This is by far the most common donor type (currently 90% of all donors belong in this category) [2]. In most Western developed countries, brain death is legally equated with death. The diagnosis of brain death rests on the irreversibility of the neurologic insult and the absence of clinical evidence of cerebral and brainstem function. The details of the clinical examination that is required to unequivocally establish brain death are described later in this chapter. Organ procurement proceeds only after brain death has been diagnosed and death has been declared.

Increases in this donor category are to be expected over coming years (Fig. 185.1) [1,2,24,26,27]. Most frequently, families of unconscious patients with severe irreversible traumatic or cerebrovascular brain injury, who do not fulfill the formal criteria of brain death, decide to forgo any further life support treatment and wish to donate the organs of their family member. Time and place of death are therefore controlled. The prospective donor is brought to the operating room and life support treatment is discontinued. Organ procurement is initiated once death has been pronounced by a physician not belonging to the organ recovery and transplant team [26].

An alternative, by far less common scenario—uncontrolled death—involves a patient who expires, for example, in the emergency room following massive trauma or a sudden cardiovascular event. In the interest of minimizing warm ischemia time, flushing cannulas would then have to be inserted and possibly even perfusion of internal organs with cold preservation solution would already have to be started while consent to proceed with organ donation is obtained from the patient’s family. Issues that specifically surround this category of donation after cardiac death (DCD) donors have generated considerable debate within the medical community. These issues include ethical concerns centered on when to stop the resuscitation effort and whether it is ethical to perform a procedure (i.e., insertion of flushing cannulas) that presumes consent before actually obtaining it from the family. Other considerations that pertain to both controlled and uncontrolled death DCD donors and that have undergone intense debate, too, include establishing a definition of death after discontinuing life support (there is no commonly accepted definition of, for example, the minimal duration of asystole after the patient expires following withdrawal of support before death can be pronounced; this is currently subject to considerable interinstitutional variation), the possibility of the patient at least temporarily surviving the withdrawal of support systems (backup plans must be clearly defined by each individual institutional DCD donor protocol), and the conflict between providing optimal care for the patient and promoting suitable organ procurement and maintaining donor organ viability [28,29]. Nevertheless, these concerns must be contrasted with the right of self-determination and the final wishes of a competent patient family. Further debate by the medical community and general public is crucial to resolving these complex moral and ethical issues [28,29]. Without such thorough consideration, the deceased donor concept and the donation system that is currently in place might be harmed or discredited.

Currently, patients undergoing kidney transplants from deceased donors exhibit excellent graft survival rates (91% and 68% at 1 and 5 years, respectively) [1,2]. Renal transplantation dramatically improves life expectancy and quality of life, decreases cardiovascular morbidity, and rehabilitates the recipients from a social perspective. Kidney transplants are also less expensive from a socioeconomic standpoint than is chronic hemodialysis. For pediatric patients with chronic renal failure, a functioning renal allograft is the only way to preserve normal growth and ensure adequate central nervous, mental, and motor development.

Patients with end-stage liver failure die unless they receive a transplant. Liver transplants are an effective treatment for many patients, pediatric and adult, regardless of the cause of liver failure: congenital (i.e., structural or metabolic defects), acquired (i.e., due to infection, trauma, or intoxication), or idiopathic (e.g., cryptogenic cirrhosis, autoimmune hepatitis). A dramatic improvement in graft survival occurred after the introduction of cyclosporin A (Table 185.2). Currently, there are no reliable means to substitute, even temporarily, for a failing liver other than with a transplant. Extracorporeal perfusion, using either animal livers or bioartificial liver devices (e.g., hepatocytes suspended in bioreactors), may someday bridge the gap between complete liver failure and a liver transplant, but these therapeutic modalities are still investigational and are far from becoming standard clinical tools. Use of hepatocyte and stem cell transplants to treat fulminant liver failure and to correct congenital enzyme deficiencies is also in the preliminary stages of study.

