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的合适剂量尚不清楚 建议差异很大，临床医生几乎没有合适的 信息(以及许多我们认为是错误的轶事建议) 指导他们的实践。我们认为有很大的差异 新生儿对芬太尼的剂量要求，这些差异是 根据芬太尼的药代动力学和 这些患者的药效学。我们的首要目标是研究成熟度 新生儿阿片类药物的药效学变化--与芬太尼比较 吗啡。我们的兴趣来自于观察到，基于 呼吸效应新生儿对吗啡“敏感” 儿童和成人，可能是由于他们的渗透性增加 血脑屏障。相似的“敏感度”(通气性和 止痛剂)被称为芬太尼，导致临床医生调整芬太尼 剂量不当，以仅适用于吗啡的假设为指导。 根据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 呼吸抑制或止痛)随年龄变化最小。研究 在1-35天龄的狗身上进行。输注芬太尼或吗啡 足以抑制呼吸或延长反应潜伏期的剂量 对有害刺激；血浆阿片类药物浓度和 通风或止痛符合药代动力学/药效学 模特。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，这是主要决定因素 新生儿血浆芬太尼浓度的变化。我们的兴趣是从 新生儿芬太尼清除量差异很大，限制了 麻醉师选择合适的芬太尼剂量的能力 单个新生儿。因为芬太尼在肝脏中代谢，所以因子 可能会影响肝脏血流或肝功能 导致了这种可变性。我们已经确定了七个因素，可能 对新生儿芬太尼清除量的影响；出生后年龄，胎龄， 腹内压升高，低碳酸血症和高碳酸血症，低氧， 吸入麻醉药和前列腺素的使用 E1。我们假设新生儿芬太尼清除量的变异性是 归因于这些因素；然而，每个因素的相对重要性是 未知。建议进行七项研究；六项在羔羊身上进行，一项在羊羔身上进行 在人类身上。在羔羊中，芬太尼进入稳定状态后，肝脏 血流量、肝脏芬太尼拔除和肝脏芬太尼清除 在不同出生年龄和生理过程中测定的动物 增加腹内压等干预措施。在人类身上， 以人群为基础的药代动力学研究在早产儿和 用NONMEM进行分析。这些研究使我们能够 评估这七个因素中的每一个在 确定芬太尼清除量。药代动力学综合知识 芬太尼在新生儿中的药效学将为临床医生提供 合理选择芬太尼个体剂量的依据 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.