The economic impact of machine perfusion technology in liver transplantation.

INTRODUCTION: Several clinical studies have demonstrated the safety, feasibility, and efficacy of machine perfusion in liver transplantation, although its economic outcomes are still underexplored. This review aimed to examine the costs related to machine perfusion and its associated outcomes. METHODS: Expert opinion of several groups representing different machine perfusion modalities. Critical analysis of the published literature reporting the economic outcomes of the most used techniques of machine perfusion in liver transplantation (normothermic and hypothermic ex situ machine perfusion and in situ normothermic regional perfusion). RESULTS: Machine perfusion costs include disposable components of the perfusion device, perfusate components, personnel and facility fees, and depreciation of the perfusion device or device lease fee. The limited current literature suggests that although this upfront cost varies between perfusion modalities, its use is highly likely to be cost-effective. Optimization of the donor liver utilization rate, local conditions of transplant programs (long waiting list times and higher MELD scores), a decreased rate of complications, changes in logistics, and length of hospital stay are potential cost savings points that must highlight the expected benefits of this intervention. An additional unaccounted factor is that machine perfusion optimizing donor organ utilization allows patients to be transplanted earlier, avoiding clinical deterioration while on the waiting list and the costs associated with hospital admissions and other required procedures. CONCLUSION: So far, the clinical benefits have guided machine perfusion implementation in liver transplantation. Albeit there is data suggesting the economic benefit of the technique, further investigation of its costs to healthcare systems and society and associated outcomes is needed.

Development of 3D Biofabricated Cell Laden Hydrogel Vessels and a Low-Cost Desktop Printed Perfusion Chamber for In Vitro Vessel Maturation.

The vascular system represents the key supply chain for nutrients and oxygen inside the human body. Engineered solutions to produce sophisticated alternatives for autologous or artificial vascular implants to sustainably replace diseased vascular tissue still remain a key challenge in tissue engineering. In this paper, cell-laden 3D bioplotted hydrogel vessel-like constructs made from alginate di-aldehyde (ADA) and gelatin (GEL) are presented. The aim is to increase the mechanical stability of fibroblast-laden ADA-GEL vessels, tailoring them for maturation under dynamic cell culture conditions. BaCl2 is investigated as a crosslinker for the oxidized alginate-gelatin system. Normal human dermal fibroblast (NHDF)-laden vessel constructs are optimized successfully in terms of higher stiffness by increasing ADA concentration and using BaCl2 , with no toxic effects observed on NHDF. Contrarily, BaCl2 crosslinking of ADA-GEL accelerates cell attachment, viability, and growth from 7d to 24h compared to CaCl2 . Moreover, alignment of cells in the longitudinal direction of the hydrogel vessels when extruding the cell-laden hydrogel crosslinked with Ba2+ is observed. It is possible to tune the stiffness of ADA-GEL by utilizing Ba2+ as crosslinker. In addition, a customized, low-cost 3D printed polycarbonate (PC) perfusion chamber for perfusion of vessel-like constructs is introduced.

A Cost-Effectiveness Analysis of Organ Preservation Methods for Deceased Donor Kidneys at High Risk for Delayed Graft Function in Brazil.

The clinical benefit of machine perfusion (MP) was recently assessed in a 1-year Brazilian multicenter prospective randomized trial, that showed that the use of MP was associated with a reduced incidence of delayed graft function (DGF) compared to static cold storage (SCS) in kidney transplant recipients (45% vs 61%). The objective of the present analysis is to consider the cost-effectiveness of MP relative to SCS based on clinical data from this Brazilian cohort. A decision tree model was constructed to simulate a population of 1000 kidney transplant recipients based on data derived from this Brazilian multicenter clinical trial. The model accounts for different health state utilities to estimate the cost-effectiveness of deceased donor kidney transplantation in Brazil comparing 2 kidney preservation methods: MP and SCS. The model accounts for 3 possible graft outcomes at 1 year post-transplantation: success (an immediate functioning kidney), failure (primary nonfunction requiring a return to dialysis), or DGF 1 year post-transplant. MP provided 612 total quality-adjusted life years (QALYs) (0.61 QALYs per patient) as compared to SCS (553 total QALYs, 0.55 QALYs per patient). MP was cost effective relative to SCS (US$22,117/QALY, R$70,606/QALY). The use of MP also resulted in more functioning grafts than SCS (821 vs 787), leading to a cost per functioning graft of US$38,033 (R$121,417). In conclusion, this analysis indicates that, despite the initial added cost associated with MP, the use of MP results in more functioning grafts (821 vs 787) and higher patient quality of life relative to SCS in Brazil.

