The term “end-stage liver disease” is synonymous with advanced liver disease, liver failure, and decompensated cirrhosis, given the general irreversibility of these conditions. Liver transplantation is currently the preferred treatment for end-stage liver failure. Thus, there is an increased demand for liver donors which has led to a critical organ shortage. This challenge has given rise to efforts to identify potential brain-dead donors (DBDs) and to the splitting of grafts to benefit more recipients. Another alternative is living donor transplantation, which poses a high risk for adults.
In DBDs the aorta is clamped and perfusion starts at the same time: therefore the organs rapidly change from a warm, oxygenated and metabolically active state to a cold, hypoxic and metabolically inactive state. Cellular and tissue hypoxia, anaerobic metabolism and lactic acidosis are minimized.
The extended criteria include what were previously known as marginal livers. These include older and steatotic grafts, as well as livers donated after cardiac death.
Donation after cardiac death (DCD) was pioneered by kidney transplantation surgery and its categories were consensuated in 1995 in Maastricht. Non-heart beating donors (NHBDs) were classified into controlled and uncontrolled situations in order to differentiate livers with a lower and higher degree of ischemia, respectively.
Controlled DCD refers to the planned removal of life-sustaining treatment, whereas uncontrolled DCD involves an unexpected cardio-pulmonary arrest with unsuccessful resuscitation. In these cases, once death is declared, a cardiac resuscitation called “organ resuscitation” is carried out until the perfusion of the organs is achieved, usually by femoral cannulation.
Donations after circulatory death are now classified into 5 categories depending on the circumstances of death, as shown in the figure.
DCD currently represents as much as 20% of the liver donor pool in some European countries. There are legal limitations, specially for Maastricht category III donors, which forbid these practices in some countries.
Various liver retrieval techniques for DCD or NHBD have been described in the last decades.
– D’Allessandro et al. (University of Wisconsin): femoral cannulation, en bloc removal, back-table dissection.
– Intravascular perfusion with cold preservation fluids and organ extraction in the operating room.
– Cassavilla et al. (Pittsburgh group): super-rapid technique, with organ perfusion within 4 minutes after the patient is pronounced dead, by aortic cannulation.
Due to the fast growth of NHBD liver transplantation there is an increased concern regarding the establishment of common guidelines for practice.
Higher rates of biliary complications and inferior graft survival have been registered in patients with livers from NHBD compared to donation after brain death.
There are some donor-specific risk factors associated with poorer graft survival outcomes:
– Donor warm ischemic time (WIT) > 20-30 minutes
– Cold ischemia time (CIT) > 8-10h
– Donor age >40-60
However, some centers have reported similar graft survival rates in liver donors older than 60. Nevertheless there is a tendency to use stricter criteria for DCD livers, since up to 45% of NHBD livers are turned down in situ, and even more for uncontrolled DCD donors. These underused livers from DCDs require an ongoing review of the current procedures.
Organs from NHBDs are not procured under ideal conditions.
They can be separated into 3 main phases based on organ temperature. The first phase represents WIT after withdrawal of life support, in which organs may suffer from a period of hypoxia leading to cellular and tissue damage that needs to be recovered (if possible) after reperfusion. After explantation, the liver is flushed with a cold preservation solution, thus ending WIT and starting the second phase, CIT. This lasts until the organ is successfully transplanted in the recipient. Restoration of the blood flow, in a third phase, can also aggravate the cellular injury, in what is known as an ischemia reperfusion injury, which is variable and more severe in NHBD grafts.
Severe injuries can lead to delayed graft function or primary graft non-function.
In contemporary series, equivalent incidences of primary graft non-function and hepatic artery thrombosis have been described in NHBD grafts. Biliary complications remain the main concern, specially ischemic-type biliary stricture (ITBS). A higher rate of ITBS has been reported in NHBD grafts, and it is caused by many factors, including ischemia-reperfusion injury. It can be localized and manageable radiologically or endoscopically or it can be diffuse and lead to retransplantation. Liver function usually remains normal and patients with ITBS have difficulties regaining access to retransplantation in an MELD-based allocation.
In order to improve the results in NHBD liver transplantation, minimal primary warm ischemic damage should be achieved. A clear definition of WIT has not yet been established. Moreover, severe hypotension following withdrawal of life support before death can also produce warm ischemia. The standard use of heparin to prevent thrombosis has proved to be insufficient and thrombolytic drugs have been proposed. CIT should also be minimized since it is related to the graft failure rate.
Uncontrolled NHBDs have been approached through machine perfusion methods (both normothermic and hypothermic) to minimize the detrimental damage caused by ischemia. Liver perfusion by an extracorporeal membrane oxygenation (ECMO) technology has been proved to be feasible. When death occurs after unsuccessful resuscitation ECMO is commenced through the cannulation of the femoral vessels to allow the organs to recover from the warm ischemic damage. The retrieval can be performed more methodically afterwards. Donation occurs, when consented to, whilst the ECMO continues.
With careful selection, NHBDs can be a valuable source of livers for transplantation which can be performed along with donation due to brain death. Recent literature has brought evidence to support the noninferiority of DCD with respect to DBD in terms of patient and graft outcomes, probably due to adherence to strict protocols and surgical techniques. Further work is needed to recover grafts obtained after cardiac arrest, and organ preservation techniques need to improve to minimize both WIT and CIT. There is potentially room to further expand in donation after circulatory death. It is both an ethical and a medical challenge.