Sanctity and organ donation’s societal value

Individual sanctity is an essential component of humanness with deep roots in culture, religion, and law. Indeed, an individual’s sanctity transcends even death, persisting in the minds of those who knew or know of the decedent.

Dr. Murray

Dr. Murray

Society’s valuation of whole organ donation began cautiously with the successful transplantation of a 23-year-old monozygotic twin’s kidney into his twin brother on December 23, 1954. The Peter Bent Brigham Hospital team sought to minimize its ethical issues by advance airing in public fora and preliminary skin graft exchanging to verify their compatibility. Yet, as noted by Joseph E. Murray, MD, FACS (see photo, this page), in his 1990 Nobel Prize address, “For the first time in medical history, a normal, healthy person was to be subjected to a major surgical operation not for his own benefit.”1The recipient lived for eight years free of dialysis, and the donor lived to age 79, but Dr. Murray would not achieve success with a cadaveric renal allograft until 1962.

Whole organ allotransplantation for hearts began in December 1967, with dismal results. As of October 23, 1968, only two of the world’s 65 heart allograft recipients had survived for five or more months.2 Some viewed excising a donor heart as tantamount to ripping out the soul, and with these results, one could argue, “For what purpose?” Most early proponents paused to regroup, as Thomas Starzl, MD, FACS, had done with livers in 1963.3 In the U.S., Norman Shumway, MD, FACS (see photo), pressed on at Stanford, as did his former associate Richard Lower, MD, FACS, who had moved to the Medical College of Virginia (MCV) in 1965 to add hearts to the busy renal transplant program headed by David Hume, MD, FACS (see photos below). Technical hurdles still had to be overcome, but the real culprits were the marginal therapeutic index of available immunosuppressants along with donor warm ischemia time and its ultimate companion, reperfusion injury.

B-D and Tucker v. Lower

Belgian surgeon Guy Alexandre, who had been a research fellow in Dr. Murray’s laboratory, minimized warm ischemia by harvesting a kidney from a beating-heart, severely head-injured, comatose donor at Louvain’s Saint Pierre Hospital on June 3, 1963, after convincing his chief, Jean Morelle, of the irreversibility of the patient’s coma dépassé (beyond coma).4 By 1966, he had harvested and transplanted kidneys from nine severely head-injured donors. In 1968, a Harvard ad hoc review panel essentially endorsed Alexandre’s work, defining irreversible coma as complete unresponsiveness, with no spontaneous movement, including breathing; and a flat electroencephalogram in the absence of confounding factors such as drugs or hypothermia.5

Dr. Shumay (inset and at patient’s left) performing the first adult U.S. heart transplant with Edward Stinson, January 7, 1968.

Dr. Shumay (inset and at patient’s left) performing the first adult U.S. heart transplant with Edward Stinson, January 7, 1968.

Bruce Tucker was a 56-year-old intoxicated man, who sustained a basal skull fracture and was brought unaccompanied to MCV around 6:00 pm on May 24, 1968. An emergency craniotomy to evacuate a subdural hematoma and tracheotomy for ventilation failed to halt his deteriorating neurological status.6 Drs. Lower and Hume had been training their team for three years and were actively seeking a potential heart donor for a patient already in the hospital. They asked other people involved in the case, including the police, to search for Mr. Tucker’s family to discuss donation of his heart and kidneys, but no contact was ever made. Shortly after noon on May 25, a neurologist concluded that Tucker’s brain was dead, allowing the surgeons to move him to the operating room for removal of his heart and kidneys. The respirator was temporarily disconnected and after five minutes of apnea, the medical examiner agreed to begin the organ retrieval, despite a Virginia law requiring a two-day waiting period before disposing of unclaimed bodies. Mr. Tucker had been in the hospital for just 23 hours, and there is no record indicating whether his heart ever ceased beating or was restarted when ventilation was resumed.

William Tucker came to the hospital that evening, which was just down the street from his shoe repair shop, to inquire about his injured brother and was told that he had died in the afternoon, without mentioning his having been the world’s sixteenth heart transplant donor. Dick Lower was a remarkably sensitive and unassuming person, but in this situation he neither recognized nor respected Bruce Tucker’s sanctity. Bruce was black in a society that was still desegregating, but not the abandoned derelict he was presumed to be. The recipient of this ninth U.S. heart transplant was white and survived for just seven days before becoming the first heart recipient to die from acute rejection.

