Eur J Cardiothorac Surg 2007;31:929-933. doi:10.1016/j.ejcts.2007.01.074
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Cardiac arrest in the organ donor does not negatively influence recipient survival after heart transplantation
Ayyaz A. Ali*,
Eric Lim,
Mohan Thanikachalam,
Catherine Sudarshan,
Paul White,
Jayan Parameshwar,
Kumud Dhital,
Stephen R. Large
Department of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, Cambridge CB3 8RE, United Kingdom
Received 14 September 2006;
received in revised form 5 January 2007;
accepted 15 January 2007.
* Corresponding author. Address: Department of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, Cambridge CB3 6DS, United Kingdom. Tel.: +44 1480 830 541; fax: +44 1480 831 540. (Email: ayyaz75{at}gmail.com).
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Abstract
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Objective: Cardiac arrest in the organ donor raises concerns about the possibility of ischemic cardiac damage. We evaluated the outcome of heart transplantation in patients receiving an organ from donors who had suffered a period of cardiac arrest. Methods: Demographics, operative details and outcome data were obtained retrospectively. Actuarial survival was reported using Kaplan–Meier analysis and compared with the log rank test. Cox proportional hazards regression was used to model risk adjusted survival. Results: Between 1 January 1991 and 1 November 2004 38 patients were transplanted with hearts from multiorgan donors who were resuscitated after a cardiac arrest. The mean (standard deviation) duration of cardiac arrest was 15 (8) min. The interval between donor cardiac arrest and organ excision was 69 (5) h. The 30-day mortality was 2.6% (1/38). In the same interim 566 patients underwent cardiac transplantation with hearts from organ donors without a cardiac arrest. Median time to follow up was 61 months (IQR 15–166). One and 5-year survival comparing the arrest and non-arrest groups was 94.2% versus 83.6% and 79.8% versus 74.5%, respectively, p
= 0.35. Donor cardiac arrest was not an adverse predictor of mortality on multivariate analysis, the adjusted odds ratio was 0.86 (95% CI 0.60–1.25, p
= 0.42). Conclusions: With careful case selection, there was no evidence that survival after cardiac transplantation was worse following a period of cardiac arrest in the organ donor. A history of cardiac arrest in the organ donor should not exclude an organ from being considered for transplantation.
Key Words: Heart transplantation • Organ donor • Cardiopulmonary arrest
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1. Introduction
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A small but important proportion of organ donors suffer cardiac arrest, either in relation to their terminal event or in association with their subsequent management and treatment. Cardiopulmonary resuscitation can restore cardiac function in these donors, often with a return to hemodynamic stability. The dilemma in this situation is whether the heart should still be considered for transplantation. Depending on the length of cardiac arrest, there are obvious concerns about cardiac ischemia leading to significant myocardial injury. Considering that the organ must then endure a substantial period of ischemia associated with excision and storage, the possibility of post-transplant organ dysfunction in the recipient is a genuine concern. The impact of a period of donor cardiac arrest on post-transplant cardiac function is unknown. We have evaluated the outcome of heart transplantation in patients receiving an organ from donors who had been resuscitated following a period of cardiac arrest.
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2. Methods
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We performed a retrospective review of patients in our institution who underwent cardiac transplantation using hearts from donors who had been resuscitated following cardiac arrest. In order to ascertain the impact of this event on outcome following heart transplantation, we compared early and late survival to patients who underwent heart transplantation with an organ from a donor without a history of cardiac arrest. Demographic, operative and mortality data were obtained from individual hospital notes and standard donor-log information forms used by our transplant coordinators. Recipients had been previously placed on the waiting list for cardiac transplantation after fulfilling a comprehensive transplant evaluation protocol.
Baseline characteristics were presented as means ± standard deviation (SD) or medians with interquartile ranges (IQR) for normally and non-normally distributed measures, respectively. Patients were grouped according to whether they received an organ from a donor with or without a history of cardiac arrest and dichotomous outcome compared using 
2 or Fisher's exact text. Actuarial survival was calculated using Kaplan–Meier product limit method and compared with the log rank test. Cox proportional hazards regression was utilized to determine risk adjusted survival. Statistical analyses were performed on S Plus Version 6.0 (Insightful, Washington, USA).