Small bowel transplants are being performed increasingly in patients with congenital or acquired short gut, especially if liver dysfunction occurs because of long-term administration of total parenteral nutrition and if difficulty in establishing or
maintaining central venous access occurs. If liver disease is advanced, a combined liver–small bowel or, in highly selected cases, a multivisceral transplant (liver, stomach, small bowel, with or without pancreas) can be performed. Current results are encouraging, and a further increase in the number of small bowel and multivisceral transplants can be expected over the next decade [1,2,34].

Primary prevention of type 1 insulin-dependent diabetes mellitus is not possible at present, but transplantation of the entire pancreas or isolated pancreatic islets can correct the endocrine insufficiency once it occurs. Glucose sensor systems that continuously monitor blood sugar levels coupled with real-time command of an insulin delivery system (implantable pump) are not yet available for routine clinical use. Development of bioartificial and hybrid biomechanical insulin-secreting devices is in the experimental stages. The only effective current option to consistently restore continuous near-physiologic normoglycemia, however, is a pancreas transplant [35,36,37]. Good metabolic glycemic control decreases the incidence and severity of secondary diabetic complications (neuropathy, retinopathy, gastropathy and enteropathy, and nephropathy). Most pancreas transplants are performed simultaneously with a kidney transplant in preuremic patients with significant renal dysfunction or in uremic patients with end-stage diabetic nephropathy. Selected nonuremic patients with brittle type 1 diabetes mellitus (with progression of the autonomic neuropathy to the point of hypoglycemic unawareness, and with repetitive episodes of diabetic ketoacidosis) can benefit from a solitary pancreas transplant (without a concomitant kidney transplant) to improve their quality of life and to prevent the manifestation and progression of secondary diabetic complications. Evidence suggests that a successful pancreas transplant can achieve these goals in uremic and in nonuremic recipients and decrease mortality [35]. Islet transplants are undergoing intensive clinical investigation. Results of transplanting alloislets from deceased donors are encouraging in the short term [36]; however, long-term results have been relatively disappointing [37]. Nonetheless, with further progress to be expected, islet transplants may become a routine form of therapy for patients with complicated diabetes within the next 10 years.

Heart transplants are the treatment of choice for patients with end-stage congenital and acquired parenchymal and vascular diseases and are recommended generally after all conventional medical or surgical options have been exhausted. After a widely publicized start in 1967, poor results were observed over the ensuing decade. In the 1980s, however, the field of cardiac transplantation experienced dramatic growth (Table 185.1) because of significant improvements in outcome, probably most directly related to immunosuppressive therapy and to refinements in diagnosis and treatment of rejection episodes [38]. Mechanical pumps, such as ventricular assist devices or the bioartificial heart, serve only to bridge the time between end-stage cardiac failure and a transplant and are by no means a permanent substitute for the transplant itself.

Heart–lung and lung transplants are effective treatment for patients with advanced pulmonary parenchymal or vascular disease, with or without primary or secondary cardiac involvement. This field has evolved rapidly since the first single-lung transplant with long-term success was performed in 1983 (Table 185.1). The significant increase in lung transplants is mainly due to technical improvements resulting in fewer surgical complications, as well as to the extremely limited availability of heart–lung donors. Previously, many patients with end-stage pulmonary failure would have waited for an appropriate heart–lung donor. Currently, they undergo a single or a bilateral single-lung transplant instead [39]. Bilateral single-lung transplants are specifically indicated in patients with septic lung diseases (e.g., cystic fibrosis, α₁-antitrypsin deficiency) in which the remaining native contralateral lung could cross-contaminate a single transplanted lung. Double en bloc lung transplants have been abandoned because of technical difficulties related to the bronchial anastomotic blood supply. Mechanical ventilation or extracorporeal membrane oxygenation can be used as a temporary bridge to this type of transplant, but use of these modalities does not obviate the need for organ replacement therapy.

