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Multivisceral Transplant, The Prince Charles Experience
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2019) -, -–1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.10.012
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Multivisceral Transplant, The Prince Charles Experience Fiona E. Doig, MBSS a,*, Rishendran Naidoo, FRACS a, Joseph Hwang, MBBS a, Charlotte Frost, MBBS a, Douglas Wall, FRACS a, Peter Tesar, FRACS a, Vinod Sharma, MBBS a, Andreas Fiene, FRACP b, Peter Hopkins, FRACP b a
Department of Cardiothoracic Surgery, The Prince Charles Hospital, Chermside, Brisbane, Qld, Australia Department of Lung Transplant, The Prince Charles Hospital, Chermside, Brisbane, Qld, Australia
b
Received 3 March 2019; received in revised form 19 August 2019; accepted 4 October 2019; online published-ahead-of-print xxx
Background
Multi-visceral organ transplant is uncommon. As a result of the rarity of these surgeries, there are limited reports making it difficult to interpret outcomes and identify specific patient complications. We aim to assess the indications for multi-organ transplant, the time on the wait-list and evaluate outcomes including patient survival, graft survival and postoperative complications in an Australian context.
Methods
Patients undergoing multi-organ transplant from 1993 to the present at The Prince Charles Hospital were retrospectively reviewed, looking at baseline characteristics and post-transplant morbidity, mortality and graft survival.
Results
A total of 37 patients were included in the study, comprising 22 heart-lung transplants, eight heart-kidney transplants and seven heart-lung-liver transplants. There were six domino heart transplants performed in the heart-lung-liver transplant group. The mean age at transplant was 37 years and the mean wait-list time was 10 months. One patient, receiving a heart-lung transplant, required re-transplantation (bilateral lung) at 3 years. One-year (1-year) survival was 91% for heart-lung transplants, 86% for heart-lung-liver transplants and 87.5% for heart-kidney transplants. Five- and ten-year (5- and 10-year) survival was 79% for both in heartlung transplant, 43% and 29% for heart-lung-liver transplant and 87.5% for both in heart-kidney transplant.
Conclusion
Patients undergoing multi-organ transplant at our unit had long-term survival and organ function comparable to international data. In addition, waitlist time for multi-organ transplant was not found to be excessive.
Keywords
Multi-organ transplant Heart transplant Heart2lung transplant
Introduction Multi-organ transplantation is an uncommon, technically challenging undertaking. Given the relative rarity of these operations, it is difficult to assess outcomes. This, in turn, increases the challenges of preoperative patient selection and the tailoring of postoperative management for individual patients. Multi-organ transplant is further complicated by the issue of resource allocation, i.e., the transplantation of several organs for one patient which would otherwise be used to
transplant several patients. However, this issue is partly mitigated by the concept of domino transplants. Indications for multi-organ transplant include idiopathic pulmonary hypertension, congenital heart disease, cystic fibrosis and alpha-1 antitrypsin deficiency to name a few. The recently published International Society for Heart and Lung Transplantation (ISHLT) report has found that, between 1990 and 2016, 3,251 heart-lung transplants were performed worldwide, accounting for 5.3% of all transplants. The report also noted that, whilst the number of lung2liver,
*Corresponding author at: Department of Cardiothoracic Surgery, The Prince Charles Hospital, Chermside, Brisbane, Qld 4032, Australia., Email: fi[email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Doig FE, et al. Multivisceral Transplant, The Prince Charles Experience. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.10.012
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lung2kidney and other multi-organ transplants have increased during this period, the number of heart2lung transplants and heart2lung2other transplants has decreased in recent years. A total of 58 heart-lung only transplants were performed internationally in 2016. The oneyear survival is lower for all multi-organ transplants however 10-year survival is comparable to lung-transplant alone. Survival has also improved with the era of transplant, from a median of 2.1 years for heart2lung transplants performed before 1993 to 5.8 years for those operated after 2004. An association between multi-organ transplant and the reduced incidence of rejection and bronchiolitis obliterans syndrome (BOS) compared to lung transplant alone was also noted [1]. Studies examining outcomes following multi-organ transplant are generally in small cohorts. Yi et al. reported a series of eight combined lung2liver transplants (with one heart2lung2liver transplant). They found patient and graft survival of 87.5% at 30 days and 71.4% at 1 year, with the predominant cause of death attributed to sepsis. Increased Lung Allocation Score (LAS) was identified as a poor prognostic marker, similar to lung transplant alone [2]. Reviewing combined heart2lung2liver transplant in a cohort of nine patients, Praseedom found a 33% mortality at 30 days, again predominately as a result of sepsis, and a reduced rate of pulmonary rejection compared to lung transplant alone (33% v 73%) [3]. Dennis et al., reported excellent long-term functional outcomes in their series of four patients, with preserved pulmonary and hepatic function as well as NYHA 1 status up to 100 months postoperatively [4]. Data published from our institution reviewed five patients undergoing heart2lung2liver transplant for cystic fibrosis. We found a prolonged waiting time, greater hospital length of stay and lesser rates of rejection compared to lung transplant alone [5]. Results in patients undergoing multi-organ transplant have been shown to be improved by a fast-track recovery program, with early extubation and physiotherapy where possible [6]. There have also been larger series reporting the outcomes of heart2kidney transplants. In a series of 83 cases from Los Angeles comparing transplant across two eras, 5-year survival was 93% in patients operated 2009–2015 and 70% in patients operated 1992–2009 respectively. Postoperative dialysis was required in 31% in this group of patients, with postoperative hospital length of stay of 51642 days [7]. A further series of 22 patients identified acute cardiac rejection in 41% of patients, no renal allograft rejection and requirement for re-transplantation in 18% over a mean follow-up of 6.766.4 years [8]. It is clear that these are, indeed, uncommon procedures and there is a paucity of evidence on the increasing frequency of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices, either as a bridge to transplant or as postoperative support for these patients. In view of the changing nature of multi-organ transplantation as well as the infrequent review of outcomes for these patients, we conducted an analysis of patients undergoing multi-organ transplant at our institution with the aim to report the indications for multi-organ transplant, preoperative status and postoperative outcomes.
