Experimental postoperative ileus: is Th2 immune response involved?

Rationale: Postoperative ileus (POI) is a frequent complication arising after gastrointestinal surgery but pathogenesis of POI is still not fully understood. While Th1 immune cells are implicated in POI, the involvement of Th2 cells has not yet been clarified. Given the impact of reactive oxygen species (ROS) in the regulation of Th1 and Th2 balance, we hypothesized that not only Th1 but also Th2 immune response can be involved in the development of experimental POI. Methods: The intestinal transit test was performed using carbon gum arabic. Electron microscopy was employed to assess tissue morphology and the presence of immune cells. Cytokines, IgE and ROS were measured. Immune cells from Peyer's patches were analyzed by Flow Cytometry and toluidine blue staining was used for detection of mast cells. Transcriptional factors were analyzed by Western blot. Results: POI is associated with an increase in both Th2 cytokines and Th2 cells. We have further demonstrated that POI induces a Th2-dependent activation of memory and non-memory B cells. This was accompanied by an increase in a number of mast cells in the colon of POI mice as well by an increased IgE and histamine plasma levels. We found that POI-induced accumulation of ROS was associated with an increased expression of the transcriptional factors HMBGI, NF-κB, and p38. This increased expression seemed to be associated with a Th2 response. Conclusion: Th2 immune response can be involved in the activation of mast cells in POI, which was associated with ROS mediated activation of NF-κB and p38 MAPK signaling pathway.

Laparoscopic Surgery Within an Enhanced Recovery after Surgery (ERAS) Protocol Reduced Postoperative Ileus by Increasing Postoperative Treg Levels in Patients with Right-Side Colon Carcinoma.

BACKGROUND The aim of this study was to determine the effects of laparoscopic surgery within an ERAS program on outcomes and immunological function in patients with a carcinoma in the right colon. MATERIAL AND METHODS Patient data were acquired from a prospectively maintained database, and 176 patients diagnosed with right colon carcinoma with surgery were selected from the database. These patients were divided into a laparoscopic group (Lap group, n=86) and an open operation group (Open group, n=90). All patients received treatment according to a standardized ERAS protocol. We collected data on CRP levels, CD4+/CD8+ ratios, and Treg values in peripheral blood, baseline and surgical characteristics, postoperative complications, and postoperative ileus (POI). RESULTS Circulating CD4+/CD8+ ratios and Treg values were decreased and CRP levels were increased in both groups after the operation. However, the values in the Lap group patients recovered much more quickly than those of patients in the Open group (P<0.05). Patients undergoing laparoscopic surgery had significantly less preoperative bleeding (P<0.01), reduced ratio of overall POI (mainly early ileus), and shorter postoperative hospital stay (P=0.03). Multivariate logistic regression analysis showed that POD1 Treg value was an independent predicator for postoperative ileus in patients with right colon carcinoma resection. CONCLUSIONS In patients with a carcinoma in the right colon, laparoscopic surgery within an ERAS protocol leads to better immunity preservation after surgery, and POD1 Treg value may be an independent predicator for postoperative ileus, which could, at least in part, explain the shorter hospital stay after surgery.

Relation between postoperative ileus and anastomotic leakage after colorectal resection: a post hoc analysis of a prospective randomized controlled trial.

