Donor evaluation in heart transplantation: The end of the beginning

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Donor Evaluation in Heart Transplantation: The End of the Beginning Evan P. Kransdorf MD, PhD, Josef Stehlik MD, MPH

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J Heart Lung Transplant

Cite this article as: Evan P. Kransdorf MD, PhD, Josef Stehlik MD, MPH, Donor Evaluation in Heart Transplantation: The End of the Beginning, J Heart Lung Transplant, http://dx.doi.org/10.1016/j.healun.2014.05.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Donor Evaluation in Heart Transplantation: The End of the Beginning

Evan P. Kransdorf MD PhD1, Josef Stehlik MD MPH2

1

Division of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ, 85054, U.S.A.

2

Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City, UT,

84132, U.S.A.

Corresponding author: Josef Stehlik, MD, Division of Cardiovascular Medicine, University of Utah Health Sciences Center, U.T.A.H. Cardiac Transplant Program, 50 North Medical Drive, 4A100 SOM, Salt Lake City, UT 84132. Telephone: 801-585-2340. Fax: 801-581-7735. E-mail address: [email protected].

Running title: Donor Evaluation Key Words: heart transplantation; organ donation; tissue and organ procurement; tissue donor; transplant outcomes. Abbreviations: DCD = donation after circulatory death; EVHP = ex vivo heart perfusion; LVAD = left ventricular assist device; EF = ejection fraction; HDS = heart donor score; HLA = human leukocyte antigens; KDPI = kidney donor profile index; LV = left ventricle; LVH = left ventricular hypertrophy; MELD = Model for End-Stage Liver Disease; OPO = organ procurement organization; PMP = per million population; PSE = pharmacologic stress echocardiography; TMOCS = TransMedics Organ Care System Heart; UNOS = United Network for Organ Sharing; US = United States. Word count: Abstract 184; manuscript 4315. Financial support: None

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Abstract The evaluation of organ donors is of critical importance in all areas of solid organ transplantation. Donor characteristics have been shown to have robust effects on heart transplant recipient outcomes, and evaluation of the donor for suitability for heart transplantation is therefore very comprehensive. The donor evaluation process is composed of several steps, beginning with the identification of a potential organ donor and ending with the transplantation of a donor heart. The purpose of this review is to dissect the complex process of donor evaluation into its component steps, and to highlight the diverse approaches used by transplant clinicians around the world to optimize outcomes at each step. We provide a summary of donor characteristics that have been associated with increased recipient mortality, and discuss areas of uncertainty. Recent additions to the literature present novel insights and solutions to vexing problems in donor evaluation, such as how to make a more accurate assessment of allograft quality. Continued advancement in the evaluation of donors is essential to maintain heart transplantation as a viable therapy that provides excellent long-term survival for patients with end-stage heart failure.

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Text ―Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.‖ Winston Churchill, 1942.

The imbalance between the number of patients with end-stage heart failure in need of a donor heart and the number of organs available for transplantation was recognized soon after the first heart transplantation was performed in 1967 1. Expanding clinical application of solid organ transplantation, improvement in the donation and organ allocation processes, and other factors resulted in a continued increase in organ donation in the United States (US) and other countries between 1999 and 2005. However, for the past decade, the number of donated hearts has remained without significant change 2. In addition, as the mean population age has increased in many countries, and traffic safety has improved 3, it has become increasingly difficult to limit donor organ use to ‗optimal‘ allografts, with a substantial increase in the mean age for cardiac allograft donors in Europe and to a lesser degree in non-European countries 4. The number of heart transplants that take place in a year is the result of several serial steps, each with a variable success rate (Figure 1). This process starts with identification of a potential deceased donor and concludes with transplantation of the donor heart into the recipient. In this review, we discuss each step of the donor evaluation, and highlight the diverse approaches used by transplant clinicians to optimize outcomes at each step. Recent additions to the literature offer novel insights into some of the problems in donor evaluation. We describe possible solutions to these problems, as improved performance in several of these steps could potentially lead to an increased supply of cardiac allografts around the globe.

