Aortic Versus Dual Perfusion for Retrieval of the Liver After Brain Death: A National Registry Analysis.

There is lack of consensus in the literature regarding the comparative efficacy of in situ aortic-only compared with dual (aortic and portal venous) perfusion for retrieval and transplantation of the liver. Recipient outcomes from the Australia/New Zealand Liver Transplant Registry (2007-2016), including patient and graft survival and causes of graft loss, were stratified by perfusion route. Subgroup analyses were conducted for higher-risk donors. A total of 1382 liver transplantation recipients were analyzed (957 aortic-only; 425 dual perfusion). There were no significant differences in 5-year graft and patient survivals between the aortic-only and dual cohorts (80.1% versus 84.6% and 82.6% versus 87.8%, respectively) or in the odds ratios of primary nonfunction, thrombotic graft loss, or graft loss secondary to biliary complications or acute rejection. When analyzing only higher-risk donors (n = 369), multivariate graft survival was significantly less in the aortic-only cohort (hazard ratio, 0.49; 95% confidence interval, 0.26-0.92). Overall, there was a trend toward improved outcomes when dual perfusion was used, which became significant when considering higher-risk donors alone. Inferences into the ideal perfusion technique in multiorgan procurement will require further investigation by way of a randomized controlled trial, and outcomes after the transplantation of other organs will also need to be considered.

A systematic review and meta-analysis of cold in situ perfusion and preservation of the hepatic allograft: Working toward a unified approach.

The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route (aortic or dual) or perfusion/preservation solution in donation after brain death (DBD) liver transplantation. The Embase, MEDLINE, and Cochrane databases were used (1980-2017). Random effects modeling was used to estimate effects on transplantation outcomes based on (1) aortic or dual in situ perfusion and (2) the use of University of Wisconsin (UW), histidine tryptophan ketoglutarate (HTK), Celsior, and/or Institut Georges Lopez-1 (IGL-1) solutions for perfusion/preservation. A total of 22 articles were included (2294 liver transplants). The quality of evidence ranged from very low to moderate Grading of Recommendations, Assessment, Development and Evaluations score. Meta-analyses were conducted for 14 eligible studies. Although there was no difference in the primary nonfunction (PNF) rate, a higher peak alanine aminotransferase (ALT) was recorded in dual compared with aortic-only UW-perfused livers (standardized mean difference, 0.24; 95% confidence interval, 0.01-0.47); a back-table portal venous flush was undertaken in the majority of aortic-only perfused livers. There were no relevant differences in peak enzymes, PNF, thrombotic graft loss, biliary complications, or 1-year graft survival in comparisons between dual-perfused livers using UW, HTK, Celsior, or IGL-1. In conclusion, there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes, and it may be favored because of its simplicity. However, there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others. Liver Transplantation 23 1615-1627 2017 AASLD.

A systematic review and meta-analysis of cold in situ perfusion and preservation for pancreas transplantation.

BACKGROUND: This study aimed to identify the most effective solution for in situ perfusion/preservation of the pancreas in donation after brain death donors, in addition to optimal in situ flush volume(s) and route(s) during pancreas procurement. METHODS: Embase, Medline and Cochrane databases were utilized (1980-2017). Articles comparing graft outcomes between two or more different perfusion/preservation fluids (University of Wisconsin (UW), histidine-tryptophan-ketoglutarate (HTK) and/or Celsior) were compared using random effects models where appropriate. RESULTS: Thirteen articles were included (939 transplants). Confidence in available evidence was low. A higher serum peak lipase (standardized mean difference 0.47, 95% CI 0.23-0.71, I2 = 0) was observed in pancreatic grafts perfused/preserved with HTK compared to UW, but there were no differences in one-month pancreas allograft survivals or early thrombotic graft loss rates. Similarly, there were no significant differences in the rates of graft pancreatitis, thrombosis and graft survival between UW and Celsior solutions, and between aortic-only and dual aorto-portal perfusion. CONCLUSION: UW cold perfusion may reduce peak serum lipase, but no quality evidence suggested UW cold perfusion improves graft survival and reduces thrombosis rates. Further research is needed to establish longer-term graft outcomes, the comparative efficacy of Celsior, and ideal perfusion volumes.