F.E. Doig et al.
Methods Patients undergoing multi-organ transplant from the commencement of the transplant program in January 1993 to November 2018 at The Prince Charles Hospital were identified. Data and charts were retrospectively reviewed. Information collected included baseline characteristics, intraoperative details, postoperative complications, patient and graft survival. Acute kidney injury was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria [9]. All transplants were conducted via a median sternotomy, in addition to either a laparotomy or subcostal incision in the case of heart-lung-liver transplant and a curvilinear Gibson’s incision for heart2kidney transplant. All heart2lung2liver transplants were performed with en-bloc implantation of all three organs with an incision made in the diaphragm to accommodate the intact inferior vena cava. The diaphragmatic incision was usually repaired with a bovine pericardial patch rather than direct closure. Femoral or central cannulation for cardiopulmonary bypass was used, depending on the circumstances, and, more recently, we have used a combination of femoral and percutaneous superior vena cava cannulation via the right internal jugular vein for heart/lung transplantation in the setting of previous cardiac surgery. Our immunosuppression protocol has been stable since 1997, consisting of a calcineurin inhibitor, mycophenolate mofetil (MMF) and prednisolone. Two (2) transplants performed before this date received prednisolone, azathioprine and cyclosporin. Induction therapy with basiliximab was introduced in 2012. Prior to that, IL-2 receptor blockers were reserved for patients with high panel reactive antibody testing or those at risk of acute renal injury early posttransplant. Diagnosis of rejection was made in accordance with the International Society for Heart and Lung Transplantation (ISHLT) guidelines [10,11]. Surveillance transbronchial biopsies were performed at 3, 6 and 12-weeks post-transplant for all heart2lung and heart2lung2liver patients. Liver and myocardial biopsies were not routinely performed for these patients. Surveillance for heart-kidney transplants involves cardiac biopsy at 126 weeks, 8, 12, 18 and 26 weeks and clinical review every 6 months once clinically stable. Ethics approval was sought and received by the institution’s ethics board. Survival was measured from the date of operation to the date of death or date of analysis (September 2018). Survival analysis was performed for the groups of heart2lung transplant, heart2kidney transplant, and heart2lung2liver transplants. Survival was calculated by the Kaplan2Meier method using the SPSS system, version 25.0 (IBM Corp, Armonk, NY, USA).
Results A total of 37 patients were included in the study, comprising 22 heart2lung transplants, eight heart2kidney transplants and seven heart-lung-liver transplants. There were six
Please cite this article in press as: Doig FE, et al. Multivisceral Transplant, The Prince Charles Experience. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.10.012
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domino heart transplants performed in this cohort, all of which were performed in the heart2lung2liver group. The mean age at transplant was 37 years (13–62 years) and 51% were male. The mean wait-list time was 10.1 months (0.25–29 months). Heart2lung2liver patients waited longer (16.4 months) compared to heart2lung (5.5 months) and heart2kidney (8.3 months) patients (Table 1). One (1) patient with cystic fibrosis, awaiting heart2lung2liver transplant died on the waiting list.
Heart2Lung Transplant Heart2lung transplant was most commonly performed for congenital heart disease (45%), followed by idiopathic pulmonary arterial hypertension (22.7%) and cystic fibrosis (18%). The remaining indications are listed in Table 2. Two (2) patients underwent redo transplantation, the first patient had undergone heart-lung transplant for Eisenmenger’s syndrome and developed bronchiolitis obliterans syndrome (BOS), and the second patient had undergone bilateral lung transplant and subsequently developed vanishing airways syndrome. A single patient was bridged to transplant with veno-arterial extra-corporal membrane oxygenation (ECMO). The mean organ ischaemic time was 300 minutes (Table 1). Postoperatively,
mechanical support was provided with intra-aortic balloon pump (IABP) in three patients and veno-arterial ECMO in one patient (Table 3). Postoperative morbidity included acute kidney injury in 14 patients (64%) with six (20%) of these patients required dialysis, pericardial effusion (n=2), chylothorax (n=1) and left vocal cord paralysis (n=1). Rejection occurred in five patients (23%), with grade A2 rejection in one patient, BOS in one patient and a single patient developed chronic lung allograft dysfunction (CLAD) requiring re-do bilateral lung transplantation. There were two (9%) early deaths (Table 4). Overall survival at 30-days, 1 year, 5 years and 10 years was 91%, 91%, 79% and 79% respectively (Figure 1).
Heart2Lung2Liver Transplant Heart2lung2liver transplant was performed exclusively in patients with cystic fibrosis with associated cirrhosis and portal hypertension. Domino heart transplant was performed in five out of the seven patients in this group and mean organ ischaemic time was 163 minutes. Complications particular to this group included return to theatre for stenting of a common bile duct anastomotic stricture (n=2), abdominal washout for biliary peritonitis (n=2) and thoracoscopic washout for empyema (n=1). The mean Intensive
Table 1 Baseline characteristics. Variable
All
Heart-Lung
Heart-Lung-Liver
Heart-Kidney
Number
37
22
7
8
Age at transplant (Mean)
38
36
30
47
Male n (%)
19 (51)
10 (45)
5 (71)
4 (50)
BMI
23.1
21.9
20
27.5
LAS INTERMACS Score
21.2 5.5
21.7 5.6
20.8 6.7
N/A 4.3
MELD Score (mean)
8.7
N/A
8.7
N/A
Donor Specific Antibodies
0
0
0
0
A positive
9 (24)
2 (9)
3 (43)
4 (50)
A negative
2 (5)
2 (9)
0
0
O positive
15 (41)
9 (41)
4 (57)
2 (25)
O negative AB
2 (5) 2 (5)
2 (9) 2 (9)
0 0
0 0
B positive
4 (11)
4 (18)
0
0
B negative
1 (3)
1 (5)
0
1 (13)
Waitlist time (months)
10.1
5.5
16.4
8.3
Blood Group
Organ Ischaemic Time (min)
224.3
300
163
210 1 OCS
Pre-transplant ECMO
1 (2.7%)
1 (2.7%)
0
0
Previous sternotomy
5.5 (15%)
9 (41%)
0
2 (25%)
X-clamp time(min) CPB time(min)
103.3 181.5
117.4 227.2
136.7 218.4
55.7 99
Abbreviations: LAS, Lung Allocation Score; ECMO, extra-corporal membrane oxygenation; BMI, body mass index; MELD, model for end-stage liver disease; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; CPB, cardiopulmonary bypass; X-clamp, cross-clamp.