Identification of potential organ donors The responsibility of identifying potential organ donors falls to medical teams that manage patients with critical injuries that threaten neurological function, often led by critical care

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or neurocritical care physicians. The possibility of organ donation should be addressed in all patients who have reached brain death and when progression to brain death appears imminent 5

. The specific details on when to conduct and who should conduct these discussions varies by

country, but these conversations are typically initiated by personnel specifically trained for these situations and knowledgeable with the organ donation and organ transplantation process. These personnel may be hospital-based transplant coordinators 6 or staff of an independent organ procurement organization (OPO) 7. The family is approached and the process of organ donation is discussed. In some countries, consent for organ donation is presumed unless patients opt-out 6. Other countries require that consent be explicitly provided, and donor registries are now available in many countries that allow individuals to record their intention to donate 8. In the US, 46 states have adopted the 2006 Anatomical Gift Act update, which establishes legal protection for the donor designation and makes this decision legally binding 9,10

. However, even in the presence of an established intention to donate, most countries still

require next-of-kin consent/assent to donation 11. Once a consent for donation is established, a potential donor becomes an actual donor. Large variations in the rate of organ donation are observed between different countries (Figure 2) 12 13. Interestingly, even within a country, large variations in the rate of organ donation are observed between different geographic regions 6. In the US, geographic variation manifests as a substantial variation in the number of deceased donors per million population (PMP) identified by each of the 58 OPOs 14. There is also substantial variation among the OPOs in the proportion of potential donors where a consent for donation is established (consent rate), and in the proportion of consented donors whose organs are actually used for transplantation (conversion rate). Recently, Sheehy et al. found that regional variation in the incidence of diseases that lead to brain death may explain a large part of the variation in the number of potential deceased donors between OPOs 15. Other major factors include variations

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in the referral process for organ donors, the type of consent system, and the ethnic and socioeconomic background of the donor. Referral process. A study from 6 European counties demonstrated that, on average, 25% of potential deceased donors were not identified. In addition, 22% of deceased patients correctly identified as potential donors were not referred to the procurement teams for evaluation 16. In the US, regulatory bodies such as the Joint Commission for Hospital Accreditation and the Center for Medicare and Medicaid Services require hospitals to notify the local OPO of all deaths and imminent deaths, and to assure that families of potential organ donors are approached by specifically trained personnel regarding donation of organs and tissues 5. Despite this requirement, reliable data on the efficiency of the referral process are lacking and enforcement of the referral requirements appears less strict than that or rules directly related to patient care. Therefore, it is likely that gaps in the referral process are present in many US hospitals. Consent legislation: presumed vs. explicit consent. Rithalia et al. examined changes in organ transplantation volumes in response to presumed consent legislation approval in Spain, Austria, and Belgium 17. This change appeared to have modest positive effects on organ transplantation rates. However, others have argued that even when presumed consent policies are in place, family consent/assent to proceed with donation is also typically pursued, and thus the differences in donation between countries with presumed and explicit consent may be smaller than expected 18. In either consent system, increasing the consent rate could have a significant impact on the number of organs available for transplantation. Race and ethnicity. Donation consent rates in the US have been reported to be significantly lower among ethnic minorities, with an odds of providing consent of 0.54 in Hispanics, 0.35 in African-Americans, and 0.31 in Asians 19. Improving public understanding of the donation process, the benefits of organ transplantation, and of the applicable laws can positively

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influence attitudes towards organ donation and transplantation 20,21. Social media may also have a role in increasing awareness of organ donation and donor registry enrollment 22. Given the complexities discussed above, the optimal practices that maximize the number of actual deceased donors to sustain transplantation within a country are not firmly established. However, intervention at multiple steps in the organ donation process can dramatically raise donation rates, as was demonstrated by Spain‘s achievement of increasing deceased donation rates from 14.3 donors PMP in 1989 to 35.1 donors PMP in 2013 23. Innovations within their system included presumed consent legislation, early identification and referral of possible deceased donors and utilization of in-hospital transplant coordinators, who are frequently physicians. Perhaps most importantly, Spain has a robust quality assurance program to monitor performance for each of the processes of the deceased donor evaluation. Their program is composed of both internal (performed by the in-hospital transplant coordinator) and external evaluations 24. There appear to be no critical barriers that would prevent implementation of many of the features of this system in other countries. For example, utilization of in-house nurse transplant coordinators at 3 US hospitals increased the donor conversion rate from 63% to 77% 25.