AIM: Anastomotic leakage (AL) following abdominal surgery is a critical determinant of postoperative recovery, of which the aetiology is largely unknown. Interestingly, interventions aimed at reducing the inflammatory response and postoperative ileus (POI) have an unexpected effect on AL. The aim of this study was to investigate the relation of POI with inflammation and AL after colorectal resection. METHOD: A post hoc analysis of a prospective randomized controlled trial in which patients underwent a colorectal resection was performed. Patients undergoing a colorectal resection were stratified into having or not having POI. The incidence of AL and other clinical parameters was registered prospectively. Intestinal fatty acid binding protein (I-FABP, a marker for tissue damage) and the inflammatory response in plasma and colon tissue were determined. RESULTS: AL was present in nine of 43 patients in the POI group, and in one of 65 in the group without POI (P < 0.001). There was a significant association between POI and AL (OR 12.57, 95% CI: 2.73-120.65; P = 0.0005). Patients with POI had significantly higher plasma levels of soluble tumour necrosis factor receptor 1 (TNFRSF1A) at 4 h postoperatively (0.89 ng/l, interquartile range 0.56) than patients without POI (0.80 ng/l, interquartile range 0.37; P = 0.04) and higher plasma levels of C-reactive protein on the second day postoperatively (234 ± 77 vs 163 ± 86 mg/l; P = 0.001). Patients who developed AL had significantly higher plasma levels of I-FABP compared with patients without AL at 24 h after onset of surgery. CONCLUSION: POI is associated with a higher prevalence of AL and an increased inflammatory response.

[SIGNIFICANCE OF CHANGES OF RENAL FUNCTIONING PROGNOSTICATION IN THE PURULENT­SEPTIC COMPLICATIONS COURSE AFTER AN URGENT INTERVENTIONS, PERFORMED ON INTESTINE].

Rate and severity of the renal function changes in an acute ileus (AI) in dynamics, aiming on determination of early diagnostic criteria for the purulent­septic complications (PSC) occurrence, were studied. Retrospective analysis of clinical and laboratory indices of renal functional state was conducted in 413 patients, and prospective investigations of 174 patients, operated for AI of various origin was done. Concentration index of creatinine, the glomerular filtration reduction, absolute and relative reabsorption of water, the sodium clearance, level of standardized excretion of protein and sodium, as well as of proximal and distal reabsorption of sodium, the middle­molecular mass peptides content in the blood serum and their concentration indices constitutes the most informative early diagnostic criteria of the PSC occurrence.

Efficacy of Gum Chewing on Bowel Movement After Open Colectomy for Left-Sided Colorectal Cancer: A Randomized Clinical Trial.

BACKGROUND: Prolonged intestinal paralysis can be a problem after gastrointestinal surgery. Several systematic reviews and meta-analyses have suggested the efficacy of gum chewing for the prevention of postoperative ileus. OBJECTIVE: The purpose of this study was to examine the efficacy of gum chewing for the recovery of bowel function after surgery for left-sided colorectal cancer and to determine the physiological mechanism underlying the effect of gum chewing on bowel function. DESIGN: This was a single-center, placebo-controlled, parallel-group, prospective randomized trial. SETTINGS: The study was conducted at a general hospital in Japan. PATIENTS: Forty-eight patients with left-sided colorectal cancer were included. INTERVENTIONS: The patients were randomly assigned to a gum group (N = 25) and a control group (N = 23). Four patients in the gum group and 1 in the control group were subsequently excluded because of difficulties in continuing the trial, resulting in the analysis of 21 and 22 patients in the respective groups. Patients in the gum group chewed commercial gum 3 times a day for ≥5 minutes each time from postoperative day 1 to the first day of food intake. MAIN OUTCOME MEASURES: The time to first flatus and first bowel movement after the operation were recorded, and the colonic transit time was measured. Gut hormones (gastrin, des-acyl ghrelin, motilin, and serotonin) were measured preoperatively, perioperatively, and on postoperative days 1, 3, 5, 7, and 10. RESULTS: Gum chewing did not significantly shorten the time to the first flatus (53 ± 2 vs. 49 ± 26 hours; p = 0.481; gum vs. control group), time to first bowel movement (94 ± 44 vs. 109 ± 34 hours; p = 0.234), or the colonic transit time (88 ± 28 vs. 88 ± 21 hours; p = 0.968). However, gum chewing significantly increased the serum levels of des-acyl ghrelin and gastrin. LIMITATIONS: The main limitation was a greater rate of complications than anticipated, which limited the significance of the findings. CONCLUSIONS: Gum chewing changed the serum levels of des-acyl ghrelin and gastrin, but we were unable to demonstrate an effect on the recovery of bowel function.

