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

Abstract

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.

Figures

Figure 1

Chemical structure of propofol (2,6- diisopropylphenol) depicting the key propofol moieties, most notably, the phenolic hydroxyl group (−OH) and the number and arrangement of methyl groups (−CH3) at the 2- and 6- positions that determine the potency and the efficacy of the receptor – drug interaction.

Figure 2

Diagrammatic representation of the gamma-aminobutyric acid (GABA) A receptor in the cell membrane with its α, β and γ subunits where propofol mainly interacts to cause its anesthetic effect in the central nervous system. The “P” starred structures represent propofol drug molecules. On interacting with the GABAA receptor, chloride ion influx happens through the central Chloride channel (represented by arrow).

Figure 3

Model-based predictions of population clearance estimates of propofol vs. age for patients with different total body weights. shows both the allometric increase of propofol clearance with TBW as the distance between the weight classes decreases with increasing TBW, and the bilinear relationship of propofol clearance with age (Reprinted unchanged from “An Integrated Population Pharmacokinetic Meta-Analysis of Propofol in Morbidly Obese and Nonobese Adults,Adolescents, and Children,” by J Diepstraten et. al.[69] CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e73, p 5, published by Nature Publishing Group, licensed for reprinting under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 License).

Figure 4

Diagrammatic representation of propofol effects on the mitochondrial electron transport chain: The electron transport chain is located in the inner membrane of mitochondria: During oxidative phosphorylation, electrons from reduced coenzyme Nicotinamide Adenine Dinucleotide (NADH) and Succinate (formed from citric acid cycle) enter the electron transport chain (ETC) via Complex I and II respectively. Electrons are then fed to Coenzyme Q, which passes them to Complex III, Cytochrome C, and Complex IV sequentially. This electron flow leads to proton translocation and build up in the intermembrane space creating an electromechanical gradient which drives the synthesis of ATP by ATP synthase. Propofol brings about uncoupling of oxidative phosphorylation by its inhibitory effects on various complexes involved in the process (denoted by black arrows).