Download Ex vivo perfusion of the heart with the use of the Organ Care System

EDITORIAL
European Journal of Cardio-Thoracic Surgery 49 (2016) 1318–1320
doi:10.1093/ejcts/ezw075
Cite this article as: Leprince P, Popov AF, Simon AR, Benk C, Siepe M. Ex vivo perfusion of the heart with the use of the Organ Care System. Eur J Cardiothorac Surg
2016;49:1318–20.
Ex vivo perfusion of the heart with the use of the Organ Care System
Pascal Leprincea, Aron Frederik Popovb, Andre R. Simonb, Christoph Benkc and Matthias Siepec,*
a
b
c
Department of Thoracic and Cardiovascular Surgery, Pitié-Salpêtrière Hospital, University Pierre et Marie Curie, Paris, France
Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital,
Harefield, UK
Department of Cardiovascular Surgery, Heart Centre Freiburg University, Freiburg, Germany
* Corresponding author. Department of Cardiovascular Surgery, Heart Centre Freiburg University, Hugstetter Str. 55, 79106 Freiburg, Germany.
Tel: +49-761-2117046; e-mail: [email protected] (M. Siepe).
Keywords: Ex vivo perfusion • Heart transplantation • Donor conditioning • Donation after circulatory death • Organ Care System
Although cardiac transplantation remains the gold standard surgical treatment for end-stage heart failure and many efforts have
been made on donor selection, recipient care and immunosuppression treatment, cardiac graft preservation is still based on cold
ischaemic storage. It is well demonstrated that the duration of
cold ischaemia negatively impacts the outcome of transplanted
patients and thus can adversely affect organ use.
During the last decade, attempts were made to perfuse withdrawn organs. The use of a kidney perfusion machine is routine in
case of a cardiac arrested donor with the aim not only to decrease
ischaemic time but also to assess the quality of the organ. Similarly,
in the field of lung transplantation, ex vivo perfusion allowed a
wider use of organs by efficiently resuscitating marginal lungs.
Regarding cardiac transplantation, the only ex vivo perfusion device
available is the Organ Care System (OCS) from Transmedics. The
OCS is a sophisticated, portable platform designed to perfuse a
withdrawn heart with warm, oxygenated, nutrient-enriched donor
blood. The concept of OCS is to stabilize the perfusion of the
cardiac graft as assessed through the mean aortic pressure and coronary blood flow before transporting it towards the cardiac transplantation centre. Furthermore, adequate perfusion is assessed by
comparing inflow and outflow serum lactate concentrations,
ending with the decision not to use the organ if cardiomyocyte metabolism remains anaerobic, which highlights an ongoing ischaemic
process despite perfusion.
In a prospective, non-randomized, single institutional clinical
study, Koerner et al. [1] reported a better outcome in terms of 1and 2-year survival rates, primary graft failure and acute cellular rejection rate in low-risk cardiac transplant patients transplanted with
non-marginal donor hearts if the organ was perfused with warm
blood (n = 29) in comparison with cold ischaemic storage (n = 130).
The PROCEED II trial was designed to assess such a clinical comparison in a randomized study [2]. One hundred and thirty patients
were assigned to either OCS (n = 67) or to standard cold storage
(n = 63). Only non-marginal donors were included. The 30-day
patient (as well as graft) survival was similar in both groups (OCS:
94%; cold storage: 97%), concluding in non-inferiority in the OCS
group in an intention-to-treat population, because, in both groups,
some patients were excluded, or cross-over, as-treated as well as
per-protocol analyses were performed and did show similar findings. Moreover, secondary end-points (i.e. intensive care unit stay
and cardiac adverse event rates) did not significantly differ between
groups. Interestingly, in the OCS group, five cardiac grafts were
deemed unacceptable for transplantation while on the OCS and
were thus discarded. One of these hearts could not be connected
to the OCS because of frailty of the aorta related to connective
tissue disorder and another one showed a significant aortic regurgitation which resulted in inability to stabilize aortic perfusion pressure. The first heart could have been perhaps successfully used with
standard cold storage and the second one could have been diagnosed with aortic regurgitation on donor transoesophageal echocardiography and used with concomitant aortic valve replacement.
On the other hand, three hearts were discarded because of high
lactate concentration. Histopathological exam of those hearts
showed significant myocardial contusion in one and myocardial
scarring and necrosis compatible with cocaine use in another.
