KINETICS AND DYNAMICS OF FENTANYL ANESTHESIA IN NEONATES

尽管芬太尼是一种阿片类药物，被广泛用作新生儿的麻醉剂， 芬太尼对个别新生儿合适剂量是未知的，剂量 建议差异很大，临床医生几乎没有合适的 信息（以及我们认为错误的许多轶事建议）， 指导他们的实践。 我们认为， 芬太尼的新生儿剂量要求，这些差异是 根据芬太尼的药代动力学知识， 这些患者的药效学。 我们的第一个目标是学习成熟 阿片类药物在新生儿中的药效学变化，比较芬太尼和 吗啡 我们的兴趣来自于这样一种观察， 新生儿对吗啡比较敏感， 儿童和成人，大概是由于他们的渗透性增加， 血脑屏障 类似的"敏感性"（包括解释性和 镇痛剂）被指控为芬太尼，导致临床医生调整芬太尼 剂量不当，由仅适用于吗啡的假设指导。 基于临床观察和初步研究，我们假设， 对芬太尼的敏感性（定义为产生芬太尼的血浆浓度） 抑郁症或镇痛）随年龄变化很小。 研究 在1 - 35日龄的狗中进行。 注射芬太尼或吗啡 足以抑制通气或延长反应潜伏期的剂量 有害刺激;血浆阿片样物质浓度和值 通气或镇痛符合药代动力学/药效学 模型 这些研究使我们能够确定是否有成熟的 芬太尼的药效学变化。 我们的第二个目标是 确定影响芬太尼清除率的因素， 血浆芬太尼浓度。 我们的兴趣来自于 观察到芬太尼清除率在新生儿中变化很大， 麻醉师选择适当芬太尼剂量的能力 个别新生儿。 因为芬太尼在肝脏中代谢， 可能影响肝血流或肝功能 有助于这种变化。 我们已经确定了七个因素， 影响新生儿芬太尼清除率;出生后年龄，胎龄， 腹内压升高，低碳酸血症和高碳酸血症，缺氧， 吸入麻醉剂的施用和前列腺素的施用 e1. 我们假设新生儿芬太尼清除率的变异性 这些因素都是重要的，但是，每个因素的相对重要性是 未知 提出了七项研究;六项在羔羊中进行，一项在羔羊中进行。 在人类身上。 在羔羊中，芬太尼输注至稳态后， 血流、肝芬太尼提取和肝芬太尼清除率 在不同出生后年龄的动物和生理期间测定 例如增加腹内压。 在人类中， 基于人群的药代动力学研究在早产儿和 足月人并使用NONMEM分析。 这些研究使我们能够 评估这七个因素中每一个的相对重要性， 测定芬太尼清除率 药代动力学的综合知识 芬太尼在新生儿中的药效学将为临床医生提供 为个体选择合适芬太尼剂量的合理依据 新生儿

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.