Dr. Lower (left) and Dr. Hume

Dr. Lower (left) and Dr. Hume

This ethical debacle assured a lawsuit, if not a murder charge, and could have provoked massive public disapproval. In fact, Prof. Jura Wada at Sapporo Medical University in Hokkaido was charged with murder for not doing more to revive a brain-death (B-D) donor, whose heart was used in Japan’s first heart transplant on August 8, 1968. The murder charge was eventually dropped due to insufficient evidence, but Japan would not allow another heart transplant for 31 years. In the U.S., Lower continued to perform heart transplants and had the pleasure of seeing a later 1968 recipient live for an additional 6.5 years.

The inevitable trial commenced on May 25, 1972. William Tucker, represented by future Virginia Gov. Doug Wilder, sued Dr. Lower and MCV, alleging that Dr. Lower had hastened Bruce Tucker’s death by shutting off the ventilator for the purpose of obtaining his heart and kidneys. The issue of consent was moot because the statute of limitations expired before the case was filed. Members of Harvard’s ad hoc panel testified for the defense, apparently persuading the judge to direct the jury to consider “among other things the time of complete and irreversible loss of all function of the brain” in determining the time of death. Drs. Lower and Hume must not have believed that the neurologist’s declaration that Mr. Tucker’s brain was “dead” meant that Tucker was dead. Why else would they have exposed a donor heart to five minutes of apnea? The jury did not have all the medical facts, including uncertainty about the pre-excision status of Mr. Tucker’s heart, and simply concluded that no wrongful death had occurred. The judge’s instruction to the jury ensured Dr. Lower’s exoneration, but did not redefine death as proclaimed in the contemporary press. Neither Harvard’s ad hoc committee, nor Tucker vs. Lower, could turn medically defined B-D into a legal criterion of being dead.7

The dead donor rule

The dead donor principle states that vital organs should be taken only from dead patients and that retrieval of vital organs for transplantation should not lead to death.8 B-D became compatible when it was codified by the Uniform Determination of Death Act (UDDA), drafted in 1980 by the National Conference of Commissioners on Uniform State Laws. The UDDA states that: “An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards.” It was quickly endorsed by the American Bar and Medical Associations, and adopted by 45 states. The others relied on precedent-setting court cases but also cited the UDDA. Iterative improvements in donor management, ex vivo preservation, immunosuppression, and diagnosing acute rejection, along with a computer-based United Network for Organ Sharing (UNOS) had now advanced whole organ transplantation to a predictable and widely applicable therapy. Burgeoning demand and an ever-widening gap between society’s need and organ availability now obliged ethicists, who had previously focused on protecting donor sanctity, to also ponder means whereby an ethically defensible goal could be achieved with the least discomfort.

Why they say “no”

Neal Garrison, MD, FACS, of the University of Louisville, KY, was the first to advocate decoupling discussions of being brain dead and organ donation.9 He and his colleagues found that raising the two issues together, ostensibly to create some good out of a bad situation, resulted in only 18 percent of 62 families consenting to donation; whereas, proposing donation after the family had time to assimilate B-D’s implications resulted in a significantly greater, 57 percent (53/93), consent conversion rate. Subsequent experience has repeatedly validated this observation.

Some surgeons’ personal perspectives may taint their ability to be convincing organ donation advocates. A New York University and Albert Einstein College of Medicine survey of 30 surgical attendings, 41 surgical residents, and 35 medical students revealed 61 percent overall willingness to be organ donors, with proportionally more older and experienced respondents expressing refusal.10 Among all responders, only 49 percent had declared themselves as organ donors on their driver’s licenses. Both institutions have busy transplant centers, and 13 percent of those who would not permit removal of their own organs indicated that their refusal stemmed from observing or being involved in a procurement procedure.