These lesions could have led to cardiac graft dysfunction. Indeed, it
was shown by Hamed et al. [3], based on the early global experience with the OCS, that elevated ending lactates was a powerful
predictor of graft failure. Finally, the third heart with elevated lactates was diagnosed with myocardial hypertrophy that was overlooked by the harvesting team. The conclusion of this trial
remained humble and stated that cardiac graft preservation with
OCS yielded a similar clinical outcome to cold storage. Moreover, it
is interesting to note that even if the mean total preservation time
was significantly longer for OCS grafts (324 min) in comparison
with cold storage (195 min), this did not negatively affect patient
outcome. This is in favour of the efficiency of the OCS for long-term
organ preservation.
The other obvious advantage of the ex vivo perfusion of donor
hearts is the extension of the donor pool and acceptance of marginal donors. Therefore, a registry was initiated in Germany in
order to compare marginal donors procured with the use of the
OCS with normal hearts receiving standard of care in a prospective observational and non-randomized fashion. Seven centres
agreed to the protocol which comprises the following extended
donor criteria with subsequent use of the OCS: age between 55
and 65, a reduced left ventricular (LV) function (left ventricular
© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
1319
EDITORIAL
P. Leprince et al. / European Journal of Cardio-Thoracic Surgery
Figure 1: (A) The transport unit of the Organ Care System (Transmedics) with ex vivo perfusion of a porcine heart. The ascending aorta is connected to an artificial circulation circuit filled with donor blood. An inserted oxygenator ensures gas exchange. During warm pump run with controlled perfusion pressure and flow, the heart
function is assessed visually together with haemodynamic and laboratory parameters. (B) The heart is connected to the perfusion line with a connector at the ascending aorta (*). A venous return cannula (#) is placed into the right ventricle via the pulmonary artery with the caval veins being closed. The left ventricle is vented additionally (§). Photos courtesy of Transmedics.
ejection fraction > 30 and <50%), coronary one-vessel disease, significant but not detrimental catecholamine support, moderate LV
hypertrophy (>13 and <17 mm) and/or distance resulting in an
expected warm ischaemic time >180 min. This Germany registry
was introduced in 2013. During that time, organ donation experienced a significant decrease in Germany for various reasons.
Whatever the reason, the acceptance of using the OCS for marginal donors by the study centres was low and only very few transplantations with the use of the OCS were performed with only 18
OCS-using transplantations over one and a half years. The study
has been ongoing since February 2015 in order to investigate the
intermediate results in those few cases in the four OCS-using
centres. So far, we can conclude from this German OCS registry
that there is need for adequate exposure to the technology with a
reasonable number of transplants performed by the local teams
using the technology in order to allow broad acceptance and safe
use in marginal donors.
In the UK, as in the most European countries, a recent annual decrease in heart transplants has been observed. In 2011, there were
131 heart transplants in an overall estimated population in the UK
of 64 million [4]. Notwithstanding subsequent attempts to increase
numbers, the annual number of heart transplants remained low in
relation to the population of the UK. Following approval of the OCS
Heart System for clinical use, the Harefield group implemented the
system in 2011 to overcome donor shortage and declining number
of heart transplants. The OCS Heart System was initially employed
for geographically distant donors with consequent longer ischaemic time deemed prohibitive for traditional (icebox) donor runs.
Subsequently, the system was also utilized for high-risk recipients
[e.g. redo operation, left ventricular assist device (LVAD) in situ or
infected LVADs] where prolonged dissection/ischaemic time was
expected. Following 30 heart transplants using the OCS Heart
System, the Harefield group published their initial experience and
showed that the use of the OCS Heart System was associated with
markedly improved short-term outcomes and transplant activity by
allowing use of organs previously deemed unsuitable for transplantation or by selection of higher-risk recipients, or both [5].
In the wake of these promising results, routine use of the OCS
Heart System was incorporated into institutional clinical practice.
So far, the Harefield group has transplanted more than 60 donor
hearts with the OCS Heart System, reflected by the increased
number of heart transplantations in the UK in 2014 to n = 198 [1].
Notably, the Harefield group documented improved outcomes
with use of the OCS Heart System, particularly in patients with
LVAD [6].
With ongoing experience, the Harefield group established an
animal model of ex vivo heart perfusion after cardiocirculatory
death. They demonstrated that hearts from non-heparinized donation after circulatory death (DCD) porcine donors can be successfully resuscitated using the OCS Heart System in a scenario
that closely simulates clinical conditions [7]. A research group from
Brussels uses a different device for ex vivo perfusion in an animal
model of DCD with similar results [8]. Other groups reported
ex vivo perfusion even in small animal models using a self-made
device [9, 10]. Concurrently, an Australian group showed in a
porcine orthotopic heart transplant model that DCD porcine
donors was successful only when the OCS Heart System was used
instead of cold storage with Celsior solution after a 30-min warm
ischaemic time [11]. The group from Sydney was also the first in
the world using the OCS in DCD in a clinical scenario with remarkable success [12].