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F.E. Doig et al.
Table 2 Indications for multi-organ transplant. Multi-organ group
Indication for multi-organ transplant
Number of patients
Heart2lung
CHD with PAH
9
PAH with RV Failure
4
CF with RV Failure
2
COPD with RV Failure
2
CF and bronchial sizing issues CF and Vanishing Airways Syndrome
1 1
Histiocytosis X and RV Failure
1
HOCM with RV Failure and Pulmonary Hypertension
1
DCM with RV Failure and PH
1
Heart2lung2liver
CF with associated liver disease
7
Heart2kidney
DCM and cardiorenal syndrome
3
DCM and polycystic kidney disease
1
Peripartum DCM and Acute Tubular Necrosis Ischaemic cardiomyopathy and cardiorenal syndrome
1 1
Ischaemic cardiomyopathy and polycystic kidney disease
1
DCM and glomerulosclerosis
1
Abbreviations: CHD, congenital heart disease; PAH, pulmonary hypertension; RV, right ventricular; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; HOCM, hypertrophic obstructive cardiomyopathy; , DCM, dilated cardiomyopathy.
diagnosed with diffuse B cell lymphoma and subsequently died 3 years post-transplant of chronic lung allograft dysfunction. Other deaths occurred as a result of BOS, pneumonia and a ruptured splenic artery aneurysm (Table 4, Figure 2). Rejection, grade A2, occurred in one patient. This was successfully treated with steroids. No patients required retransplantation. Overall 30-day, 1 year, 5-year and 10-year survival was 86%, 71% 43% and 29% respectively (Figure 1).
Care Unit (ICU) stay and hospital length of stay was 6.7 days and 29.6 days respectively (Table 3). There was a single 30day mortality (14%) at 16 days related to primary graft dysfunction after a period of support with veno-arterial ECMO. A further consideration in this patient was a sizemismatch of the thoracic organs. In long-term follow-up, one patient required a right upper lobectomy for non-small cell lung cancer (NSCLC), was also
Table 3 Postoperative course. Variable
All
Heart2lung
Heart2lung2liver
Heart2kidney 0
ECMO
2 (5%)
1
1
IABP
4 (11%)
3
1
0
Ventilation (hrs)
61.8
68
93.4
23.9
ICU length-of-stay(days) Hospital length-of-stay(days)
7.9 23.8
6.9 20.9
6.7 29.6
10.3 20.9 0
Return to theatre for bleeding
8 (22%)
6 (27%)
2 (29%)
AKI requiring dialysis
7 (19%)
6 (27%)
0
1 (13%)
Transfusion (PRBC)
33 (89%)
19 (86%)
7 (100%)
7 (88%)
Transfusion (Non-PRBC)
30 (81%)
17 (77%)
7 (100%)
6 (75%)
Rejection
10 (24%)
5 (23%)
1 (14%)
4 (50%)
Rejection .A2
2 (5%)
1 (5%)
1 (14%)
0
BOS/CLAD Retransplant
4 (14%) 1 (3%)
2 (9%) 1 (5%)
2 (29%) 0
N/A 0
30-day Mortality
3 (8%)
2 (9%)
1 (14.3%)
0
Abbreviations: BOS, bronchiolitis obliterans syndrome; CLAD, chronic lung allograft dysfunction; PRBC, packed red blood cells; AKI, acute kidney injury; ECMO, extra-corporal membrane oxygenation; IABP, intra-aortic balloon pump.
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Table 4 Mortality following multi-organ transplant. Transplant type
Cause of death
Age at transplant
Time to death
Heart2kidney
Unknown
53
14 years
Heart2kidney
Sepsis, portal vein thrombosis
31
16 years
Heart2kidney
Hypersensitivity vasculitis, fungal lung abscess, UGIH
41
44 days
Heart2lung
Cerebral post-transplant lymphoproliferative disorder
49
3.5 years
Heart2lung
Sepsis
54.6
14.5 years
Heart2lung2liver Heart2lung
Bronchiolitis obliterans syndrome Death on table, unable to wean from CPB
25.4 40.7
3 years 0 days
Heart2lung
Bronchiolitis obliterans syndrome
38.8
4.5 years
Heart2lung2liver
Sepsis (pneumonia)
31
7.5 years
Heart2lung2liver
Primary graft dysfunction
29.1
16 days
Heart2lung2liver
Ruptured splenic artery aneurysm
37.4
5 months
Heart2lung2liver
Chronic lung allograft dysfunction
28.8
3 years
Heart2lung
Multi-organ failure
18
15 days
Abbreviations: UGIH, upper gastrointestinal haemorrhage; CPB, cardiopulmonary bypass.
Heart2Kidney Transplant Indications included idiopathic dilated cardiomyopathy (n=3, 37.5%) followed by ischaemic cardiomyopathy (n=2, 25%), cardiomyopathy secondary to valvular disease (n=2, 25%) and familial dilated cardiomyopathy (n=1, 12.5%). Renal disease included cardiorenal syndrome (n=4, 50%), polycystic kidney
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disease (n=2, 25%), glomerulosclerosis (n=1, 12.5%) and acute tubular necrosis (n=1, 12.5%). Mean donor ischaemic time was 210 minutes and one of the hearts was retrieved using the organ care system (TRANSMEDICSTM, TransMedics Inc., Andover, MA, USA). None of the patients required bridging to transplant with ECMO or ventricular assist devices. One
Figure 1 Kaplan2Meyer survival curve for all multi-organ transplants.
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F.E. Doig et al.
