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      Postoperative Ileus and Postoperative Gastrointestinal Tract Dysfunction: Pathogenic Mechanisms and Novel Treatment Strategies Beyond Colorectal Enhanced Recovery After Surgery Protocols

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          Abstract

          Postoperative ileus (POI) and postoperative gastrointestinal tract dysfunction (POGD) are well-known complications affecting patients undergoing intestinal surgery. GI symptoms include nausea, vomiting, pain, abdominal distention, bloating, and constipation. These iatrogenic disorders are associated with extended hospitalizations, increased morbidity, and health care costs into the billions and current therapeutic strategies are limited. This is a narrative review focused on recent concepts in the pathogenesis of POI and POGD, pipeline drugs or approaches to treatment. Mechanisms, cellular targets and pathways implicated in the pathogenesis include gut surgical manipulation and surgical trauma, neuroinflammation, reactive enteric glia, macrophages, mast cells, monocytes, neutrophils and ICC’s. The precise interactions between immune, inflammatory, neural and glial cells are not well understood. Reactive enteric glial cells are an emerging therapeutic target that is under intense investigation for enteric neuropathies, GI dysmotility and POI. Our review emphasizes current therapeutic strategies, starting with the implementation of colorectal enhanced recovery after surgery protocols to protect against POI and POGD. However, despite colorectal enhanced recovery after surgery, it remains a significant medical problem and burden on the healthcare system. Over 100 pipeline drugs or treatments are listed in Clin.Trials.gov. These include 5HT 4R agonists (Prucalopride and TAK 954), vagus nerve stimulation of the ENS—macrophage nAChR cholinergic pathway, acupuncture, herbal medications, peripheral acting opioid antagonists (Alvimopen, Methlnaltexone, Naldemedine), anti-bloating/flatulence drugs (Simethiocone), a ghreline prokinetic agonist (Ulimovelin), drinking coffee, and nicotine chewing gum. A better understanding of the pathogenic mechanisms for short and long-term outcomes is necessary before we can develop better prophylactic and treatment strategies.

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          Most cited references187

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          Evidence-based surgical care and the evolution of fast-track surgery.

          Optimization of postoperative outcome requires the application of evidence-based principles of care carefully integrated into a multimodal rehabilitation program. To assess, synthesize, and discuss implementation of "fast-track" recovery programs. Medline MBASE (January 1966-May 2007) and the Cochrane library (January 1966-May 2007) were searched using the following keywords: fast-track, enhanced recovery, accelerated rehabilitation, and multimodal and perioperative care. In addition, the synthesis on the many specific interventions and organizational and implementation issues were based on data published within the past 5 years from major anesthesiological and surgical journals, using systematic reviews where appropriate instead of multiple references of original work. Based on an increasing amount of multinational, multicenter cohort studies, randomized studies, and meta-analyses, the concept of the "fast-track methodology" has uniformly provided a major enhancement in recovery leading to decreased hospital stay and with an apparent reduction in medical morbidity but unaltered "surgery-specific" morbidity in a variety of procedures. However, despite being based on a combination of evidence-based unimodal principles of care, recent surveys have demonstrated slow adaptation and implementation of the fast-track methodology. Multimodal evidence-based care within the fast-track methodology significantly enhances postoperative recovery and reduces morbidity, and should therefore be more widely adopted. Further improvement is expected by future integration of minimal invasive surgery, pharmacological stress-reduction, and effective multimodal, nonopioid analgesia.
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            Long-term consequences of postoperative cognitive dysfunction.

            Postoperative cognitive dysfunction (POCD) is common in elderly patients after noncardiac surgery, but the consequences are unknown. The authors' aim was to determine the effects of POCD on long-term prognosis. This was an observational study of Danish patients enrolled in two multicenter studies of POCD between November 1994 and October 2000. The cohort was followed up from the date of surgery until August 2007. Cognitive function was assessed by a neuropsychological test battery at three time points: before, at 1 week after, and at 3 months after noncardiac surgery. Data on survival, labor market attachment, and social transfer payments were obtained from administrative databases. The Cox proportional hazards regression model was used to compute relative risk estimates for mortality and disability, and the relative prevalence of time on social transfer payments was assessed by Poisson regression. A total of 701 patients were followed up for a median of 8.5 yr (interquartile range, 5.3-11.4 yr). POCD at 3 months, but not at 1 week, was associated with increased mortality (hazard ratio, 1.63 [95% confidence interval, 1.11-2.38]; P = 0.01, adjusted for sex, age, and cancer). The risk of leaving the labor market prematurely because of disability or voluntary early retirement was higher among patients with 1-week POCD (hazard ratio, 2.26 [1.24-4.12]; P = 0.01). Patients with POCD at 1 week received social transfer payments for a longer proportion of observation time (prevalence ratio, 1.45 [1.03-2.04]; P = 0.03). Cognitive dysfunction after noncardiac surgery was associated with increased mortality, risk of leaving the labor market prematurely, and dependency on social transfer payments.
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              Resolution of inflammation: the beginning programs the end.

              Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid-derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. Consequently, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-beta1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics. Understanding these and further details of the mechanism required for inflammation resolution may underpin the development of drugs that can resolve inflammatory processes in directed and controlled ways.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                24 November 2020
                2020
                : 11
                : 583422
                Affiliations
                [1] 1Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
                [2] 2Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
                Author notes

                Edited by: Luca Antonioli, University of Pisa, Italy

                Reviewed by: Nathalie Stakenborg, KU Leuven, Belgium

                Oksana Zayachkivska, Danylo Halytsky Lviv National Medical University, Ukraine

                *Correspondence: Fievos L. Christofi fedias.christofi@ 123456osumc.edu

                This article was submitted to Gastrointestinal and Hepatic Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                583422
                10.3389/fphar.2020.583422
                7774512
                33390950
                4c7e5071-0cb3-43ff-9e24-be06093ca356
                Copyright © 2020 Mazzotta, Villalobos-Hernandez, FIORDA-DIAZ, Harzman and Christofi

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 July 2020
                : 29 September 2020
                Page count
                Pages: 0
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                postoperative gastrointestinal tract dysfunction,postoperative ileus,colorectal enhanced recovery after surgery,gastrointestinal surgery,enteric glia,prokinetic agents,mechanosensation,5ht4 receptor

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