Patient Selection for Oesophagectomy: Impact of Age and Comorbidities on Outcome.

INTRODUCTION: Surgical resection of oesophageal cancer is a major procedure with potential for significant morbidity and mortality. Patient selection can be challenging, as operative benefit must be balanced against risk and impact on quality of life. This study defines modern trends in patient selection, and evaluates the impact of age, stage, and comorbidities on complications and survival following oesophagectomy, in a tertiary Australian experience. METHODS: Data were compiled across two 15-year operative eras ('Era 1': 1981-1995; and 'Era 2': 1996-2010), with patients followed minimum 3 years. A total of 180 unselected records were analysed (powered for a relative hazard ratio of 0.5). Analyses defined patient selection trends, and for Era 2, the impact of age, comorbidities (Charlson score), and disease (T/N stage) on complications (Clavien-Dindo grade) and survival (Kaplan-Meier). A further sub-analysis was conducted with data divided into three 10-year periods. RESULTS: The age of operated patients increased from Era 1 to 2 (mean+5 years; P<0.001), but survival and complication rates were unchanged, including in patients≥75 years (P>0.5). In Era 2, reflecting recent practice, survival duration matched T/N stage (P<0.001) but was independent of age at surgery (P=0.56) and comorbidity score (P=0.78). However, grade of worst post-operative complication, including death (rate: 3.8%), was correlated with both age (P<0.01) and comorbidity score (P<0.01). DISCUSSION: Older patients are now undergoing oesophagectomy. However, if they are selected appropriately, then older patients and those with comorbidities can expect similar stage-matched survival outcomes to younger fitter patients, despite their higher operative risk. Poor outcomes persist in patients with locally advanced disease, and selection in this group should prioritise quality of life.

Significant elevations of serum lipase not caused by pancreatitis: a systematic review.

BACKGROUND: Many authors advocate lipase as the preferred serological test for the diagnosis of pancreatitis and a cut-off level of three or more times the upper limit of normal (ULN) is often quoted. The literature contains no systematic review that explores alternative causes of a lipase level over three times as high as the ULN. Such a review was therefore the objective of this study. METHODS: The EMBASE and MEDLINE databases (1985 to August 2013) were searched for all eligible articles. Predetermined data were extracted and independently analysed by two reviewers. RESULTS: In total, data from 58 studies were included in the final analysis. The following causes other than pancreatitis of lipase levels exceeding three times the ULN were found: reduced clearance of lipase caused by renal impairment or macrolipase formation; other hepatobiliary, gastroduodenal, intestinal and neoplastic causes; critical illness, including neurosurgical pathology; alternative pancreatic diagnoses, such as non-pathological pancreatic hyperenzymaemia, and miscellaneous causes such as diabetes, drugs and infections. CONCLUSIONS: A series of differential diagnoses for significant serum lipase elevations (i.e. exceeding three times the ULN) has been provided by this study. Clinicians should utilize this knowledge in the interpretation and management of patients who have lipase levels over three times as high as the ULN, remaining vigilant for an alternative diagnosis to pancreatitis. The medical officer should be aware of the possibility of incorrect diagnosis in the asymptomatic patient.

Process measure aimed at reducing time to haemorrhage control: outcomes associated with Code Crimson activation in exsanguinating truncal trauma.