These experiences and promising results from animal studies
led to the first human DCD (non-heart beating) heart transplantation in Harefield hospital in 2015 with the use of the OCS Heart
System (Fig. 1).
CONCLUSION
With our considerable combined experience, the authors believe
that the ex vivo perfusion of the heart is able to enhance viability
of donor organs by reducing time-dependent ischaemic injury.
Also, the unique opportunity to assess the function of the organ ex
vivo and enable resuscitation of the organ and potentially improve
function following procurement will increase the donor pool and
potentially increase the numbers of successful heart transplants in
the near future. However, there is a need for proper experience
with this new technology and a reasonable number of cases to
1320
P. Leprince et al. / European Journal of Cardio-Thoracic Surgery
allow safe use of the OCS system in a transplant programme. Of
course, further trials will be indispensable to show that the OCS
type of system cannot only be used safely but can also significantly
improve the preservation of cardiac grafts from non-marginal
donors as well as help to screen for non-suitable organs.
[6]
[7]
Conflict of interest: none declared.
[8]
REFERENCES
[1] Koerner MM, Ghodsizad A, Schulz U, El Banayosy A, Koerfer R, Tenderich
G. Normothermic ex vivo allograft blood perfusion in clinical heart transplantation. Heart Surg Forum 2014;17:E141–5.
[2] Ardhali A, Esmailian F, Deng M, Soltesz E, Hsich E, Naka Y et al. Ex-vivo
perfusion of donor hearts for human heart transplantation (PROCEED II): a
prospective, open-label, multicentre, randomised non-inferiority trial.
Lancet 2015;385:2577–84.
[3] Hamed A, Tsui S, Huber J, Lin R, Poggio EC, Ardehali A. Serum lactate is a
highly sensitive and specific predictor of post cardiac transplant outcomes
using the Organ Care System. J Heart Lung Transplant 2009;28:S71.
[4] NHS Blood and Transplant. Organ Donation and Transplantation, Activity
Report 2013/2014. https://nhsbtmediaservices.blob.core.windows.net/
organ-donation-assets/pdfs/activity_report_2013_14.pdf (8 December
2015, date last accessed).
[5] García Sáez D, Zych B, Sabashnikov A, Bowles CT, De Robertis F, Mohite
PN et al. Evaluation of the organ care system in heart transplantation
[9]
[10]
[11]
[12]
with an adverse donor/recipient profile. Ann Thorac Surg 2014;98:
2099–105.
García Sáez D, Zych B, Mohite PN, Sabashnikov A, Patil NP, Popov A et al.
LVAD bridging to heart transplantation with ex vivo allograft preservation
shows significantly improved: outcomes: a new standard of care? J Heart
Lung Transplant 2015;34:S95.
García Sáez D, Elbetanony A, Lezberg P, Hassanein A, Bowles CT, Popov AF
et al. Ex-vivo heart perfusion after cardiocirculatory death: a porcine
model. J Surg Res 2015;195:311–4.
Van Caenegem O, Beauloye C, Bertrand L, Horman S, Lepropre S,
Sparavier G et al. Hypothermic continuous machine perfusion enables
preservation of energy charge and functional recovery of heart grafts in an
ex vivo model of donation following circulatory death. Eur J Cardiothorac
Surg 2016;49:1348–53.
Tolboom H, Olejníčková V, Reser D, Rosser B, Wilhelm MJ, Gassmann M
et al. Moderate hypothermia during ex vivo machine perfusion promotes
recovery of hearts donated after cardiocirculatory death†. Eur J
Cardiothorac Surg 2016;49:25–31.
Tolboom H, Makhro A, Rosser BA, Wilhelm MJ, Bogdanova A, Falk V.
Recovery of donor hearts after circulatory death with normothermic
extracorporeal machine perfusion. Eur J Cardiothorac Surg 2015;47:
173–9.
Iyer A, Gao L, Doyle A, Rao P, Cropper JR, Soto C et al. Normothermic ex
vivo perfusion provides superior organ preservation and enables viability
assessment of hearts from DCD donors. Am J Transplant 2015;15:371–80.
Dhital KK, Iyer A, Connellan M, Chew HC, Gao L, Doyle A et al. Adult heart
transplantation with distant procurement and ex-vivo preservation of
donor hearts after circulatory death: a case series. Lancet 2015;385:
2585–91.