Introduction: Postoperative ileus (POI) is a significant complication following abdominal surgery, increasing morbidity and mortality. The cholinergic anti-inflammatory response is one of the major pathways involved in developing POI, but current recommendations to prevent POI do not target this. This review aims to summarise evidence for the use of acetylcholinesterase inhibitors, neostigmine and pyridostigmine, to reduce the time to return of gastrointestinal function (GI) following abdominal surgery. Methods: A systematic search of various databases was performed from 1946 to May 2023. Randomised controlled trials (RCTs) on acetylcholinesterase inhibitors in intra-abdominal surgery were included. Data on time to flatus and/or stool and side effects were extracted. Results: Among 776 screened manuscripts, 8 RCTs (703 patients) investigating acetylcholinesterase inhibitors in intra-abdominal surgery were analysed. Five studies showed a significant reduction in time to flatus and/or stool by 17–47.6 h. Methodological variations, differing procedure types, and potential bias were observed. Limited studies reported side effects or length of stay. Conclusion: Acetylcholinesterase inhibitors may reduce the time for GI to return. However, current evidence is limited and biased. Further studies incorporating acetylcholinesterase inhibitors in an enhanced recovery protocol are required to address this question, especially for patients undergoing colorectal surgery.

Postoperative ileus (POI) is the delay in return of gastrointestinal function (GI) following abdominal surgery, occurring in up to 30% of patients [1, 2]. This complication is characterised by intolerance of oral diet and absence of flatus and stool, meaning that patients with POI suffer from vomiting, predisposing them to malnutrition, delayed wound healing, anastomotic leak, and pneumonia [2, 3]. As a result, patient recovery is negatively impacted, significantly increasing length of stay and inpatient stay costs [4‒8].

The mechanism of POI can be described as a two-phase process. The initial, neurogenic phase occurs during surgery as a response to surgical stimuli [9]. The secondary, inflammatory phase begins around 3 h postoperatively, with the release of inflammatory mediators affecting bowel function for a varied length of time [9, 10]. This inflammatory cascade is mediated, in part, by the cholinergic anti-inflammatory pathway (CAIP) [11‒13].

To reduce the negative impact of POI, research has focused on improving surgical recovery and reducing postoperative hospital stay as part of enhanced recovery protocols (ERPs) [14]. Several novel therapies such as alvimopan, methylnaltrexone, prucalopride and trials using laxatives, chewing gum, and coffee have been investigated with varying degrees of success [14‒19]. However, limited ERP strategies target the CAIP [9, 19‒21]. This is despite acetylcholinesterase inhibitors, such as neostigmine and pyridostigmine, being readily available and having their direct mechanism of action via this pathway. In abdominal surgery, these drugs are mostly known for treating acute colonic pseudo-obstruction (ACPO) by stimulating gastrointestinal mass movement [22]. While they have also been suggested for use in reducing the time to return of GI, evidence for their use remains sparse, as highlighted in our previous scoping clinical review [23‒28]. Previous studies have variability in the subspecialty, do not reside within modern ERPs or laparoscopic surgery, and are not colorectal specific where POI is most common [23‒29]. Therefore, our focus of this systematic review was to establish the evidence base, namely, randomised controlled trials (RCTs), for the use of acetylcholinesterase inhibitors in abdominal surgery to reduce the time to return of GI.

This study was registered prospectively with the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021250387). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [30] guidelines were used for conducting and reporting the results of this study.

Search Strategy

Two independent reviewers (L.T. and N.D.-V.) performed a systematic search of PubMed (1956–2023), Ovid MEDLINE (1946–2023), Embase (1974–2023), Cochrane Library (2005–2023), ClinicalTrials.gov, and Cumulative Index of Nursing and Allied Health Literature (CIANHL) databases (1984–2023). Studies were included until May 31, 2023. Medical subject headings and keyword search terms related to “acetylcholinesterase inhibitors”, “neostigmine”, “pyridostigmine”, “abdominal”, “surgery”, “postoperative”, “gut motility”, and “ileus” were used. The search strategies are provided in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000535753).

Eligibility Criteria

Studies were included for full-text review if they were related to POI or gut motility following surgery. The articles needed to be available in full text and published in English. Inclusion criteria were RCTs, human patients over 18 years of age undergoing elective or emergency abdominal surgery, diagnosed with POI, investigating bowel function, and given acetylcholinesterase inhibitors as an intervention. As a limited number of papers were identified on preliminary screening, all intra-abdominal surgical cases at risk of POI were included. Articles were excluded if POI resulted from mechanical obstruction or the study related to ACPO. Due to the primary outcome being identified, non-RCTs, prospective and retrospective cohort studies, case-control and cross-sectional studies were excluded.

Study Selection

Studies were selected using Covidence systematic review software (Veritas Health Innovation, Melbourne, VIC, Australia). Both reviewers individually screened titles and abstracts. Full-text review was performed with the references checked to identify potential additional articles. Any disagreements were resolved by consensus arbitrated by a third author (S.B.).

Data Extraction and Synthesis

Two reviewers (L.T. and N.D.-V.) extracted the data independently using a predefined standard data extraction form. Extracted baseline data included author name, country, year, patient population, surgery type, number of patients, drug route, and type of intervention. The primary outcomes extracted included time to passage of first stool and flatus. Secondary outcomes that were extracted included side effects and length of stay. Data were corroborated following extraction and any discrepancies in the extracted data were resolved by the third reviewer (S.B.).

Risk of Bias in Individual Studies

Risk of bias was recorded using the Cochrane risk of bias for randomised trials (RoB 2) [31] and was tabulated using ROBVIS [32].