A Customizable, Low-Cost Perfusion System for Sustaining Tissue Constructs.

The fabrication of engineered vascularized tissues and organs requiring sustained, controlled perfusion has been facilitated by the development of several pump systems. Currently, researchers in the field of tissue engineering require the use of pump systems that are in general large, expensive, and generically designed. Overall, these pumps often fail to meet the unique demands of perfusing clinically useful tissue constructs. Here, we describe a pumping platform that overcomes these limitations and enables scalable perfusion of large, three-dimensional hydrogels. We demonstrate the ability to perfuse multiple separate channels inside hydrogel slabs using a preprogrammed schedule that dictates pumping speed and time. The use of this pump system to perfuse channels in large-scale engineered tissue scaffolds sustained cell viability over several weeks.

Integrated continuous biomanufacturing platform with ATF perfusion and one column chromatography operation for optimum resin utilization and productivity.

A new integrated continuous biomanufacturing platform for continuous production of antibodies at fixed cell volumes and cell concentrations for extended periods with immediate capture is presented. Upstream antibody production has reached technological maturity, however, the bottleneck for continuous biomanufacturing remains the efficient and cost-effective capture of therapeutic antibodies in an initial chromatography step. In this study, the first successful attempt at using one-column continuous chromatography (OCC) for the continuous capture of therapeutic antibodies produced through alternating tangential flow perfusion is presented. By performing upstream media optimizations, the upstream perfusion rate was reduced to one vessel volume per day (vv/d), increasing antibody titer and reducing the volume of perfusate. In addition, process improvements were performed to increase productivity by 80% over previously reported values. In addition, a real-time method for evaluating column performance to make column switching decisions was developed. This improved productivity coupled with the use of a single-column improved process monitoring and control in OCC compared to multi-column systems. This approach is the first report on using a single column for the implementation of an integrated continuous biomanufacturing platform and offers a cost-effective and flexible platform process for the manufacture of therapeutic proteins.

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK.

BACKGROUND: Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. OBJECTIVE: The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. DESIGN: A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. SETTING: Multicentre study involving all five UK officially designated NHS adult lung transplant centres. PARTICIPANTS: Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. INTERVENTION: The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. MAIN OUTCOME MEASURES: The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. RESULTS: Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. CONCLUSIONS: Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN44922411. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.

Economic impact of the introduction of machine perfusion preservation in a kidney transplantation program in the expanded donor era: cost-effectiveness assessment.

BACKGROUND: Kidney transplantations (KT) from expanded criteria donors (ECD) show a higher rate of delayed graft function (DGF) that increases postoperative costs because of the prolonged hospital stay as well as the needs for dialysis and additional diagnostic procedures. Hypothermic machine perfusion (MP) might be superior to cold storage (CS) to reduce the relative risks of DGF and primary nonfunction (PNF) as well as to increase 1-year graft survival. OBJECTIVE: The aim of the study was to determine the relative cost-effectiveness of two different storage methods: MP versus CS. METHODS: A probabilistic decision tree was developed to compare MP and CS as graft preservation methods. The structure of the model was populated by review of the literature and outcomes of KT from ECD in our center. The model estimated budget impact and incremental cost-effectiveness ratio in terms of DGF and PNF cases. The cost comparison of methods for KT preservation included: hospitalization and intermediate care unit stay; post-KT dialysis; graft removal; immunosuppressive regimen; treatment of acute rejection episodes; as well as costs of preservation solutions and pulsatile preservation device or storage containers. RESULTS: Resource consumption for CS stratified by graft function varied from $8,159 for immediate graft function (IGF) recipients to $10,865 for DGF recipients to $25,933 for PNF recipients. Meanwhile, resource consumption for MP varied from $9,522 for IGF to $12,228 for DGF to $27,297 for PNF recipients. The main components of resource consumption were hospitalization stay (41.5%-53.9%); graft explantation (20.2%), and the need for dialysis (16.0%). The budget impact per patient for the introduction of MP was $505. However, the incremental cost-effectiveness ratio was $3,369 for each DGF- or PNF- saved case. CONCLUSIONS: The introduction of the MP preservation technology in a KT program form ECD is cost-effective in terms of savings for DGF and PNF cases.