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3. Results
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Between 1 January 1991 and 1 November 2004, 38 patients were transplanted with hearts from multi-organ donors who were resuscitated after a cardiac arrest. The mean (SD) duration of cardiac arrest was 15 (8) min. The interval between donor cardiac arrest and organ excision was 69 (5) h. In no instances was the heart procured immediately after cardiac arrest. In the same interim, 566 patients underwent cardiac transplantation with hearts from organ donors without a history of cardiac arrest. There was no difference between groups with regards to recipient age or sex. Arrested organ donors however, were significantly younger than non-arrested organ donors (arrest 29 ± 12 years vs non-arrest 35 ± 13 years, p
= 0.003). There were a variety of causes of death for the arrested donor group (Table 1
). There were no differences between the two donor groups in overall duration of brain death or in the interval between diagnosis of brainstem death and application of donor cross clamp and organ excision. The duration of intubation for arrested organ donors was significantly longer (Table 2
). Overall total ischemic times for organs from both donor groups were similar. There was a trend towards a greater inotropic requirement for donors suffering cardiac arrest compared with donors without cardiac arrest (arrested 79% vs non-arrested 65%, p
= 0.077). The 30-day mortality for recipients receiving an organ from an arrested donor was 2.6% (1/38). In recipients of an organ from a non-arrested donor this figure was 8.0% (44/566), this difference did not reach statistical significance (p
= 0.230). The single death in the arrested organ recipient group was from donor organ dysfunction.
Median time to follow up was 61 months (IQR 15–166). One and 5-year survival comparing the arrest and non-arrest groups was 94.2% versus 83.6% and 79.8% versus 74.5%, respectively (p
= 0.35, Fig. 1
).
There were no significant differences between the two recipient groups in terms of postoperative outcomes. Specifically, there was no greater requirement for additional circulatory support with an intra-aortic balloon pump or mechanical assist device in recipients receiving an organ from an arrested donor. The incidence of respiratory failure, renal dysfunction and gastrointestinal complications was not statistically different. Importantly, there was no difference in the frequency of donor organ failure in patients receiving an organ from donors with a history of cardiac arrest (Table 3
).
Using Cox proportional hazard survival regression analysis, the following were identified as adverse prognostic factors: donor age (p
= 0.001), postoperative renal (p
= 0.001) and respiratory failure (p
= 0.001), gastro-intestinal complications (p
= 0.001) and the requirement for postoperative circulatory support with an intra-aortic balloon pump (p
= 0.001) or ventricular assist device (p
< 0.001, Table 4
). Multivariable analysis confirmed the following as independent predictors of mortality: donor age (p
= 0.007), need for post-operative support with a ventricular assist device (p
< 0.001), renal failure (p
< 0.001) and respiratory failure (p
< 0.001). Donor cardiac arrest was not an adverse predictor of mortality on multivariable analysis, the adjusted hazard ratio for mortality was 0.86 (95% CI 0.60–1.25, p
= 0.42, Table 5
).
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4. Discussion
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We sought to determine whether an episode of cardiopulmonary arrest in the cardiac organ donor had any impact on early mortality or long-term outcome in recipients transplanted with hearts procured from these donors. We were unable to identify any differences in either 30-day mortality or overall survival between recipients of hearts with or without a donor history of cardiac arrest. Furthermore, there did not appear to be any difference in the frequency of important postoperative complications such as donor organ dysfunction, the need for mechanical circulatory support, renal failure, respiratory failure or the development of gastrointestinal complications. A period of cardiac arrest in the organ donor prior to cardiac procurement did not appear to have any negative influence on the postoperative course or clinical outcome following heart transplantation.
There continues to be a steady decline in the number of donor organs available for transplantation [1,2]. This is particularly true for heart transplantation where the number of transplants has decreased dramatically over the past decade. The scarcity of suitable organs demands that we carefully evaluate all potential donor organs, resuscitating them optimally and basing a decision on whether a heart is suitable for transplantation on firm hemodynamic data [1]. The current climate in organ transplantation has led to a greater interest in evaluating and resuscitating ‘borderline’ donor organs. Such organs are not functioning optimally but are felt to be amenable to resuscitation with the scope for functional improvement. We have demonstrated that heart transplantation using such organs does not lead to a significantly increased risk of mortality in the recipient [3]. Donors that have suffered a period of cardiopulmonary arrest are often approached with caution. There are concerns that cardiac arrest may result in irreversible ischemic cardiac damage rendering the heart unsuitable for transplantation. However we have demonstrated in this study that many such donors can be resuscitated from such an arrest with subsequent normalization of hemodynamic parameters.
