Efficacy and Safety of Neostigmine Adjunctive Therapy in Patients With Sepsis or Septic Shock: A Randomized Controlled Trial

Mona M El-Tamalawy, Moetaza M Soliman, Amany F Omara, Amal Rashad, Osama M Ibrahim, Mamdouh M El-Shishtawy, Mona M El-Tamalawy, Moetaza M Soliman, Amany F Omara, Amal Rashad, Osama M Ibrahim, Mamdouh M El-Shishtawy

Abstract

Background: Neostigmine has been found to improve survival in animal models of sepsis. However, its feasibility, efficacy, and safety in patients with sepsis or septic shock have not been investigated. Aim: This parallel randomized controlled double-blinded design aimed to investigate the efficacy and safety of neostigmine as an adjunctive therapy in patients with sepsis or septic shock. Patients and Methods: A total of 167 adult patients with sepsis or septic shock were assessed for eligibility; 50 patients were randomized to receive a continuous infusion of neostigmine (0.2 mg/h for 120 h; neostigmine arm) or 0.9% saline (control arm) in addition to standard therapy. The primary outcome was the change in Sequential Organ Failure Assessment (SOFA) scores 120 h after therapy initiation. Secondary outcomes included mortality rates and changes in procalcitonin level. Results: The median (interquartile range) change in SOFA scores improved significantly in the neostigmine arm [-2 (-5, 1)] as compared with the control arm [1.5 (0, 2.8); p = 0.007]. Progression from sepsis to septic shock was more frequent in the control arm (p = 0.01). The incidence of shock reversal in patients with septic shock was significantly lower in the control arm than in the neostigmine arm (p = 0.04). Differences in 28-days mortality rates did not reach statistical significance between the control and neostigmine arms (p = 0.36). Percentage change in procalcitonin levels was similar in both arms (p = 0.74). Conclusion: Neostigmine adjunctive therapy may be safe and effective when administered in patients with sepsis or septic shock. Clinical Trial Registration: NCT04130230.

Keywords: SOFA score; choline esterase inhibitor; cholinergic anti-inflammatory pathway; procalcitonin; sepsis; septic shock.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 El-Tamalawy, Soliman, Omara, Rashad, Ibrahim and El-Shishtawy.

Figures

GRAPHICAL ABSTRACT
GRAPHICAL ABSTRACT
FIGURE 1
FIGURE 1
Flowchart of patient enrollment. * Management other than study intervention/placebo administration were provided for all patients in accordance to surviving sepsis campaign guidelines (Rhodes et al., 2016). Follow-up was 28 days for 28-days mortality and shock reversal, and 5 days for other outcomes.
FIGURE 2
FIGURE 2
Change in Sequential Organ Function Assessment (SOFA) score in the control and neostigmine arms. (A) In all patients. (B) In patients with sepsis. (C) In patients with septic shock. *p-value <0.05.
FIGURE 3
FIGURE 3
SOFA scores at baseline and at 120 h in the control and neostigmine arms. *p < 0.05.
FIGURE 4
FIGURE 4
Kaplan–Meier survival estimates of 28-days mortality.
FIGURE 5
FIGURE 5
Kaplan–Meier survival estimates of ICU discharge.
FIGURE 6
FIGURE 6
Hemodynamics (mean arterial pressure [MAP], heart rate, and respiratory rate) at 120 h after treatment initiation in patients with septic shock.

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