KINETICS AND DYNAMICS OF FENTANYL ANESTHESIA IN NEONATES

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Although fentanyl, an opioid, is widely used as an anesthetic for neonates, the appropriate dose of fentanyl for individual neonates is unknown, dose recommendations vary widely, and clinicians have little appropriate information (and much anecdotal advice that we believe is mistaken) to guide their practice. We propose that there are large differences in neonatal dose requirements for fentanyl and that these differences are predictable based on knowledge of fentanyl's pharmacokinetics and pharmacodynamics in these patients. Our first aim is to study maturational changes in pharmacodynamics of opioids in neonates, comparing fentanyl to morphine. Our interest evolves from the observation that, based on ventilatory effects neonates are "sensitive" to morphine compared to children and adults, presumably a result of increased permeability of their blood-brain barrier. Similar "sensitivity" (both ventilatory and analgesic) is alleged for fentanyl, leading clinicians to adjust fentanyl doses inappropriately, guided by assumptions that apply solely to morphine. Based on clinical observations and preliminary studies, we hypothesize that sensitivity to fentanyl (defined as the plasma concentration that produces ventilatory depression or analgesia) varies minimally with age. Studies are performed in dogs aged 1-35 days. Fentanyl or morphine are infused in doses sufficient to depress ventilation or prolong latency of the response to a noxious stimulus; plasma opioid concentrations and values for ventilation or analgesia are fit to a pharmacokinetic/pharmacodynamic model. These studies permit us to determine whether there are maturational changes in the pharmacodynamics of fentanyl. Our second aim is to determine factors influencing fentanyl clearance, the primary determinant of plasma fentanyl concentration, in neonates. Our interest evolves from the observation that fentanyl clearance varies widely in neonates, limiting anesthesiologist's ability to select appropriate fentanyl doses for individual neonates. Because fentanyl is metabolized in the liver, factors that influence either hepatic blood flow or hepatic function likely contribute to this variability. We have identified seven factors that may influence fentanyl clearance in neonates; postnatal age, gestational age, increased intraabdominal pressure, hypocapnea and hypercapnea, hypoxia, administration of inhaled anesthetics, and administration of prostaglandin E1. We hypothesize that variability of fentanyl clearance in neonates is attributable to these factors; however, the relative importance of each is unknown. Seven studies are proposed; six to be performed in lambs, and one in humans. In lambs, after fentanyl is infused to steady state, hepatic blood flow, hepatic fentanyl extraction and hepatic fentanyl clearance are determined in animals of various postnatal ages and during physiologic interventions such as increased intraabdominal pressure. In humans, population-based pharmacokinetic studies are performed in premature and fullterm humans and analyzed using NONMEM. These studies permit us to assess the relative importance of each of these seven factors in determining fentanyl clearance. Combined knowledge of the pharmacokinetics and pharmacodynamics of fentanyl in neonates will provide clinicians a rational basis for selecting appropriate fentanyl doses for individual neonates.