Pathophysiology Of Postoperative Ileus Research Articles

Inflammation and Impaired Gut Physiology in Post-operative Ileus: Mechanisms and the Treatment Options.

Post-operative ileus (POI) is the transient cessation of coordinated gastrointestinal motility after abdominal surgical intervention. It decreases quality of life, prolongs length of hospital stay, and increases socioeconomic costs. The mechanism of POI is complex and multifactorial, and has been broadly categorized into neurogenic and inflammatory phase. Neurogenic phase mediated release of corticotropin-releasing factor (CRF) plays a central role in neuroinflammation, and affects both central autonomic response as well hypothalamic-pituitary-adrenal (HPA) axis. HPA-stress axis associated cortisol release adversely affects gut microbiota and permeability. Peripheral CRF (pCRF) is a key player in stress induced gastric emptying and colonic transit. It functions as a local effector and interacts with the CRF receptors on the mast cell to release chemical mediators of inflammation. Mast cells proteases disrupt epithelial barrier via protease activated receptor-2 (PAR-2). PAR-2 facilitates cytoskeleton contraction to reorient tight junction proteins such as occludin, claudins, junctional adhesion molecule, and zonula occludens-1 to open epithelial barrier junctions. Barrier opening affects the selectivity, and hence permeation of luminal antigens and solutes in the gastrointestinal tract. Translocation of luminal antigens perturbs mucosal immune system to further exacerbate inflammation. Stress induced dysbiosis and decrease in production of short chain fatty acids add to the inflammatory response and barrier disintegration. This review discusses potential mechanisms and factors involved in the pathophysiology of POI with special reference to inflammation and interlinked events such as epithelial barrier dysfunction and dysbiosis. Based on this review, we recommend CRF, mast cells, macrophages, and microbiota could be targeted concurrently for efficient POI management.

Post‐operative ileus: definitions, mechanisms and controversies

Post-operative ileus (POI) is a syndrome of impaired gastrointestinal transit which occurs following abdominal surgery. There are few effective targeted therapies for ileus, and research has been limited by inconsistent definitions and an incomplete understanding of the underlying pathophysiology. Despite considerable effort, there remains no widely-adopted definition of ileus, and recent work has identified variation in outcome reporting is a major source of heterogeneity in clinical trials. Outcomes should be clearly-defined, clinically-relevant, and reflective of the underlying biology, impacts on hospital resources and quality of life. Further collaborative efforts will be needed to develop consensus definitions and a core outcome set for postoperative gastrointestinal recovery. Investigation into the pathophysiology of POI has been hindered by use of low-resolution techniques and difficulties linking cellular mechanisms to dysmotility patterns and clinical symptoms. Recent evidence has suggested the common assumption of post-operative GI paralysis is incorrect, and that the distal colon becomes hyperactive following surgery. The post-operative inflammatory response is important in the pathophysiology of ileus, but the time course of this in humans remains unclear, with the majority of evidence coming from animal models. Future work should investigate dysmotility patterns underlying ileus, and identify biomarkers which may be used to diagnose, monitor and stratify patients with ileus.

Mast cell degranulation inhibits motor patterns of human ileum and sigmoid colon in vitro: relevance for postoperative ileus.

Local release of mast cell proteases during gastrointestinal surgery is associated with the inhibition of motility and postoperative ileus (POI). We determined whether activation of intramuscular mast cell affects the motor patterns of the human ileum and colon and whether proteases are involved. Motor response of ileal and colonic circular muscle strips was measured in organ bath. Mast cell degranulation was induced by compound 48/80 (c48/80; 25-675 μg/mL). Motor response was quantified as tone, rhythmic phasic contractions (RPCs) and contractions to electric field stimulation (EFS; 40 Hz), and bethanechol-evoked contractions. Ketotifen (10(-6) mol/L) and a protease inhibitor cocktail (P8340) were used to evaluate the role of mast cell mediators. (a) c48/80 impaired the spontaneous and the electrically evoked motor response in small bowel and colonic strips (sigmoid colon EC50 : 460.0 μg/mL for RPCs and 8.9 μg/mL for electrically evoked contraction amplitudes) and bethanechol-evoked contractions. (b) Preincubation with ketotifen (10(-6) mol/L, 1 h) prevented the impairment of RPCs and EFS-evoked contractions in the sigmoid colon and ileum but not in the right colon. (c) Preincubation with P8340 also prevented the impairment of contractions in the sigmoid colon but not in the ileum or the right colon. Mast cell degranulation by c48/80 inhibits the spontaneous and the nerve-mediated motor response in the human ileum and colon. The effect is partially mediated by mast cell proteases and could be relevant in the pathophysiology of POI.