Families’ concerns about whole organ donation include a basic core that should be anticipated and discussed at points in the conversation when a family seems less forthcoming. Ambiguity about brain death is the basis for many of their issues.11 They worry that consenting might result in withholding a treatment that could conceivably give the patient a slim chance at recovery, that the patient will feel additional pain from diminished medication or as part of the procurement procedure, and that they cannot be with the patient at the time of death. Families also worry about additional hospital charges, problems with preparation of the body for viewing, and religious concerns about delaying burial.

Ethnicity of organ donors and U.S. population

In 1978, Clive O. Callender, MD, FACS, an early transplanter and former chair of the department of surgery at Howard University in Washington, DC, convened a group of 40 individuals to address why minorities, and African-Americans in particular, were reluctant to become organ donors.12 The result was the 1982 creation of a DC Organ Donor Program that stressed “face-to-face presentations by culturally sensitive and ethnically similar community messengers who were health care providers, transplant recipients, persons awaiting transplants, donors and donor family members.” Within one decade, these transplantation stakeholders increased the number of Washington residents signing donor cards from 25 to 750 per month and raised the percentage of African-American organ donations from 3 percent to nearly 12 percent. In 1995, Dr. Callender leveraged this success into a national Minority Organ Tissue Transplant Education Program, known as MOTTEP. National Institutes of Health (NIH) funding allowed MOTTEP to create specific programs for Hispanics, Asian, Pacific Islanders, and Native Americans in community-based MOTTEPs, which stretch from Honolulu to the U.S. Virgin Islands. African-American donor rates now surpass those of white donors, and Hispanics and Asian donor rates are moving toward parity with their proportional presence in the U.S. population (see table).

Time to take the gloves off?

Figure 1. UNOS waiting list, December 2, 2011

Although often initially viewed as contentiously intrusive, the U.S. government’s role in advancing organ donor management has been remarkably enlightened, beginning with its 1984 establishment of not-for-profit Organ Procurement Organizations (OPOs) and The Organ Procurement and Transplantation Network (OPTN).13 The U.S. Department of Health and Human Services’ Health Resources and Services Administration (HRSA) underwrites OPTN’s cost and contracts with not-for-profit UNOS to direct its programs. OPTN lists 112,447 persons waiting for organs in the U.S. as of December 2, 2011 (see Figure 1); 80.3 percent are waiting for a solitary kidney.14 Based on the last two years, this need will be only partially fulfilled by 8,000 deceased donors, providing a mean 2.75 organs transplanted per donor (OTPD), along with 6,600 living donors, yielding 28,600 organs for all of 2011. Fewer than 17,000 (<60 percent) of these will be kidneys. Deceased donors peaked at 8,085 in 2007, and for the past decade, at least 7,000 wait-listed people have died annually.

Are these data sufficiently compelling to warrant the government shifting its stance from facilitating organ donation to legislating presumed consent? A citizen wishing to avoid becoming a potential donor would then have to opt out by registering refusal in a government-maintained database. Austria, Belgium, Singapore, and Spain, among others, have this system. In Austria, where the law was implemented in 1982, a pre-enactment seven-year baseline average of 4.6 donors per million of population per year (DMY) rose to 27.2 DMY by the fifth “opt-out” year.

Mandated consent is a halfway step requiring only that all adults consider organ donation and enter their decisions into an electronic database. The New Jersey Hero Act, passed on July 22, 2008, requires that starting in 2013 all New Jersey drivers indicate whether they are willing to be a donor, or acknowledge being adequately informed without consenting to be a donor.15 Interim measures ensure having an informed citizenry well before then. Since 2009, New Jersey grades 9–12 public schools and colleges must include information about organ and tissue donation in their core curricula, and all New Jersey medical and nursing schools must include organ donation and recovery as a condition for graduation. As of this year, physicians licensed before the act are encouraged to complete an online, credit-based course, and previously licensed nurses are required to take an online, one credit-hour course to be relicensed.

B-D’s discomforting hegemony

B-D’s broad acceptance is pragmatic, especially valued for the recovering of thoracic organs and, despite some discomforting facts, served as the source of virtually all deceased donor organs throughout the 1980s. The brain is not always completely dead. Viable areas with neurologic functions unrelated to clinical B-D criteria remain, such as those regulating hypothalamic hormone secretion. Patients with irreversible coma look disconcertingly normal, as if they have adjusted to the ventilator and are asleep. Mechanical ventilation and nutritional support can allow such individuals to metabolize enteric feedings, excrete waste, and survive for months, for example, to give birth to near-term babies by caesarean section.