Figure 2 Kaplan2Meyer survival curve comparing transplant era (pre- and post-2004).
patient returned to the operating theatre for debridement of a sternal wound dehiscence and another patient underwent imaging-guided drainage of a perinephric collection. There was a single inpatient mortality in a patient that developed hypersensitivity vasculitis causing ischaemic colitis and subsequent sepsis in addition to fungal lung abscesses. The mean ICU length of stay was 10.3 days and one patient required dialysis in the postoperative period. Rejection of the cardiac allograft occurred in three patients and in the renal allograft in one patient. No patients required retransplantation. Overall survival was 87.5% at 1 year continuing out to 10 years (Figure 1). The mean cross-clamp time in all patients was 103.3 minutes and cardiopulmonary bypass time 181.5 minutes reflecting the complexity of these cases. Both cross-clamp and bypass times were lowest in heart-kidney transplant, at 55.7 minutes and 99 minutes respectively. Operating times in the heart-lung transplant group may have been skewed due to particularly difficult cases. One (1) case in particular required a total arch replacement in addition to organ transplant. Coagulopathy was an issue for all multi-organ transplants with return to theatre for bleeding in eight patients (22%) and transfusion of packed red blood cells (PRBC) and non-PRBC products in 89% and 81% respectively. There was no statistically significant difference in survival between transplant era
(pre- and post-2004, p=0.865, Figure 2) or following introduction of basiliximab induction (p=0.389, Figure 3).
Discussion Multi-organ transplantation is an uncommon and technically challenging procedure. Heart2lung transplant continues to be the most common multi-organ transplant performed at our institution, with smaller numbers of heart-lung-liver and heart-kidney transplants and we have not performed any lung2liver or lung2kidney transplants. Our review found comparable outcomes for patients operated at The Prince Charles Hospital to international standards. However, the indication for transplant in our unit comprised a greater number of patients with congenital heart disease and a lesser number with cystic fibrosis compared to the International Society of Heart and Lung Transplantation report. Survival following heart2lung transplantation was 91% at 1 year and 71% at 5 years, relating favourably to data from ISHLT which reported survival of less than 75% at 1 year and marginally less than 50% at 5 years, however this does not account for differences in transplant era between the two groups [1]. Similarly, results from the Cleveland Clinic with 82% survival at 1 year and 62% at 5 years are comparable to our cohort of patients [12].
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Figure 3 Kaplan2Meyer survival curve comparing survival pre- and post-introduction of basiliximab induction.
In our experience, we have found that while complications such as acute kidney injury, fluid overload, chylothorax, atrial fibrillation and abdominal complications are not uncommon, sepsis is the most significant contributor to mortality. Cause of death in both the early postoperative period, predominantly multi-organ failure and sepsis, and late period, of bronchiolitis obliterans syndrome, was similar to both the Cleveland Clinic and ISHLT reports. Rates of treated rejection were 23% in our cohort compared to 34% presented by the ISHLT group [1]. Rejection rates were lowest in the heart-lung-liver group followed by the heart2lung group and the heart2kidney group. However, there was a higher rate of bronchiolitis obliterans in the heart2lung2liver group, which differed from a lower rate of BOS in this group of patients from the ISHLT report. Given the possible side effects associated with immunosuppression, it is worth considering whether reduced doses of immunosuppression are feasible in heart2lung2liver transplant patients. Waiting list time for the heart-lung-liver patients was significantly longer compared to the heart2lung and heart2kidney transplants and perhaps consideration should be given to listing these patients earlier given the longer waiting times. Similarly, the issue of organ allocation is more manifest in this group, however the number of domino transplants (six out of seven patients) performed in our cohort goes some way towards justifying the use of a heart2lung2liver bloc, which is technically easier to perform than lung2liver transplant alone.
Complex surgery and prolonged bypass times, with resultant coagulopathy, contribute to a high rate of transfusion and return to theatre. These are not benign issues and have been shown to result in immune suppression, infection and increased mortality. In a patient population already immunosuppressed, this is a concern. The introduction of point of care testing and targeted management of coagulopathy at our institution has contributed to promising improvements in the rate of transfusion and postoperative blood loss [13]. In heart2kidney transplants, bleeding was less of an issue, with no patients returning to theatre for haemostasis. It may be that this reflects reduced bypass times in this group.
Limitations The limitations of this study include the small number of patients included as well as the heterogeneity of the patient group in general. The study is a single institution review of retrospectively collected data. However, patient follow-up was performed well, with only one patient lost to followup after moving overseas at 14 years post-transplant.
Conclusion Multi-visceral transplant remains an important treatment option for often young patients with both multi-organ disease and complex anatomical and physiological challenges for single organ transplant. We have demonstrated the
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success of multi-organ transplant in a geographically large country with reasonable ischaemic times and waitlist times for what are still uncommon procedures. Obstacles that remain in this cohort of patients in improving survival are reducing the complications of sepsis and bleeding.
Uncited Reference Q4
[14].
Acknowledgements Q5
There are no conflicts of interest to acknowledge.
References [1] Khush KK, Cherikh WS, Chambers DC, Goldfarb SB, Hayes D, Kucheryavaya A, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report – 2018; Focus theme: Multiorgan transplantation. J Heart Lung Transplant 2018;37(10):1155–68. [2] Yi SGBS, Loebe M, Scheinin S, Seethamraju H, Jyothula S, et al. Combined lung and liver transplantation: Analysis of a single centre experience. Liver Transplant 2015;20:46–53. [3] Praseedom RK, McNeil KD, Watson CJ, Alexander GJ, Calne RY, Wallwork J, et al. Combined transplantation of the heart, lung and liver. Lancet 2001;358:812–3. [4] Dennis CM, McNeil KD, Dunning J, Stewart S, Friend PJ, Alexander G, et al. Heart-lung-liver transplantation. J Heart Lung Transplant 1996;15(5):536–8.
F.E. Doig et al.