Mast Cells Play No Role in the Pathogenesis of Postoperative Ileus Induced by Intestinal Manipulation

IntroductionIntestinal manipulation (IM) during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI). However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC) resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3Cre/+, devoid of mast cells but with intact Kit signaling.DesignThe role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. KitW-sh/W-sh and Cpa3Cre/+ mice, and by use of the mast cell stabilizer cromolyn.Results KitW-sh/W-sh mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3Cre/+ mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3Cre/+ mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3+/+). Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI.ConclusionsHere, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast cell inhibitors as a therapeutic approach to shorten POI.

Tu1629 Spleen Tyrosine Kinase Inhibition Reduces Intestinal Inflammation and Prevents Postoperative Ileus

Background: Recent advances underline intestinal inflammation, induced by handling of the gut during surgery, as crucial mechanism in the pathophysiology of postoperative ileus (POI). Macrophages, in the muscularis layer, and mast cells are the key players in the induction of this inflammatory process. Spleen tyrosine kinase (Syk) is an important kinase involved in macrophage activation as well as in mast cell degranulation and therefore inhibition of Syk pathway may represent an interesting therapeutic approach for POI. In the current study, we have evaluated the effect of the Syk-inhibitor GSK143 as potential treatment to shorten POI. Methods: The effect of an oral single dose (3mg/kg, 1.5 hours before surgery) was evaluated in a mouse model of POI, by analyzing gastrointestinal transit and intestinal muscularis inflammation. The in vitro effect of GSK143 (1 and 3 μM) was evaluated on cultured peritoneal mast cells (pMCs) and bone marrow derived macrophages (BMDMs) stimulated with immune complexes with IgE-anti-TNP (40 ng/mL) and LPS (100 ng/ml) respectively. Results: Administration of GSK143 (3 mg/kg) resulted in a serum level of 0.38±0.24 μM 1.5 hours after oral delivery. Treatment with a single dose of GSK143 (3 mg/kg) significantly improved gastrointestinal transit after surgical intestinal manipulated mice compared to placebo (Geometric Center (GC): Placebo, 4.2 ±0.4 vs GSK143, GC; 6.9±0.6). In addition, GSK143 was able to reduce the number of recruited myeloperoxidase (MPO) positive cells (placebo, 187±30 vs GSK143, 44±8, per 0.5mm2), neutrophils (placebo, 4.6x10-5±0.2 x10-5 vs GSK143, 1.7x10-5 ±0.7 x10-5) and monocytes (placebo, 1.6x106±0.4 x10-6 vs GSK143, 0.8x10-6 ±0.25 x10-6) in the muscularis externa compared to placebo. To define the possible target cells affected, GSK143 was tested in vitro on pMCs and BMDMs. Thirty minutes after GSK143 (1 and 3 μM) or vehicle treatment, pMCs degranulation, quantified by assessment of β-hexosaminidase, was induced by immune complexes with IgE-anti-TNP. Interestingly, GSK143 significantly reduced pMCs degranulation compared to vehicle in a dose dependent manner (GSK143 1μM, 62±7.5% and GSK143 3μM, 76±3.3% inhibition vs vehicle). In line, pre-treatment of BMDMs with GSK143 (1 and 3 μM) prior to LPS challenge significantly lowered the expression of IL-6 (21±4% to 31± 3 % inhibition vs vehicle ), TNFα (39±0.8% to 54±0.7% inhibition vs vehicle ), IL1 β (31±1.3% to 39±1.06% inhibition vs vehicle) and CCL2 (33±5.3% to 43±7% inhibition vs vehicle). Conclusion: Pre-treatment with the Syk-inhibitor GSK143 attenuates intestinal inflammation and consequently restores gastrointestinal transit in a model of POI. In vitro data suggests that both macrophages and mast cells are targeted by GSK143. These findings strongly suggest that Syk inhibition may be a new therapeutical tool to shorten POI.