As a result of the ongoing organ shortage, transplant surgeons have attempted to refine procurement techniques so that maximal use of the available donor pool occurs [49] (Fig. 185.2). For example, currently more than 85% of all deceased donors are multiple-organ donors. On average, more than three organs are recovered and transplanted from each deceased donor [1,2,24,40,41] (Fig. 185.2). Extension of the organ preservation time by a variety of techniques, including new preservation solutions and pulsatile perfusion preservation, has facilitated allocation of organs to geographically distant transplant centers [44].

Marginal donors—elderly patients, patients with a history of hypertension, poisoning victims, patients with significant organ injury (e.g., liver laceration due to blunt injury), or complications of brain death (e.g., hypotension, oliguria or anuria, disseminated intravascular coagulation)—are now used almost routinely for recovery of kidneys and of extrarenal organs [1,2,24]. Procurement techniques also have been adapted to
facilitate use of older donors with significant aortic atherosclerosis [50]. Organs with anatomic abnormalities (e.g., multiple renal arteries or ureters, horseshoe kidney, annular pancreas) also are being used routinely. Improvements in operative technique permit the en bloc transplantation of two kidneys from very young donors that would have been too small to be used separately in one recipient [51,52]. Similarly, transplantation of both kidneys from an adult donor into one recipient is done to avoid discarding suboptimal kidneys with an insufficient individual nephron mass. To maximize the use of livers, adult donor livers can be split and the two size-reduced grafts transplanted into two recipients (e.g., a pediatric and an adult recipient). A similar principle has also been proposed for the pancreas and has been reported on at least one occasion [53].

Explanted livers from patients undergoing liver transplantation for hepatic metabolic disorders that cause systemic disease without affecting other liver functions (e.g., familial amyloidotic polyneuropathy, hereditary oxalosis) can be used for transplanting other patients (“domino transplant”) who are not candidates for deceased livers because of graft shortage (e.g., cirrhotic patients with hepatocellular carcinoma confined to the liver who are not in the group with good expected survival) [54]. The combination of split-liver and domino transplantation can even result in transplantation of three adult patients with one deceased donor graft [55].

The advent of single-lung transplants has made it possible to distribute the heart and lungs of one donor to three recipients. Formerly, transplanting a heart–lung bloc into one recipient was the treatment of choice for end-stage pulmonary disease. If the native heart of a heart–lung recipient is healthy, a domino transplant can be performed: The heart–lung recipient donates his or her heart to another patient in need of a heart transplant. Again, as an attempt to optimize use of scarce donor resources, the reuse of transplanted hearts, kidneys, and livers has been reported [56]. However, all these methods allow only for better use of organs from the existing donor pool. The cornerstone for an effective increase in the number of organ donors remains heightened awareness and education of the public, physicians, and other health care professionals to improve consent and conversion rates [11,12,13,24,29].

The use of living donors, traditionally limited to kidney transplants, has been expanded to the pancreas, liver, small bowel, and lung [1,2]. In the past, most living donors were genetically related to the recipient—siblings, parents, and adult children. The use of living unrelated kidney donors, who are either emotionally related to the recipient (e.g., spouses, close friends), or emotionally unrelated to the recipient (nondirected, “altruistic” donors) has considerably increased over the past 15 years as a result of the organ shortage [1,2]. In 2008, the 5,968 live donor kidney transplants constituted 34% of all kidney transplants that were done that year [1] (Fig. 185.1). In order to increase that proportion even further, paired-kidney-exchange programs and living donor chain transplants have been implemented [57,58]. In that setting, the supply of organs is increased for instance by exchanging kidneys from living donors who are ABO or cross-match incompatible with their intended recipients, but ABO or cross-match compatible with another donor-recipient pair [donor A would provide a kidney to (ABO or cross-match compatible) recipient B, and donor B would provide a kidney to (ABO or cross-match compatible) recipient A] [57,58]. In cases when paired kidney exchange or donor chain transplants are not available or feasible, it is alternatively possible to precondition the intended recipient of an ABO or cross-match incompatible kidney (by use of plasmapheresis and/or intravenous immunoglobulin and pharmacologic intervention) to still facilitate a successful living donor kidney transplant.

