Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons.

OBJECTIVES: Vagus 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. DESIGN: Using 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. RESULTS: EFS 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. CONCLUSION: Enteric 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 NUMBER: NCT02425774.

A systematic review of the intervention components, adherence and outcomes of enhanced recovery programmes in older patients undergoing elective colorectal surgery.

BACKGROUND: Enhanced recovery programmes (ERPs) aim to attenuate the surgical stress response and accelerate recovery after surgery, but are not specifically designed for older patients. The objective of this study was to review the components, adherence and outcomes of ERPs in older patients (≥65 years) undergoing elective colorectal surgery. METHODS: Pubmed, Embase and Cinahl were searched between 2000 and 2017 for randomised and non-randomised controlled trials, before-after studies, and observational studies. The methodological quality of the studies was evaluated using the MINORS quality assessment. The review was performed and reported according to the PRISMA guidelines. RESULTS: Twenty-one studies, including 3495 ERP patients aged ≥65 years, were identified. The ERPs consisted of a median of 13 intervention components. Adherence rates were reported in 9 studies and were the highest (≥80%) for pre-admission counselling, no bowel preparation, limited pre-operative fasting, antithrombotic and antimicrobial prophylaxis, no nasogastric tube, active warming, and limited intra-operative fluids. The median post-operative length of stay was 6 days. The median post-operative morbidity rate (Clavien-Dindo I-IV) was 23.5% in-hospital and 29.8% at 30 days. The in-hospital post-operative mortality rate was 0% in most studies and amounted to a median of 1.4% at 30 days. The median 30-day readmission rate was 4.9% and the median reoperation rate was 5.0%. CONCLUSIONS: ERPs in older patients were in accordance with the ERP consensus guidelines. Although the number of intervention components applied increased over time, outcomes in earlier and later studies remained comparable. Adherence rates were under-reported. Future studies should explore adherence and age-related factors, such as frailty profile, that could influence adherence. TRIAL REGISTRATION: PROSPERO 2018 CRD42018084756 .

Hepatic ischemia/reperfusion injury associates with acute kidney injury in liver transplantation: Prospective cohort study.

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.

Multivisceral Transplantation for Diffuse Portomesenteric Thrombosis: Lessons Learned for Surgical Optimization.

Background: Multivisceral transplantation entails the en-bloc transplantation of stomach, duodenum, pancreas, liver and bowel following resection of the native organs. Diffuse portomesenteric thrombosis, defined as the complete occlusion of the portal system, can lead to life-threatening gastrointestinal bleeding, malnutrition and can be associated with liver and intestinal failure. Multivisceral transplantation is the only procedure that offers a definitive solution by completely replacing the portal system. However, this procedure is technically challenging in this setting. The aim of this study is to describe our experience, highlight the challenges and propose technical solutions. Materials and Methods: We performed a retrospective analysis of our cohort undergoing multivisceral transplantation for diffuse portomesenteric thrombosis at our institution from 2000 to 2020. Donor and recipient demographics and surgical strategies were reviewed in detail and posttransplant complications and survival were analyzed. Results: Five patients underwent MVTx. Median age was 47 years (23-62). All had diffuse portomesenteric thrombosis with life-threatening variceal bleeding. Major blood loss during exenteration was avoided by combining two techniques: embolization of the native organs followed by a novel, staged extraction. This prevented major perioperative blood loss [median intra-operative transfusion of 3 packed red blood cell units (0-5)]. Median CIT was 330 min (316-416). There was no perioperative death. One patient died due to invasive aspergillosis. Four others are alive and well with a median follow-up of 4.1 years (0.3-5.9). Conclusions: Multivisceral transplantation should be considered in patients with diffuse portomesenteric thrombosis that cannot be treated by any other means. We propose a standardized surgical approach to limit the operative risk and improve the outcome.

A retrospective observational study of enhanced recovery after surgery in older patients undergoing elective colorectal surgery.

