 |
 |
Recent Developments in |
Liver Transplantation | ||
Contents
Liver transplantation has always been governed by the availability of donor organs. Lack of a legal definition of brain death hindered early efforts to obtain organs for transplantation. Donation was deferred until cardiac function ceased. The donors were observed (sometimes for days) until their hearts stopped. The femoral vessels were quickly cannulated and extracorporeal perfusion was instituted. Following perfusion the organs were removed for transplantation. The time interval between donor death and reperfusion of the organs was generally two to three hours, ensuring that the donor organs could only be recovered in the transplant center or a center nearby. Because of the small number of patients in whom transplantation was considered, there was little need to decide between waiting recipients.
Today, with a firm definition of brain death, a person who is brain dead can be recognized quickly as a potential donor. A call goes to a specialized organization which sends a coordinator to the donor hospital to obtain consent from the family and manage the donor until organ recovery. A series of phone calls is made to those transplant centers with patients who are waiting for transplants and a potential recipient is found. After allocation of the organs, the donor is taken to the operating room. Dissection of the major vessels and the liver is performed. The liver is perfused with a preservation solution that allows successful preservation for up to 24 hours. After removal, the liver may be flown across the country for implantation in a patient thousands of miles away.
These radical changes required changes in both the legal and medical system. Probably the most profound change had to do with the passage by states of brain death laws in the 1970s and the adoption of the 1978 Uniform Determination of Death Act. These allowed the identification of individuals who were brain dead but whose hearts remained beating. The use of brain dead donors with beating hearts permitted the optimal preservation of the organs. The Uniform Anatomical Gift Act in 1968 allowed for the next of kin to donate the decedent's organs and provided the legal mechanisms for the donation processes to occur.
In 1984 The National Organ Transplant Act created a national organ sharing system that was to be managed by the National Organ Procurement and Transplantation Network (OPTN). The network consisted of organ procurement organizations (OPOs) and transplant centers. The OPOs were responsible for procuring and distributing the organs to the transplant centers. The OPTN awards a contract to an organization that will administer the network. This contract was subsequently awarded to the United Network for Organ Sharing (UNOS). Subsequent legislation has required that all OPOs be federally certified and have a service area that is of sufficient size to assure maximum effectiveness and efficiency.
This legislation has led to the improvement in the process of organ procurement and distribution. Despite these improvements, serious organ shortages persist and have led to painful discussions about how these organs should best be distributed among those who are waiting.
Two elements determine the allocation of livers for transplantation. The first is the system of prioritization, currently comprised of two factors: the length of time a patient has been waiting and the degree of illness. The prioritization system determines to which patient, within a waiting list of patients, the organ will be allocated. The second element affects the distribution of organs among different areas of the country. This part of the system determines to which waiting list the liver will be offered to first and the order of waiting lists for subsequent offers. Because these elements are so closely linked, the distribution scheme may act as a de facto prioritization scheme. For instance, if it is decided that the sickest patient will always be offered (allocated) the organ first, this would be an example of a prioritization scheme. If the entire country is the allocation unit, the allocation system has no effect on the prioritization scheme, but if the initial allocation unit is anything less than the entire country, and the organs are allocated within that unit first, and to the rest of the country second, there will be a significant chance that the sickest patient in the country will not reside in that unit; the organ will then go to the sickest patient in the unit prior to going to the sickest patient in the country. Accordingly, as the number of distribution units increases, the probability of having the sickest patient within the distribution unit becomes smaller, and therefore, if the organs are distributed on anything less than a national basis, the size of the distribution unit (an important component of the allocation system) will affect prioritization. In the discussion that follows, the distribution scheme is described first and then the allocation scheme is outlined. Clearly, this separation is somewhat arbitrary.
The distribution system offers the organ first to patients in the local area who are waiting, then to the regional area, and finally to the nation at large. The local area is generally defined as the service area of the Organ Procurement Organization (OPO). The area that an OPO covers is based on historical boundaries and can vary in size from part of a city to a whole state. Each OPO may serve none, one, or more than one liver transplant center. Currently, each OPO that has a liver transplant program in its service area has a single list of patients who are awaiting transplantation. In the state of California, for example, there are five OPOs one each in the San Francisco Bay area, Sacramento and San Diego and two that divide the greater Los Angeles area. Since liver transplant programs exist in all of the OPOs, five separate waiting lists exist in California.
The regions are eleven geographic areas that encompass the United States. Each region usually contains several OPOs; consequently there can be many separate lists within the region.
A patient who is awaiting a liver transplant at one of the centers in San Francisco will serve as an example of the distribution system. This patient is placed on a waiting list that includes all patients waiting at the three centers that offer liver transplantation in the San Francisco Bay area. These centers are members of the organ procurement organization that is responsible for procurement and allocation of organs within the area. A liver that becomes available in the local area is to be offered to the patient who had the most priority on the local waiting list. The local center decides whether or not the liver was appropriate for the patient to whom it is offered. If it is not accepted for that patient, it will be offered to the next patient on the list in terms of priority until all of the centers either refuse it or it is accepted for a particular patient.