C-reactive protein level as a possible predictor for early postoperative ileus following elective surgery for colorectal cancer.

BACKGROUND/AIMS: Inflammatory reactions are par- tially responsible for postoperative ileus (POI). Serum C-reactive protein (CRP) is an acknowledged marker of inflammation. In this study the CRP response with respect to POI in elective colorectal surgery was exam- ined to define the role of serum CRP as an early predic- tor of POI. METHODOLOGY: Three hundred eighty-three patients who underwent elective colorectal resection were identified for inclusion in this study. We defined early POI as that occurring within 30 days following the surgery. Thirty-five patients with POI were com- pared to a subgroup of 348 patients with an unevent- ful postoperative course, and the correlation between postoperative serum CRP levels and POI in colorectal surgery was investigated. RESULTS: In the univariate analysis, length of operation, surgical blood loss, and serum CRP were factors significantly associated with POI following colorectal surgery; however, these fac- tors lost their significance on multivariate analysis. CONCLUSION: Our results suggest that an increase in CRP levels alone is not a predictor for POI following surgery for colorectal surgery. Although inflammatory responses are known to contribute to the ileus, ad- ditional study is required to identify risk factors that would be more useful for prediction of POI.

Anti-inflammatory effect of ginsenoside Rb1 contributes to the recovery of gastrointestinal motility in the rat model of postoperative ileus.

Ginsenoside Rb1 (GRb1), one of the principle active components of Panax ginseng, has been reported to reduce inflammation in various diseases. In the present study, we investigated whether GRb1 has an anti-inflammatory effect on postoperative ileus (POI) and further contributes to the recovery of gastrointestinal motility. POI was induced in rats by intestinal manipulation. The POI rats received 5, 10 and 20 mg/kg GRb1 orally via gavage four times before and after surgery. Gastrointestinal motility was assessed by charcoal transport. Systemic inflammation was assessed by serum tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and IL-10 concentrations, whereas intestinal inflammation was assessed by the activity of myeloperoxidase, and concentrations and gene expression of TNF-α, IL-1ß, IL-6 and IL-10 in the ileum tissue. The results revealed that GRb1 increased rat gastrointestinal transit with POI. The increased levels of systemic and intestinal inflammatory parameters in POI rats were also reduced by GRb1. In addition, GRb1 reduced systemic and intestinal inflammation and increased the gastrointestinal transit of POI rats in a dose-dependent manner, and with significance at doses of 10 and 20 mg/kg. These results suggest that GRb1 has a potent anti-inflammatory effect on POI and further contributes to the recovery of gastrointestinal motility. GRb1 may be a promising treatment for POI prophylaxis.

Colectomy in patients with liver disease: albumin-bilirubin score accurately predicts outcomes.

BACKGROUND: Patients with liver disease undergoing colectomy have higher rates of complications and mortality. The Albumin-Bilirubin score is a recently developed system, established to predict outcomes after hepatectomy, that accounts for liver dysfunction. METHODS: All patients undergoing colectomy were identified in the 2015-2018 American College of Surgeons National Surgical Quality Improvement Program colectomy-targeted database. Demographics and outcomes were compared between patients with Albumin-Bilirubin Grade 1 vs. 2/3. Multivariable regression was performed for outcomes including colorectal-specific complications. Areas under the receiver operative characteristic curves were calculated to determine accuracy of the Albumin-Bilirubin score. RESULTS: Of 86,273 patients identified, 48% (N = 41,624) were Albumin-Bilirubin Grade 1, 45% (N = 38,370) Grade 2 and 7% (N = 6,279) Grade 3. Patents with Grade 2/3 compared to Grade 1 had significantly increased mortality (7.2% vs. 0.9%, p < 0.001) and serious morbidity (31% vs. 12%, p < 0.001). Colorectal-specific complications including anastomotic leak (3.7% vs. 2.8%, p < 0.001) and prolonged ileus (26% vs. 14%, p < 0.001) were higher in patients with Grade 2/3. Grade 2/3 had increased risk of mortality (odds ratio 3.07, p < 0.001) and serious morbidity (1.78, p < 0.001). Albumin-Bilirubin had excellent accuracy in predicting mortality (area under the curve 0.81, p < 0.001) and serious morbidity (0.70, p < 0.001). CONCLUSION: Albumin-Bilirubin is easily calculated using only serum albumin and total bilirubin values. Grade 2/3 is associated with increased rates of mortality and morbidity following colectomy. Albumin-Bilirubin can be applied to risk-stratify patients prior to colectomy.