An inexpensive technique of selective antegrade cerebral perfusion.

Surgery on the aortic arch is often combined with intraluminal cannulation of the arch vessels for selective antegrade cerebral perfusion and better neurological protection. We report a simple and inexpensive technique for this purpose.

Distributed perfusion educational model: a shift in perfusion economic realities.

In recent years, a steady decline in the number of perfusion education programs in the United States has been noted. At the same time, there has been a parallel decline in the number of students graduated from perfusion educational programs in the United States. Also, as noted by several authors, there has been an increase in demand for perfusion graduates. The decline in programs and graduates has also been noted in anesthesia and surgical residency programs. The shift is caused by a combination of economic and clinical factors. First, decreased reimbursement has led to reallocation of hospital resources. Second, the original enthusiasm for beating heart coronary artery bypass surgery was grossly overestimated and has led to further reallocation of hospital resources and denigration of cardiopulmonary bypass. This paper describes two models of perfusion education programs: serial perfusion education model (SPEM) and the distributed perfusion education model (DPEM). Arguments are presented that the SPEM has some serious limitations and challenges for long-term economic survival. The authors feel the DPEM along with dependence on tuition funding can survive the current clinical and economic conditions and allow the profession to adapt to changes in scope of practice.

Machine perfusion for kidneys: how to do it at minimal cost.

Due to a shortage of organs for transplantation, many centres use marginal grafts to increase their donor pool. As kidneys from non-heart-beating donors (NHBD) have sustained initial ischaemic damage, their viability is difficult to predict. Hypothermic pulsatile perfusion has not only been used to improve the condition of such grafts, but also allows viability assessment. Suitable systems are becoming more readily available, but they are expensive. We have used existing dialysis equipment with modified sterilised inserts to create a pulsatile hypothermic perfusion system. With this system, 41 NHBD kidneys were perfused for up to 8 h; their intravascular renal resistance (IRVR), flow characteristics as well as glutathione S transferase (GST) measurements were performed to assess viability. This hypothermic pulsatile perfusion system is now an integral component of our NHBD programme.

Technical and economic feasibility of reusing disposable perfusion cannulae.

The reuse of disposable devices is a potential source of significant cost savings to hospitals. Venous and arterial perfusion cannulae under new and reused conditions were selected to identify the clinical, safety, technical, logistic, and economic issues that must be addressed to realize these savings. Single- and dual-stage venous and arterial cannulae from two manufacturers were tested when new, after initial clinical use, and after a single clinical use plus up to nine simulated reuses. Reuse was simulated by end-to-end bending, coupling and uncoupling the connectors, and by two 1-hour soaks in plasma at 4 degrees C and 40 degrees C, respectively. Cannulae were decontaminated and then sterilized by a peracetic acid based liquid chemical sterilization system following each use/reuse. Sterilization was validated by eliminating Bacillus subtilis spores from the cannulae on each of five consecutive cycles. Cannulae were tested for physical changes, functional integrity, biocompatibility, and in vivo performance in sheep. A cost minimization analysis was also performed. No clinically important differences were found between new and reused cannulae, even after nine simulated reuses. Mechanical changes were less than 20% on all variables studied and were undetectable by experienced cardiac surgeons in selective evaluation. Sterilization was successfully achieved. Reusing cannulae for times would reduce the cost per procedure from $53 to $19 (64%). Perfusion cannulae tested can be safely and efficaciously used five times. This study suggests that reuse would result in a small incremental savings; however, with more expensive devices and higher-volume sterilization procedures, the savings could be exponentially greater. Although this study demonstrates that it may be technically feasible and cost-effective to reuse disposable cannulae, the U.S. Food and Drug Administration does not sanction the reuse of disposable cannulae.