If all centers in the OPO refuse the liver for any of the patients on the local waiting list, it is then offered to patients within the region. The region in this example encompasses six states (California, Nevada, Utah, Hawaii, New Mexico, and Arizona). Patients in the region are prioritized on a single list. If the liver is not used in the region, it is then offered to patients waiting elsewhere in the nation, with all of the patients in the nation ranked in order of priority on a single list.
Having a single list within the OPO allows equal access to patients within the OPO but not between OPOs based on priority. The organ is not offered outside of the OPO until it has been refused for all of the patients within the OPO, regardless of the relative priority of the patients within the OPO and those patients outside of it. In this manner, the distribution scheme takes precedence over the priority scheme, which is based on waiting time and medical factors.
Inequities in this system are obvious: a patient who is listed with one OPO and has acquired a high priority within that OPO does not have access to organs from a neighboring OPO. In Los Angeles, for example, a critically ill patient listed with one OPO within the city may die without a transplant, while a less ill patient listed with the other OPO in the city may receive a transplant.
The reason that the current distribution system operates in this way is historical. Prior to the formation of the national system in 1987, many OPOs existed and each served its own area. When the national system was introduced, these boundaries were maintained. It was assumed, without supporting data, that members of the OPO would work harder to increase organ donation and recovery if they knew that the organs would benefit the patients waiting at their own transplant center. The concept of initial local use of the organs has been called " local primacy."
Because of the concept of "local primacy," the current system ties the OPOs as units for organ procurement with the units for organ distribution. The factors that determine the best geographical boundaries for organ procurement may not be expected to be the same factors that determine the best unit of organ distribution. The best unit for organ distribution should be determined separately from the decision on the unit of organ procurement. For example, a state may be the most equitable unit of distribution, but may be too large to be the best unit for optimal organ procurement.
Many reasons have been given to justify the current system of local use. First, it allows organ sharing without the added costs in both dollars and time (which requires preservation solution) to transport the organs. It allows the local centers control over which patients are transplanted. For example, if an OPO serves only one transplant center, that transplant center dictates which patients are transplanted, allowing the center to follow its own policies in deciding the priority of patients to transplant. The effect of this policy on the overall survival of patients with liver disease in the country as a whole is unknown. It is possible that the use of an organ in a less ill patient locally may mean the death of a more ill patient who would have survived with an immediate transplant. This would decrease the overall survival of patients awaiting transplantation.
The system of "local primacy," by maintaining a separate list for each OPO, also isolates the OPO from the effect of longer waiting times around the country. For example, an OPO that lists relatively few patients for transplantation compared to its number of donors will have shorter waiting times than another OPO that lists more recipients than donors. If a donor becomes available in the OPO with the short list, it is used within the OPO despite patients with longer waiting times and/or higher priority on other OPO waiting lists. Because of the priority given to local use of the organ, there are wide discrepancies in waiting times among OPOs within the United States.
The policy of local primacy has had the side effect of fostering the development of new transplant centers. This is because if a new center is established within an OPO that does not have a center, the center's patients are at the top of the list in the OPO despite the waiting times in surrounding OPOs. This allows the center to immediately open its doors, since it can begin transplanting patients who have recently been listed. Otherwise, the center's patients would need to gain enough waiting time to compete for organs with patients who have long waiting times at established centers.
Another side effect of "local primacy" has been the movement of centers from OPOs with longer lists to those OPOs with shorter lists in order to gain access to organs for the center's patients within a shorter time. As long as discrepancies exist in waiting times among OPOs, this pressure to circumvent the system will exist.
Within the local, regional, and national waiting lists, patients are assigned priority scores in order to allocate the organs. Priority depends on the length of time on the waiting list and degree of illness. The degree of illness is indicated by the patient's status code. At the time of writing, the status codes are numbered one through four with four being the highest severity. To provide a classification consistent with those used for other organs, the order of the codes is soon to be reversed — status 1 will become the highest code. The discussion below utilizes the new status code order.
Top priority is given to patients who are in the ICU and expected to live less than seven days. This status can be renewed for another seven days if the patient is not transplanted or does not die within this time period. Patients in this category compete only with those patients of the same status. Patients are ranked by how long they have been at status 1 without regard to the prior waiting time they may have accumulated at a lower status. This is to allow patients with acute liver failure or primary graft nonfunction to compete successfully for available organs with patients who have slowly progressive chronic liver disease. Without this provision, the former patients might not accrue enough waiting time to be salvaged by a transplant. Because patients with fulminant hepatic failure do very well following transplantation, this provision is a wise one.