BACKGROUND: Major trauma activation is a process that mobilizes personnel and resources required to care for severely injured patients. Exsanguinating truncal trauma patients require an additional response beyond major trauma activation aimed at expediting haemorrhage control. To address this requirement, 'Code Crimson' (CC) activation was developed. Our aim was to examine the performance of CC activation as a process measure in the identification and management of patients with exsanguinating truncal trauma. METHODS: Retrospective cohort study (2010-2015) of all adult patients who underwent operative intervention within 6 h of arrival for truncal trauma was performed. Patients were classified into: (i) major haemorrhage (assessment of blood consumption score ≥2, base deficit ≥5 and/or transfusion ≥5 U of red blood cells pre-/intra-operatively), or (ii) no major haemorrhage. We evaluated the proportion of patients with/without major haemorrhage in which a CC was activated as well as time to operating theatre across groups. RESULTS: A total of 210 patients were included with a median Injury Severity Score of 20 (interquartile range (IQR) 9-29) and overall mortality of 13%. Eighty-nine patients were classified as major haemorrhage and 61 patients underwent CC activation. The majority of CC activations (92%) fulfilled major haemorrhage criteria (sensitivity 63%, specificity 96%). Time to theatre was lower in those with CC activation with median time of 23 min (IQR 15-39.5) versus non-CC with median of 95 min (IQR 43-180, P < 0.001). CONCLUSION: CC was primarily activated in patients with major haemorrhage and led to a decrease in time to theatre for patients with operative truncal trauma.

Beware the band adhesion: an unexpected cause of double obstruction following intraperitoneal kidney transplantation.

Small bowel obstruction (SBO) following intraperitoneal renal transplantation, either solitary or due to simultaneous pancreas-kidney transplantation, is a known complication. While SBO is most commonly due to adhesions, there have been documented cases of internal herniation following simultaneous pancreas-kidney transplantation with enteric drainage due to the formation of a mesenteric defect. We present a unique complication in which the transplant ureter has caused strangulation and necrosis of a length of small intestine. The transplant ureter was mistaken for a band adhesion and divided. Post-operative anuria signalled this difficult diagnosis. Subsequent re-look laparotomy and ureteric reimplantation with Boari flap were required. Therefore, it is important to consider the ureter as a cause of internal herniation in kidney transplant patients and recognize that a band adhesion within the pelvis may in fact be the transplant ureter, obstructing a loop of small intestine beneath its course.

Pharmacologic targeting of renal ischemia-reperfusion injury using a normothermic machine perfusion platform.

Normothermic machine perfusion (NMP) is an emerging modality for kidney preservation prior to transplantation. NMP may allow directed pharmacomodulation of renal ischemia-reperfusion injury (IRI) without the need for systemic donor/recipient therapies. Three proven anti-IRI agents not in widespread clinical use, CD47-blocking antibody (αCD47Ab), soluble complement receptor 1 (sCR1), and recombinant thrombomodulin (rTM), were compared in a murine model of kidney IRI. The most effective agent was then utilized in a custom NMP circuit for the treatment of isolated porcine kidneys, ascertaining the impact of the drug on perfusion and IRI-related parameters. αCD47Ab conferred the greatest protection against IRI in mice after 24 hours. αCD47Ab was therefore chosen as the candidate agent for addition to the NMP circuit. CD47 receptor binding was demonstrated by immunofluorescence. Renal perfusion/flow improved with CD47 blockade, with a corresponding reduction in oxidative stress and histologic damage compared to untreated NMP kidneys. Tubular and glomerular functional parameters were not significantly impacted by αCD47Ab treatment during NMP. In a murine renal IRI model, αCD47Ab was confirmed as a superior anti-IRI agent compared to therapies targeting other pathways. NMP enabled effective, direct delivery of this drug to porcine kidneys, although further efficacy needs to be proven in the transplantation setting.

Brief Normothermic Machine Perfusion Rejuvenates Discarded Human Kidneys.

