REVIEWS Heart transplantation with donation after circulatory determination of death Sarah L. Longnus, Veronika Mathys, Monika Dornbierer, Florian Dick, Thierry P. Carrel and Hendrik T. Tevaearai Abstract | The constant shortage of available organs is a major obstacle and limiting factor in heart transplantation; the discrepancy between the number of donors and potential recipients leads to waitinglist mortality of 10–12% per year in Europe and the USA. If adopted for heart transplantation, donation after circulatory determination of death (DCDD) would be expected to improve the availability of organs substantially for both adults and children. With DCDD, however, hearts to be transplanted undergo a period of warm ischaemia before procurement, which is of particular concern because tissue damage occurs rapidly and might be sufficient to preclude transplantation. Nonetheless, the heart is able to withstand limited periods of warm ischaemia, which could provide a window of opportunity for DCDD. Development of clinical approaches specifically for DCDD is critical for the exploitation of these organs, because current practices for donor heart procurement, evaluation, and storage have been optimized for conventional donation after brain death, without consideration of warm ischaemia before organ procurement. Establishment of clinical protocols and ethical and legal frameworks for DCDD of other organs is underway. This Review provides a timely evaluation of the potential for DCDD in heart transplantation. Longnus, S. L. et al. Nat. Rev. Cardiol. 11, 354–363 (2014); published online 15 April 2014; doi:10.1038/nrcardio.2014.45
Introduction
Department of Cardiovascular Surgery, Inselspital, Berne University Hospital and University of Berne, Murtenstrasse 35, CH‑0310, Switzerland (S.L.L., V.M., M.D., F.D., T.P.C., H.T.T.). Correspondence to: H.T.T. hendrik.tevaearai@ insel.ch
Organ shortage is a critical problem in heart transplantation. In European countries, 3,290 patients were registered on waiting lists for heart transplantation at the end of 2010.1 In the following year, a total of 2,024 heart transplantations were performed, and 412 patients (~12.5%) died while awaiting transplantation.2 Similar statistics were published for the USA, where 3,183 patients were waiting for a heart transplantation on 31 December 2010, 2,376 patients underwent heart transplantation in 2011, and 331 patients (~10.4%) died while on the waiting list.1,2 This problem is expected to worsen as waiting lists continue to grow, while no change in donor-organ availability is anticipated. One possible strategy to increase availability is to use organs obtained from donors who have experienced permanent cessation of circulatory function, in addition to conventionally obtained organs from donation after brain death (DBD). Donation after circulatory determination of death (DCDD) for kidney, liver, pancreas, and lung transplantation has received much attention over the past 15 years.3,4 For heart transplantation, organ availability might also be substantially increased by DCDD, with the greatest benefit expected for transplantation in paedi atric patients.3,5–8 Nevertheless, concerns persist regarding cardiac susceptibility to warm ischaemic injury, and transplantation teams remain sceptical about cardiac DCDD. Indeed, with DCDD, a 2–10 min ‘no-touch’ period after Competing interests The authors declare no competing interests.
354 | JUNE 2014 | VOLUME 11
circulatory arrest is legally and ethically required, during which time cardioprotective interventions are limited.9 Nonetheless, a healthy heart retains sufficient integrity if warm ischaemia is limited to ≤20 min.10–13 Therefore, a window of opportunity exists that might be worth exploiting, especially if the mid-term and long-term functional status of donor hearts can be reliably and practicably predicted at the time of harvesting. In this Review, we discuss some of the major problems that must be addressed before adoption of cardiac DCDD in clinical practice. Several promising, clinically relevant approaches are outlined that might help to overcome the challenges associated with this type of heart donation.