Statistical Analysis

Data were analysed using descriptive statistics and presented as time in hours, frequency, and percentages as appropriate. Due to the mixture of median (range), median (IQR), and mean (SD), the differences in patient population, and type of surgery, the results of the studies were unable to be pooled into a meta-analysis.

The literature search identified 776 studies, of which 167 were duplicates and were removed. Of the 609 studies, 588 were excluded after they did not meet the predefined inclusion criteria on screening the title and abstract. Twenty studies were screened in full-text review, with eight meeting the inclusion criteria (Fig. 1) [23‒27, 33‒35].

Fig. 1.

PRISMA flow chart.

Fig. 1.

PRISMA flow chart.

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Characteristics of Studies

The eight included RCTs spanned seven countries and were published between 1986 and 2019, including 703 patients. There was heterogeneity in surgery types ranging from general surgery, gynaecology and vascular, and a mix of laparoscopic and open cases. Five studies were double-blinded RCT [23‒25, 27, 34], of which three provided power calculations for recruitment targets [23, 27, 34]. Three studies were single blinded [26, 33, 35], with one of these studies blinding only the participants [33]. Of the eight studies, only three were embedded in a standard ERP [27, 34, 35]. The full study characteristics are provided in Table 1.

Table 1.

Characteristics of included studies

ReferenceCountryYearOperationsSurgical approachPatients, nInterventionRoute of administrationBlinding
interventioncontroltotal
An et al. [34Korea 2020 Cholecystectomy Lap 53 49 102 Pyridostigmine IV Double 
Caliskan et al. [27Turkey 2008 Abdominal aortic surgery Open 18 16 34 Neostigmine Thoracic epidural Double 
Garcia-Caballero and Vara-Thorbeck [26Spain 1993 Cholecystectomy Open/Lap 76 20 96 Neostigmine + propranolol±bupivacaine SC Single (patients) 
Hallerback et al. [25Sweden 1987 Cholecystectomy Open 34 17 51 Neostigmine±propranolol SC Double 
Madsen et al. [24Denmark 1986 Gastric, pancreatic, intestinal Open 24 24 48 Neostigmine IM Double 
Maleknejad et al. [33Iran 2018 Gynaecological, gastric, bowel 20 20 40 Pyridostigmine NG Single (patients) 
Myrhoj et al. [23Denmark 1988 Gastric, pancreatic, intestinal Open 42 44 86 Neostigmine IM Double 
You et al. [35China 2018 Gastrectomy Open/lap 193 53 246 Neostigmine Acupoint or IM Single (investigators) 
ReferenceCountryYearOperationsSurgical approachPatients, nInterventionRoute of administrationBlinding
interventioncontroltotal
An et al. [34Korea 2020 Cholecystectomy Lap 53 49 102 Pyridostigmine IV Double 
Caliskan et al. [27Turkey 2008 Abdominal aortic surgery Open 18 16 34 Neostigmine Thoracic epidural Double 
Garcia-Caballero and Vara-Thorbeck [26Spain 1993 Cholecystectomy Open/Lap 76 20 96 Neostigmine + propranolol±bupivacaine SC Single (patients) 
Hallerback et al. [25Sweden 1987 Cholecystectomy Open 34 17 51 Neostigmine±propranolol SC Double 
Madsen et al. [24Denmark 1986 Gastric, pancreatic, intestinal Open 24 24 48 Neostigmine IM Double 
Maleknejad et al. [33Iran 2018 Gynaecological, gastric, bowel 20 20 40 Pyridostigmine NG Single (patients) 
Myrhoj et al. [23Denmark 1988 Gastric, pancreatic, intestinal Open 42 44 86 Neostigmine IM Double 
You et al. [35China 2018 Gastrectomy Open/lap 193 53 246 Neostigmine Acupoint or IM Single (investigators) 

IM, intramuscular; IV, intravenous; LAP, laparoscopic; NG, nasogastric; SC, subcutaneous.

Interventions

The studies used several routes of administration, dosing, and type of acetylcholinesterase inhibitors. The route of administration of the acetylcholinesterase inhibitor also differed between studies and included two subcutaneous (SC) [25, 26], one intravenous (IV) [34], one thoracic epidural [27], one nasogastric (NG) [33], two intramuscular (IM) [23, 24], and one acupoint (acupuncture site injection) and IM administration [35]. Six studies gave the control drug via the same route [23‒25, 27, 33, 34]. Two studies compared the intervention to standard therapy [26, 35].

Six studies used neostigmine as intervention [23‒27, 35] and two used pyridostigmine [33, 34]. The six studies investigating neostigmine differed in terms of intervention, control, and timing of administration. Caliskan et al. [27] compared a neostigmine epidural against a placebo given at the end of surgery and 8 h postoperatively in abdominal aortic surgery. Two studies compared SC neostigmine following cholecystectomy, given until the first stool [25, 26]. The other three studies gave IM neostigmine with one of them also giving neostigmine via acupoint injection postoperatively [23, 24, 35]. Myrhoj et al. [23] gave three IM doses of neostigmine over 1 day following laparotomy for gastric, pancreatic, and intestinal surgery whereas Madsen et al. [24] gave three IM neostigmine doses, 3 days following a laparotomy for gastric, pancreatic, and intestinal surgery. You et al. [35] gave neostigmine via acupoint and IM injections following gastrectomy until first bowel action.

The two studies investigating pyridostigmine also demonstrated variability in timing and type of intervention. An et al. [34] studied IV pyridostigmine against sugammadex to reverse neuromuscular blockade following laparoscopic cholecystectomy and its effect on gastrointestinal recovery. Maleknejad et al. [33] gave oral pyridostigmine via NG 3 days after the development of POI and compared this to a placebo. The interventions in the selected trials are summarised in Table 2.

Table 2.

