Neostigmine infusion in septic shock linked to lower TNF-alpha and 28-day mortality in single-center RCT

OBJECTIVE: The cholinergic anti-inflammatory pathway (ChAP) is the key regulator of the dysregulated cytokine storm in sepsis, with acetylcholine acting on alpha-7 nicotinic acetylcholine receptors (α7nAChRs) to suppress excessive inflammation. The objective of this study was to evaluate whether neostigmine administration modulates the inflammatory response in sepsis by enhancing cholinergic anti-inflammatory activity. DESIGN: A single-center, prospective, randomized, double-blinded, placebo-controlled study. SETTING: One adult ICU at a tertiary academic medical institution. INTERVENTION: Patients were randomized to receive neostigmine at a fixed rate of 0.2 mg/hr (2 mL/hr) or placebo. Study drug was administered for 5 days. MEASUREMENTS AND RESULTS: The primary outcome measure was decrease in tumor necrosis factor-alpha levels, in patients treated with neostigmine adjuvant therapy vs. the standard therapy. The secondary outcomes were hemodynamic parameters, septic shock reversal, changes in procalcitonin levels, and organ failure scores. The mean tumor necrosis factor-alpha levels were significantly lower in the neostigmine group (40 ± 36 pg/mL, mean ± sd ) on day 5 as compared with the control group (67 ± 43 pg/mL; p = 0.002). There was a significant reduction in Sequential Organ Failure Assessment scores from day 1 to day 5 ( p < 0.001) and 28-day mortality was also lower in the neostigmine group (26%) as compared with control group (54%, p = 0.02). CONCLUSIONS: The neostigmine infusion modulates the ChAP by potentiating the acetylcholine release leading to reduced systemic inflammation and decreased cytokine levels in septic shock patients. (Clinical Trial Registry of India number: CTRI/2023/07/ 055054).