Robert Truog, MD, an anesthesiologist-ethicist at Boston Children’s Hospital, and Franklin Miller, MD, of the NIH’s Bioethics Department, concluded that “…although it may be perfectly ethical to remove vital organs for transplantation from patients who satisfy the diagnostic criteria of B-D, the reason that it is ethical cannot be that we are convinced that they are really dead.”16 They viewed valid consenting for withdrawal of life support, or for organ donation, as being separate but similarly proper ethical bases for their respective actions. James Bernat and his Dartmouth colleagues diffused these concerns by separating detectable but “random and purposeless cellular physiologic activity” from the brain’s irreplaceable systemic integrated functioning, but some countries and the world’s three monotheistic religions have wrestled with reservations about B-D’s parity with circulatory demise for years.17

The Danish Council on Ethics actually abrogated the dead donor rule in 1988, agreeing to the recovery of organs once brain function had ceased “during the death process” but reasserting that the time of death was when the heart later stopped.18 The council then promoted unprecedented public debate by widely distributing its deliberations. Public opinion was 80 percent in favor of the council’s minority recommendation of declaring death to have happened when B-D criteria were satisfied, which led the Danish Parliament to endorse the public’s sentiment in 1990.

Japan had difficulty overcoming repercussions from the Jura Wada case, delaying passage of an Organ Transplant law until 1997. The prevailing attitude toward B-D remained tentative, so its qualification for organ recovery was statutorily differentiated from cardiac death. B-D donation required advanced written consent by the potential donor, and family members could override the donor’s intention, resulting in just 86 B-D donors over 12 years. The law was revised in 2009 to accept family consenting for B-D donation if the potential donor had not intentionally opted out. Despite retention of the family veto, 16 B-D donor recoveries occurred within the first three months under the new law.19

Judaism is generally supportive of B-D, but had to subordinate the principle of “Ain dochin nefesh mipnei nefesh—that one life may not be set aside to assure another life applies with full force even where the life to be terminated is of short duration and seems to be lacking meaning or purpose” and to reinterpret a responsibility into an empowerment. “…God has imposed on man the awesome responsibility of defining the moment of death…after which the needs of the dead…must be subordinated to those of the currently living.”20

“In Islam, the killing of a terminally ill person, whether through voluntary active euthanasia or physician-assisted suicide, is judged an act of disobedience against God.”21 However, intent and consideration for a patient’s well-being can create a situation in which the act of disobedience is acceptable: Jordan’s Council of Islamic Jurisprudence (majma` al-fiqh al-islami) incorporated “complete cessation of all functions of the brain, when expert physicians ascertain that the cessation is irreversible and the brain is in the state of degeneration” into the Shari`a guidelines to determine death.22 The council’s amendment concludes with: “God knows the best!”

The Catholic Church is unique in having a succession of single, infallible, earthly leaders to limit wavering, yet its publicly aired views typify the ruffling effect of inherent contradiction. Lucetta Scaraffia, professor of contemporary history at Rome’s La Sapienza University, authored the front page article of the September 3, 2008, L’Osservatore Romano, recounting the Pontifical Academy of Science’s 2005 dissention with the Vatican’s original 1985 posture endorsing irreversible coma, reinforced by John Paul II in 1989 and again in 2000.23 On November 7, 2008, Benedict XVI, speaking to Rome’s international congress on A Gift for Life: Considerations on Organ Donation, left some doubt as to his position by saying: “Over recent years, science has made further progress in ascertaining the death of a patient. It is good, then, that the achieved results receive the consensus of the entire scientific community in favor of looking for solutions that give everyone certainty…and where total certainty has not been reached, the principle of caution should prevail.”24

Donation after cardiac death (DCD)

