Assessment and Transplantation of Orphan Donor Livers: A Back-to-Base Approach to Normothermic Machine Perfusion.

Globally, a large proportion of donor livers are discarded due to concerns over inadequate organ quality. Normothermic machine perfusion (NMP) allows for hepatocellular and biliary viability assessment prior to transplantation and might therefore enable the safe use of these orphan donor livers. We describe here the first Australasian experience of NMP-preserved liver transplants using a 'back-to-base' approach, where NMP was commenced at the recipient hospital following initial static cold storage. In the preclinical phase, 10 human donor livers declined for transplantation (7 from donation after circulatory death [DCD] and 3 from donation after brain death [DBD]) were perfused using a custom-made NMP setup. Subsequently, 10 orphan donor livers (5 from DCD and 5 from DBD) underwent NMP and viability assessment on the OrganOx metra device (OrganOx Limited, Oxford, United Kingdom). Both hepatocellular and biliary viability criteria were used. The median donor risk index was 1.53 (1.16-1.71), and the median recipient Model for End-Stage Liver Disease score was 17 (11-21). In the preclinical phase, 'back-to-base' NMP was deemed suitable and feasible. In the clinical phase, each graft met predefined criteria for implantation during NMP and was subsequently transplanted. Five (50%) recipients developed early allograft dysfunction based on peak aspartate aminotransferase. To date, all grafts function satisfactorily, and none of the 5 recipients who received a DCD liver have developed cholangiopathy. The OrganOx metra using a back-to-base approach has enabled the safe use of 10 high-risk orphan donor livers with 100% 6-month patient and graft survival. NMP improved surgeon confidence to use orphan donor livers and has enabled a safe expansion of the donor pool.

Exploring the relation between preoperative physical functioning and the impact of major complications in patients following pancreatic resection.

BACKGROUND: This study aimed to evaluate the association between preoperative level of physical functioning and time to recovery of physical functioning, postoperative complications, and the impact of postoperative major complications in patients undergoing elective pancreatic resection. Additionally, prediction models to identify high-risk patients for developing a major complication were externally validated. METHODS: Perioperative data of patients who underwent pancreatic resection were analysed. Primary outcomes were time to recovery of physical functioning and postoperative major complications. Impact of a major complication was explored by evaluating its effect on time to recovery of physical functioning. Risk-prediction models were retrieved following a systematic review. RESULTS: Multivariable analysis (n = 63) showed that ASA grade III (OR 3.498) and preoperative platelet count (OR 1.005) were associated with major complications, whereas aerobic capacity (OR 0.347) was associated with time to recovery of physical functioning. Age, preoperative aerobic capacity, functional mobility, and perceived level of functional capacity were associated with the impact of a major complication. The AUC of two risk prediction models were 0.556 and 0.701. CONCLUSION: Preoperative parameters of physical function were associated with postoperative outcomes and may be useful in outcome prediction, although future approaches should not only register the incidence of major complications but also take the impact of a complication on a patient's physical functioning into account.

Low-Dose Lipopolysaccharide Causes Biliary Injury by Blood Biliary Barrier Impairment in a Rat Hepatic Ischemia/Reperfusion Model.

This study explored whether bacterial endotoxins, in the form of lipopolysaccharides (LPS), could have an injurious effect on the biliary tract in conjunction with ischemia. A total of 64 rats were randomly assigned to 4 groups: sham operation (sham group), 1 mg/kg LPS intraperitoneal (LPS group), hepatic ischemia/reperfusion (IR; IR group), and IR combined with LPS (IR+LPS group). Following 1 or 6 hours of reperfusion, serum liver tests, bile duct histology, immunofluorescence microscopy (zonula occludens-1 [ZO-1]), bile composition (bile salts, phospholipids, lactate dehydrogenase), hepatic gene expression (bile salt transporters and inflammatory mediators), as well as serum and biliary cytokine concentrations were quantified and compared between the study groups. In addition, the integrity of the blood biliary barrier (BBB) was assayed in vivo using horseradish peroxidase (HRP). LPS administration induced severe small bile duct injury following 6 hours of reperfusion. Furthermore, total bile salts and bilirubin concentrations in serum were increased in the LPS groups compared with sham controls (LPS, + 3.3-fold and +1.9-fold; IR+LPS, + 3.8-fold and +1.7-fold, respectively). The BBB was impaired in the LPS groups as evidenced by elevated levels of HRP in bile (+4.9-fold), and decreased expression of claudin 1 (-6.7-fold) and claudin 3 (-3.6-fold). LPS was found to be a potent inducer of small bile duct injury following hepatic ischemia and 6 hours of reperfusion. This injury was associated with increased permeability of the BBB and impaired hepatic bile salt clearance. Liver Transplantation 23 194-206 2017 AASLD.

Does proteolysis explain glutamine release from the septic brain?