Donor management Once consent for organ donation of a deceased donor is obtained, this step is focused on optimizing organ function and assessment of suitability of the organs for transplantation. The hemodynamics of a brain dead donor can be tenuous, not only as a result of the original lifethreatening insult, but also due to the pathophysiology of brain death. Initially, cerebral ischemia leads to sympathetic nervous system activation, with concomitant hypertension, tachycardia, and possibly myocardial ischemia and dysfunction 26 27. As brain death proceeds, sympathetic tone diminishes, leading to vasodilation, hypotension, and often further cardiac dysfunction. Donor management interventions are critical to counterbalance these effects of

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brain death and to optimize organ function prior to transplantation. Donor management goals should include achievement of favorable mean arterial pressure, euvolemia, normalization of ejection fraction and cardiac output, correction of acidemia, anemia, and hyponatremia, proper respiratory gas exchange, and utilization of a single vasopressor agent 28,29. It has been shown that clearly establishing and meeting these standardized donor management goals is associated with a higher likelihood of heart transplantation 29. In the early days of heart transplantation, organ donors were identified within the same institution as the potential transplant recipient, or were transported to the recipient‘s hospital to minimize allograft ischemic time. In the late 1970s, the Medical College of Virginia and Stanford groups showed that a donor heart could be procured at a distant hospital and transported back to the home hospital for transplantation, with similar outcomes 30,31. While now the standard of care, this approach has drawbacks in that urgent travel is costly and can be unsafe 32. In a contrasting strategy, Doyle et al. have recently reported their 10 year experience with a hospitalindependent organ recovery facility, to which organ donors are transported for management and procurement 33. In their analysis, use of this facility for liver transplants resulted in decreased organ cold ischemic time, surgeon travel time, and overall cost, without loss of donors or a deleterious effect on graft survival. This approach to organ donor management may be particularly suitable to urban areas with multiple transplant centers, and could lead to improvements in donor management and thus organ yield, in addition to reducing organ ischemic and travel time.

Heart allograft allocation After consent has been obtained, heart allografts are allocated (‗offered‘) to individual transplant candidates based on the pertinent (and diverse) allocation algorithms present in their specific jurisdictions. In the US, allocation to a candidate is based on their geographic zone, medical urgency status, ABO compatibility, and then priority bin (based on time spent on the

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waiting list) 34. Other determinants of donor-recipient compatibility include the permissible weight difference and any unacceptable human leukocyte antigens (HLA), which are specified by the candidates‘ transplant program. The transplant program can accept the offer for a candidate or decline the offer. If the offer is declined, the allograft is then offered to the next transplant candidate on the waiting list based on the allocation algorithm. The reasons for offer decline may include high-risk donor behaviors, positive donor infectious disease serologies, suboptimal organ quality, and an undesirable combination of characteristics between the donor and the recipient, among others. If all transplant programs decline the allograft, the heart is not recovered for transplantation (nonused). Between 40 and 80% of hearts available for donation are not recovered for transplantation 35-37. The current US allocation algorithm was revised in 2006 to allow for greater regional sharing of donor hearts. Since this change, regional (non-local from the donor standpoint) urgent status candidates (status 1A and 1B) have been prioritized over local non-urgent candidates 38. This policy change contributed to a 17% decrease in mortality on the waiting list 39

. Interestingly, Schulze et al. showed that more recently, there has been a nationwide

increase in waiting times for urgent status patients, with a disproportionate increase in waiting time in certain regions of the US 40. It is likely not coincidental that these regions also had a substantial increase in mechanical circulatory support use. This increased regional disparity in waiting time for urgent status patients, along with concerns regarding an allocation advantage for LVAD patients 41 42 43, has lead to plans for the United Network for Organ Sharing (UNOS) to revise the current allocation rules, likely into a multi-tiered status system 44. Recent advances in antibody detection technology have also expanded the opportunity for allosensitized transplant candidates to receive a compatible allograft. Previously, the need to perform a prospective crossmatch in allosensitized patients limited organ allocation to the local procurement area, resulting in long times on the waiting list. Accurate definition of the specificities of anti-HLA antibodies with single-antigen beads now allows for determination of