Nonbeating heart donors were the primary source of cadaveric renal allografts for almost 20 years and the source of the heart for Christiaan Barnard’s second, and the world’s first successful, heart transplant.25 Heart-beating, B-D criteria sourced organs are associated with better outcomes but comprise only a fraction of inhospital deaths. Controlled DCD began with the University of Pittsburgh (PA) Medical Center’s 1992 “Policy for the Management of Terminally Ill Patients Who May Become Organ Donors After Removal of Life Support.”26 These patients are ventilator- and often pressor-dependent. The patient and family do not wish to continue supportive care and would readily consent to its withdrawal. Their potential for organ donation depends on a separate consent to donate and the likelihood that support withdrawal will shortly result in cessation of effective circulation. Cessation within an hour is in the best interests of all parties and is somewhat predictable based on the PaO2/FIO2 ratio, pressor requirements before withdrawal, and respiratory parameters 10 minutes after withdrawal.

The potential donor’s physicians discontinue the support, provide comfort care, administer heparin, and in most instances, insert femoral cannulae under local anesthesia to be used for in-situ cooling. As originally described, they pronounce the patient dead after no pulse can be appreciated for a two-minute interval thought to be sufficient to preclude cardiac autoresuscitation. The transplant team is then called to assume management of the decedent. This has to be a tightly protocoled sequence of compassionate care and hand off that considers the patient, the family, and the quality of the organs that will transplanted.

Health care professionals and families were discomforted by the imprecision of basing the end of a life on two minutes without feeling a pulse. In 1997, the Institute of Medicine suggested that “accepted medical detection standards include electrocardiographic changes consistent with absent heart function, [along with] zero pulse pressure [as monitored] through an arterial catheter,” and also suggested that five, rather than two, minutes be adopted as an arbitrary, but reasonable, standard.27 Now almost all OPOs endorse five minutes. Electrocardiographic silence is not required, because the criterion determining death is the absence of effective circulation.

“Irreversible”—the elephant in the room

Irreversibility is not an absolute phenomenon. Irreversible is a conditional adjective that needs constraints specifying the

Figure 2. Proportional increase of DCD donors

situation surrounding the noun that is being labeled. Its unconstrained use introduces ambiguity into Harvard’s definition of profound coma and the UDDA’s stipulation of cessation of circulatory and respiratory functions and of all functions of the entire brain, including the brain stem, as the two legitimate routes to being declared dead. The controlled DCD process shines a bright light on the elephant. Two or five minutes without effective circulation from ventricular fibrillation or stand still is typically reversible in an operating room. It is irreversible in DCD because the caregivers have determined with the family’s consent that the patient should die. Busy procurement coordinators say that they have experienced a resumption of a shallow pressure tracing when they began measures to curtail warm ischemia, which they address by asking the donor’s physicians to return for another five-minute countdown.

Public acceptance of DCD is surprisingly good, as judged by the proportional increase of DCD donors (see Figure 2, this page). Registration to be a donor is not a consent to withdraw life support. Rarely is a suitable potential DCD donor able to give valid consent for withdrawing his own life support, making DCD essentially a family affair, affirming Truog-Miller’s consent-based ethicality.

Mitigation of brain injury’s systemic effects

Brain death is associated with vascular instability and a leaky blood-brain barrier that unleashes a barrage of inflammatory cytokines. Novitzky and his colleagues at Cape Town’s Groote Schuur Hospital countered this with an intravenous “cocktail” of 2μg of triiodothyronine, 100mg of cortisol, and 10–30 IU of insulin given as often as hourly to 26 potential B-D donors from the time of consent until recovery of the heart.28 They observed significant improvements in donor mean arterial pressure (MAP) and base deficit, as well as a related halving of the dopamine required.

Methylprednisolone has been prospectively studied in 100 B-D criteria liver donors randomized to receive or not receive a 250 mg bolus of methylprednisolone at the time of consent and subsequent infusion of 100 mg/h until organ recovery.29 Methylprednisolone resulted in significant downregulation of inflammatory signaling factors, less ischemia/reperfusion injury, as evidenced by lower AST and ALT levels over the first 10 post-transplantation days, and lower total serum bilirubin levels at 10 days and out to six months.

T4 or its synthetic analog, L-thyroxine, act synergistically with vasopressors in brain injured patients, increasing their efficacy at lower doses to the point of sometimes being able to discontinue them.30 The same study has shown that despite T4’s selective use in more unstable donors, its use was associated with a significantly higher 3.9 OTPD rate versus 3.2 from donors not requiringT4.

