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)

Abstract

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).

Keywords: Antilirium; Cholinergic anti-inflammatory pathway; Cholinesterase inhibitor; Continuous administration; Critically ill; Eserine; Eseroline; Intra-abdominal infection; Physostigma venenosum; Sequential Organ Failure Assessment (SOFA) score.

Conflict of interest statement

Ethics approval and consent to participate

The clinical trial protocol and the corresponding documents have been approved by the Federal Institute for Drugs and Medical Devices (BfArM) and the Ethics Committee, Medical Faculty of Heidelberg University (AFmu-447/2012).

The members of the study group must inform eligible patients, both orally and in writing in an intelligible form about its nature, significance, and implications. Before participants can be enrolled in Anticholium® per Se, they must consent to participation in writing. For potential trial participants who are incapable there is a locally established procedure [29].

If a legal guardian already exists, they are duly informed in accordance with the regulations and subsequently consent to participation in writing. If no legal guardian exists, participants are enrolled in the clinical trial after a near family member has been informed about its nature, significance, and implications and has agreed to participation in the study mindful of the interest of the patient concerned (also by telephone). In summary proceedings, the designation of a legal guardian is begun at the district court. If no near family member is available, participants are enrolled after a guardianship judge has been informed about its nature, significance, and has agreed to participation in the study mindful of the interest of the patient concerned (also by telephone). A near family member is appointed legal guardian as earlier as possible; they are duly informed in accordance with the regulations and subsequently consent to participation in writing (delayed consent). In any case, informed consent of study participants is sought retrospectively once they are capable of giving consent again.

Consent for publication

Not applicable.

Competing interests

JBZ, NP, TBru, ML, JM, TBre, THT and SS declare no competing interests. MAW and SH have served as speakers for and SH has received tangible means (reagents and a device for cholinesterase measurement) from Dr. Franz Köhler Chemie GmbH.

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