Normothermic machine perfusion (NMP) may allow resuscitation and improved assessment of kidneys before transplantation. Using discarded human kidneys, we investigated the mechanistic basis and translational potential of NMP compared with cold static storage (CS). METHODS: Discarded deceased donor kidneys (n = 15) underwent 1-hour NMP following CS. Renal perfusion, biochemical, and histologic parameters were recorded. NMP was directly compared with CS in paired donor kidneys using simulated transplantation with allogeneic whole blood, followed by assessment of the aforementioned parameters, in addition to RNA sequencing. RESULTS: Kidneys were successfully perfused, with improved renal blood flows and resistance over the course of perfusion, and evidence of urine output (median 21 mL), in all but one kidney. NMP completely resolved nonperfused regions in discarded donation after circulatory death kidneys. In paired kidneys (n = 4 pairs), transcriptomic analyses showed induction of stress and inflammatory pathways in NMP kidneys, with upregulation of pathways promoting cell survival and proliferation. Furthermore, the NMP pairs had significantly better renal perfusion (1.5-2 fold improvement) and functional parameters, and amelioration of cell death, oxidative stress, and complement activation. CONCLUSIONS: In this pilot preclinical study using simulated transplantation of paired kidneys, NMP of discarded marginal kidneys demonstrated some significant mechanistic benefits in comparison to CS alone. NMP may have potential to reduce organ discards and enhance early graft function in such kidneys.

The Evolution of Kidney Transplantation Surgery Into the Robotic Era and Its Prospects for Obese Recipients.

Robotic-assisted kidney transplantation (RAKT) represents the most recent innovation in the evolution of kidney transplantation surgery. Vascular techniques enabling kidney transplantation have existed since the early 20th century and contributed to the first successful open kidney transplant procedure in 1954. Technical advances have since facilitated minimally invasive laparoscopic and robotic techniques in live-donor surgery, and subsequently for the recipient procedure. This review follows the development of surgical techniques for kidney transplantation, with a special focus on the advent of robotic-assisted transplantation because of its potential to facilitate transplantation of those deemed previously too obese to transplant by standard means. The different techniques, indications, advantages, disadvantages, and future directions of this approach will be explored in detail. Robot-assisted kidney transplantation may become the preferred means of transplanting morbidly obese recipients, although its availability to such recipients remains extremely limited and strategies targeting weight loss pretransplantation should never be abandoned in favor of a "RAKT-first" approach.

Extra-corporeal normothermic machine perfusion of the porcine kidney: working towards future utilization in Australasia.

BACKGROUND: The ongoing supply-demand gap with respect to donor kidneys for transplantation necessitates the increased use of higher kidney donor profile index and/or donation after circulatory death (DCD) kidneys. Machine perfusion (MP) preservation has become increasingly popular as a means to preserve such organs. Human data regarding normothermic kidney MP (NMP) is in its infancy, and such a system has not been established in the Australasian clinical setting. METHODS: Modified cardio-pulmonary bypass technology was utilized to develop a viable NMP kidney perfusion system using a porcine DCD model. System development and optimization occurred in two stages, with system components added in each experiment to identify optimal perfusion conditions. RESULTS: Device functionality was demonstrated by the successful perfusion of and urine production by, eight porcine kidneys. Urine production diminished in the presence of colloid in the perfusate. Pressure-controlled (compared with flow-controlled) perfusion is preferable as a safe perfusion pressure range can be maintained. More physiologic perfusion conditions are achieved if oxygenation is provided by an oxygen/carbon dioxide mixture compared to 100% oxygen. CONCLUSION: A viable and reproducible NMP system was established and tested in porcine kidneys, which was able to simulate graft function extra-corporeally. Further work is required to identify the most optimal perfusion conditions. Prior to its utilization in clinical transplantation, the system should be tested in non-transplanted human kidneys.

Advances in organ preservation for transplantation.

Organ transplantation provides the best available therapy for a myriad of medical conditions, including end-stage renal disease, hepatic failure and type I diabetes mellitus. The current clinical reality is, however, that there is a significant shortage of organs available for transplantation with respect to the number of patients on organ waiting lists. As such, methods to increase organ supply have been instituted, including improved donor management, organ procurement and preservation strategies, living organ donation, transplantation education and the increased utilization of donation after circulatory death and expanded criteria donors. In particular, especially over the last decade, we have witnessed a significant change in the way donor organs are preserved, away from static cold storage methods to more dynamic techniques centred on machine perfusion (MP). This review highlights the current state and future of organ preservation for transplantation, focusing on both abdominal and thoracic organs. In particular, we focus on MP preservation of renal, hepatic, pancreatic, cardiac and lung allografts, also noting relevant advances in Australasia. MP of organs after procurement holds considerable promise, and has the potential to significantly improve graft viability and function post-transplantation, especially in donors in whom acceptance criteria have been expanded.

