Memphis Veterans Affairs Medical Center Research Service, Departments of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
Pulmonary, Critical Care, and Sleep Medicine Service and Research Service, Memphis Veterans Affairs Medical Center, 1030 Jefferson Avenue, Suite room #CW444, Memphis, TN, 38104, USA.
Intensive Care Med. 2020 Dec;46(12):2284-2296. doi: 10.1007/s00134-020-06289-8. Epub 2020 Nov 4.
Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs' findings, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic-pituitary-adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.
目前关于指导 ARDS 中糖皮质激素 (GC) 给药的药理学原则的文献很少。这种信息的缺乏可能导致了治疗方案的异质性和对现有发现的误解。GC 是与 GC 受体 (GR) 结合产生药理反应的激动剂化合物。临床疗效取决于 GR 的暴露程度和持续时间。我们更新了关于 GC 治疗 ARDS 的随机试验的荟萃分析，重点关注治疗方案和反应。我们综合了目前关于 GR 在 GC 治疗中的作用的文献，包括基因组和非基因组效应，并整合了各种 GC（包括氢化可的松、甲基强的松龙和地塞米松）的当前临床药理学知识。这篇综述探讨了剂量、开始时间、给药方式、持续时间和逐渐减少在实现 ARDS 中 GC 治疗最佳反应中的作用。基于 RCT 的发现、GC 血浆浓度-时间曲线和药效学研究，早期干预、初始推注剂量以实现接近最大 GRα 饱和，随后持续输注以在整个治疗期间维持高反应水平，最有可能获得最佳结果。此外，接受类似 GC 剂量的患者可能会出现血浆浓度的个体间显著差异，从而影响临床反应。GC 应根据剂量调整，并持续给药，以达到临床和实验室改善的目标，然后逐渐减少剂量，以实现受抑制的下丘脑-垂体-肾上腺 (HPA) 轴的逐渐恢复。这些发现具有实际的临床意义。未来的 RCT 应在研究设计和结果解释中考虑这些药理学原则。