Summary of study interventions and outcomes related to gastrointestinal recovery

ReferenceInterventionControlTiming of interventionPrimary outcomeSecondary outcome
An et al. [34Pyridostigmine 0.2 mg/kg + glycopyrrolate 0.008 mg/kg IV Sugammadex 2 mg/kg IV stat Intraoperative Time to first passage of flatus and defecation Stool type 
Caliskan et al. [27Neostigmine 5 mL (1 μg/kg) epidural Placebo End of surgery and 8 h postoperatively Time to flatus and defection Length of hospital stay 
Postoperative complications 
Garcia-Caballero and Vara-Thorbeck [26(1) Open cholecystectomy + intraoperative bupivacaine 20 mL 0.5% Open cholecystectomy with no intervention Intraoperatively and postoperatively until first stool Time to passage of first flatus and stool Adverse effects 
(2) Open cholecystectomy + neostigmine 0.5 mg SC BD + propranolol 7.5 mg Q8H IV 
(3) Both 1+2 
(4) Laparoscopic cholecystectomy 
Hallerback et al. [25Neostigmine 0.5 mg SC BD and/or propranolol 10 mg IV Placebo Postoperatively until first stool Time to passage of first stool Adverse effects 
Madsen et al. [24Neostigmine 5 μg/kg IM Ceruletide Postoperatively from day 3, every 3 h until passage of flatus or stool or 3 injections Passage of flatus or stool (%) 
Maleknejad et al. [33Pyridostigmine 60 mg NG BD Placebo Postoperatively from day 3 Time to passage of flatus and stool Frequency of response 
Myrhoj et al. [23Neostigmine 0.5 mg IM Placebo Postoperative for 3 doses Passage of flatus or stool (%) 
You et al. [35(1) ST36 acupuncture OD Standard therapy Postoperative until bowel recovery Time to first flatus, first defecation Drug-related adverse events 
(2) ST36 acupoint neostigmine injection 0.5 mg OD 
(3) Neostigmine IM 0.5 mg OD 
ReferenceInterventionControlTiming of interventionPrimary outcomeSecondary outcome
An et al. [34Pyridostigmine 0.2 mg/kg + glycopyrrolate 0.008 mg/kg IV Sugammadex 2 mg/kg IV stat Intraoperative Time to first passage of flatus and defecation Stool type 
Caliskan et al. [27Neostigmine 5 mL (1 μg/kg) epidural Placebo End of surgery and 8 h postoperatively Time to flatus and defection Length of hospital stay 
Postoperative complications 
Garcia-Caballero and Vara-Thorbeck [26(1) Open cholecystectomy + intraoperative bupivacaine 20 mL 0.5% Open cholecystectomy with no intervention Intraoperatively and postoperatively until first stool Time to passage of first flatus and stool Adverse effects 
(2) Open cholecystectomy + neostigmine 0.5 mg SC BD + propranolol 7.5 mg Q8H IV 
(3) Both 1+2 
(4) Laparoscopic cholecystectomy 
Hallerback et al. [25Neostigmine 0.5 mg SC BD and/or propranolol 10 mg IV Placebo Postoperatively until first stool Time to passage of first stool Adverse effects 
Madsen et al. [24Neostigmine 5 μg/kg IM Ceruletide Postoperatively from day 3, every 3 h until passage of flatus or stool or 3 injections Passage of flatus or stool (%) 
Maleknejad et al. [33Pyridostigmine 60 mg NG BD Placebo Postoperatively from day 3 Time to passage of flatus and stool Frequency of response 
Myrhoj et al. [23Neostigmine 0.5 mg IM Placebo Postoperative for 3 doses Passage of flatus or stool (%) 
You et al. [35(1) ST36 acupuncture OD Standard therapy Postoperative until bowel recovery Time to first flatus, first defecation Drug-related adverse events 
(2) ST36 acupoint neostigmine injection 0.5 mg OD 
(3) Neostigmine IM 0.5 mg OD 

BD, twice daily; IM, intramuscular; IV, intravenous; kg, kilogram; μg, microgram; mg, milligram; mL, millilitre; NG, nasogastric; OD, once daily; Q8H, 8 hourly; SC, subcutaneous.

Assessment of Risk of Bias

An et al. [34] had low risk of bias due to a robust methodology. Six studies were considered to have concerns for risk of bias [23‒27, 35]. This related to concerns about bias of reported results, often missing adverse effects and results. One study, Maleknejad et al. [33], had a high risk of bias with potential for deviations in measured outcomes. These data are presented in a summary and traffic light plot, Figures 2 and 3, respectively.

Fig. 2.

Summary plot.

Fig. 3.

Traffic light plot.

Fig. 3.

Traffic light plot.

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Gastrointestinal Recovery

Among the included studies, five reported time to flatus [26, 27, 33‒35], six reported time to first stool [25‒27, 33‒35], and two studies reported the frequency of patients passing flatus or stool within 9 h postoperatively or after commencing treatment [23, 24]. Notably, of all included studies none offered a strict clinical definition for POI.

Acetylcholinesterase inhibitors showcased enhanced gastrointestinal recovery in five studies compared to alternative treatment or placebo [25‒27, 33, 35]. Of studies that compared against placebo [25, 27, 33, 35], Caliskan et al. [27] found a 15-h reduction in time to flatus and a 17-h reduction in time to first stool in open abdominal aortic surgery (p < 0.05). Additionally, Hallerback et al. [25] also demonstrated a reduction in time to first stool after open cholecystectomy with neostigmine and propranolol, with a reduction of 22 h (p < 0.01), and You et al. [35] reported significant reductions following open and laparoscopic gastrectomy for acupoint and IM neostigmine in both time to first flatus and time to first stool, with greatest results in the acupoint group (p < 0.01). Furthermore, Maleknjad et al. [33] with NG pyridostigmine reported a significant reduction in time to the first flatus of 27.0 h and time to the first stool of 31.3 h with pyridostigmine (p = 0.001). Lastly, Garcia-Caballero and Vara-Thorbeck [26] demonstrated a significant reduction in time to flatus of 21 h and 40 h to first stool following open cholecystectomy with a combination of intramesenteric bupivacaine, SC neostigmine, and IV propranolol compared to open cholecystectomy without intervention (p < 0.01).