Relationships between serum electrolyte concentrations and ileus: A joint clinical and mathematical modeling study.

AIM: Prolonged postoperative ileus (PPOI) occurs in around 15% of patients after major abdominal surgery, posing a significant clinical and economic burden. Significant fluid and electrolyte changes may occur peri-operatively, potentially contributing to PPOI; however, this association has not been clearly elucidated. A joint clinical-theoretical study was undertaken to evaluate peri-operative electrolyte concentration trends, their association with ileus, and predicted impact on bioelectrical slow waves in interstitial cells of Cajal (ICC) and smooth muscle cells (SMC). METHODS: Data were prospectively collected from 327 patients undergoing elective colorectal surgery. Analyses were performed to determine associations between peri-operative electrolyte concentrations and prolonged ileus. Biophysically based ICC and SMC mathematical models were adapted to evaluate the theoretical impacts of extracellular electrolyte concentrations on cellular function. RESULTS: Postoperative day (POD) 1 calcium and POD 3 chloride, sodium were lower in the PPOI group (p < 0.05), and POD3 potassium was higher in the PPOI group (p < 0.05). Deficits beyond the reference range in PPOI patients were most notable for sodium (Day 3: 29.5% ileus vs. 18.5% no ileus, p = 0.04). Models demonstrated an 8.6% reduction in slow-wave frequency following the measured reduction in extracellular NaCl on POD5, with associated changes in cellular slow-wave morphology and amplitude. CONCLUSION: Low serum sodium and chloride concentrations are associated with PPOI. Electrolyte abnormalities are unlikely to be a primary mechanism of ileus, but their pronounced effects on cellular electrophysiology predicted by modeling suggest these abnormalities may adversely impact motility recovery. Resolution and correction of electrolyte abnormalities in ileus may be clinically relevant.

The clinical and economical impact of postoperative ileus in patients undergoing colorectal surgery.

BACKGROUND: Colorectal surgery is associated with postoperative ileus (POI). Despite its widespread manifestation, the influence of POI on recovery, quality of life (QoL), and costs is largely unknown. The aim of this study was to assess whether the inflammatory processes found in experimental studies are also evident in patients undergoing colorectal surgery. In addition, the impact of POI on short and long-term QoL and costs was investigated. METHODS: We analyzed the outcomes of the SANICS-II trial, including prospective evaluation of inflammatory parameters in blood samples, costs from a societal perspective and QoL, using validated questionnaires. Outcomes were compared between patients with and without POI, and in particular patients with POI as unique complication. KEY RESULTS: A total of 265 patients (POI, n = 66 vs non-POI, n = 199) were included and 38/66 had POI as only complication. CRP levels were significantly increased on postoperative day (POD) 1, 2, 3, and 4 in patients with POI. Furthermore, plasma levels of cytokines IL-6, Il-8 and IL-10 were significantly increased the first 2 days after resection. Patients with POI had a higher overall complication rate and a reduced QoL 3 months postoperatively, even in the only POI group. Moreover, mean societal cost per patient with POI was 38%-47% higher at 3 months postoperatively. CONCLUSIONS & INFERENCES: Supporting findings from experimental studies, inflammatory parameters were increased in patients with only POI and comparable with all patients with POI. These results demonstrate the impact and large contribution of POI in postoperative inflammation, costs and QoL in patients undergoing colorectal surgery.

Plasma procalcitonin in patients with ileus. Relations to other inflammatory parameters.

