Liver transplantation (LT) is one of the marvels of modern medicine. Over a period of 50 years, LT has gone from a procedure performed in desperate situations to one that is now almost routine. Along the way, we have developed a better understanding of liver failure physiology and made major advances in all aspects of patient care, including immunosuppression, surgical and anesthesia technique, and perioperative care. In the United States, over 7000 LT were performed in 2015. Before 2015, there was a noticeable decline in the rate of transplantation. The single most significant limitation to LT is the lack of available organs. Considering that almost 15 000 patients are currently on the waiting list, increasing the number of transplantable organs must be a priority.
To increase the number of transplantable organs, the use of discarded and extended criteria grafts (ECG), such as those obtained from donation after cardiac death (DCD), has increased. The number of discarded organs has been relatively stable for the last 15 years (8% to 11%, Organ Procurement and Transplantation Network data). Since the first DCD transplantation in 1993, the use of this type of graft has slowly increased in the United States, reaching 5.7 % in 2016 (OPTN data). The relatively low utilization of DCD organs is because of inferior outcomes in comparison to when donation after brain death (DBD) grafts are used.1 We must develop strategies to ensure these grafts are of the highest quality. Continuous graft perfusion before transplantation is one of these strategies.
In this issue, Compagnon et al2 evaluated the feasibility of using a transportable perfusion system (Airdrive) to preserve DCD liver grafts in pigs. The authors used a continuously oxygenated hypothermic pulsatile perfusion (HMP) system. This approach enables initiating graft perfusion early, subsequently shortening cold ischemia time (CIT).
Perfusing grafts to improve quality is not a new idea. Since the 1970s, HMP was used to preserve kidney grafts.3 Perfusion of the liver is much more challenging. Historically, 2 experimental perfusion paradigms were used, normothermic and hypothermic.
The advantages of normothermic preservation are that it maintains physiological conditions during preservation and has been shown to attenuate the risk of endothelial damage.4 Fondevila et al5 have demonstrated that normothermic perfusion for uncontrolled DCD human liver grafts is feasible. Patient and graft survivals were similar in comparison to a matched DBD group.
Currently, HMP is the most frequently used approach. It maintains the physiology of both endothelial cells and hepatocytes and has been shown to improve the condition of marginal grafts.6 This approach is also associated with preserved mitochondrial function and decreased release of reactive oxygen species.7 In a recent prospective evaluation, Guarrera et al8 demonstrated that patients who received an ECG, which was declined by United Network for Organ Sharing but preserved with continuous HMP, had superior outcomes in comparison to patients receiving ECGs preserved under static cold storage.
The study performed by Compagnon et al is an excellent example of a well-designed evaluation. In this prospective study, the authors chose a prolonged warm ischemia time of 60 minutes for both DCD groups and were able to demonstrate the superiority of HMP. For the control group, the authors used grafts from beating heart donors preserved under hypothermic conditions (4°C). Hemodynamic parameters after graft reperfusion in the DCD, nonperfusion group were significantly worse in comparison to those in the HMP group, as well as in controls. Animals receiving HMP, and controls, had significantly better survival than those in the DCD, nonperfusion group. After transplantation, the HMP group was associated with both decreased hepatocellular damage and sinusoidal dilatation, compared with nonperfused DCD grafts. Histological changes in the HMP group 5 days after transplantation were comparable to controls (beating heart donors). In addition, mitochondrial function, adenosine triphosphate storage, adenosine triphosphate recovery, and inflammation were improved after HMP. Evaluation of mitochondrial function, energy metabolism, and extensive histological assessment were performed meticulously in this study. The decision to use beating heart donors as a control group made this evaluation stronger because it provided a comparison with the standard approach.
The most promising aspect of the Airdrive system is the possibility to start perfusion immediately after organ procurement and continue during transport to decrease CIT. The association between duration of CIT and outcome is well known.9 The next step in Airdrive system efficacy analysis would be to determine if early HMP significantly improved ECG quality. To evaluate this aspect of the system, another control group with delayed HMP would need to be introduced. Another potential target of investigation is system stability during transport. Although the Airdrive system was found to be stable under experimental conditions, the system was not evaluated under clinical conditions imitating transport. Prolonged transport can be associated with significant vibration and bubble generation. Despite these minor issues, the results of the study are convincing. Without a doubt, the Airdrive system is a significant step forward in organ preservation and presents a real opportunity to increase organ availability.
Continuous perfusion of ECG before transplantation has great potential. The feasibility of this approach has been demonstrated in a number of studies using a variety of surgical techniques and perfusate temperatures. In the last few years, almost all transplantation journals have published reports related to this topic. Many of these studies evaluated new perfusion machines, frequently using just a few small animals. The results of these very limited evaluations have unclear significance for human transplantation. Considering that recent research has clearly demonstrated the effectiveness of the graft perfusion concept in big animals and also in humans, this is the time to consolidate our intellectual and financial resources to find the best perfusion technique for ECG. This will allow us to significantly increase the availability of high-quality grafts for transplantation.
1. Monbaliu D, Pirenne J, Talbot D. Liver transplantation using donation after cardiac death donors. J Hepatol
2. Compagnon P, Levesque E, Hentati H, et al. An oxygenated and transportable machine perfusion system fully rescues liver grafts exposed to lethal ischemic damage in a pig model of DCD liver transplantation. Transplantation
3. Johnson RW, Morley A, Swinney J, et al. The comparison of 24-hour preservation by hypothermic perfusion and cold storage on canine kidneys damaged by warm ischaemia. Br J Surg
4. Butler AJ, Rees MA, Wight DG, et al. Successful extracorporeal porcine liver perfusion for 72 hr. Transplantation
5. Fondevila C, Hessheimer AJ, Ruiz A, et al. Liver transplant using donors after unexpected cardiac death: novel preservation protocol and acceptance criteria. Am J Transplant
6. Dutkowski P, de Rougemont O, Clavien PA. Machine perfusion for “marginal” liver grafts. Am J Transplant
7. Dutkowski P, Krug A, Krysiak M, et al. Detection of mitochondrial electron chain carrier redox status by transhepatic light intensity during rat liver reperfusion. Cryobiology
8. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation facilitates successful transplantation of “orphan” extended criteria donor livers. Am J Transplant
9. Stahl JE, Kreke JE, Malek FA, et al. Consequences of cold-ischemia time on primary nonfunction and patient and graft survival in liver transplantation: a meta-analysis. PLoS One