Current situation Definition of DCDD In this article, DCDD describes organ donation from patients with permanent circulatory arrest. Alternative terms include ‘donation after cardiac death’, ‘donation after (cardio)circulatory death’, ‘donation after declaration of (cardio)circulatory death’, and ‘non-heart-beating donors’. Five categories of donor patients have been distinguished in the modified Maastricht classification of DCDD (Table 1).4,14,15 With DCDD, a no-touch period is ethically and legally required after circulatory arrest and before declaration of death, during which time interventions aimed at organ preservation are limited.9 The duration of the no-touch period is critical; sufficient time must elapse to ensure that cessation of the circulation is permanent, but the
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Shortage of organs limits the number of heart transplantations performed; waiting-list mortality is 10–12% per year in Europe and the USA ■■ Adoption of donation after circulatory determination of death (DCDD) in heart transplantation could substantially improve organ availability for both adults and children ■■ Very limited clinical evidence already supports the feasibility of heart transplantation with DCDD ■■ Tissue injury resulting from exposure of the donor heart to warm, noncardioplegic ischaemia before procurement is the major obstacle for DCDD in heart transplantation ■■ Strategies for procurement, storage, and evaluation must be optimized for DCDD in heart transplantation; effective approaches remain to be identified ■■ Establishment of DCDD in heart transplantation also requires careful consideration of ethical and legal aspects
Table 1 | Modified Maastricht DCDD categories Modified Maastricht category*
Description
Conditions surrounding circulatory arrest
I
Dead on arrival at hospital
Uncontrolled‡
II
Unsuccessful resuscitation
Uncontrolled‡
III
Anticipated circulatory arrest
Controlled
IV
Circulatory arrest in a patient previously declared dead according to neurological criteria (brain death)
Controlled
V
Circulatory arrest in hospital
Uncontrolled‡
*Modified categories were designated in several reports.4,14,15 ‡The precise course of circulatory arrest is not known. Abbreviation: DCDD, donation after circulatory determination of death.
time period must also be limited to keep ischaemic organ damage within an acceptable range. No international consensus currently exists regarding the minimum no-touch duration,16 which varies by country between 2 min and 10 min (Table 2).
Feasibility of cardiac DCDD Clinical experience is very limited, but supports the feasibility of cardiac DCDD. In 1967, the first human heart transplantation was performed with DCDD (the concept of brain death was introduced later).17 In the past 5–6 years, donor-organ shortages have renewed interest in cardiac DCDD,3,4,18 and successful heart transplantation using DCDD has been reported in one adult (heterotopic procedure)13 and in three infants (orthotopic procedure), albeit with short no-touch periods (1.25–3.00 min).4,12 Experimental, ex vivo functional assessment of DCDD hearts has also been described. 10,11 These encouraging reports provide impetus for further investigation of clinically applicable strategies for reliable DCDD cardiac transplantation. DCDD and donor heart availability Cardiac DCDD might substantially increase the donor pool, given that cardiopulmonary death is more common than brain death.19 Furthermore, in the past decade in European countries, the overall number of organs avail able through DCDD has increased, whereas the number of organs from DBD has remained stable.20 Singhal and colleagues retrospectively reviewed records of patients
in a local donor database for the period 2001–2003 to examine the potential of cardiac DCDD.5 A total of 119 patients in the donor register experienced circulatory death during the study period, and 12–18% of these patients met the proposed inclusion criteria for cardiac DCDD. The investigators estimated that cardiac DCDD could have increased cardiac donation by 4–6% during the period studied.5 Similar findings were reported by Osaki and colleagues, who retrospectively reviewed a donor database for the period 2004–2006. 3 The researchers screened the 78 patients who had experienced circulatory death during the time period against proposed criteria for cardiac DCDD, and estimated that 15% of these patients were potential cardiac donors. Osaki et al. estimated that cardiac DCDD could have increased cardiac donation by 17% during the 3‑year period studied.3 These estimates should be interpreted with care, as variations in the proposed inclusion criteria might have considerably influenced the findings. For instance, Osaki and colleagues considered suitable cardiac donors as being aged ≤50 years, with no cardiac abnormalities, and ≤30 min of cardiac warm ischaemia time (WIT).3 In the same study, ‘ideal’ cardiac donors were considered to be men aged ≤30 years, with no cardiac abnormalities, and ≤20 min of cardiac WIT, which reduced the proportion of potential cardiac DCDD donors to 2.5% and the corresponding estimated increase in cardiac donation to 2.8%.3 The potential of DCDD for cardiac transplantation might, however, be underestimated in these two reports, because the inclusion criteria for DCDD grafts used might be unnecessarily conservative.5 On the basis of DBD registries, more-flexible criteria might be acceptable for DCDD. For example, Singhal and colleagues reported that only 54.5% of the patients with successfully transplanted DBD hearts actually met all the DCDD inclusion criteria, which included age 75% preischaemic value) for ≤20 min of ischaemia, but abruptly declined to