Inhibition of spleen tyrosine kinase as treatment of postoperative ileus

ObjectiveIntestinal inflammation resulting from manipulation-induced mast cell activation is a crucial mechanism in the pathophysiology of postoperative ileus (POI). Recently it has been shown that spleen tyrosine kinase (Syk) is...

Changes in beta‐adrenergic neurotransmission during postoperative ileus in rat circular jejunal muscle

To explore postoperative changes in β-adrenergic neurotransmission that participate in pathophysiology of postoperative ileus. Contractile activity of circular jejunal muscle strips was studied. Groups (n = 6/group) were: naïve controls, sham controls 1 and 7 days after laparotomy, and rats 12 h, 1, 3, and 7 days after laparotomy with standardized small bowel manipulation (postoperative ileus). Dose-responses to the β-agonist isoprenaline (3 × 10(-10) - 10(-7) mol L(-1)) were studied in presence/absence of tetrodotoxin (global neural blockade; 10(-6) mol L(-1) ), N6-(1-iminoethyl)-l-lysine (inhibition of inducible nitric oxide synthesis; 10(-4) mol L(-1)), nimesulide (cyclooxygenase-2 inhibition; 10(-5) mol L(-1)), or propranolol (β-blockade; 5 × 10(-6) mol L(-1)). Histochemistry for inflammatory cells and intestinal transit were studied. Intramural inflammation and delayed transit (postoperative ileus) occurred only in ileus groups. The inhibitory potential of isoprenaline decreased in all postoperative groups including sham (P < 0.05). Tetrodotoxin enhanced isoprenaline-induced inhibition in ileus and sham groups (P < 0.05). N6-(1-iminoethyl)-l-lysine and nimesulide decreased isoprenaline-induced inhibition in ileus groups 12 h, 1, and 7 days, and in sham controls 7 days postoperatively (P < 0.05). Propranolol prevented isoprenaline effects in all groups (P < 0.05). Inhibitory effects of isoprenaline on contractile activity were decreased for 7 days postoperatively. Changes in β-adrenergic neurotransmission do not induce postoperative ileus and appear to be caused by anesthesia and laparotomy rather than bowel manipulation.

New therapeutic strategies for postoperative ileus

Patients undergoing an abdominal surgical procedure develop a transient episode of impaired gastrointestinal motility or postoperative ileus. Importantly, postoperative ileus is a major determinant of recovery after intestinal surgery and leads to increased morbidity and prolonged hospitalization, which is a great economic burden to health-care systems. Although a variety of strategies reduce postoperative ileus, including multimodal postoperative rehabilitation (fast-track care) and minimally invasive surgery, none of these methods have been completely successful in shortening the duration of postoperative ileus. The aetiology of postoperative ileus is multifactorial, but insights into the pathogenesis of postoperative ileus have identified intestinal inflammation, triggered by surgical handling, as the main mechanism. The importance of this inflammatory response in postoperative ileus is underscored by the beneficial effect of pharmacological interventions that block the influx of leukocytes. New insights into the pathophysiology of postoperative ileus and the involvement of the innate and the adaptive (T-helper type 1 cell-mediated immune response) immune system offer interesting and important new approaches to prevent postoperative ileus. In this Review, we discuss the latest insights into the mechanisms behind postoperative ileus and highlight new strategies to intervene in the postoperative inflammatory cascade.