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unacceptable donor antigens, and ‗virtual‘ crossmatch can therefore be used to allocate an organ from a distant donor to an allosensitized patient. Virtual crossmatch has been shown to correlate well with direct cytotoxic crossmatch 45, and its application in heart transplantation has been shown to reduce time on the waiting list for allosensitized patients while preserving favorable post-transplant outcomes 46.

Assessment of donor risk The sheer number of donor and recipient characteristics that need to be considered when a donor allograft becomes available makes this step difficult. Over the years, multiple studies have identified donor characteristics that may be associated with increased recipient mortality. These studies included analyses from single institutions, analyses of national and international registries, and employed various approaches to statistical analysis. Some of the donor characteristics that are believed to confer an increased risk of recipient mortality include increasing age, stroke as the donor cause of death, donor positivity for hepatitis C, and the presence of obstructive coronary artery disease (Figure 3) 47 48 4. Other donor factors, such as history of diabetes mellitus, gender, HLA disparity, left ventricular hypertrophy (LVH), and weight, have been shown to have interactions with other donor or recipient characteristics, increasing mortality only when specific combinations of characteristics are present (e.g. LVH and longer allograft ischemic time) 49 43 4 50

. Some donor characteristics such as high-dose inotropic support, high-risk behaviors,

and cardiac arrest, that based on clinical experience would be expected to affect recipient mortality have not been consistently found to affect outcomes when the experience with those characteristics was examined systematically 51 52 53 54. The precise significance of other characteristics is more controversial. Elevated donor serum troponin has been shown to be associated with graft dysfunction and organ nonuse in one study, but lacked an association with recipient mortality in another 55 56. Donor heart LV

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dysfunction is a common reason for allograft nonuse 57, but at the same time LV dysfunction is common and a potentially reversible sequela of brain death 58. There is evidence that allografts with a depressed left ventricular ejection fraction (EF) 59 60 or hemodynamic abnormalities 61,62 that improve (even if they don‘t normalize) during donor management yield acceptable outcomes after heart transplantation. Furthermore, as the LV dysfunction associated with brain death resembles stress cardiomyopathy, application of emerging biomarker testing for stress cardiomyopathy might help identify allografts expected to improve once transplanted 27,63. Another strategy that has been used to assess suitability of cardiac allografts in donors with high cardiovascular risk is pharmacologic stress echocardiography (PSE) 64, Bombardini et al. reported their experience with using dobutamine or dipyridamole PSE in ‗marginal‘ donors, defined as age > 50 years or < 50 years with concomitant risk factors such as cocaine use, hypertension, and diabetes) 65. There were 39 donors that met the definition, of which 11 had resting abnormalities on echocardiogram and were excluded. PSE was performed in 28 donors with a mean age of 56 years, and was normal in 19 and abnormal in 9. Allografts from 16 of the 19 donors with normal PSE were used for heart transplantation, which resulted in good cardiac outcomes in 15. The 9 allografts with abnormal PSE were all found to have coronary artery disease or other cardiac pathology on further testing. Additional factors relating to the heart transplant surgery itself, but not related to the donor per se, may also affect recipient mortality. Chief among these is the allograft ischemic time, which is pertinent when the donor age is greater than 20 years 66. Increased intraoperative utilization of blood products also has been identified to increase 1-year and 5year mortality 67. As the number of transplant candidates on the waiting list continues to increase, it may be expected that the rate of nonuse of allografts would be decreasing; however, this has not been the case. Nativi et al. analyzed data from the Cardiac Transplant Research Database and