Three studies did not identify significant improvements in gastrointestinal recovery. Madsen et al. [24] and Myrhoj et al. [23] despite reported improved rates of passage of flatus or stool within 9 h did reach statistical significance. Additionally, An et al. [34] reported a significant reduction in time to flatus of 5.82 h with sugammadex in comparison to pyridostigmine in laparoscopic cholecystectomy (p = 0.001) and a non-statistical significant reduction in time to stool. A summary of the findings is provided in Table 3.

Table 3.

Reported results for gastrointestinal recovery

ReferenceInterventionControlTime to flatus, hTime to stool, hTrial arm favoured
interventionncontrol/comparisonnp valueinterventionncontrol/comparisonnp value
An et al. [34Pyridostigmine + glycopyrrolate Sugammadex 20.85 (6.36–20.25) 53 15.03 (16.34–25.86) 49 0.001 47.26 (38.72–68.54) 53 38 (25.07–64.74) 49 0.087 Sugammadex 
Caliskan et al. [27Neostigmine Placebo 21±15 18 36±19 16 <0.05 58±41 18 75±48 16 <0.05 Neostigmine 
Garcia-Caballero and Vara-Thorbeck [26Neostigmine + propranolol Open cholecystectomy with no intervention 48 (45–72) 17 60 (24–90) 20 NS 96 (45–125) 17 96 (60–125) 20 NS Neostigmine + propranolol + bupivacaine 
Neostigmine + propranolol + bupivacaine 39 (24–69) 19 <0.01 56 (24–69) 19 <0.01 
Neostigmine + bupivacaine 48 (24–96) 20 NS 72 (36–120) 20 <0.001 
Laparoscopic 10 (8–14) 20 <0.001 36 (24–40) 20 <0.05 
Hallerback et al. [25Neostigmine + propranolol Placebo 68±6 16 90±7 17 <0.01 Neostigmine + propranolol 
Neostigmine 82±6 18 NS 
Maleknejad et al. [33Pyridostigmine Placebo 5.4±4.7 20 32.4±9.9 20 0.001 4.9±3.4 20 36.2±10.3 20 0.001 Pyridostigmine 
You et al. [35Acupoint Standard therapy 2.3±0.56 67 44.15±1.69 53 <0.01 2.43±0.61 67 50.02±1.63 53 <0.01 Neostigmine 
IM 8.13±1.38 63 <0.01 9.78±1.66 67 <0.01 
Acupuncture 40.34±2.22 59 NS 47.44±1.56 59 NS 
ReferenceInterventionControlTime to flatus, hTime to stool, hTrial arm favoured
interventionncontrol/comparisonnp valueinterventionncontrol/comparisonnp value
An et al. [34Pyridostigmine + glycopyrrolate Sugammadex 20.85 (6.36–20.25) 53 15.03 (16.34–25.86) 49 0.001 47.26 (38.72–68.54) 53 38 (25.07–64.74) 49 0.087 Sugammadex 
Caliskan et al. [27Neostigmine Placebo 21±15 18 36±19 16 <0.05 58±41 18 75±48 16 <0.05 Neostigmine 
Garcia-Caballero and Vara-Thorbeck [26Neostigmine + propranolol Open cholecystectomy with no intervention 48 (45–72) 17 60 (24–90) 20 NS 96 (45–125) 17 96 (60–125) 20 NS Neostigmine + propranolol + bupivacaine 
Neostigmine + propranolol + bupivacaine 39 (24–69) 19 <0.01 56 (24–69) 19 <0.01 
Neostigmine + bupivacaine 48 (24–96) 20 NS 72 (36–120) 20 <0.001 
Laparoscopic 10 (8–14) 20 <0.001 36 (24–40) 20 <0.05 
Hallerback et al. [25Neostigmine + propranolol Placebo 68±6 16 90±7 17 <0.01 Neostigmine + propranolol 
Neostigmine 82±6 18 NS 
Maleknejad et al. [33Pyridostigmine Placebo 5.4±4.7 20 32.4±9.9 20 0.001 4.9±3.4 20 36.2±10.3 20 0.001 Pyridostigmine 
You et al. [35Acupoint Standard therapy 2.3±0.56 67 44.15±1.69 53 <0.01 2.43±0.61 67 50.02±1.63 53 <0.01 Neostigmine 
IM 8.13±1.38 63 <0.01 9.78±1.66 67 <0.01 
Acupuncture 40.34±2.22 59 NS 47.44±1.56 59 NS 
ReferenceInterventionControlPassing flatus or stool within 9 h postop
interventionncontrol/comparisonnp value
Madsen et al. [24Neostigmine Ceruletide 58% (36–78, 95% CI) 24 41% (22–63%, 95% CI) 24 NS 
Myrhoj et al. [23Neostigmine Placebo 19% (9–34, 95% CI) 42 34% (20–50, 95% CI) 44 
ReferenceInterventionControlPassing flatus or stool within 9 h postop
interventionncontrol/comparisonnp value
Madsen et al. [24Neostigmine Ceruletide 58% (36–78, 95% CI) 24 41% (22–63%, 95% CI) 24 NS 
Myrhoj et al. [23Neostigmine Placebo 19% (9–34, 95% CI) 42 34% (20–50, 95% CI) 44 

Data presented as mean (±SD); median (IQR); median [range]; NS, not statistically significant; 95% CI, 95% confidence interval; –, not available.