Influence of Intravenous Opioid Dose on Postoperative Ileus

Intravenous opioids represent a major component in the pathophysiology of postoperative ileus (POI). However, the most appropriate measure and threshold to quantify the association between opioid dose (eg, average daily, cumulative, maximum daily) and POI remains unknown. To evaluate the relationship between opioid dose, POI, and length of stay (LOS) and identify the opioid measure that was most strongly associated with POI. Consecutive patients admitted to a community teaching hospital who underwent elective colorectal surgery by any technique with an enhanced-recovery protocol postoperatively were retrospectively identified. Patients were excluded if they received epidural analgesia, developed a major intraabdominal complication or medical complication, or had a prolonged workup prior to surgery. Intravenous opioid doses were quantified and converted to hydromorphone equivalents. Classification and regression tree (CART) analysis was used to determine the dosing threshold for the opioid measure most associated with POI and define high versus low use of opioids. Risk factors for POI and prolonged LOS were determined through multivariate analysis. The incidence of POI in 279 patients was 8.6%. CART analysis identified a maximum daily intravenous hydromorphone dose of 2 mg or more as the opioid measure most associated with POI. Multivariate analysis revealed maximum daily hydromorphone dose of 2 mg or more (p = 0.034), open surgical technique (p = 0.045), and days of intravenous narcotic therapy (p = 0.003) as significant risk factors for POI. Variables associated with increased LOS were POI (p < 0.001), maximum daily hydromorphone dose of 2 mg or more (p < 0.001), and age (p = 0.005); laparoscopy (p < 0.001) was associated with a decreased LOS. Intravenous opioid therapy is significantly associated with POI and prolonged LOS, particularly when the maximum hydromorphone dose per day exceeds 2 mg. Clinicians should consider alternative, nonopioid-based pain management options when this occurs.

Emerging pharmacologic options for treating postoperative ileus

Characteristics of the ideal drug therapy for postoperative ileus (POI); the pharmacology, efficacy, and safety of currently available nonselective opioid antagonists and the new peripherally selective opioid antagonists methylnaltrexone and alvimopan for the treatment of POI; and formulary considerations associated with the introduction of these new POI drug therapies are discussed. The ideal drug therapy for treating POI would selectively antagonize the inhibitory effects on the gastrointestinal (GI) tract of all of the potential factors implicated in the pathophysiology of POI (neurogenic, inflammatory, hormonal, and pharmacologic mediators). The most promising target to date is inhibition of the adverse GI effects of endogenous and exogenous opioids. Selective inhibition of the mu-opioid receptors in the GI tract, without reversing centrally mediated opioid-induced analgesia, may be beneficial in reducing POI. The nonselective opioid antagonists naloxone and nalmefene have not been studied for POI, and they cross the blood-brain barrier. Therefore, they are not appropriate for preventing or treating POI. The peripherally selective opioid antagonist methylnaltrexone shortens the duration of POI and the hospital length of stay (LOS). Alvimopan, a more extensively studied peripherally selective opioid antagonist, has been shown to reduce the duration of POI, frequency of postoperative nausea and vomiting, and hospital LOS. Both methylnaltrexone and alvimopan also appear effective for treating opioid-induced constipation. Preliminary results of a long-term study of alvimopan safety have revealed some potential concerns, and the significance of the adverse effects must be understood before the most appropriate role of alvimopan in patient care can be determined. Restricting the prescribing of new POI drug therapies to certain types of patients, surgeries, and prescribers; incorporating these therapies into preoperative and postoperative policies, procedures, and protocols; and the potential cost savings from reducing hospital LOS are among the considerations in adding these agents to health-system formularies. Peripherally selective opioid receptor antagonists are promising new drug therapies that can reduce the clinical and economic burden of POI.

Does gum chewing help prevent impaired gastric motility in the postoperative period?

