Conclusion The Paedfusor performance was found to be within the accepted limits for use as a TCI system.

Accuracy of the ‘Paedfusor’ in children undergoing cardiac surgery or catheterization

Accuracy of the Paedfusor - a new propofol target-controlled infusion system for children

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Accuracy of the ‘Paedfusor’ in children undergoing cardiac surgery or catheterization

Accuracy of the Paedfusor - a new propofol target-controlled infusion system for children