New Insight in Loss of Gut Barrier during Major Non-Abdominal Surgery

PG - e3954 AB - BACKGROUND: Gut barrier loss has been implicated as a critical event in the occurrence of postoperative complications. We aimed to study the development of gut barrier loss in patients undergoing major non-abdominal surgery. METHODOLOGY/PRINCIPAL FINDINGS: Twenty consecutive children undergoing spinal fusion surgery were included. This kind of surgery is characterized by long operation time, significant blood loss, prolonged systemic hypotension, without directly leading to compromise of the intestines by intestinal manipulation or use of extracorporeal circulation. Blood was collected preoperatively, every two hours during surgery and 2, 4, 15 and 24 hours postoperatively. Gut mucosal barrier was assessed by plasma markers for enterocyte damage (I-FABP, I-BABP) and urinary presence of tight junction protein claudin-3. Intestinal mucosal perfusion was measured by gastric tonometry (P(r)CO2, P(r-a)CO2-gap). Plasma concentration of I-FABP, I-BABP and urinary expression of claudin-3 increased rapidly and significantly after the onset of surgery in most children. Postoperatively, all markers decreased promptly towards baseline values together with normalisation of MAP. Plasma levels of I-FABP, I-BABP were significantly negatively correlated with MAP at (1/2) hour before blood sampling (-0.726 (p<0.001), -0.483 (P<0.001), respectively). Furthermore, circulating I-FABP correlated with gastric mucosal P(r)CO2, P(r-a)CO2-gap measured at the same time points (0.553 (p = 0.040), 0.585 (p = 0.028), respectively). CONCLUSIONS/SIGNIFICANCE: This study shows the development of gut barrier loss in children undergoing major non-abdominal surgery, which is related to preceding hypotension and mesenterial hypoperfusion. These data shed new light on the potential role of peroperative circulatory perturbation and intestinal barrier los

Aggravation of exercise-induced intestinal injury by ibuprofen in athletes

VAN WIJCK, K., K. LENAERTS, A. A. VAN BIJNEN, B. BOONEN, L. J. C. VAN LOON, C. H. C. DEJONG, and W. A. BUURMAN. Aggravation of Exercise-Induced Intestinal Injury by Ibuprofen in Athletes. Med. Sci. Sports Exerc., Vol. 44, No. 12, pp. 2257–2262, 2012. Introduction: Nonsteroidal anti-inflammatory drugs are commonly used by athletes to prevent anticipated exercise-induced pain, thereby putatively improving physical performance. However, these drugs may have potentially hazardous effects on the gastrointestinal (GI) mucosa during strenuous physical exercise. The aim of the current study was to determine the effect of oral ibuprofen administration before exercise on GI integrity and barrier function in healthy individuals. Methods: Nine healthy, trained men were studied on four different occasions: 1) 400 mg ibuprofen twice before cycling, 2) cycling without ibuprofen, 3) 400 mg ibuprofen twice at rest, and 4) rest without ibuprofen intake. To assess small intestinal injury, plasma intestinal fatty acid binding protein (I-FABP) levels were determined, whereas urinary excretion of orally ingested multisugar test probes was measured using liquid chromatography and mass spectrometry to assess GI permeability. Results: Both ibuprofen consumption and cycling resulted in increased I-FABP levels, reflecting small intestinal injury. Levels were higher after cycling with ibuprofen than after cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen (peak I-FABP, 875 T 137, 474 T 74, 507 T 103, and 352 T 44 pgImLj1 , respectively, P G 0.002). In line, small intestinal permeability increased, especially after cycling with ibuprofen (0–2 h urinary lactulose/rhamnose ratio, 0.08 (0.04–0.56) compared with 0.04 (0.00–0.20), 0.05 (0.01–0.07), and 0.01 (0.01–0.03), respectively), reflecting loss of gut barrier integrity. Interestingly, the extent of intestinal injury and barrier dysfunction correlated significantly (RS = 0.56, P G 0.001). Conclusion: This is the first study to reveal that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals. We conclude that nonsteroidal anti-inflammatory drugs consumption by athletes is not harmless and should be discouraged. Key Words: NSAID, EXERCISE, GASTROINTESTINAL DAMAGE, PERMEABILIT

Lysophosphatidic Acid Prevents Renal Ischemia-Reperfusion Injury by Inhibition of Apoptosis and Complement Activation

Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure as observed after renal transplantation, major surgery, trauma, and septic as well as hemorrhagic shock. We previously showed that the inhibition of apoptosis is protective against renal I/R injury, indicating that apoptotic cell-death is an important feature of I/R injury. Lysophosphatidic acid (LPA) is an endogenous phospholipid growth factor with anti-apoptotic properties. This tempted us to investigate the effects of exogenous LPA in a murine model of renal I/R injury. LPA administered at the time of reperfusion dose dependently inhibited renal apoptosis as evaluated by the presence of internucleosomal DNA cleavage. I/R-induced renal apoptosis was only present in tubular epithelial cells with evident disruption of brush border as assessed by immunohistochemistry for active caspase-7 and filamentous actin, respectively. LPA treatment specifically prevented tubular epithelial cell apoptosis but also reduced the I/R-induced loss of brush-border integrity. Besides, LPA showed strong anti-inflammatory effects, inhibiting the renal expression of tumor necrosis factor-α and abrogating the influx of neutrophils. Next, LPA dose dependently inhibited activation of the complement system. Moreover, treatment with LPA abrogated the loss of renal function in the course of renal I/R. This study is the first to show that administration of the phospholipid LPA prevents I/R injury, abrogating apoptosis and inflammation. Moreover, exogenous LPA is capable of preventing organ failure because of an ischemic insult and thus may provide new means to treat clinical conditions associated with I/R injury in the kidney and potentially also in other organs

Gut mucosal cell damage in meningococcal sepsis in children:Relation with clinical outcome

Objective: The pathophysiological sequelae of meningococcal sepsis are mainly caused by deregulated microvasculature function, leading to impaired tissue blood flow. Because mature enterocytes are known to be susceptible to altered perfusion, we aimed to investigate: (1) the development of enterocyte damage; and (2) the relation between enterocyte damage and severity of disease and outcome in children with meningococcal sepsis. Design: Retrospective human study. Setting: Pediatric intensive care unit at a university hospital. Patients: Nineteen consecutive children with meningococcal sepsis were studied during their pediatric intensive care unit stay. Interventions: None. Measurement and Main Results: Circulating levels of intestinal fatty acid binding protein, a small cytosolic protein constitutively present in mature enterocytes and released on cell injury, were assessed. Severity of disease was represented by meningococcal-specific Rotterdam Score, generic Pediatric Risk of Mortality II score, and circulating interleukin-6. Clinical outcome was measured by length of pediatric intensive care unit stay and number of ventilator days. Highest plasma intestinal fatty acid binding protein values were measured on pediatric intensive care unit stay admission. At the time of admission, eight of 19 patients had higher intestinal fatty acid binding protein plasma levels than the upper reference limit of 30 healthy volunteers. In all survivors, intestinal fatty acid binding protein levels declined to normal values within 12 hrs after starting intensive treatment, whereas the three nonsurvivors maintained elevated intestinal fatty acid binding protein plasma levels. A significant correlation was found among intestinal fatty acid binding protein and Rotterdam Score, Pediatric Risk of Mortality II, interleukin-6 at admission (Spearman's r(2) = 0.402, p =.006; r(2) = 0.243, p = .045; r(2) = 0.687, p <.001, respectively). Next, a significant correlation was found between intestinal fatty acid binding protein and clinical outcome. Conclusions: Elevated plasma intestinal fatty acid binding protein is found in eight of 19 children with severe pediatric intensive care unit stay at the time of clinical presentation, suggesting the presence of enterocyte damage. Furthermore, prolonged enterocyte damage is found in nonsurvivors. Further studies are needed to clarify the potential role for assessment of plasma intestinal fatty acid binding protein in monitoring treatment of pediatric intensive care unit stay. (Crit Care Med 2010; 38:133-137

A pilot study on potential new plasma markers for diagnosis of acute appendicitis

Background: Diagnosis of acute appendicitis (AA) remains a surgical dilemma, with negative appendectomy rates of 5% to 40% and perforation suggestive for late operative intervention in 5% to 30%. The aim of this study is to evaluate new plasma markers, representing early neutrophil activation, to improve diagnostic accuracy in patients suspected for AA. Materials and Methods: Fifty-one patients who underwent surgery for AA were included (male-female = 28:23), and blood was sampled. Plasma concentrations of 2 neutrophil proteins were measured: lactoferrin (LF) and calprotectin (CP). Controls consisted of 27 healthy volunteers. C-reactive protein (CRP) and white blood cell count (WBC) concentrations were measured for routine patient care. Results: Median plasma concentrations for LF and CP were significantly higher in 51 patients with proven AA (665 and 766 ng/mL, respectively) than in 27 healthy volunteers (198 and 239 ng/mL, respectively, P < .001). No clinically relevant correlation exists between the plasma levels of LF and CP and the conventional laboratory tests for CRP and WBC. Conclusions: Circulating LF and CP levels are significantly elevated in patients with appendicitis and are detectable in plasma using relatively simple and low-cost enzyme-linked immunosorbent assays. Furthermore, plasma levels of LF and CP give additional information to conventional markers WBC and CRP, making them potential new markers for AA diagnosis