[5] Fiene A, McNeil KD, Kermeen FD, Chambers DC, Stuart K, Fawcett J, et al. The Australian experience with combined heart-lung-liver transplant. J Heart Lung Transplant 2010;29:S18. [6] Konstantinov IE, McNeil K, Yeung S, Fawcett J, Mullany D, Dunning J. Fast track recovery following en bloc heart-lung-liver transplantation in a patient with cystic fibrosis complicated by severe portal hypertension. Heart Lung Circ 2008;17:146–66. [7] Awad M, Czer LS, Esmailian F, Jordan S, De Robertis MA, Mirocha J, et al. Combined heart and kidney transplantation: A 23-year experience. Transplant Proc 2017;49:348–53. [8] Lopez-Sainz A, Barge-Cabellero E, Paniagua-Martin MJ, Marzoa Rivas R, Sanchez-Fernandez G, et al. Clinical characteristics and long-term outcomes of patients undergoing combined heart-kidney transplantation: a single-center experience. Transplant Proc 2015;47:123–6. [9] Outcomes KDIG. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int 2012;2(1). [10] Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant 2007;26(12):1229–42. [11] Berry GJ, Burke MM, Andersen C, Bruneval P, Fedrigo M, Fishbein MC, et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 2013;32(12):1147–62. [12] Idrees JJ, Pettersson GB. State of the art of combined heart-lung transplantation for advanced cardiac and pulmonary dysfunction. Curr Cardiol Rep 2016;18:36. [13] Smith I, Pearse BL, Faulke DJ, Naidoo R, Nicotra L, Hopkins P, et al. Targeted bleeding management reduces the requirements for blood component therapy in lung transplant recipients. J Cardiothorac Vasc Anesth 2017;31(2):426–33. [14] Registries - Heart/Lung Registries . Slides [Internet]. 2017 [cited 18/4/ 2018]. Available from, http://www.ishlt.org/registries/slides.asp?slides= Q2 heartLungRegistry.
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2019) -, -–1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.10.012
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Multivisceral Transplant, The Prince Charles Experience Fiona E. Doig, MBSS a,*, Rishendran Naidoo, FRACS a, Joseph Hwang, MBBS a, Charlotte Frost, MBBS a, Douglas Wall, FRACS a, Peter Tesar, FRACS a, Vinod Sharma, MBBS a, Andreas Fiene, FRACP b, Peter Hopkins, FRACP b a
Department of Cardiothoracic Surgery, The Prince Charles Hospital, Chermside, Brisbane, Qld, Australia Department of Lung Transplant, The Prince Charles Hospital, Chermside, Brisbane, Qld, Australia
b
Received 3 March 2019; received in revised form 19 August 2019; accepted 4 October 2019; online published-ahead-of-print xxx
Background
Multi-visceral organ transplant is uncommon. As a result of the rarity of these surgeries, there are limited reports making it difficult to interpret outcomes and identify specific patient complications. We aim to assess the indications for multi-organ transplant, the time on the wait-list and evaluate outcomes including patient survival, graft survival and postoperative complications in an Australian context.
Methods
Patients undergoing multi-organ transplant from 1993 to the present at The Prince Charles Hospital were retrospectively reviewed, looking at baseline characteristics and post-transplant morbidity, mortality and graft survival.
Results
A total of 37 patients were included in the study, comprising 22 heart-lung transplants, eight heart-kidney transplants and seven heart-lung-liver transplants. There were six domino heart transplants performed in the heart-lung-liver transplant group. The mean age at transplant was 37 years and the mean wait-list time was 10 months. One patient, receiving a heart-lung transplant, required re-transplantation (bilateral lung) at 3 years. One-year (1-year) survival was 91% for heart-lung transplants, 86% for heart-lung-liver transplants and 87.5% for heart-kidney transplants. Five- and ten-year (5- and 10-year) survival was 79% for both in heartlung transplant, 43% and 29% for heart-lung-liver transplant and 87.5% for both in heart-kidney transplant.
Conclusion
Patients undergoing multi-organ transplant at our unit had long-term survival and organ function comparable to international data. In addition, waitlist time for multi-organ transplant was not found to be excessive.
Keywords
Multi-organ transplant Heart transplant Heart2lung transplant
Introduction Multi-organ transplantation is an uncommon, technically challenging undertaking. Given the relative rarity of these operations, it is difficult to assess outcomes. This, in turn, increases the challenges of preoperative patient selection and the tailoring of postoperative management for individual patients. Multi-organ transplant is further complicated by the issue of resource allocation, i.e., the transplantation of several organs for one patient which would otherwise be used to
transplant several patients. However, this issue is partly mitigated by the concept of domino transplants. Indications for multi-organ transplant include idiopathic pulmonary hypertension, congenital heart disease, cystic fibrosis and alpha-1 antitrypsin deficiency to name a few. The recently published International Society for Heart and Lung Transplantation (ISHLT) report has found that, between 1990 and 2016, 3,251 heart-lung transplants were performed worldwide, accounting for 5.3% of all transplants. The report also noted that, whilst the number of lung2liver,
*Corresponding author at: Department of Cardiothoracic Surgery, The Prince Charles Hospital, Chermside, Brisbane, Qld 4032, Australia., Email: fi[email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
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lung2kidney and other multi-organ transplants have increased during this period, the number of heart2lung transplants and heart2lung2other transplants has decreased in recent years. A total of 58 heart-lung only transplants were performed internationally in 2016. The oneyear survival is lower for all multi-organ transplants however 10-year survival is comparable to lung-transplant alone. Survival has also improved with the era of transplant, from a median of 2.1 years for heart2lung transplants performed before 1993 to 5.8 years for those operated after 2004. An association between multi-organ transplant and the reduced incidence of rejection and bronchiolitis obliterans syndrome (BOS) compared to lung transplant alone was also noted [1]. Studies examining outcomes following multi-organ transplant are generally in small cohorts. Yi et al. reported a series of eight combined lung2liver transplants (with one heart2lung2liver transplant). They found patient and graft survival of 87.5% at 30 days and 71.4% at 1 year, with the predominant cause of death attributed to sepsis. Increased Lung Allocation Score (LAS) was identified as a poor prognostic marker, similar to lung transplant alone [2]. Reviewing combined heart2lung2liver transplant in a cohort of nine patients, Praseedom found a 33% mortality at 30 days, again predominately as a result of sepsis, and a reduced rate of pulmonary rejection compared to lung transplant alone (33% v 73%) [3]. Dennis et al., reported excellent long-term functional outcomes in their series of four patients, with preserved pulmonary and hepatic function as well as NYHA 1 status up to 100 months postoperatively [4]. Data published from our institution reviewed five patients undergoing heart2lung2liver transplant for cystic fibrosis. We found a prolonged waiting time, greater hospital length of stay and lesser rates of rejection compared to lung transplant alone [5]. Results in patients undergoing multi-organ transplant have been shown to be improved by a fast-track recovery program, with early extubation and physiotherapy where possible [6]. There have also been larger series reporting the outcomes of heart2kidney transplants. In a series of 83 cases from Los Angeles comparing transplant across two eras, 5-year survival was 93% in patients operated 2009–2015 and 70% in patients operated 1992–2009 respectively. Postoperative dialysis was required in 31% in this group of patients, with postoperative hospital length of stay of 51642 days [7]. A further series of 22 patients identified acute cardiac rejection in 41% of patients, no renal allograft rejection and requirement for re-transplantation in 18% over a mean follow-up of 6.766.4 years [8]. It is clear that these are, indeed, uncommon procedures and there is a paucity of evidence on the increasing frequency of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices, either as a bridge to transplant or as postoperative support for these patients. In view of the changing nature of multi-organ transplantation as well as the infrequent review of outcomes for these patients, we conducted an analysis of patients undergoing multi-organ transplant at our institution with the aim to report the indications for multi-organ transplant, preoperative status and postoperative outcomes.