Reported Side Effects

Four studies reported side effects in the intervention arms [26, 27, 34, 35] and two other studies mentioned no significant complications [23, 33]. An et al. [34] reported a significantly higher percentage of patients with dry mouth following neostigmine against sugammadex administration (32 vs. 10.2%, p = 0.008). Caliskan et al. [27] reported significantly lower levels of nausea for the intervention arm (p < 0.05), and 2 patients suffered arrhythmias in the neostigmine group (p > 0.05). Garcia-Caballero and Vara-Thorbeck [26] reported significantly lower frequency of patients with abdominal pain who were given neostigmine with and without bupivacaine (29-30%, no p value provided) compared to the open cholecystectomy control group (45%, no p value provided) [27]. You et al. [35] reported significant difference in the acupoint neostigmine against the IM neostigmine group, with reduced nausea (p = 0.013), vomiting (p = 0.027), diarrhoea (p = 0.042), epiphora (p = 0.031), delirium (p = 0.031), and anxiety (p = 0.038). The provided side effects are summarised in Table 4.

Table 4.

Reported secondary outcomes and side effects

An et al. [34]Caliskan et al. [27]Garcia-Caballero and Vara-Thorbeck [26]You et al. [35]
pyridostigminesugammadexp valueneostigmineplacebop valueopen cholecystectomy + neostigmine + propranololopen cholecystectomy + neostigmine + propranolol + bupivacaineopen cholecystectomyp valueacupointIMp value
Nausea, % 15.1 16.3 NS 16.7 56.3 <0.05 4.5 17.9 0.013 
Vomiting, % 5.7 8.2 NS 12.5 NS 13.4 0.027 
Dry mouth, % 32 10.2 0.008 
Renal failure, % 11.1 NS 
Resp failure, % 11.1 6.25 NS 
Arrhythmia, % 11.1 NS 
Abdominal discomfort 1st day, % 30 29 45 
Diarrhoea, % 40.3 56.72 0.042 
Epiphora, % 1.5 10.45 0.031 
Delirium, % 1.5 10.45 0.031 
Anxiety, % 4.5 14.9 0.038 
Length of stay, days 5±2 5±2 NS 
An et al. [34]Caliskan et al. [27]Garcia-Caballero and Vara-Thorbeck [26]You et al. [35]
pyridostigminesugammadexp valueneostigmineplacebop valueopen cholecystectomy + neostigmine + propranololopen cholecystectomy + neostigmine + propranolol + bupivacaineopen cholecystectomyp valueacupointIMp value
Nausea, % 15.1 16.3 NS 16.7 56.3 <0.05 4.5 17.9 0.013 
Vomiting, % 5.7 8.2 NS 12.5 NS 13.4 0.027 
Dry mouth, % 32 10.2 0.008 
Renal failure, % 11.1 NS 
Resp failure, % 11.1 6.25 NS 
Arrhythmia, % 11.1 NS 
Abdominal discomfort 1st day, % 30 29 45 
Diarrhoea, % 40.3 56.72 0.042 
Epiphora, % 1.5 10.45 0.031 
Delirium, % 1.5 10.45 0.031 
Anxiety, % 4.5 14.9 0.038 
Length of stay, days 5±2 5±2 NS 

Data presented as mean (±SD) or frequency (%).

NS, not statistically significant; –, not available.

Length of Hospital Stay

Only one study reported length of stay. Caliskan et al. [27] demonstrated no difference in length of stay in the neostigmine or placebo arm (mean 5 days ± 2).

In this systematic review of eight RCTs of acetylcholinesterase inhibitors to reduce GI recovery time following abdominal surgery, five studies showed a significant reduction in time to return of GI, with improvements in time to first stool ranging from 17 to 47.59 h albeit using widely variable route of administration and timing [25‒27, 33, 35]. In this review, acetylcholinesterase inhibitors were shown to improve gastrointestinal motility following abdominal surgery; however, the conclusions are limited due to the large variations in dosing, route of administration, type of surgery, and overall results leading to low quality of evidence for their use. An issue highlighted by this review is that the included studies report the time to gastrointestinal recovery and do not report the incidence of POI or use a validated gastrointestinal recovery measure such as GI-2 [36]. Furthermore, the included studies are outdated, ranging over many decades (1986–2019), with only two being published in the last 13 years, and most studies investigating open surgical approaches not based in a modern ERP setting [34, 35]. Overall, this meant a meta-analysis of data would be unreliable and of little clinical value.

This systematic review builds upon our clinical scoping review [28], which revealed the utilisation of acetylcholinesterase inhibitors in surgery. These inhibitors were shown to reverse neuromuscular blockade, treat ACPO, and potentially improve gastrointestinal recovery postoperatively. This emphasised the need for a more comprehensive examination of the most robust evidence, namely, RCTs, before we could consider the routine use of acetylcholinesterase inhibitors to improve gastrointestinal recovery postoperatively. As no previous systematic review has investigated this topic and only a limited number of papers were identified on preliminary screening, we opted to include all abdominal surgical cases at risk of POI. This inclusion meant we included cases with bowel resection [23, 33, 35] along with procedures not involving the gastrointestinal tract [24‒27, 34], albeit with an acknowledgment of this limitation.

Acetylcholinesterase inhibitors impact the return of GI through two possible mechanisms. The first is by increasing acetylcholine availability at the neuromuscular junction causing activation of the myenteric plexus, resulting in direct gastrointestinal mass movement. Through this mechanism, neostigmine is used to treat ACPO [37]. Despite ACPO and POI representing two separate pathologies, the definitions are often mixed, resulting in papers grouping patients with ACPO and POI [38]. ACPO results from severe medical or surgical illness, characterised by distention of the colon and uncoordinated bowel motility [39]. POI, on the other hand, results from surgical stimuli, leading to mainly small bowel dilatation via various mechanisms [40]. Regardless, gastrointestinal mass movement secondary to acetylcholinesterase inhibitors represents the resolution of the gastrointestinal discoordination or paralysis, which is a crucial feature of both pathologies.