Currently, there is considerable public debate on providing incentives for living kidney donation [59,60,61,62]. The debate centers on concerns that reimbursement might lead to the commercialization of organ donation, with the inherent risk of turning potential donors and transplantable organs into a commodity [60,61,62]. In the United States, those in support of compensating live donors stress that an OPTN-run transparent system of paid living donation would ensure that donors are compensated fairly, eliminate transplant tourism to other countries, greatly diminish the currently existing black market for organs in those countries, and emphasize any potentially interested donor’s autonomy—while increasing the organ supply [59,60]. In any case, paid living donation, while a reality in certain regions of the world, remains currently unlawful in the United States and most, if not all, Western Countries.

Even when assuming that (i) public attitudes toward living donation will continue to evolve favorably (Fig. 185.1), (ii) innovative approaches as described above will be increasingly used, and (iii) other alternative means for finding living donors, such as donor solicitation via the internet would ultimately be fully embraced by the transplant community and society, only modest increases of the absolute number of living donors could be expected [60,61,63,64,65,66]. Compared with renal transplantation, the proportion of living donor transplants for extrarenal organs is much smaller (less than 5% for liver and less than 0.5% for pancreas, lung, and small bowel) [1]. Thus, living donor transplants will continue to help alleviate the organ shortage for certain organs (kidney, liver) to some extent, but will never be able to completely compensate, even under the best circumstances, for the severe lack of deceased donors.

The potential for financial compensation or other rewards for deceased donor families (e.g., compensation for funeral expenses) has been considered as a means to increase donation rates [66].

Certain countries (e.g., China) use organs from executed prisoners. Use of this group would contribute only very small numbers of donors in the United States, and this concept has been rejected by the transplant community here [67]. Likewise, the use of anencephalic babies for solid-organ transplantation would not significantly alleviate the organ shortage because only a few babies fulfill all brain-death criteria. Proposals to use organs from executed prisoners or anencephalic babies would engender a very passionate, emotional debate that could have a negative impact on public opinion and thereby decrease overall organ availability [68]. Therefore, these options are not being actively explored.

Xenotransplantation of organs and tissues from animals into humans offers a potentially unlimited supply of donors [69]. Several attempts have received significant public attention [70], but numerous practical problems remain before this procedure could become clinical reality. Ethical concerns regarding the use of animal organs for transplantation have also been raised [71]. Immunologic concerns include hyperacute rejection (mediated by circulating, preformed natural antibodies), which occurs in vascularized solid-organ transplantation between virtually all discordant species. Also, the biocompatibility of protein synthesized by an animal liver and the human organism is not fully established, and infectious diseases (e.g., caused by retroviruses) could be transmitted using nonhuman primates or pigs
as donors. Genetic engineering of animals before their use as donors to overcome the immunologic barriers is an area of intensive investigation. Significant experimental progress in this area could fundamentally change the field of organ transplantation.

Presumed consent laws have been implemented in many areas of the world, most notably in several countries in Europe. These laws permit organ procurement unless the potential donor has objected explicitly. A permanently and easily accessible registry of objectors is a prerequisite for such a system. Emphasis is placed on an individual’s decision, and family input is limited. In the United States, presumed-consent legislation does not have broad support, and it is uncertain whether the public could reach a consensus on this issue. Moreover, presumed consent would not alleviate the problem of insufficient donor identification and referral [12].

The beneficial impact that such laws can have became evident in Spain. In that country, presumed consent laws coupled with the creation of a decentralized network of mostly hospital-based, specifically trained transplant coordinators (most of them physicians in intensive care units) in the early 1990s led not only to more efficient identification of eligible deceased donors but also to higher consent rates. Accordingly, the annual donation rate in Spain rose from 14.3 donors per million population (pmp) in 1989 to 34.2 pmp in 2008 (United States, 2008: 26.3 pmp) [72,73,74]. Interestingly, a similar approach (without the presumed consent component) using in-house coordinators at some hospitals the United States did yield greater consent and conversion rates, too, and underscored the advantages that such a system could have, if implemented at a larger scale [75].