F.E. Doig et al.
Methods Patients undergoing multi-organ transplant from the commencement of the transplant program in January 1993 to November 2018 at The Prince Charles Hospital were identified. Data and charts were retrospectively reviewed. Information collected included baseline characteristics, intraoperative details, postoperative complications, patient and graft survival. Acute kidney injury was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria [9]. All transplants were conducted via a median sternotomy, in addition to either a laparotomy or subcostal incision in the case of heart-lung-liver transplant and a curvilinear Gibson’s incision for heart2kidney transplant. All heart2lung2liver transplants were performed with en-bloc implantation of all three organs with an incision made in the diaphragm to accommodate the intact inferior vena cava. The diaphragmatic incision was usually repaired with a bovine pericardial patch rather than direct closure. Femoral or central cannulation for cardiopulmonary bypass was used, depending on the circumstances, and, more recently, we have used a combination of femoral and percutaneous superior vena cava cannulation via the right internal jugular vein for heart/lung transplantation in the setting of previous cardiac surgery. Our immunosuppression protocol has been stable since 1997, consisting of a calcineurin inhibitor, mycophenolate mofetil (MMF) and prednisolone. Two (2) transplants performed before this date received prednisolone, azathioprine and cyclosporin. Induction therapy with basiliximab was introduced in 2012. Prior to that, IL-2 receptor blockers were reserved for patients with high panel reactive antibody testing or those at risk of acute renal injury early posttransplant. Diagnosis of rejection was made in accordance with the International Society for Heart and Lung Transplantation (ISHLT) guidelines [10,11]. Surveillance transbronchial biopsies were performed at 3, 6 and 12-weeks post-transplant for all heart2lung and heart2lung2liver patients. Liver and myocardial biopsies were not routinely performed for these patients. Surveillance for heart-kidney transplants involves cardiac biopsy at 126 weeks, 8, 12, 18 and 26 weeks and clinical review every 6 months once clinically stable. Ethics approval was sought and received by the institution’s ethics board. Survival was measured from the date of operation to the date of death or date of analysis (September 2018). Survival analysis was performed for the groups of heart2lung transplant, heart2kidney transplant, and heart2lung2liver transplants. Survival was calculated by the Kaplan2Meier method using the SPSS system, version 25.0 (IBM Corp, Armonk, NY, USA).
Results A total of 37 patients were included in the study, comprising 22 heart2lung transplants, eight heart2kidney transplants and seven heart-lung-liver transplants. There were six
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domino heart transplants performed in this cohort, all of which were performed in the heart2lung2liver group. The mean age at transplant was 37 years (13–62 years) and 51% were male. The mean wait-list time was 10.1 months (0.25–29 months). Heart2lung2liver patients waited longer (16.4 months) compared to heart2lung (5.5 months) and heart2kidney (8.3 months) patients (Table 1). One (1) patient with cystic fibrosis, awaiting heart2lung2liver transplant died on the waiting list.
Heart2Lung Transplant Heart2lung transplant was most commonly performed for congenital heart disease (45%), followed by idiopathic pulmonary arterial hypertension (22.7%) and cystic fibrosis (18%). The remaining indications are listed in Table 2. Two (2) patients underwent redo transplantation, the first patient had undergone heart-lung transplant for Eisenmenger’s syndrome and developed bronchiolitis obliterans syndrome (BOS), and the second patient had undergone bilateral lung transplant and subsequently developed vanishing airways syndrome. A single patient was bridged to transplant with veno-arterial extra-corporal membrane oxygenation (ECMO). The mean organ ischaemic time was 300 minutes (Table 1). Postoperatively,
mechanical support was provided with intra-aortic balloon pump (IABP) in three patients and veno-arterial ECMO in one patient (Table 3). Postoperative morbidity included acute kidney injury in 14 patients (64%) with six (20%) of these patients required dialysis, pericardial effusion (n=2), chylothorax (n=1) and left vocal cord paralysis (n=1). Rejection occurred in five patients (23%), with grade A2 rejection in one patient, BOS in one patient and a single patient developed chronic lung allograft dysfunction (CLAD) requiring re-do bilateral lung transplantation. There were two (9%) early deaths (Table 4). Overall survival at 30-days, 1 year, 5 years and 10 years was 91%, 91%, 79% and 79% respectively (Figure 1).