Introduction
Department of Cardiovascular Surgery, Inselspital, Berne University Hospital and University of Berne, Murtenstrasse 35, CH‑0310, Switzerland (S.L.L., V.M., M.D., F.D., T.P.C., H.T.T.). Correspondence to: H.T.T. hendrik.tevaearai@ insel.ch
Organ shortage is a critical problem in heart transplantation. In European countries, 3,290 patients were registered on waiting lists for heart transplantation at the end of 2010.1 In the following year, a total of 2,024 heart transplantations were performed, and 412 patients (~12.5%) died while awaiting transplantation.2 Similar statistics were published for the USA, where 3,183 patients were waiting for a heart transplantation on 31 December 2010, 2,376 patients underwent heart transplantation in 2011, and 331 patients (~10.4%) died while on the waiting list.1,2 This problem is expected to worsen as waiting lists continue to grow, while no change in donor-organ availability is anticipated. One possible strategy to increase availability is to use organs obtained from donors who have experienced permanent cessation of circulatory function, in addition to conventionally obtained organs from donation after brain death (DBD). Donation after circulatory determination of death (DCDD) for kidney, liver, pancreas, and lung transplantation has received much attention over the past 15 years.3,4 For heart transplantation, organ availability might also be substantially increased by DCDD, with the greatest benefit expected for transplantation in paedi atric patients.3,5–8 Nevertheless, concerns persist regarding cardiac susceptibility to warm ischaemic injury, and transplantation teams remain sceptical about cardiac DCDD. Indeed, with DCDD, a 2–10 min ‘no-touch’ period after Competing interests The authors declare no competing interests.
354 | JUNE 2014 | VOLUME 11
circulatory arrest is legally and ethically required, during which time cardioprotective interventions are limited.9 Nonetheless, a healthy heart retains sufficient integrity if warm ischaemia is limited to ≤20 min.10–13 Therefore, a window of opportunity exists that might be worth exploiting, especially if the mid-term and long-term functional status of donor hearts can be reliably and practicably predicted at the time of harvesting. In this Review, we discuss some of the major problems that must be addressed before adoption of cardiac DCDD in clinical practice. Several promising, clinically relevant approaches are outlined that might help to overcome the challenges associated with this type of heart donation.
Current situation Definition of DCDD In this article, DCDD describes organ donation from patients with permanent circulatory arrest. Alternative terms include ‘donation after cardiac death’, ‘donation after (cardio)circulatory death’, ‘donation after declaration of (cardio)circulatory death’, and ‘non-heart-beating donors’. Five categories of donor patients have been distinguished in the modified Maastricht classification of DCDD (Table 1).4,14,15 With DCDD, a no-touch period is ethically and legally required after circulatory arrest and before declaration of death, during which time interventions aimed at organ preservation are limited.9 The duration of the no-touch period is critical; sufficient time must elapse to ensure that cessation of the circulation is permanent, but the
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Shortage of organs limits the number of heart transplantations performed; waiting-list mortality is 10–12% per year in Europe and the USA ■■ Adoption of donation after circulatory determination of death (DCDD) in heart transplantation could substantially improve organ availability for both adults and children ■■ Very limited clinical evidence already supports the feasibility of heart transplantation with DCDD ■■ Tissue injury resulting from exposure of the donor heart to warm, noncardioplegic ischaemia before procurement is the major obstacle for DCDD in heart transplantation ■■ Strategies for procurement, storage, and evaluation must be optimized for DCDD in heart transplantation; effective approaches remain to be identified ■■ Establishment of DCDD in heart transplantation also requires careful consideration of ethical and legal aspects
Table 1 | Modified Maastricht DCDD categories Modified Maastricht category*
Description
Conditions surrounding circulatory arrest
I
Dead on arrival at hospital
Uncontrolled‡
II
Unsuccessful resuscitation
Uncontrolled‡
III
Anticipated circulatory arrest
Controlled
IV
Circulatory arrest in a patient previously declared dead according to neurological criteria (brain death)
Controlled
V
Circulatory arrest in hospital
Uncontrolled‡
*Modified categories were designated in several reports.4,14,15 ‡The precise course of circulatory arrest is not known. Abbreviation: DCDD, donation after circulatory determination of death.