Patients with liver disease of several different types are classified together as status 1, but it is not clear whether they all have the same prognosis following transplantation. Patients with chronic liver disease who deteriorate to this status, often with multisystem organ dysfunction as well, may have a worse outcome than those with fulminant hepatic failure. Patients who have primary nonfunction of a transplanted liver may also have a poor prognosis. These issues of subclassification within status 1 remain unresolved.
This group is composed of hospitalized patients who are medically unable to be discharged prior to transplantation. These patients are given priority within the waiting list just below the status 1 patients. The problem with this status is with the hospitalization criterion, which may distinguish between patients with excellent social and medical supports, who can be cared for as outpatients, and patients with a similar degree of illness who lack supports. This scheme may inappropriately penalize patients who can be cared for as outpatients and therefore does not reflect severity of illness.
These patients require frequent outpatient medical care, but they may be admitted to the hospital for brief periods without a change in their status. The majority of transplants performed in the United States are in status 3 patients. The immediate survival benefit of transplantation in this group of patients is controversial. For example, patients with symptoms such as severe pruritus, which can be disabling but generally not fatal, can be considered for transplantation in this category. The relative merits of transplanting these patients, whose lives are miserable, versus those patients who are dying, is a judgment that few care to make. Clearly, however, these patients do extremely well following transplantation.
These patients are in a holding pattern prior to transplantation. Only a few percent of the patients waiting in this category are transplanted each year. The median waiting time in this group is quite long, and some of these patients are listed too early for transplantation.
The steady progression of overall waiting times for liver transplantation has now outstripped the predictive abilities of physicians to determine whether or not a patient will need liver transplantation within the expected waiting time. For example if the waiting times for transplantation are one year, a physician may not be able to decide if a particular patient would need liver transplantation within that year. The patient might therefore be listed for transplantation to gain waiting time so that if the patient deteriorates, he or she could be transplanted promptly. This process obviously leads to waiting time inflation.
To prevent waiting time inflation, standard criteria could be used to predict the disease course and guide entry onto the waiting list. Unfortunately, except for primary biliary cirrhosis and primary sclerosing cholangitis, the progression of chronic liver disease may be episodic or linear, and may proceed rapidly or gradually. Furthermore, what information exists pertains to prediction of the time to death and not of the time to the optimal point for transplantation.
The current system of organ allocation is hampered primarily by geographic inequalities in waiting times among various areas of the country. Increasing the size of the waiting lists to encompass larger geographic areas is the only practical method of equalizing waiting times. Whatever the change in geographic area that results, disconnection of the OPO as the unit of procurement from the unit of distribution will be necessary.
Because of the current discrepancies in waiting times around the country, any change to larger waiting lists will necessarily combine centers with short waiting times with centers with longer waiting times. This may cause a period of inactivity at the centers with short waiting times, until patients at these centers gain enough waiting time to compete with patients at centers with longer waiting times. Financial hardships for the centers with short waiting times could result; these centers would have to bear the fixed costs of maintaining their programs during a period of relative inactivity. Presumably, the period of inactivity would be relatively brief; nevertheless, fear of an immediate change in the number of transplants at many centers has led to resistance to changes in policy that would provide for larger lists.
It is uncertain what effect a change to larger waiting lists would have on the survival and costs of all patients awaiting transplantation. Larger waiting lists would probably increase the waiting time for some patients while decreasing it for others. The liver disease of most patients would progress during longer waiting times; consequently, these patients would be sicker at the time of transplantation, possibly resulting in decreased survival and increased costs.
A change to larger lists might also result in a shift in transplantation to those who have the highest priority. Because these patients have higher costs and shorter survivals, the results of transplantation may deteriorate. On the other hand, the increasing use of contracts for transplantation services between payors and transplant centers may limit this effect. The payors agree to pay a lump sum for transplantation without regard to the degree of illness of the patient. In this environment, the center is discouraged from transplanting the sickest patients, because their cost will exceed the contracted price. Therefore, the number of high-priority patients transplanted is likely to decrease.
Even if a system were developed to equalize waiting times across the entire country, many additional questions about organ allocation would remain. Would a change in the organ allocation system increase or decrease the number of patients with liver disease who die? If the new system decreased the number who died while waiting, would it increase the number who died following transplantation? Could a perfect system be developed to minimize both pre- and posttransplant deaths?
Unfortunately, it is not clear how the distribution of livers (or other organs for that matter) should be changed. Short of simply instituting a new system and noting its results, the only way to obtain information about the effects of such a change is computer modeling. Whether the results of such a model would be accepted by those who have taken positions on these issues is uncertain.
Considerable room for improvement exists in the current system. Better modeling of the distribution and prioritization methods should guide the changes that will hopefully improve survival for all patients with liver disease.
Please be aware that medical advice, diagnoses and physician references cannot be obtained from this site.