Pyridostigmine to enhance gastrointestinal recovery after colorectal surgery

Abstract

Postoperative ileus (POI) refers to the delayed return of gastrointestinal (GI) function and is a common complication following colorectal surgery. POI increases morbidity, mortality, and healthcare costs. The cholinergic anti-inflammatory pathway (CAIP) is crucial in developing POI, but limited preventive strategies target this pathway. This thesis examines acetylcholinesterase inhibitors (ACIs), such as pyridostigmine and neostigmine, as a method to impact the CAIP and improve GI recovery, culminating in a novel randomised controlled trial (RCT). This thesis comprises seven papers, beginning with a comprehensive literature review summarising the current applications of ACIs in abdominal surgery, including neuromuscular reversal during anaesthesia, resolving acute colonic pseudo-obstruction, and POI. A systemic review of RCTs examines ACIs efficacy in improving GI recovery after abdominal surgery, revealing that five of eight studies had a reduction in time to first stool. Despite variations in methodology and bias concerns, the evidence supported using ACIs to improve GI function recovery. However, it emphasises the need for an RCT embedded in a modern enhanced recovery protocol (ERP), especially for colorectal surgery patients. Additionally, in a 335-patient cohort study, neostigmine/glycopyrrolate administration during neuromuscular reversal delayed GI function recovery (GI-2 (validated measure of time to first stool and tolerance of oral diet) median 3 vs. 2 days, p=0.035) without affecting POI rates. Furthermore, we investigate the financial impact of POI, providing Australian first data for 415 colorectal patients, revealing an increase in total hospital cost by 26.4% (AU$37,690 vs. AU$29,822, p<0.001) due to increased length of stay and complications. Giving a broader perspective, we present the first meta-analysis examining the global financial burden of POI following abdominal surgery, demonstrating a 66.3% increase (95%CI [34.8-97.9], p<0.0001, I2=98.4%) in total hospital cost. This study estimates POI amounts to a US$4.1 billion burden annually in the USA, underscoring the need to reduce its incidence with adjunctive therapies. The primary study of this thesis is the first double blinded RCT that evaluates the addition of pyridostigmine to the current ERP following colorectal surgery. With 130 patients, the study shows a significant reduction in time to GI-2 with the addition of pyridostigmine (2 (IQR 1-3) vs. 3 (2-4) days; p=0.015), supporting the hypothesis that it improves GI recovery. However, no significant differences were observed in POI, length of hospital stay or 30-day complications. Furthermore, we employed machine learning techniques to identify new POI risk factors and guide preventative strategies. Using multivariate logistic regression and comparing it to machine learning models, particularly radial basis function, decision trees and multiple layer perceptron (MLP), MLP outperformed the other models and identified sarcopenia as a potentially modifiable risk factor for POI. This thesis provides novel findings, highlighting the significant financial burden of POI following abdominal surgery. It provides evidence for the efficacy of pyridostigmine in improving GI recovery. These findings contribute to understanding GI recovery and emphasise the importance of targeted prevention strategies to reduce the incidence of POI.