To discuss the pathophysiology of postoperative ileus (POI) and the addition of gum chewing to a multimodal treatment plan. Review of current literature of the pathophysiology of POI, multimodal treatment options, and current research on gum chewing and its effects on the prevention of POI. Studies have documented that gum chewing decreases time to flatus and first defecation after surgery. Studies indicate that gum chewing can decrease the length of hospital stay by 1 day. There were no documented adverse effects of gum chewing. The addition of gum chewing to a multimodal treatment program assists with increasing patient comfort, satisfaction, and decreasing healthcare expenditures. POI is a common complication of abdominal surgery. Research has indicated that gum chewing has assisted with increasing gastric motility, decreasing lengths of hospital stays, and decreasing healthcare expenditures. Gum chewing is an inexpensive and safe option to add to a multimodal program for the prevention of POI.

Postoperative ileus: a review.

Postoperatively, some patients experience a prolonged inhibition of coordinated bowel activity, which causes accumulation of secretions and gas, resulting in nausea, vomiting, abdominal distension, and pain. This prolonged inhibition can take days or weeks to resolve and often is referred to as postoperative paralytic ileus lasting more than three days after surgery. This article reviews the etiology, pathophysiology, and treatment options of postoperative ileus. The relevant literature from 1965 to 2003 was identified and reviewed using MEDLINE database of the U.S. Medical Library of Medicine. Both retrospective and prospective studies were included in this review. The pathophysiology of postoperative ileus is multifactorial. The duration of postoperative ileus correlates with the degree of surgical trauma and is most extensive after colonic surgery. However, postoperative ileus can develop after all types of surgery including extraperitoneal surgery. A variety of treatment options have been used to decrease the duration of postoperative ileus. However, it is difficult to compare these studies because of small sample sizes and differences in operations performed, anesthesia protocols provided both intraoperatively and postoperatively, patient comorbidities, and in the measured end points, such as the time to the presence of bowel sounds, flatus, or bowel movements, tolerance of solid food, or discharge from the hospital. However, despite these drawbacks, some conclusions can be made. Paralytic postoperative ileus continues to be a significant problem after abdominal and other types of surgery. The etiology is multifactorial and is best treated with a combination of different approaches. Currently, the important factors that could effect the duration and recovery from postoperative ileus include limitation of narcotic use by substituting alternative medications such as nonsteroidals and placing a thoracic epidural with local anesthetic when possible. The selective use of nasogastric decompression and correction of electrolyte imbalances also are important factors to consider.

Postoperative ileus: part I (Experimental results)

Postoperative gastro-intestinal motility disorders are of major importance for patient management following abdominal surgery both for clinical and economic reasons. In recent years, new pathophysiological links have been identified that contribute to postoperative ileus. The activation of sympathetic efferent neurons by visceral afferent nerve fibers, catecholamines, the stimulation of beta 3 -receptors in the gut wall, an inflammatory response of the gut wall with the consecutive release of nitric oxide, and opioids given for postoperative analgesia seem to be of major importance regarding the development of postoperative ileus. The pharmacological reduction of visceral afferent nerve fiber activity, non-steroidal anti-inflammatory drugs (NSAIDs) instead of opioids for postoperative pain, peripheral opioid receptor antagonists together with opioids for postoperative analgesia, motilides and 5-HT4 receptor agonists as prokinetic drugs are strategies that are currently evaluated to treat postoperative ileus. Our review summarizes the present knowledge on the pathophysiology of postoperative ileus and new experimental treatments that might be of importance in the future.

Pathophysiology of postoperative ileus.

In eight dogs, cellotomy, rubbing the small bowel, and exposing it to air suppressed the migrating bursts of action potentials and contractions that occur in the gastrointestinal tract during fasting and greatly slowed (one to three days) the gastrointestinal transit of 7-mm plastic spheres. The operation also caused a transient one-day increase in the concentration of epinephrine and a more prolonged five-day increase in the concentration and norepinephrine in arterial and venous plasma. Phentolamine mesylate and propranolol hydrochloride prevented the inhibition of the bursts of gastric action potentials brought about by operation, but these drugs did not alter the inhibition of the small intestinal action potentials or the speed of gastrointestinal transit of spheres.