Maximizing kidneys for transplantation using machine perfusion: from the past to the future: A comprehensive systematic review and meta-analysis.

BACKGROUND: The two main options for renal allograft preservation are static cold storage (CS) and machine perfusion (MP). There has been considerably increased interest in MP preservation of kidneys, however conflicting evidence regarding its efficacy and associated costs have impacted its scale of clinical uptake. Additionally, there is no clear consensus regarding oxygenation, and hypo- or normothermia, in conjunction with MP, and its mechanisms of action are also debated. The primary aims of this article were to elucidate the benefits of MP preservation with and without oxygenation, and/or under normothermic conditions, when compared with CS prior to deceased donor kidney transplantation. METHODS: Clinical (observational studies and prospective trials) and animal (experimental) articles exploring the use of renal MP were assessed (EMBASE, Medline, and Cochrane databases). Meta-analyses were conducted for the comparisons between hypothermic MP (hypothermic machine perfusion [HMP]) and CS (human studies) and normothermic MP (warm (normothermic) perfusion [WP]) compared with CS or HMP (animal studies). The primary outcome was allograft function. Secondary outcomes included graft and patient survival, acute rejection and parameters of tubular, glomerular and endothelial function. Subgroup analyses were conducted in expanded criteria (ECD) and donation after circulatory (DCD) death donors. RESULTS: A total of 101 studies (63 human and 38 animal) were included. There was a lower rate of delayed graft function in recipients with HMP donor grafts compared with CS kidneys (RR 0.77; 95% CI 0.69-0.87). Primary nonfunction (PNF) was reduced in ECD kidneys preserved by HMP (RR 0.28; 95% CI 0.09-0.89). Renal function in animal studies was significantly better in WP kidneys compared with both HMP (standardized mean difference [SMD] of peak creatinine 1.66; 95% CI 3.19 to 0.14) and CS (SMD of peak creatinine 1.72; 95% CI 3.09 to 0.34). MP improves renal preservation through the better maintenance of tubular, glomerular, and endothelial function and integrity. CONCLUSIONS: HMP improves short-term outcomes after renal transplantation, with a less clear effect in the longer-term. There is considerable room for modification of the process to assess whether superior outcomes can be achieved through oxygenation, perfusion fluid manipulation, and alteration of perfusion temperature. In particular, correlative experimental (animal) data provides strong support for more clinical trials investigating normothermic MP.

Hepatic resection for metastatic melanoma: a systematic review.

Melanoma metastatic to the liver has a very poor prognosis, and has traditionally been treated using systemic chemotherapy with limited efficacy. Surgery is increasingly being explored as a therapeutic option for melanoma liver metastases, with varying levels of success. A systematic review was undertaken to explore the short-term and long-term outcomes associated with hepatectomy for melanoma metastases, in addition to identifying prognostic factors favouring increased survival. All eligible studies were identified through an electronic search of Medline and Embase (January 1990-March 2013). Each study was independently analysed by two reviewers, with relevant data extracted and tabulated according to predetermined criteria. Thirteen studies were selected that fulfilled the selection criteria, with a total of 551 patients undergoing hepatic resection for melanoma metastases. Metastases to the liver occurred at a median interval of 54 months. The median perioperative morbidity and mortality were 10% (range 0-28.6%) and 0% (range 0-7.1%), respectively. The median overall survival for operative patients was 24 months, with median survival being greater in the R0 resection group (25 months; range 9.5-65.6 months) compared with the R1/2 resection group (16 months; range 11.7-29 months). Overall median 1-, 3- and 5-year survival rates were 70% (range 39-100%), 36% (range 10.2-53%) and 24% (range 3-53%), respectively. Positive prognostic factors may include single hepatic metastases, a longer time to development of hepatic metastases and R0 resection. Hepatic resection for metastatic melanoma might confer a distinct survival benefit in a select group of patients, although disease recurrence is the norm.