Plasma procalcitonin (PCT) is a highly specific marker for the diagnosis of bacterial infections and sepsis. PCT levels are usually low in viral infections, chronic inflammation or postsurgical states. The purpose of this study was to characterize PCT plasma levels in patients with various types of ileus at preoperative stage, where the other inducing factors such as a surgical stress are excluded. The prospective study was performed on 54 patients admitted to in-patient surgical department with a proven diagnosis of ileus. Patients were divided to three groups--obstructive, vascular and paralytic ileus. Plasma levels of PCT (Kryptor analysis), TNFalpha, IL-1beta, IL-6, cortisol (ELISA) and CRP (Kryptor ultrasensitive analysis) were estimated before any invasive procedure was realized. We demonstrated significant elevation of PCT in both obstructive ileus in adhesions and vascular ileus compared with healthy subjects (p 0.01). PCT levels were not elevated in paralytic ileus. The regression coefficient was the highest for PCT and CRP (r=0.78, p 0.01), for TNFalpha and IL-8 (r=0.76, p 0.01) in vascular ileus. There was no significant correlation between PCT and other inflammatory parameters. The different types of ileus induce an elevation of plasma PCT levels and PCT shows itself as an acute phase reactant. The highest PCT concentrations were presented in patients with vascular ileus, whereas paralytic ileus revealed similar cytokine and PCT pattern as in healthy subjects. Plasma PCT estimation extended to a measurement of CRP and IL-6 may become a useful complementary examination for diagnostics of acute abdomen in patients.

Determination of the source of increased serotonin (5-HT) concentrations in blood and peritoneal fluid of colic horses with compromised bowel.

REASONS FOR PERFORMING STUDY: Increased plasma (5-HT) concentrations are reported in horses predisposed to develop laminitis and after i.v. infusion of endotoxins. In the equine jejunum contractile 5-HT1A-like receptors show tachyphylaxia upon prolonged activation with 5-HT. Therefore, increased systemic 5-HT release in colic horses could play a possible role in the pathophysiology of ileus. OBJECTIVE: To investigate possible increased systemic release of 5-HT in colic horses with compromised bowel and to identify the source of 5-HT overload. METHODS: Concentrations of 5-HT were determined in plasma and peritoneal fluid (PF) of healthy horses (n = 10), strangulating small intestinal colic horses (n = 18), nonsurgical colic horses (n = 10) and cryptorchid stallions (n = 6). It was attempted to identify the source of 5-HT overload by comparing the blood and PF 5-HT concentrations within horses and by assessing the in vivo platelet activation through determination of the beta-thromboglobulin (beta-TG)/platelet factor 4 (PF4) ratio. RESULTS: All horses in the strangulating small intestinal colic group had plasma (P = 0.006) and PF (P = 0.01) 5-HT concentrations above those found in the control group. Plasma beta-TG/PF4 ratio in these horses exceeded 2 in all cases, indicating in vivo platelet activation. Concentrations of 5-HT in PF of colic horses with compromised bowel were significantly lower than the corresponding plasma concentrations (P = 0.005). POTENTIAL RELEVANCE: In horses with compromised bowel, significant amounts of 5-HT can be released into the systemic circulation, through massive release of platelet-stored 5-HT. 5-HT is a very potent proinflammatory, vasoconstrictive and immunomodulatory agent. In view of the rapid and prolonged tachyphylaxia, shown for the jejunal 5-HT1A-like receptors, this increased systemic 5-HT release could play a role in the pathophysiology of ileus in horses.

[The changes of natural resistance of the patients with acute adhesive ileus].

The state of an organism natural resistance before and after the operative intervention for an acute adhesive ileus (AAI) was investigated. There was established, that the natural resistance of organism persisting after the operative intervention conduction constitutes the diagnostic criterion of the adhesive process progression in abdominal cavity and of the AAI recurrence occurrence.

Establishing a biomarker for postoperative ileus in humans - Results of the BiPOI trial.