Berg and colleagues report on amino acid exchange across the human brain during endotoxin infusion. Lipopolysaccharide infusion induced a decrease in the ratio between branched chain amino acids and aromatic amino acids, increased unidirectional phenylalanine uptake, and increased net brain glutamine release. Cerebral proteolysis is suggested to play a role, but the question is whether this is the case and why this would happen.

Intestinal adaptation in short bowel syndrome.

Regaining enteral autonomy after extensive small bowel resection is dependent on intestinal adaptation. This adaptational process is characterized by hyperplastic growth of the remaining gut, which is accompanied by both an increase of cell division at the level of the crypt cells and by an increased rate of programmed cell death (apoptosis). Apart from the absorptive function, the small bowel also has a barrier function and plays an important role in interorgan metabolism. Also, these functions are greatly affected by a massive intestinal resection and subsequent recovery by intestinal adaptation. This review aims to give an overview of the debilitating effects of massive intestinal resection on gut function and subsequently discusses intestinal adaptation and possible factors stimulating adaptation.

The enhanced recovery after surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials.

BACKGROUND & AIMS: The aim of the Enhanced Recovery After Surgery (ERAS) pathway is to attenuate the stress response to surgery and enable rapid recovery. The objective of this meta-analysis was to study the differences in outcomes in patients undergoing major elective open colorectal surgery within an ERAS pathway and those treated with conventional perioperative care. METHODS: Medline, Embase and Cochrane database searches were performed for relevant studies published between January 1966 and November 2009. All randomized controlled trials comparing ERAS with conventional perioperative care were selected. The outcome measures studied were length of hospital stay, complication rates, readmission rates and mortality. RESULTS: Six randomized controlled trials with 452 patients were included. The number of individual ERAS elements used ranged from 4 to 12, with a mean of 9. The length of hospital stay [weighted mean difference (95% confidence interval): -2.55 (-3.24, -1.85)] and complication rates [relative risk (95% confidence interval): 0.53 (0.44, 0.64)] were significantly reduced in the enhanced recovery group. There was no statistically significant difference in readmission and mortality rates. CONCLUSION: ERAS pathways appear to reduce the length of stay and complication rates after major elective open colorectal surgery without compromising patient safety.

Interorgan ammonia trafficking in liver disease.

Patients with liver disease have reduced urea synthesis capacity resulting in reduced capacity to detoxify ammonia in the liver. The contribution of the gut to the hyperammonemic state observed during liver failure is mainly due to portacaval shunting and not the result of changes in the metabolism of ammonia in the gut. Small intestinal synthesis of ammonia is related to amino acid breakdown, predominantly glutamine, whereas large bowel ammonia production is caused by bacterial breakdown of amino acids and urea. The kidneys produce ammonia but adapt to liver failure in experimental portacaval shunting by reducing ammonia release into the systemic circulation. The kidneys have the ability to switch from net ammonia production to net ammonia excretion. Data from recent studies in patients with cirrhosis of the liver show that the kidneys have a major role in post upper gastrointestinal bleeding hyperammonemia. During hyperammonemia muscle takes up ammonia and plays a major role in (temporarily) detoxifying ammonia to glutamine. Net uptake of ammonia by the brain occurs in patients and experimental animals with acute and chronic liver failure. Insight will be given in recent developments on ammonia lowering therapies which are based on the information of interorgan ammonia trafficking.

The adaptive response of the reticuloendothelial system to major liver resection in humans.

OBJECTIVE: To evaluate the contribution of the liver to total circulatory reticuloendothelial system (RES) phagocytosis capacity in patients undergoing liver resection and to compare it with values in end-stage chronic liver disease. SUMMARY BACKGROUND DATA: The mechanism whereby major liver resection is associated with a high incidence of infection is unknown. Significant impairment of RES phagocytosis has been described in liver failure, rendering such patients susceptible to infection; and we hypothesized that similar impairment might occur following major liver resection. METHODS: A prospective study was conducted in which Tc-albumin microspheres blood clearance served as a parameter for RES phagocytosis and was studied together with indocyanine green blood clearance, actual liver volume measured by three-dimensional image analysis, and a clinical score of hepatic dysfunction in 17 patients undergoing liver resection and in 8 patients with end-stage chronic liver disease assessed for liver transplantation. RESULTS: When expressed relative to volume unit of residual liver, microspheres clearance increased significantly in the immediate postoperative period (day 1) following major (0.009% versus 0.022% min(-1) mL(-1), P < 0.001), but not minor liver resection. In contrast, the absolute rate of microsphere clearance decreased following major resection (15% min(-1) versus 10% min(-1), P < 0.001) and was comparable with the rate observed in end-stage chronic liver disease (9% min(-1)). This decrease in circulatory microspheres clearance after resection paralleled a decrease in indocyanine green clearance (R2 = 0.511, P = 0.006), and there was a trend for those with moderate liver dysfunction to have lower microspheres clearance rates (P = 0.068). CONCLUSION: Preservation of a minimum volume of functioning liver is a prerequisite for adequate RES phagocytosis capacity, and failure of this system may predispose patients undergoing major liver resection to infection as observed in clinical studies.