Pyridostigmine to enhance gastrointestinal recovery after colorectal surgery

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.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202

Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study an international prospective cohort study

We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care. We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care