AIMS: Postoperative ileus (POI) is a frequent complication after abdominal surgery, resulting from an inflammation of the muscularis externa (ME). So far no valid biomarker for occurrence, duration or intensity of POI exists. Extravasation of monocytes and neutrophils from blood circulating into the postoperative ME is well known as a hallmark of POI. In a previous study we demonstrated that a low abundant subset of TH1 cells, activated by IL-12, can be detected in the peripheral blood of a small subset of patients in response to abdominal surgery. The aim of the present study was to investigate if these specific TH1 cells, IL-12 or circulating leukocyte levels could act as a valid marker for POI occurrence. MAIN METHODS: At different time points, blood samples of patients undergoing abdominal or extraabdominal surgery were collected. Serum levels of IL-12 or TH1 cells as well as neutrophils and monocytes were analyzed. Data were compared between both groups and correlated with clinical signs of POI. KEY FINDINGS: Time until first flatus and defecation as well as solid food tolerances are delayed after abdominal compared to extraabdominal surgery. Circulating IL-12 levels and numbers of TH1 cells, neutrophils and monocytes did not differ between both groups. SIGNIFICANCE: While previous experiments indicated that specific TH1 cells play a crucial role in POI dissemination, our present data from a larger human cohort demonstrate that they do not seem to be suitable to distinguish between abdominal and extraabdominal surgery. Furthermore neither TH1 cells nor leukocytes or serum IL-12 levels are appropriate biomarkers for POI in a clinical setting.

Markers of Perioperative Bowel Complications in Colorectal Surgery Patients.

Colorectal cancer is a clinical condition whose treatment often involves intestinal resection. Such treatment frequently results in two major gastrointestinal complications after surgery: anastomotic leakage and prolonged ileus. Anastomotic leakage is a serious complication which, more often than not, is diagnosed late; to date, C-reactive protein is the only available diagnostic marker. A monocentric, prospective, open case-control study was performed in patients (n = 117) undergoing colorectal surgery. Intestinal fatty acid binding protein (i-FABP), citrulline, D-lactate, exhaled hydrogen, Escherichia coli genomic DNA, and ischemia modified albumin (IMA) were determined preoperatively, postoperatively, and on the following four consecutive days. Bacterial DNA was not detected in any sample, and i-FABP and D-lactate lacked any distinct potential to detect postoperative bowel complications. Exhaled breath hydrogen content showed unacceptably low sensitivity. However, citrulline turned out to be a specific marker for prolonged ileus on postoperative days 3-4. Using a cut-off value of 20 µmol/L, a sensitivity and specificity of ~75% was achieved on postoperative day 4. IMA was found to be an efficient predictor of anastomosis leak by calculating the difference between preoperative and postoperative values. This test had 100% sensitivity and 80% specificity and 100% negative and 20% positive predictive value.

Immunoreactive trypsin levels in neonates with meconium ileus.

Serum immunoreactive trypsin (IRT) is used as a screening test for cystic fibrosis (CF) in neonates in many countries. Variations in IRT levels are observed in healthy and cystic neonates within the first few weeks of life. Fifteen percentage of CF neonates present with meconium ileus (MI). We hypothesised that there may be differences in serum IRT levels in cystic babies with simple and complicated MI. The aim of this study was to investigate the serum levels of IRT in neonates with CF presenting with MI. IRT levels were sequentially measured in neonates (n = 29) with CF with intestinal obstruction due to simple or complicated MI. These were compared to levels obtained from non-cystic neonates/controls admitted with a variety of other intra-abdominal pathologies (n = 49) IRT levels were significantly higher in the CF-MI group than the non-cystic controls (P < 0.001). There was no statistical difference in IRT levels between the simple or complicated MI groups. In the MI group there was no statistical difference between those who required operation, no difference between the pre- and post-operative IRT levels and no significant relationship between IRT levels and birth weight or gestation. Serum IRT levels are significantly elevated in neonates with CF and MI compared with non-cystic, non-MI neonates. The results of this observational study highlight that a single raised level of IRT in a neonate should prompt the analysis for CF regardless of any underlying surgical pathology.