Heart2Lung2Liver Transplant Heart2lung2liver transplant was performed exclusively in patients with cystic fibrosis with associated cirrhosis and portal hypertension. Domino heart transplant was performed in five out of the seven patients in this group and mean organ ischaemic time was 163 minutes. Complications particular to this group included return to theatre for stenting of a common bile duct anastomotic stricture (n=2), abdominal washout for biliary peritonitis (n=2) and thoracoscopic washout for empyema (n=1). The mean Intensive
Table 1 Baseline characteristics. Variable
All
Heart-Lung
Heart-Lung-Liver
Heart-Kidney
Number
37
22
7
8
Age at transplant (Mean)
38
36
30
47
Male n (%)
19 (51)
10 (45)
5 (71)
4 (50)
BMI
23.1
21.9
20
27.5
LAS INTERMACS Score
21.2 5.5
21.7 5.6
20.8 6.7
N/A 4.3
MELD Score (mean)
8.7
N/A
8.7
N/A
Donor Specific Antibodies
0
0
0
0
A positive
9 (24)
2 (9)
3 (43)
4 (50)
A negative
2 (5)
2 (9)
0
0
O positive
15 (41)
9 (41)
4 (57)
2 (25)
O negative AB
2 (5) 2 (5)
2 (9) 2 (9)
0 0
0 0
B positive
4 (11)
4 (18)
0
0
B negative
1 (3)
1 (5)
0
1 (13)
Waitlist time (months)
10.1
5.5
16.4
8.3
Blood Group
Organ Ischaemic Time (min)
224.3
300
163
210 1 OCS
Pre-transplant ECMO
1 (2.7%)
1 (2.7%)
0
0
Previous sternotomy
5.5 (15%)
9 (41%)
0
2 (25%)
X-clamp time(min) CPB time(min)
103.3 181.5
117.4 227.2
136.7 218.4
55.7 99
Abbreviations: LAS, Lung Allocation Score; ECMO, extra-corporal membrane oxygenation; BMI, body mass index; MELD, model for end-stage liver disease; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; CPB, cardiopulmonary bypass; X-clamp, cross-clamp.
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F.E. Doig et al.
Table 2 Indications for multi-organ transplant. Multi-organ group
Indication for multi-organ transplant
Number of patients
Heart2lung
CHD with PAH
9
PAH with RV Failure
4
CF with RV Failure
2
COPD with RV Failure
2
CF and bronchial sizing issues CF and Vanishing Airways Syndrome
1 1
Histiocytosis X and RV Failure
1
HOCM with RV Failure and Pulmonary Hypertension
1
DCM with RV Failure and PH
1
Heart2lung2liver
CF with associated liver disease
7
Heart2kidney
DCM and cardiorenal syndrome
3
DCM and polycystic kidney disease
1
Peripartum DCM and Acute Tubular Necrosis Ischaemic cardiomyopathy and cardiorenal syndrome
1 1
Ischaemic cardiomyopathy and polycystic kidney disease
1
DCM and glomerulosclerosis
1
Abbreviations: CHD, congenital heart disease; PAH, pulmonary hypertension; RV, right ventricular; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; HOCM, hypertrophic obstructive cardiomyopathy; , DCM, dilated cardiomyopathy.
diagnosed with diffuse B cell lymphoma and subsequently died 3 years post-transplant of chronic lung allograft dysfunction. Other deaths occurred as a result of BOS, pneumonia and a ruptured splenic artery aneurysm (Table 4, Figure 2). Rejection, grade A2, occurred in one patient. This was successfully treated with steroids. No patients required retransplantation. Overall 30-day, 1 year, 5-year and 10-year survival was 86%, 71% 43% and 29% respectively (Figure 1).
Care Unit (ICU) stay and hospital length of stay was 6.7 days and 29.6 days respectively (Table 3). There was a single 30day mortality (14%) at 16 days related to primary graft dysfunction after a period of support with veno-arterial ECMO. A further consideration in this patient was a sizemismatch of the thoracic organs. In long-term follow-up, one patient required a right upper lobectomy for non-small cell lung cancer (NSCLC), was also
Table 3 Postoperative course. Variable
All
Heart2lung
Heart2lung2liver
Heart2kidney 0
ECMO
2 (5%)
1
1
IABP
4 (11%)
3
1
0
Ventilation (hrs)
61.8
68
93.4
23.9
ICU length-of-stay(days) Hospital length-of-stay(days)
7.9 23.8
6.9 20.9
6.7 29.6
10.3 20.9 0
Return to theatre for bleeding
8 (22%)
6 (27%)
2 (29%)
AKI requiring dialysis
7 (19%)
6 (27%)
0
1 (13%)
Transfusion (PRBC)
33 (89%)
19 (86%)
7 (100%)
7 (88%)
Transfusion (Non-PRBC)
30 (81%)
17 (77%)
7 (100%)
6 (75%)
Rejection
10 (24%)
5 (23%)
1 (14%)
4 (50%)
Rejection .A2
2 (5%)
1 (5%)
1 (14%)
0
BOS/CLAD Retransplant
4 (14%) 1 (3%)
2 (9%) 1 (5%)
2 (29%) 0
N/A 0
30-day Mortality
3 (8%)
2 (9%)
1 (14.3%)
0
Abbreviations: BOS, bronchiolitis obliterans syndrome; CLAD, chronic lung allograft dysfunction; PRBC, packed red blood cells; AKI, acute kidney injury; ECMO, extra-corporal membrane oxygenation; IABP, intra-aortic balloon pump.
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Table 4 Mortality following multi-organ transplant. Transplant type
Cause of death
Age at transplant
Time to death
Heart2kidney
Unknown
53
14 years
Heart2kidney
Sepsis, portal vein thrombosis
31
16 years
Heart2kidney
Hypersensitivity vasculitis, fungal lung abscess, UGIH
41
44 days
Heart2lung
Cerebral post-transplant lymphoproliferative disorder
49
3.5 years
Heart2lung
Sepsis
54.6
14.5 years
Heart2lung2liver Heart2lung
Bronchiolitis obliterans syndrome Death on table, unable to wean from CPB
25.4 40.7
3 years 0 days
Heart2lung
Bronchiolitis obliterans syndrome
38.8
4.5 years
Heart2lung2liver
Sepsis (pneumonia)
31
7.5 years
Heart2lung2liver
Primary graft dysfunction
29.1
16 days
Heart2lung2liver
Ruptured splenic artery aneurysm
37.4
5 months
Heart2lung2liver
Chronic lung allograft dysfunction
28.8
3 years
Heart2lung
Multi-organ failure
18
15 days
Abbreviations: UGIH, upper gastrointestinal haemorrhage; CPB, cardiopulmonary bypass.