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found that the use of donors with some higher risk characteristics such as diabetes or an abnormal echocardiogram increased from 1990-1995 to 1996-2002 but then decreased in the years 2003-2007 68. Khush et al. found that cardiac allograft use decreased by 4.2% per year, from 56% in 2002 to 37% in 2008 36. While more than one factor is probably responsible for this trend, it is likely that the increasing utilization of left ventricular assist devices (LVAD) has allowed clinicians to be more discriminating in selection of hearts to be used for patients already supported with a LVAD. The implications of this trend are not clear. This strategy would be advisable if preferential selection of lower-risk donor hearts leads to improved post-transplant outcomes for LVAD patients. However, a situation where donor-associated risk is overestimated and a higher proportion of donors is declined could also occur. Decreased access to transplantation could potentially impair long-term outcomes in patients on LVAD therapy awaiting heart transplantation 4,69. The challenge that transplant clinicians face is that they are required to make a binary decision (i.e. to accept or not to accept an allograft) based on a qualitative analysis of multiple variables. Given this complexity, which are the factors that influence clinicians‘ decision to use an allograft? Khush et al. addressed this question by determining donor factors associated with nonuse of cardiac allografts in a single OPO. These factors included age > 50 years, female sex, death attributable to cerebrovascular accident, hypertension, diabetes mellitus, a positive troponin assay, left ventricular dysfunction, and LVH 36. However, among hearts used for transplantation, factors associated with worse recipient outcome were donor cause of death and donor history of diabetes mellitus. It is hence likely that donor utilization decisions based on an individual donor characteristic have low specificity to identify future allograft dysfunction and recipient mortality. It is therefore important to ask the following question: Would a scoring system that takes multiple donor variables into consideration facilitate a better risk-assessment of an allograft? Such an approach has been implemented for kidney transplantation in the US, with the goals of

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improving long-term graft survival and decreasing the discard rate of extended criteria kidneys 70

. Since March 2012, the United Network for Organ Sharing (UNOS) has displayed the Kidney

Donor Profile Index (KDPI) in its allocation software. As implemented by UNOS, the KDPI is a set of 10 donor variables that are used to calculate a score between 0% and 100% for each donor kidney 71. Lower KDPI values predict a higher long-term graft survival rate (KDPI of 5% predicts 93.5% graft function at 5 years) and a higher KDPI value predicts a lower long-term graft survival rate (KDPI of 95% predicts 48.9% graft function at 5 years) 72. It has also been proposed that KDPI be introduced into the kidney allocation algorithm to match donor allografts with recipients in a manner that would maximize the number of years these allografts would expect to function in surviving recipients 73. Smits et al. addressed the question of donor quality in heart transplantation by better quantifying the likelihood of donor nonuse in the Eurotransplant region 37. They identified 12 donor variables that were associated with nonuse (Table 1); but maybe more importantly, they examined each variable in more granular detail (e.g. coronary angiogram results were stratified into 6 categories). A multivariable regression model was used to identify donor variables independently associated with donor nonuse, and a point value was assigned to each variable from the model. A ‗heart donor score‘ (HDS) was then generated for each donor from the sum of the points. As would be expected, there was a linear relationship between the HDS and the allograft nonuse rate (Figure 4). The investigators validated this score in a later Eurotransplant donor cohort, finding that HDS above the median were associated with a higher percentage of organ nonuse (35%), as compared to HDS below the median (7% nonuse). Clearly, it would be important to know whether the HDS also provides information regarding recipient survival. Only donor age and LVH, as individual donor variables, were statistically significant predictors of mortality at 3 years after heart transplant. However, the HDS was an independent predictor of survival in a multivariable model considering other confounding factors such as recipient age, urgency at the time of transplant, weight match, gender match, and ischemic time; each HDS

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point above 17 increased the predicted 3-year mortality by 4%. We believe that the Eurotransplant HDS is an important step towards better quantification of donor risk in heart transplantation. Another donor risk score was developed by Weiss et al. using the UNOS database 74. Their final donor risk score model included four variables: ischemic time, donor age, donorrecipient race mismatch, and BUN/creatinine ratio