The second method by which acetylcholinesterase inhibitors may influence development of POI, and facilitate the return of GI, is via modulation of the CAIP. This is a key pathway in the secondary inflammatory phase of POI, starting from around 3 h postoperatively [9‒11, 39]. During this time, the CAIP has the potential to be modulated by acetylcholinesterase inhibitors. In the included studies of this systematic review, only three were timed to commence their interventional treatment before the potential establishment of the CAIP mechanism and continued until the recovery of bowel function [25, 26, 35]. Given the potential to modulate the CAIP and direct gastrointestinal stimulation, there is scope for a trial using acetylcholinesterase inhibitors to prevent POI.

Pyridostigmine provides a potential option to improve the return of GI and prevent prolonged POI as part of an ERP. It can be given orally and early with a preference over neostigmine which is administered intravenously and requires cardiac monitoring due to concerns of cardiac arrhythmia. An et al. [34] in their use of pyridostigmine in reversal of neuromuscular blockade demonstrated that sugammadex resulted in an earlier return of flatus but no difference in return to stool. This is likely a result of co-administration of glycopyrrolate with pyridostigmine to counteract its cholinergic side effects. Given pyridostigmine is not used commonly in reversal of neuromuscular blockade due to its prolonged onset of action, the evidence for pyridostigmine in this setting is of little benefit. Maleknejad et al. [33] in their single-blind RCT demonstrated a reduction in time to first stool using pyridostigmine to treat established POI. However, this study had a high risk of bias and did not use pyridostigmine to modulate the development of POI via the CAIP and improve return of GI. This study also used mainly obstetric patients and excluded colorectal patients, who carry the greatest risk of POI.

Acetylcholinesterase inhibitors have well-known cholinergic side effects, including abdominal pain, hypersalivation, and vomiting. In particular, neostigmine can cause bradycardia, heart block, and life-threatening arrhythmias [37]. Due to the cholinergic effects, acetylcholinesterase inhibitor use is contraindicated in patients with a risk of arrhythmia due to cardiac disease, as well as asthma and neurological disorders such as Parkinson’s disease and epilepsy [41]. In our review, there was a significant increase in patients with dry mouth following neostigmine against sugammadex administration (32 vs. 10.2%, p = 0.008) [34]. As well, only one study reported arrhythmias associated with neostigmine use; however, this did not reach statistical significance [27]. In our own experience, we have performed a 15-patient pilot study looking at pyridostigmine to improve return of GI following colorectal surgery [29]. This study demonstrated no significant side effects and a median time to return of GI of 2 days (1–4).

In addition to the limitations mentioned above, we noted a significant lack of data in patients undergoing colorectal resection, despite these patients having the greatest risk of POI in abdominal surgery [1]. The included studies have low samples sizes, significant concerns of bias, and lack of follow-up and adverse events data, which reduces the overall quality of the studies. Therefore, the benefits of administering acetylcholinesterase inhibitors to improve the return of GI remain inconclusive.

Currently, we are conducting a double-blinded RCT investigating if pyridostigmine as part of an ERP to improve the return of GI and prevent POI (registered at https://www.anzctr.org.au/ – ACTRN12621000530820). This study addresses the gaps identified in this review, focusing on POI in high-risk colorectal surgery patients. Pyridostigmine, chosen for its convenience as an oral tablet and no need for cardiac monitoring, is being evaluated with the validated gastrointestinal outcome measure (GI-2) [36]. This study includes 130 patients, with statistical power for the primary outcome measure. Additionally, in contrast to prior studies, our RCT defines POI as participants not achieving GI-2 by day 4. Notably, our research also places a particular focus on patient-reported side effects and complications, an aspect that was often inadequately reported in the included studies in this review.

This systematic review highlights that there is limited supportive evidence for using acetylcholinesterase inhibitors to improve the return of GI or prevent POI; however, studies are heterogenous and of low-grade quality. To answer if acetylcholinesterase inhibitors can reduce the time to return of GI, high-quality double-blinded RCTs are required.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare. Informed consent: not applicable. Ethical review board: not applicable.

L.T. was supported by Royal Adelaide Hospital Colorectal Research Group and Dawes Scholarships (a1175080) and University of Adelaide Research Training Program Stipend (a1175080).

L.T.: conceptualisation; methodology; investigation; writing – original draft; and writing – review and editing. N.D.-V.: methodology; validation; investigation; writing – original draft; and writing – review and editing. S.B.: investigation; writing – original draft; and writing – review and editing. H.M.K.: writing – original draft and writing – review and editing. J.W.M. and T.S.: writing – original draft; writing – review and editing; and supervision.

All available data were taken from published literature. Further enquiries can be directed to the corresponding author.