time period must also be limited to keep ischaemic organ damage within an acceptable range. No international consensus currently exists regarding the minimum no-touch duration,16 which varies by country between 2 min and 10 min (Table 2).
Feasibility of cardiac DCDD Clinical experience is very limited, but supports the feasibility of cardiac DCDD. In 1967, the first human heart transplantation was performed with DCDD (the concept of brain death was introduced later).17 In the past 5–6 years, donor-organ shortages have renewed interest in cardiac DCDD,3,4,18 and successful heart transplantation using DCDD has been reported in one adult (heterotopic procedure)13 and in three infants (orthotopic procedure), albeit with short no-touch periods (1.25–3.00 min).4,12 Experimental, ex vivo functional assessment of DCDD hearts has also been described. 10,11 These encouraging reports provide impetus for further investigation of clinically applicable strategies for reliable DCDD cardiac transplantation. DCDD and donor heart availability Cardiac DCDD might substantially increase the donor pool, given that cardiopulmonary death is more common than brain death.19 Furthermore, in the past decade in European countries, the overall number of organs avail able through DCDD has increased, whereas the number of organs from DBD has remained stable.20 Singhal and colleagues retrospectively reviewed records of patients
in a local donor database for the period 2001–2003 to examine the potential of cardiac DCDD.5 A total of 119 patients in the donor register experienced circulatory death during the study period, and 12–18% of these patients met the proposed inclusion criteria for cardiac DCDD. The investigators estimated that cardiac DCDD could have increased cardiac donation by 4–6% during the period studied.5 Similar findings were reported by Osaki and colleagues, who retrospectively reviewed a donor database for the period 2004–2006. 3 The researchers screened the 78 patients who had experienced circulatory death during the time period against proposed criteria for cardiac DCDD, and estimated that 15% of these patients were potential cardiac donors. Osaki et al. estimated that cardiac DCDD could have increased cardiac donation by 17% during the 3‑year period studied.3 These estimates should be interpreted with care, as variations in the proposed inclusion criteria might have considerably influenced the findings. For instance, Osaki and colleagues considered suitable cardiac donors as being aged ≤50 years, with no cardiac abnormalities, and ≤30 min of cardiac warm ischaemia time (WIT).3 In the same study, ‘ideal’ cardiac donors were considered to be men aged ≤30 years, with no cardiac abnormalities, and ≤20 min of cardiac WIT, which reduced the proportion of potential cardiac DCDD donors to 2.5% and the corresponding estimated increase in cardiac donation to 2.8%.3 The potential of DCDD for cardiac transplantation might, however, be underestimated in these two reports, because the inclusion criteria for DCDD grafts used might be unnecessarily conservative.5 On the basis of DBD registries, more-flexible criteria might be acceptable for DCDD. For example, Singhal and colleagues reported that only 54.5% of the patients with successfully transplanted DBD hearts actually met all the DCDD inclusion criteria, which included age 75% preischaemic value) for ≤20 min of ischaemia, but abruptly declined to