30 (Table 1). In a validation cohort, an

increasing number of points in the risk score correlated with a higher risk of mortality at 1 and 5 years after transplant. Finally, while allograft ischemic time reflects transport and surgical times more than donor quality per se, it has been shown to have an interaction with donor characteristics such as donor age or donor heart hypertrophy 75 66 76. Both allograft ischemic time and donor age are components of the RADIAL score that assesses the risk of primary graft failure 77. If successfully validated in other prospective cohorts, the Eurotransplant HDS and UNOS Donor Risk Score could find uses similar to the KDPI and assist clinicians in making decisions to accept or reject an allograft offer for a particular recipient. The next important step would be integration of donor risk information with measures of recipient acuity and predicted outcome 78. If these approaches are shown to be reproducible and sufficiently accurate, a consideration could be given to a more sophisticated approach to donor-recipient allocation. Certainly, as long as the anticipated changes in kidney transplant allocation discussed above are implemented, hearts would become (at least in the US) the last major solid organ without allocation based on an objective measure of recipient acuity or predicted recipient survival, such as the Lung Allocation Score 34 used in lung transplantation, the Model for End-Stage Liver Disease (MELD) in liver transplantation 79, or the kidney Estimated Posttransplant Survival Score 73.

Emerging and potential solutions 13

Griepp at al. published the first retrospective analysis of heart transplant donors in 1971 80

. Since that time the debate over how much liberty to take in donor acceptance has continued,

including in this journal nearly 20 years ago 81. Based on the data discussed here, we present possible improvement opportunities to problematic areas in the steps of donor evaluation (Table 2). In this section we also discuss two emerging solutions that may increase the supply of cardiac allografts: donation after circulatory death and ex vivo heart perfusion. In the setting of a plateau in the availability of organs procured from brain dead donors, organs procured from donation after circulatory death (DCD) donors have emerged as an additional source of organs, primarily for use in liver and kidney transplantation. Initially used in Europe, the use of DCD donors is increasing in the US, with 14% of kidney and 4% of liver allografts coming form DCD donors in 2012 82,83. DCD donors are now also being used in lung transplantation, and preliminary studies have shown outcomes equivalent to those in brain dead donors 84. Heart allografts from donors with circulatory death have been used for heart transplantation; in the initial stages heart transplantation in the 1960‘s before brain death criteria were defined 85, and more recently as part of a pilot clinical study by Boucek at al. in pediatric heart transplantation 86. Use of DCD donors in heart transplantation could increase the donor pool by 4 to 11% by some estimates 87,88. The impediments to implementation of this approach in clinical practice are concerns regarding the impact of the warm-ischemia period on long-term outcomes, as well as ethical concerns over using a heart for transplant from a donor whose death was declared based on cessation of cardiac function. Nevertheless, clinical protocols are in development, and the emerging technology of ex vivo heart perfusion may aid in reducing the impact of ischemia-reperfusion injury and in selecting organs suitable for transplantation 89. The longstanding recognition of the important contribution of ischemia-reperfusion to cardiac allograft injury, as manifested by the important relationship between increasing allograft ischemic time and decreasing survival after heart transplantation, has led to development of technology for continuous, ex vivo perfusion of cardiac allografts 90,91. Ex vivo heart perfusion

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(EVHP) has been shown to decrease contractile impairment and tissue damage in a porcine model 92. The TransMedics Organ Care System Heart (TM-OCS) has been recently evaluated in the PROCEED II clinical trial where 128 patients underwent heart transplantation using allografts randomized to EVHP (allograft preserved via TM-OCS) vs. standard allograft preservation 93. Preliminary data presented at the International Society for Heart and Lung Transplantation Scientific Sessions in April 2014 indicated that serious adverse events, biopsyproven ISHLT grade 2/3R rejection, length of ICU stay, and 30-day survival were not different between the two groups 94. As we await the longer term results of this trial, the potential impact of EVHP in heart transplantation is apparent. This may include reduction of allograft preservation injury, the potential for assessment and conditioning of allografts perceived as suboptimal at the time of procurement, or expansion of regional sharing beyond that currently possible.