B-D’s sympathicomimetic inflammatory milieu increases both hepatic gluconeogenesis and peripheral insulin resistance while impairing its release from the pancreas. Free-water loss from depressed or absent vasopressin secretion requires substantial dextrose water infusion to combat hypernatremia and doubles the imperative for closely monitored intravenous insulin administration to prevent glucosuria compounding diabetes insipidus’ free water clearance. A study is in progress using a computer-based insulin delivery system to target donor glucose levels between 100 and 140mg/dL.31 The baseline delivery protocol has been sufficient for nearly 75 percent of organ donors. The others have shown remarkable insulin resistance, frequently requiring 30–40U boluses and infusion rates up to 40–50U/h.

Protocol controlled donor management

HRSA launched an Organ Donation Breakthrough Collaborative in 2003 to study retrieval processes at high-performing institutions and to disseminate best practices to what eventually became 950 of the nation’s largest hospitals. In 2004, the collaborative set a 75 percent consent conversion rate as a national goal, and in 2005, they added achieving a yield rate of 3.75 OTPD and a secondary goal that DCDs should comprise at least 10 percent of an institution’s deceased donors.32

UNOS Region 11 (Kentucky, Tennessee, Virginia, North Carolina, and South Carolina) developed a Donor Management Goal (DMG) panel of clinical variables aimed at meeting HRSA’s target for organs transplanted per donor.33 Among 467 donors, 82 percent of recovered organs were transplanted yielding an overall 3.34 OTPD. When all eight DMGs were achieved, the transplant yield was 3.45 OTPD versus 2.59 when they were not. Limited pressor use, followed by PaO2, and CVP were the primary predictors that a donor’s recovered organs would be transplanted.

The Los Angeles County Hospital and the University of Southern California Medical Center manage potential donors according to a protocol first introduced in 1998 that requires floating a catheter into the pulmonary artery to monitor aggressive fluid resuscitation. If volume replacement does not yield a MAP ≥70mmHg (true in most instances), they begin a vasopressor, moving up to a maximum 10μg/kg/minute, and then turn to their 50 percent dextrose, 2g methylprednisolone, 20U insulin, 20μgT4 bolused cocktail to be followed by continuous infusion of T4 at 10μg/h. The protocol stresses vigilance and quick intervening to treat expected 50 percent incidences of diabetes insipidus and thrombocytopenic coagulopathy with desmopressin, fresh-frozen plasma, cryoprecipitate, and platelets. Protocol adoption was associated with an 87 percent drop in potential donors lost from hemodynamic instability.34 The protocol not only saves lost organs, but also lost hospital revenue because the Centers for Medicare & Medicaid Services pays all otherwise uncovered hospital charges back to when B-D was declared.

Normothermic ex vivo perfusion and repair

Cold perfusion has been the mainstay of organ preservation but is known to damage mitochondria through Adensoine-5´-triphosphate (ATP) depletion and alter plasma membrane lipids, cell structure, and microtubules, resulting in time-related cell lysis. Normothermic perfusion avoids these cellular debilities and offers opportunities for ex vivo functional assessment, quelling inflammation, and restorative conditioning. Although animal studies have shown that these benefits are applicable to all organs and a single clinical study of normothermic perfusion of hearts has begun enrollment, clinical work has focused on the lung.35 Lungs do not tolerate DCD associated ischemia and are prone to injury from B-D related inflammation, aspiration, and barotrauma, resulting in less than 20 percent of donated lungs being transplanted.