1.
Wolthuis
AM
,
Bislenghi
G
,
Fieuws
S
,
de Buck van Overstraeten
A
,
Boeckxstaens
G
,
D’Hoore
A
.
Incidence of prolonged postoperative ileus after colorectal surgery: a systematic review and meta-analysis
.
Colorectal Dis
.
2016
18
1
O1
9
.
2.
Vather
R
,
Bissett
I
.
Management of prolonged post-operative ileus: evidence-based recommendations
.
ANZ J Surg
.
2013
;
83
(
5
):
319
24
.
3.
Scarborough
JE
,
Schumacher
J
,
Kent
KC
,
Heise
CP
,
Greenberg
CC
.
Associations of specific postoperative complications with outcomes after elective colon resection: a procedure-targeted approach toward surgical quality improvement
.
JAMA Surg
.
2017
;
152
(
2
):
e164681
.
4.
Mao
H
,
Milne
TGE
,
O’Grady
G
,
Vather
R
,
Edlin
R
,
Bissett
I
.
Prolonged postoperative ileus significantly increases the cost of inpatient stay for patients undergoing elective colorectal surgery: results of a multivariate analysis of prospective data at a single institution
.
Dis Colon Rectum
.
2019
;
62
(
5
):
631
7
.
5.
Iyer
S
,
Saunders
WB
,
Stemkowski
S
.
Economic burden of postoperative ileus associated with colectomy in the United States
.
J Manag Care Pharm
.
2009
;
15
(
6
):
485
94
.
6.
Asgeirsson
T
,
El-Badawi
KI
,
Mahmood
A
,
Barletta
J
,
Luchtefeld
M
,
Senagore
AJ
.
Postoperative ileus: it costs more than you expect
.
J Am Coll Surg
.
2010
;
210
(
2
):
228
31
.
7.
Traeger
L
,
Koullouros
M
,
Bedrikovetski
S
,
Kroon
HM
,
Thomas
ML
,
Moore
JW
et al
.
Cost of postoperative ileus following colorectal surgery: a cost analysis in the Australian public hospital setting
.
Colorectal Dis
.
2022
;
24
(
11
):
1416
26
.
8.
Traeger
L
,
Koullouros
M
,
Bedrikovetski
S
,
Kroon
HM
,
Moore
JW
,
Sammour
T
.
Global cost of postoperative ileus following abdominal surgery: meta-analysis
.
BJS Open
.
2023
7
3
zrad054
.
9.
Boeckxstaens
GE
,
de Jonge
WJ
.
Neuroimmune mechanisms in postoperative ileus
.
Gut
.
2009
;
58
(
9
):
1300
11
.
10.
Millan
M
,
Biondo
S
,
Fraccalvieri
D
,
Frago
R
,
Golda
T
,
Kreisler
E
.
Risk factors for prolonged postoperative ileus after colorectal cancer surgery
.
World J Surg
.
2012
;
36
(
1
):
179
85
.
11.
Matteoli
G
,
Gomez-Pinilla
PJ
,
Nemethova
A
,
Di Giovangiulio
M
,
Cailotto
C
,
van Bree
SH
et al
.
A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen
.
Gut
.
2014
;
63
(
6
):
938
48
.
12.
The
FO
,
Boeckxstaens
GE
,
Snoek
SA
,
Cash
JL
,
Bennink
R
,
Larosa
GJ
et al
.
Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice
.
Gastroenterology
.
2007
;
133
(
4
):
1219
28
.
13.
Mazzotta
E
,
Villalobos-Hernandez
EC
,
Fiorda-Diaz
J
,
Harzman
A
,
Christofi
FL
.
Postoperative ileus and postoperative gastrointestinal tract dysfunction: pathogenic mechanisms and novel treatment strategies beyond colorectal enhanced recovery after surgery protocols
.
Front Pharmacol
.
2020
;
11
:
583422
.
14.
Dudi-Venkata
NN
,
Kroon
HM
,
Bedrikovetski
S
,
Moore
JW
,
Sammour
T
.
Systematic scoping review of enhanced recovery protocol recommendations targeting return of gastrointestinal function after colorectal surgery
.
ANZ J Surg
.
2020
90
1–2
41
7
.
15.
Vaughan-Shaw
PG
,
Fecher
IC
,
Harris
S
,
Knight
JS
.
A meta-analysis of the effectiveness of the opioid receptor antagonist alvimopan in reducing hospital length of stay and time to GI recovery in patients enrolled in a standardized accelerated recovery program after abdominal surgery
.
Dis Colon Rectum
.
2012
;
55
(
5
):
611
20
.
16.
de Leede
EM
,
van Leersum
NJ
,
Kroon
HM
,
van Weel
V
,
van der Sijp
JRM
,
Bonsing
BA
et al
.
Multicentre randomized clinical trial of the effect of chewing gum after abdominal surgery
.
Br J Surg
.
2018
;
105
(
7
):
820
8
.
17.
Dudi-Venkata
NN
,
Kroon
HM
,
Bedrikovetski
S
,
Lewis
M
,
Lawrence
MJ
,
Hunter
RA
et al
.
Impact of STIMUlant and osmotic LAXatives (STIMULAX trial) on gastrointestinal recovery after colorectal surgery: randomized clinical trial
.
Br J Surg
.
2021
;
108
(
7
):
797
803
.
18.
Beavers
J
,
Orton
L
,
Atchison
L
,
Medvecz
A
,
Dennis
B
,
Guillamondegui
O
et al
.
The efficacy and safety of methylnaltrexone for the treatment of postoperative ileus
.
Am Surg
.
2022
;
88
(
3
):
409
13
.
19.
Gong
J
,
Xie
Z
,
Zhang
T
,
Gu
L
,
Yao
W
,
Guo
Z
et al
.
Randomised clinical trial: prucalopride, a colonic pro-motility agent, reduces the duration of post-operative ileus after elective gastrointestinal surgery
.
Aliment Pharmacol Ther
.
2016
;
43
(
7
):
778
89
.
20.
Chapman
SJ
,