Conclusions In this review we dissected the component steps that make up the donor evaluation, summarized donor risk factors associated with increased recipient mortality, and identified interventions that may further improve the donor evaluation process. Advances in mechanical circulatory support, the emerging clinical use of EVHP and DCD will continue to affect the donor evaluation, selection, and allocation processes. The comprehensive understanding of the impact of combinations of donor and recipient characteristics on outcomes as discussed here may represent the ‗beginning of the end‘ to the traditional approach to donor and recipient matching. Continued advancement in the assessment of donors is essential to maintain heart transplantation as the therapy that provides the optimal long-term outcome for patients with endstage heart failure.

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Disclosure Statement The authors thank Dr. Jon Kobashigawa for his comments on the manuscript. The authors have no conflicts of interest to disclose.

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Figure Legends Figure 1: Steps in the donor evaluation process, starting with identification of a potential organ donor and concluding with transplantation of a donor heart into a recipient. We have defined ‗nonuse‘ as failure to allocate an allograft to a transplant candidate (usually due to quality concerns), whereas ‗discard‘ refers to failure to procure an organ at the time of donor cardiectomy.

Figure 2: Rates of deceased donation vary widely between different countries (2012 data). PMP = per million population. Source: Global Observatory on Donation and Transplantation 13.

Figure 3: Donor characteristics associated with increased recipient mortality after heart transplantation.

Figure 4: Eurotransplant heart donor score and heart allograft nonuse rate. Solid line: nonuse rate. Grey bar: number of hearts reported. Black bar: number of hearts transplanted. Adapted from: Smits et al. 37.

30

FIG 1

31

Fig 2

32

Fig 3

33

Fig 4

34

Table 1: Donor variables independently associated with donor nonuse and the range of points for each variable in the Eurotransplant heart donor score. Donor characteristics

Range of points

Eurotransplant Heart Donor Score (Smits et al.) Age

1 (age < 45) to 11 (age

Cause of death

1 (drugs) to 7 (carbon monoxide intoxication)

History of malignancy, sepsis, drug abuse, meningitis, or positive virology

1 (no) vs. 19 (yes)

Hypertension

1 (no) vs. 2 (yes)

Cardiac arrest

1 (no) vs. 2 (yes)

Left ventricular function

1 (EF > 55%) to 22 (EF < 45%)

Valvular function

1 (normal) to 7 (abnormal)

Left ventricular hypertrophy

1 (10 mm) to 4 (> 14 mm)

Coronary angiogram

1 (normal) to 70 (> 1-vessel stenosis)

Serum sodium

1 (< 130 mmol/L) to 3 ( 170 mmol/L)

Norepinephrine therapy

1 (not used) to 5 (> 0.8 g/kg/min)

Dopamine/dobutamine therapy

1 (not used) to 2 (> 10 g/kg/min)

60)

UNOS Donor Risk Score (Weiss et al.) Ischemic time

1 (< 2 hours) to 5 ( 8 hours)

Age

0 (age < 40) to 5 (age

Race mismatch

0 (no) vs. 2 (yes)

BUN/creatinine ratio

30

0 (no) vs. vs 3 (yes)

35

50)

Table 2: Donation processes and potential interventions that could increase the number of allografts available for transplant. Process

Interventions for Improvement

Identification of Potential Donors and Consent for Organ Donation Donor referral

-Health care provider education -Clinical triggers for timely referrals -Enhancing hospital-OPO communication -Hospital monitoring of compliance with referral process -Donation after circulatory death

Donor consent

-Trained individuals to approach families for consent -Raising of public awareness -Community education tailored to ethnicity/religion -Establishment of donor registries -Social media campaigns for donation awareness -Updates on donor legislation Donor Management, Selection, and Allocation

Management goals

-Education of providers in management of donors and potential donors (crticial care) -Standardized management goals -Quality assurance

Donor recovery facilities

-Reduced organ ischemic time -Reduced surgeon travel time -Increased participation in donor management research

Diagnosis of stress cardiomyopathy

-Extending donor management time, repeated cardiac assessment -Biomarker testing?

Allograft quality assessment

-Application of donor scoring system?

Maximizing allograft survival

-Novel heart allocation score? -Ex vivo heart perfusion to reduce ischemic time?

36