水杨酸毒扁豆碱（安替可林®）在围手术期脓毒症和感染性休克中的辅助应用：一项随机、双盲、安慰剂对照、单中心试验（安替可林®自身对照试验）的研究方案
Adjunctive use of physostigmine salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se).
作者信息
Zimmermann Johannes B, Pinder Nadine, Bruckner Thomas, Lehmann Monika, Motsch Johann, Brenner Thorsten, Hoppe-Tichy Torsten, Swoboda Stefanie, Weigand Markus A, Hofer Stefan
机构信息
Department of Anaesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
Pharmacy Department, University Hospital Heidelberg, Im Neuenheimer Feld 670, 69120, Heidelberg, Germany.
出版信息
Trials. 2017 Nov 10;18(1):530. doi: 10.1186/s13063-017-2231-x.
BACKGROUND
Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival.
METHODS
Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with physostigmine salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization.
DISCUSSION
This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication.
TRIAL REGISTRATION
EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).
背景
即使在现代重症监护条件下，严重脓毒症和脓毒性休克仍然是一项重大挑战。在德国，每年约有68000名患者死于脓毒症相关疾病，其特征为复杂的全身炎症反应。对潜在感染进行病因治疗是脓毒症成功治疗的关键，但支持性和辅助性措施也能对病程产生积极影响。胆碱能抗炎通路（CAP）代表了脓毒症相关疾病辅助治疗的一种新方法，可通过乙酰胆碱酯酶抑制剂毒扁豆碱（安蒂胆碱®）进行药理学激活。在脓毒症的多种体外和体内模型中都发现了其有前景的效果，比如促炎细胞因子减少以及生存率提高。
方法
“安蒂胆碱®单药研究”是一项随机、双盲、安慰剂对照的单中心试验，旨在评估胆碱能抗炎通路能否从实验室应用于临床。在这项初步研究中，纳入了20例因腹腔内感染导致围手术期脓毒症和脓毒性休克的患者。根据随机分组，参与者接受水杨酸毒扁豆碱治疗（治疗组）或0.9%氯化钠治疗（安慰剂组），最长治疗5天。治疗期间及随后长达14天的重症监护期间的平均序贯器官衰竭评估（SOFA）评分用作替代结局（主要终点）。次要结局指标包括30天和90天死亡率。一项嵌入式药代动力学和药效学研究考察毒扁豆碱及其代谢产物依色林的血浆浓度。进一步分析将有助于我们理解各种细胞因子在人类脓毒症病理生理学中的作用。采用计算机生成的列表进行区组随机化。
讨论
这项随机、对照的单中心试验首次研究了毒扁豆碱（安蒂胆碱®）在围手术期脓毒症和脓毒性休克患者中的辅助应用，可能是朝着该适应证临床应用迈出的关键一步。
试验注册
欧盟临床试验注册号：2012-001650-26（2012年8月14日录入），美国国立医学图书馆临床试验标识符：NCT03013322（2017年1月1日注册）。
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