Pharmacokinetic/pharmacodynamic modeling of anesthetics in children: therapeutic implications

Modeling the pharmacokinetics and pharmacodynamics of anesthetics in children is performed as a response to the clinical need for safe and efficacious administration of drugs with a low therapeutic index. Rates and concentrations of these drugs, which are the primary parameters used by anesthesiologists, depend on physiologic parameters that are markedly affected by development. Volatile anesthetics have been used for >50 years in pediatric patients. The pharmacokinetics of inhalation agents are context sensitive, but little difference between age groups has been described. These agents are not only eliminated unchanged by the lung but they are also metabolized by the liver. Halothane has Michaelis-Menten kinetics, with up to 40% of the administered dose metabolized by the liver. For volatile anesthetics, the effect measured is the minimum alveolar concentration (MAC) that leads to movement of the limb in response to skin incision in 50% of the patients studied. The MAC is higher in infants than in children and adults. Infants aged 6 months have a MAC 1.5-1.8 times the MAC observed in adults aged 40 years. Children have a greater clearance and volume of distribution of propofol than adults. In order to achieve similar plasma concentrations, children require three times the initial dose used in adults. In adults, an increased sensitivity to propofol has been demonstrated with aging, but nothing is known about the effects in children. However, it is clear that equipotent doses of propofol induce marked deleterious hemodynamic effects in infants compared with children. Regional anesthesia is used in pediatrics, both in combination with general anesthesia during surgery or alone for postoperative analgesia. A marked decrease in protein binding has been described in infants. In the postoperative period, a rapid increase in binding because of inflammation decreases the free fraction, but the free drug concentration remains constant because of the resulting decrease in total clearance. A low clearance because of liver function immaturity has been observed during the first year(s) of life for bupivacaine and ropivacaine. Pharmacodynamic interactions between general anesthesia and regional anesthesia need to be modeled. This is one of the future tasks for pharmacokineticists. Methods such as the Dixon up-and-down allocation and the isobolographic technique are promising in this field.