BACKGROUND: Enhanced recovery programs (ERPs) in colorectal surgery have demonstrated beneficial effects on postoperative complications, return of bowel function, length of stay, and costs, without increasing readmissions or mortality. However, ERPs were not specifically designed for older patients and feasibility in older patients has been questioned. AIM: The aim of this study was to assess ERP adherence and outcomes in older patients and to identify risk factors for postoperative complications and prolonged length of stay. METHOD: Retrospective analysis of consecutive patients (≥70 years) undergoing elective colorectal resection in a tertiary referral hospital in 2017. RESULTS: Ninety-six patients were included. Adherence rates were above 80% in 18 of 21 ERP interventions considered. The lowest adherence rates were noted for preoperative carbohydrate loading and cessation of intravenous fluids. Postoperative complications (Clavien-Dindo ≥2) and prolonged postoperative length of stay (>75th percentile) were observed in 39.6% and 26.3%, respectively. Median length of stay was 7 days. The 30-day mortality, readmission and reoperation rates were 2.1%, 12.6% and 8.3%, respectively. Multivariable analysis indicated that polypharmacy and site of surgery were independent risk factors for postoperative complications, while higher age, American Society of Anesthesiologists class and preoperative radiotherapy were independent risk factors for prolonged postoperative length of stay. CONCLUSION: ERP adherence in older patients undergoing colorectal resection is high and ERP is therefore considered feasible. Postoperative complications and prolonged postoperative length of stay are common, so at risk patients should be targeted with tailored geriatric interventions.

Combined liver and (heart-)lung transplantation in liver transplant candidates with refractory portopulmonary hypertension.

BACKGROUND: Portopulmonary hypertension (PPHT) has a prevalence of 5-10% in liver transplantation (LiTx) candidates. Mild PPHT is reversible with LiTx, but more severe PPHT is a contraindication to LiTx given the high intraoperative mortality due to heart failure. Prostacyclin can reduce PPHT to a level at which LiTx can be performed. In patients refractory to that treatment, combined (heart-)lung-LiTx is the only life-saving option. METHODS: We report two cases of (heart-)lung-LiTx in patients with refractory severe PPHT. RESULTS: Patient 1, a 52-year-old female with viral cirrhosis and severe refractory PPHT, received a double-lung Tx followed by LiTx. After liver reperfusion, fatal heart failure occurred. Patient 2, a 42-year-old male with viral hepatitis and congenital liver fibrosis, also suffered from severe refractory PPHT. He successfully received an en bloc heart-lung Tx followed by LiTx. The rationale to replace the heart was an anticipated risk of intraoperative right heart failure after liver reperfusion and the technical ease of heart-lung versus double-lung Tx. CONCLUSION: Severe refractory PPHT is a fatal condition seen as a contraindication to LiTx. This condition can be treated by replacing thoracal organs in addition to the liver. Additional evidence via development of a registry is required to further support application of liver-(heart-)lung Tx in patients with severe refractory PPHT.

Steroid-free immunosuppression during and after liver transplantation--a 3-yr follow-up report.

BACKGROUND/AIMS: Steroids are traditionally used in liver transplantation as a part of a triple or quadruple immunosuppressive regimen. Steroids act non-specifically and cause multiple side-effects. Most liver transplantation centers reduce the dosage of steroids and eventually withdraw them after various time intervals. A few steroid-free trials have been recently conducted after liver transplantation but long-term data are not yet available. In addition, in these trials steroids were usually given during surgery. We report the long-term (median = 40 months) follow-up data of a prospective pilot study designed to determine whether liver transplantation could be performed with no steroids at all (neither during nor after surgery). METHODS: Twenty-one consecutive liver transplantations in 20 adult patients between August 1998 and July 1999 were prospectively included in an ab initio steroid-free immunosuppressive protocol. Mean age was 54 yr (40-67 yr). Tacrolimus (through levels, 8-10 ng/mL) and azathioprine (1-2 mg/kg) were started after liver transplantation. Patients were not given steroids during or after liver transplantation except in the event of rejection or in case of tacrolimus or azathioprine toxicity requiring significant dose reduction and/or withdrawal. RESULTS: There has been no case of primary graft dysfunction or non-function. Eleven of 21 liver transplantations (52%) received no steroids throughout the whole study. Rejection developed in five of 21 liver transplantations (23.5%). These rejections responded to standard i.v. steroids (plus ATG in one patient), followed by an oral steroid taper stopped 3 months after rejection. Steroids were transiently given in six liver transplantations for non-immune reasons: two with tacrolimus-induced neurotoxicity, three cases where azathioprine was discontinued, and one for an allergic reaction; four of these six patients are off steroids at last follow-up. The 3-yr graft and patient survival is 95 and 100%, respectively. CONCLUSIONS: Steroids are not necessary in more than 50% of liver transplantations. Steroids were transiently needed to treat acute rejection in 23.5% liver transplantations and for toxicity of calcineurin inhibitors or azathioprine or other reason in 28%. Of the patients who received steroids, the majority (70%) was eventually taken off steroids. This prospective single-center pilot study shows that liver transplantation without steroids is feasible and yields no penalty in terms of acute and chronic rejection, immune graft loss, graft function, patient and graft survival.