Physostigmine for prevention of postoperative delirium and long-term cognitive dysfunction in liver surgery: A double-blinded randomised controlled trial

Eur J Anaesthesiol. 2021 Sep 1;38(9):943-956. doi: 10.1097/EJA.0000000000001456.


Background: Anecdotally, cholinergic stimulation has been used to treat delirium and reduce cognitive dysfunction.

Objective: The aim of this investigation was to evaluate whether physostigmine reduced the incidence of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) in patients undergoing liver resection.

Design: This was a double-blind, randomised, placebo-controlled trial. Between 11 August 2009 and 3 March 2016, patients were recruited at the Charité - Universitätsmedizin Berlin in Germany. Follow-ups took place at 1 week (T1), 90 days (T2) and 365 days (T3) after surgery.

Setting: This single-centre study was conducted at an academic medical centre.

Participants: In total, 261 participants aged at least 18 years scheduled for elective liver surgery were randomised. The protocol also included 45 non-surgical matched controls to provide normative data for POCD and neurocognitive deficit (NCD).

Intervention: Participants were allocated to receive either intravenous physostigmine, as a bolus of 0.02 mg kg-1 body weight followed by 0.01 mg kg-1 body weight per hour (n = 130), or placebo (n = 131), for 24 h after induction of anaesthesia.

Main outcomes and measures: Primary outcomes were POD, assessed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-4-TR) twice daily up to day 7 after surgery, and POCD assessed via the CANTAB neuropsychological test battery, and two paper pencil tests on the day before surgery, and on postoperative days 7, 90 and 365.

Results: In total, 261 patients were randomised, 130 to the physostigmine and 131 to the placebo group. The incidence of POD did not differ significantly between the physostigmine and placebo groups (20 versus 15%; P = 0.334). Preoperative cognitive impairment and POCD frequencies did not differ significantly between the physostigmine and placebo groups at any time. Lower mortality rates were found in the physostigmine group compared with placebo at 3 months [2% (95% confidence interval (CI), 0 to 4) versus 11% (95% CI, 6 to 16), P = 0.002], and 6 months [7% (95% CI, 3 to 12) versus 16% (95% CI, 10 to 23), P = 0.012] after surgery.

Conclusion: Physostigmine had no effect on POD and POCD when applied after induction of anaesthesia up to 24 h.

Trial registration: DOI 10.1186/ISRCTN18978802, EudraCT 2008-007237-47, Ethics approval ZS EK 11 618/08 (15 January 2009).

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Cognitive Dysfunction* / epidemiology
  • Cognitive Dysfunction* / etiology
  • Cognitive Dysfunction* / prevention & control
  • Delirium* / diagnosis
  • Delirium* / epidemiology
  • Delirium* / prevention & control
  • Humans
  • Liver
  • Physostigmine
  • Postoperative Complications / epidemiology
  • Postoperative Complications / prevention & control


  • Physostigmine