In 2007, Stig Steen of Sweden’s Lund University reported the first clinical transplantation of an ex vivo reconditioned lung. The contused lung was recovered from a young B-D accident victim whose final PaO2 was 67mmHg with an FiO2 of 0.7 (P:F ratio of 95.7). The reconditioning began with a slow <20mmHg pulmonary artery perfusion of deoxygenated blood diluted in proprietary Steen solution* to a 15 percent hematocrit at 25˚C, gradually warming the perfusate to 37˚C and ventilating to maintain end-expiratory pressure at 5cmH20.13 Mean pulmonary artery pressures decreased from 12 to 7mmHg and pulmonary venous P:F stabilized at 500. The lung was implanted in a 70-year-old man, raising his pretransplant FEV1 from 20 percent of predicted to 74 percent and allowing him to be quite active for 11 months until he died of immunosuppression related sepsis.36

Figure 3. Cypel ex-vivo lung circuit.  EVLP normothermic lung circuit allowing both functional assessment and repair. Note insert’s red tank indicating a hypoxic gas. Source: Cypel et al.40

Cypel and colleagues in Toronto, ON, have shown that as few as four hours of normothermic ex vivo lung perfusion (EVLP) significantly improved P:F ratios to a median of 443 in 20 of 23 lungs with pre-perfusion <300 P:F ratios37 (see Figure 3). The outcomes of transplanting these 20 reconditioned lungs, including nine from DCD donors, were compared with those of 116 contemporaneous normal-criteria lung recipients. The incidence of 72-hour primary graft dysfunction (P:F <300) was 15 percent in the EVLP conditioned lungs versus 30 in the control group. Bronchial dilatation was needed for 5 percent and 4 percent, and hospital stays were 23 and 27 days, respectively. Two DCD donor EVLP recipients died of non-graft causes within 30 days, nearly doubling the 5.2 percent 30-day mortality accruing from six control group deaths. At one year, 80 percent of EVLP recipients and 84 percent of control recipients were alive with their grafts.

Sadaria and her Denver, CO, and Nashville, TN, colleagues assessed oxygenation, histology, and cytokine expression in seven transplant-unsuitable human lungs over 12 hours of normothermic EVLP.38 P:F ratios improved significantly during the first two hours, and all lungs met transplant oxygenation criteria by 12 hours. Biopsies were obtained at one, six, and 12 hours for histology and cytokine concentrations. The histologic sections were all normal. Several pro-inflammatory cytokines were progressively upregulated, including MCP-1 (monocyte chemotactic protein -1), which has been clinically associated with primary graft dysfunction. Interleukin-10, a notable anti-inflammatory cytokine, was never detected.39

The latter finding was particularly interesting because the Toronto group has transfected transplant-unsuitable human lungs undergoing normothermic EVLP with an airway-delivered adenoviral vector encoding human Interleukin-10. A similar EVLP only control group developed acceptable P:F ratios; whereas, IL-10 transfected lungs achieved significantly higher P:F ratios, lower pulmonary vascular resistance, and a favorable shift from pro-inflammatory to anti-inflammatory cytokine expression. The authors have yet to report transplantation of an IL-10 transfected human lung, but have shown that ex vivo IL-10 gene therapy significantly inhibited swine IL-6 and IL-1b release from pig lung tissue after four hours as an allotransplant.40

Ex vivo organ reconditioning is a rudimentary example of regenerative medicine’s potential to permit in-situ repair or replacement with autologous, induced pluripotent stem cells.41 The genome of these reprogrammed cells will be edited to promote in vitro growth of a specified single stem cell type, which will home to injured or diseased isogenous tissue when injected into an artery that serves the targeted organ.

Epilogue

Optimal donor management, ex vivo organ conditioning, opt-out legislation, and a cultural shift whereby organ donation becomes regarded as an obligation stemming from the gift of life at birth and an expansion of individual sanctity, which it is, should double the number of deceased U.S. donors and achieve HSRA’s goal of 3.75 OTPD.41 This unprecedented ratio of 51.8 donors per million of population (312 million as of August 29, 2011) could yield 60,000 organs, but no more than 32,000 kidneys, a shortfall that would require an unrealistic nearly nine-fold increase in live donors for fulfillment. An implantable artificial kidney may be on the horizon, but early intervention in causes leading to end-stage renal disease is currently the only realistic solution and will always be the most cost-effective strategy.42


Editor’s note
This article is an abridged and updated revision of “Sanctity and the Societal Value of Organ Donation,” published in the Alumni News of the New York-Presbyterian Hospital/Columbia University Department of Surgery, Vol. 13, No 1, Summer 2010, which can be accessed at http://www.columbiasurgery.org/news/john/jjss_su10.pdf.


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