The Uniform Anatomical Gift Act, adopted in 1968 and in force throughout the United States, allows any adult individual (over age 18 years) to donate all or part of the body for transplantation, research, or education. That act provides also the legal basis for procurement of organs from both DCD and brain-dead (vide infra) donors. Explicit consent, which can be revoked at any time, is required. The act also permits legal next of kin to give consent for donation [77]. Donor cards or driver’s licenses, on which individuals indicate their consent to postmortem organ donation, are promoted by many states but are legally nonbinding and thus serve ultimately only as a tool to heighten public awareness. In most instances, consent from the next of kin is still sought. Therefore, educational efforts must urge potential donors to make their wishes known to their next of kin [11,13].

Over the past four decades, brain death has legally become equated with death in most Western developed countries. Brain death means that all brain and brainstem function has irreversibly ceased, and circulatory and ventilatory functions are maintained temporarily. The recognition of brain death became possible only after substantial advances in intensive care medicine (e.g., cardiovascular support, prolonged mechanical ventilation). The first classic description of brain death was published in 1959 in France and termed coma dépassé (beyond coma). An ad hoc commission of the Harvard Medical School defined brain-death criteria in the United States in 1968 [78]. These criteria were judged by some as being too extensive and too exclusive. In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research formulated the Uniform Determination of Death Act, which established a common ground for statutory and judicial law related to the diagnosis of brain death. The commission stated that “an individual who has sustained… irreversible cessation of all functions of the entire brain, including the brainstem, is dead,” and left the criteria for diagnosis to be determined by “accepted medical standards.”

Those standards were defined in a related report to the President’s Commission on the diagnosis of death by 56 medical consultants in 1981 [79]. The guidelines in that report have now been accepted as the standard for determining brain death in the United States. They are as follows: “Cessation is recognized when (1) all cerebral functions and (2) all brainstem functions are absent. The irreversibility is recognized when (1) the cause of the coma is established and is sufficient to account for the loss of brain functions, (2) the possibility of the recovery of any brain functions is excluded, and (3) the cessation of cerebral and brainstem function persists for an appropriate period of observation and/or trial of therapy” [79]. Confusion regarding this well-founded and accepted medicolegal concept of the equivalence of brain death and death of a human persists to this date among physicians, other health care professionals, and the general public [11,13]. Specifically, in the field of transplantation, it should be unequivocally clear to the potential donor’s family and anyone involved in the patient’s care that the time of death is the time at which the diagnosis of brain death is established and not the time of cardiac arrest during the organ retrieval. Providing education targeted specifically at these groups and society at large is of paramount importance to optimize consent rates [11,13].

Required request laws have now been enacted in all states in the United States. They obligate hospitals to notify an OPO of potential donors and to offer the option of donation to the families of potential donors (brain-dead or DCD donors).

The clinical diagnosis of brain death rests on three criteria: (a) irreversibility of the neurologic insult, (b) absence of clinical evidence of cerebral function, and, most important, (c) absence of clinical evidence of brainstem function [79,80,81] (Table 185.4). Irreversibility is established if structural disease (e.g., trauma, intracranial hemorrhage) or an irreversible metabolic cause is known to have occurred. Hypothermia, medication side effects, drug overdose, or intoxication need to be ruled out when testing for brain death. Plasma concentrations of sedative or analgesic drugs sometimes correlate poorly with cerebral effects. Therefore, residual effects of those drugs can be excluded only by passage of time, if any doubts exist. The observation period (the waiting time between two sequential brain-death examinations) should be at least 6 hours for structural causes and preferably 12 to 24 hours for metabolic causes, drug overdose, or intoxication [80]. Even with potentially reversible metabolic alterations (e.g., hepatic or uremic encephalopathy), recovery has not been described after duration of the brain-death state for more than 12 hours. Clinical testing of cerebral and brainstem function is detailed in Table 185.4 [79,80,81,82]. It should be noted that brain-death criteria are more stringent for very young pediatric patients, particularly newborns, in whom criteria for brain death also include demonstration of the absence of blood flow on cerebral flow studies.