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ObjectivesVagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive muscularis macrophages (mMφ) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human.DesignUsing Ca2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMφ activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1–5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and α7nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI.ResultsEFS reduced the ATP-induced Ca2+ response of mMφ, an effect that was dampened by neurotoxins tetrodotoxin and ω-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in α7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery.ConclusionEnteric neurons dampen mMφ activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI.Trial registration numberNCT02425774.

Abdominal VNS is feasible and safe in humans and has anti-inflammatory properties. As abdominal VNS improves POI similar to cervical VNS in mice, our data indicate that peroperative abdominal VNS may represent a novel approach to shorten POI in man.

Solid clinical prospective studies investigating the association between hepatic ischemia/reperfusion injury (HIRI) and acute kidney injury (AKI) after liver transplantation are missing. HIRI, reflected by transaminase release, induces AKI in rodents, and retrospective studies suggest a similar association in humans. This prospective cohort study determined risk factors for AKI in 80 adult liver-only recipients. AKI defined by Risk, Injury, Failure, Loss, and End-Stage Kidney Disease (RIFLE) criteria developed in 21 (26%) recipients at 12 hours after reperfusion (interquartile range, 6 hours to postoperative day [POD] 1); 13 progressed from "risk" to "injury"; 5 progressed to "failure." In AKI patients, creatinine (Cr) increased during liver transplantation and was higher versus baseline at 6 hours to POD 4, whereas perioperative Cr remained stable in those without AKI. Plasma heart-type fatty acid-binding protein was higher 12 hours after reperfusion in AKI patients, though urinary kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin were similar between those with or without AKI. Peak aspartate aminotransferase (AST), occurring at 6 hours, was the only independent risk factor for AKI (adjusted odds ratio, 2.42; 95% confidence interval, 1.24-4.91). Early allograft dysfunction occurred more frequently in AKI patients, and intensive care and hospital stays were longer. Patient survival at 1 year was 90% in those with AKI versus 98% in those without AKI. Chronic kidney disease stage ≥ 2 at 1 year was more frequent in patients who had had AKI (89% versus 58%, respectively). In conclusion, AKI is initiated early after liver reperfusion and its association with peak AST suggests HIRI as a determinant. Identifying operating mechanisms is critical to target interventions and to reduce associated morbidity. Liver Transplantation 23 634-644 2017 AASLD.

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