Helliwell
JA
,
Naylor
M
,
Tassinari
C
,
Corrigan
N
,
Jayne
DG
.
Noninvasive vagus nerve stimulation to reduce ileus after major colorectal surgery: early development study
.
Colorectal Dis
.
2021
;
23
(
5
):
1225
32
.
21.
Stakenborg
N
,
Labeeuw
E
,
Gomez-Pinilla
PJ
,
De Schepper
S
,
Aerts
R
,
Goverse
G
et al
.
Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons
.
Gut
.
2019
;
68
(
8
):
1406
16
.
22.
Ponec
RJ
,
Saunders
MD
,
Kimmey
MB
.
Neostigmine for the treatment of acute colonic pseudo-obstruction
.
N Engl J Med
.
1999
;
341
(
3
):
137
41
.
23.
Myrhöj
T
,
Olsen
O
,
Wengel
B
.
Neostigmine in postoperative intestinal paralysis. A double-blind, clinical, controlled trial
.
Dis Colon Rectum
.
1988
;
31
(
5
):
378
9
.
24.
Madsen
PV
,
Olsen
O
,
Hagen
K
.
Ceruletide and neostigmine in postoperative intestinal paralysis. A double-blind clinical controlled trial
.
Dis Colon Rectum
.
1986
;
29
(
11
):
712
3
.
25.
Hallerbäck
B
,
Ander
S
,
Glise
H
.
Effect of combined blockade of beta-adrenoceptors and acetylcholinesterase in the treatment of postoperative ileus after cholecystectomy
.
Scand J Gastroenterol
.
1987
;
22
(
4
):
420
4
.
26.
García-Caballero
M
,
Vara-Thorbeck
C
.
The evolution of postoperative ileus after laparoscopic cholecystectomy. A comparative study with conventional cholecystectomy and sympathetic blockade treatment
.
Surg Endosc
.
1993
;
7
(
5
):
416
9
.
27.
Caliskan
E
,
Turkoz
A
,
Sener
M
,
Bozdogan
N
,
Gulcan
O
,
Turkoz
R
.
A prospective randomized double-blind study to determine the effect of thoracic epidural neostigmine on postoperative ileus after abdominal aortic surgery
.
Anesth Analg
.
2008
;
106
(
3
):
959
64
, table of contents.
28.
Traeger
L
,
Kroon
HM
,
Bedrikovetski
S
,
Moore
JW
,
Sammour
T
.
The impact of acetylcholinesterase inhibitors on ileus and gut motility following abdominal surgery: a clinical review
.
ANZ J Surg
.
2022
92
1–2
69
76
.
29.
Dudi-Venkata
NN
,
Kroon
HM
,
Bedrikovetski
S
,
Traeger
L
,
Lewis
M
,
Lawrence
MJ
et al
.
PyRICo-Pilot: pyridostigmine to reduce the duration of postoperative ileus after colorectal surgery – a phase II study
.
Colorectal Dis
.
2021
;
23
(
8
):
2154
60
.
30.
Moher
D
,
Liberati
A
,
Tetzlaff
J
,
Altman
DG
PRISMA Group
.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
.
J Clin Epidemiol
.
2009
;
62
(
10
):
1006
12
.
31.
Sterne
JAC
,
Savovic
J
,
Page
MJ
,
Elbers
RG
,
Blencowe
NS
,
Boutron
I
et al
.
RoB 2: a revised tool for assessing risk of bias in randomised trials
.
BMJ
.
2019
366
l4898
.
32.
McGuinness
LA
,
Higgins
JPT
.
Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments
.
Res Synth Methods
.
2021
;
12
(
1
):
55
61
.
33.
Maleknejad
A
,
Khazaei
A
,
Bouya
S
.
Evaluation of the effect of oral pyridostigmine on the ileus after abdominal surgery: a blinded randomized clinical trial
.
J Clin Med
.
2018
;
7
(
5
):
104
.
34.
An
J
,
Noh
H
,
Kim
E
,
Lee
J
,
Woo
K
,
Kim
H
.
Neuromuscular blockade reversal with sugammadex versus pyridostigmine/glycopyrrolate in laparoscopic cholecystectomy: a randomized trial of effects on postoperative gastrointestinal motility
.
Korean J Anesthesiol
.
2020
;
73
(
2
):
137
44
.
35.
You
X
,
Wang
Y
,
Wu
J
,
Liu
Q
,
Liu
Y
,
Qian
Y
et al
.
Zusanli (ST36) acupoint injection with neostigmine for paralytic postoperative ileus following radical gastrectomy for gastric cancer: a randomized clinical trial
.
J Cancer
.
2018
;
9
(
13
):
2266
74
.
36.
van Bree
SH
,
Bemelman
WA
,
Hollmann
MW
,
Zwinderman
AH
,
Matteoli
G
,
El Temna
S
et al
.
Identification of clinical outcome measures for recovery of gastrointestinal motility in postoperative ileus
.
Ann Surg
.
2014
;
259
(
4
):
708
14
.
37.
Valle
RG
,
Godoy
FL
.
Neostigmine for acute colonic pseudo-obstruction: a meta-analysis
.
Ann Med Surg
.
2014
;
3
(
3
):
60
4
.
38.
Kram
B
,
Greenland
M
,
Grant
M
,
Campbell
ME
,
Wells
C
,
Sommer
C
.
Efficacy and safety of subcutaneous neostigmine for ileus, acute colonic pseudo-obstruction, or refractory constipation
.
Ann Pharmacother
.
2018
;
52
(
6
):
505
12
.
39.
Batke
M
,
Cappell
MS
.
Adynamic ileus and acute colonic pseudo-obstruction
.
Med Clin North Am
.
2008
;
92
(
3
):
649
70
, ix.
40.
Wells
CI
,
Milne
TGE
,
Seo
SHB
,
Chapman
SJ
,
Vather
R
,
Bissett
IP
et al
.
Post-operative ileus: definitions, mechanisms and controversies
.
ANZ J Surg
.
2022
92
1–2
62
8
.
41.
Australian Medicine Handbook. Pyridostigmine
Adelaide
AMH
.
2023
.