Heart2Kidney Transplant Indications included idiopathic dilated cardiomyopathy (n=3, 37.5%) followed by ischaemic cardiomyopathy (n=2, 25%), cardiomyopathy secondary to valvular disease (n=2, 25%) and familial dilated cardiomyopathy (n=1, 12.5%). Renal disease included cardiorenal syndrome (n=4, 50%), polycystic kidney
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disease (n=2, 25%), glomerulosclerosis (n=1, 12.5%) and acute tubular necrosis (n=1, 12.5%). Mean donor ischaemic time was 210 minutes and one of the hearts was retrieved using the organ care system (TRANSMEDICSTM, TransMedics Inc., Andover, MA, USA). None of the patients required bridging to transplant with ECMO or ventricular assist devices. One
Figure 1 Kaplan2Meyer survival curve for all multi-organ transplants.
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Figure 2 Kaplan2Meyer survival curve comparing transplant era (pre- and post-2004).
patient returned to the operating theatre for debridement of a sternal wound dehiscence and another patient underwent imaging-guided drainage of a perinephric collection. There was a single inpatient mortality in a patient that developed hypersensitivity vasculitis causing ischaemic colitis and subsequent sepsis in addition to fungal lung abscesses. The mean ICU length of stay was 10.3 days and one patient required dialysis in the postoperative period. Rejection of the cardiac allograft occurred in three patients and in the renal allograft in one patient. No patients required retransplantation. Overall survival was 87.5% at 1 year continuing out to 10 years (Figure 1). The mean cross-clamp time in all patients was 103.3 minutes and cardiopulmonary bypass time 181.5 minutes reflecting the complexity of these cases. Both cross-clamp and bypass times were lowest in heart-kidney transplant, at 55.7 minutes and 99 minutes respectively. Operating times in the heart-lung transplant group may have been skewed due to particularly difficult cases. One (1) case in particular required a total arch replacement in addition to organ transplant. Coagulopathy was an issue for all multi-organ transplants with return to theatre for bleeding in eight patients (22%) and transfusion of packed red blood cells (PRBC) and non-PRBC products in 89% and 81% respectively. There was no statistically significant difference in survival between transplant era
(pre- and post-2004, p=0.865, Figure 2) or following introduction of basiliximab induction (p=0.389, Figure 3).
Discussion Multi-organ transplantation is an uncommon and technically challenging procedure. Heart2lung transplant continues to be the most common multi-organ transplant performed at our institution, with smaller numbers of heart-lung-liver and heart-kidney transplants and we have not performed any lung2liver or lung2kidney transplants. Our review found comparable outcomes for patients operated at The Prince Charles Hospital to international standards. However, the indication for transplant in our unit comprised a greater number of patients with congenital heart disease and a lesser number with cystic fibrosis compared to the International Society of Heart and Lung Transplantation report. Survival following heart2lung transplantation was 91% at 1 year and 71% at 5 years, relating favourably to data from ISHLT which reported survival of less than 75% at 1 year and marginally less than 50% at 5 years, however this does not account for differences in transplant era between the two groups [1]. Similarly, results from the Cleveland Clinic with 82% survival at 1 year and 62% at 5 years are comparable to our cohort of patients [12].
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Figure 3 Kaplan2Meyer survival curve comparing survival pre- and post-introduction of basiliximab induction.
In our experience, we have found that while complications such as acute kidney injury, fluid overload, chylothorax, atrial fibrillation and abdominal complications are not uncommon, sepsis is the most significant contributor to mortality. Cause of death in both the early postoperative period, predominantly multi-organ failure and sepsis, and late period, of bronchiolitis obliterans syndrome, was similar to both the Cleveland Clinic and ISHLT reports. Rates of treated rejection were 23% in our cohort compared to 34% presented by the ISHLT group [1]. Rejection rates were lowest in the heart-lung-liver group followed by the heart2lung group and the heart2kidney group. However, there was a higher rate of bronchiolitis obliterans in the heart2lung2liver group, which differed from a lower rate of BOS in this group of patients from the ISHLT report. Given the possible side effects associated with immunosuppression, it is worth considering whether reduced doses of immunosuppression are feasible in heart2lung2liver transplant patients. Waiting list time for the heart-lung-liver patients was significantly longer compared to the heart2lung and heart2kidney transplants and perhaps consideration should be given to listing these patients earlier given the longer waiting times. Similarly, the issue of organ allocation is more manifest in this group, however the number of domino transplants (six out of seven patients) performed in our cohort goes some way towards justifying the use of a heart2lung2liver bloc, which is technically easier to perform than lung2liver transplant alone.
Complex surgery and prolonged bypass times, with resultant coagulopathy, contribute to a high rate of transfusion and return to theatre. These are not benign issues and have been shown to result in immune suppression, infection and increased mortality. In a patient population already immunosuppressed, this is a concern. The introduction of point of care testing and targeted management of coagulopathy at our institution has contributed to promising improvements in the rate of transfusion and postoperative blood loss [13]. In heart2kidney transplants, bleeding was less of an issue, with no patients returning to theatre for haemostasis. It may be that this reflects reduced bypass times in this group.
Limitations The limitations of this study include the small number of patients included as well as the heterogeneity of the patient group in general. The study is a single institution review of retrospectively collected data. However, patient follow-up was performed well, with only one patient lost to followup after moving overseas at 14 years post-transplant.
Conclusion Multi-visceral transplant remains an important treatment option for often young patients with both multi-organ disease and complex anatomical and physiological challenges for single organ transplant. We have demonstrated the
Please cite this article in press as: Doig FE, et al. Multivisceral Transplant, The Prince Charles Experience. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.10.012
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success of multi-organ transplant in a geographically large country with reasonable ischaemic times and waitlist times for what are still uncommon procedures. Obstacles that remain in this cohort of patients in improving survival are reducing the complications of sepsis and bleeding.
Uncited Reference Q4
[14].
Acknowledgements Q5
There are no conflicts of interest to acknowledge.
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Please cite this article in press as: Doig FE, et al. Multivisceral Transplant, The Prince Charles Experience. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.10.012
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