Early Diagnosis of Intestinal Ischemia Using Urinary and Plasma Fatty Acid Binding Proteins

Objective: This study aims at improving diagnosis of intestinal ischemia, by measuring plasma and urinary fatty acid binding protein (FABP) levels. Methods: Fifty consecutive patients suspected of intestinal ischemia were included and blood and urine were sampled at time of suspicion. Plasma and urinary concentrations of intestinal FABP (I-FABP), liver FABP (L-FABP) and ileal bile acid binding protein (I-BABP) were measured using enzyme linked immunosorbent assays. Results: Twenty-two patients suspected of intestinal ischemia were diagnosed with intestinal ischemia, 24 patients were diagnosed with other diseases, and 4 patients were excluded from further analysis fulfilling exclusion criteria. Median plasma concentrations of I-FABP and L-FABP and urinary concentrations of all 3 markers were significantly higher in patients with proven intestinal ischemia than in patients suspected of intestinal ischemia with other final diagnoses (plasma I-FABP; 653 pg/mL vs. 109 pg/mL, P = 0.02, plasma L-FABP; 117 ng/mL vs. 25 ng/mL, P = 0.006, urine I-FABP; 3377 pg/mL vs. 115 pg/mL, P = 0.001, urine L-FABP; 1,199 ng/mL vs. 37 ng/mL, P = 0.004, urine I-BABP; 48.6 ng/mL vs. 0.6 ng/mL, P = 0.002). Positive and negative likelihood ratios significantly increased positive posttest probability and decreased negative posttest probability on intestinal ischemia. In patients with intestinal ischemia a trend to higher plasma I-BABP levels was observed when the ileum was involved (18.4 ng/mL vs. 2.9 ng/mL, P = 0.05). Conclusion: Plasma and especially urinary I-FABP and L-FABP levels and urinary I-BABP levels can improve early diagnosis of intestinal ischemia. Furthermore, plasma I-BABP levels can help in localizing ileal ischemia

Rapid reversal of human intestinal ischemia-reperfusion induced damage by shedding of injured enterocytes and reepithelialisation.

BACKGROUND: Intestinal ischemia-reperfusion (IR) is a phenomenon related to physiological conditions (e.g. exercise, stress) and to pathophysiological events (e.g. acute mesenteric ischemia, aortic surgery). Although intestinal IR has been studied extensively in animals, results remain inconclusive and data on human intestinal IR are scarce. Therefore, an experimental harmless model for human intestinal IR was developed, enabling us to clarify the sequelae of human intestinal IR for the first time. METHODS AND FINDINGS: In 30 patients undergoing pancreatico-duodenectomy we took advantage of the fact that in this procedure a variable length of jejunum is removed. Isolated jejunum (5 cm) was subjected to 30 minutes ischemia followed by reperfusion. Intestinal Fatty Acid Binding Protein (I-FABP) arteriovenous concentration differences across the bowel segment were measured before and after ischemia to assess epithelial cell damage. Tissue sections were collected after ischemia and at 25, 60 and 120 minutes reperfusion and stained with H&E, and for I-FABP and the apoptosis marker M30. Bonferroni's test was used to compare I-FABP differences. Mean (SEM) arteriovenous concentration gradients of I-FABP across the jejunum revealed rapidly developing epithelial cell damage. I-FABP release significantly increased from 290 (46) pg/ml before ischemia towards 3,997 (554) pg/ml immediately after ischemia (p<0.001) and declined gradually to 1,143 (237) pg/ml within 1 hour reperfusion (p<0.001). Directly after ischemia the intestinal epithelial lining was microscopically normal, while subepithelial spaces appeared at the villus tip. However, after 25 minutes reperfusion, enterocyte M30 immunostaining was observed at the villus tip accompanied by shedding of mature enterocytes into the lumen and loss of I-FABP staining. Interestingly, within 60 minutes reperfusion the epithelial barrier resealed, while debris of apoptotic, shedded epithelial cells was observed in the lumen. At the same time, M30 immunoreactivity was absent in intact epithelial lining. CONCLUSIONS: This is the first human study to clarify intestinal IR induced cell damage and repair and its direct consequences. It reveals a unique, endogenous clearing mechanism for injured enterocytes: rapid detachment of damaged apoptotic enterocytes into the lumen. This process is followed by repair of the epithelial continuity within an hour, resulting in a normal epithelial lining