An appreciation of the impact of ischemia-reperfusion injury [4–6] on myocyte function is necessary to understand our findings. Our current practice of organ preservation and storage has been based on the natural course of events that follow the interruption of blood supply to the myocardium. The myocardial threshold for reversibility of hypoxic ischemic injury has been the subject of extensive investigation [6,7]. Limited periods of ischemia can be tolerated and the resulting injury from such short-lived insults is known to be reversible [4]. This process of ischemic tolerance by virtue of cellular adaptation is also referred to as ischemic preconditioning. The exact period at which ischemia leads to permanent cellular injury culminating in cell death is unclear, but it is believed that this duration may be longer than previously suspected [7]. Following ischemic and hypoxic injury, the heart immediately enters a hypocontractile state. The underlying metabolic processes however, seem to remain viable [8,9] with the potential to regain normal contractile function upon timely restoration of perfusion and oxygenation [10]. When this reduction of coronary blood flow is severe or prolonged, as in cardiopulmonary arrest, abnormalities of cellular function develop [11,12] with the consequence of depleted cellular energy stores and eventual cell death and necrosis. Half the myocardial adenosine triphosphate (ATP) content is depleted within 10 min following the onset of ischemia [4,5]. In this state, the ability to replenish ATP is markedly impaired as myocytes shift to an anaerobic and therefore, less efficient means of ATP production. Once a critical period of ischemia is exceeded, a subsequent reperfusion of the myocardium leads to further cell damage without possibility of recovery. This reperfusion injury is related to the generation of toxic oxygen-free radicals, imbalance in ionic homeostasis, disturbance of cell volume regulation and impairment of cell membrane and gap-junction integrity [12].
However, if the myocyte is reperfused at an early stage, before the onset of irreversible damage to subcellular organelles, it can recover function over a period of time [4]. During this recovery period, cardiac function is transiently impaired due to the phenomenon of myocardial stunning where contractile proteins become less responsive to calcium [10,11]. In the context of organ donation it needs to be remembered that ischemic injury may be compounded by the deleterious effects of brain stem death. Brain stem death leads to a massive surge in circulating catecholamines which is known to have important negative consequences for myocardial function [13–16].
We were unable to demonstrate any differences between the two groups in either early or late survival. The 30-day mortality and 1- and 5-year survival were not significantly different. It may be reasonable to assume that myocardial stunning following cardiac arrest may result in an increased incidence of donor organ dysfunction following transplantation. Only one patient who received an organ from an arrested donor developed this complication. This patient subsequently died as a result. Interestingly, this heart was procured from a donor in whom the duration of cardiac arrest was short at only 3 min. The mean duration of arrest in donors who required cardiopulmonary resuscitation (CPR) was 15 min. This time includes the initial period when it was established that cardiac output was absent, as well as the duration of resuscitative measures. Arrest times as long as 40 min were recorded in our arrested donor population. Even in instances of such prolonged arrest and resuscitation cardiac output was restored and hemodynamic stability was achieved, albeit in some instances aided by inotropic support. There was a trend towards an increased requirement for inotropes in donors requiring CPR, although this did not affect outcome. Three CPR donors were hanging victims and had been asystolic at the scene for an indeterminate period of time. After arrival of emergency staff these donors were then resuscitated until cardiac output was restored. In this group of donors the true duration of cardiac arrest is likely to have been quite prolonged. Recipients of hearts from these three donors did not develop any complications and had an unremarkable postoperative course. This suggests that a substantial duration of cardiac arrest may well be tolerated by the donor heart without the development of any irreversible injury. Both groups were similar with respect to the total intubation time and the time interval from the confirmation of brain stem death to procurement. The arrested donors were significantly younger than those donors who did not suffer cardiac arrest. We analyzed the frequency of important postoperative complications but were unable to document any statistically important differences between groups. A similar percentage of patients in both groups required temporary circulatory support with an intra-aortic balloon pump. No patient who received a heart from an arrested organ donor required a ventricular assist device (VAD) for formal circulatory support following transplantation. Nine (1.6%) recipients of a non-arrested donor organ required mechanical circulatory support with a VAD. The frequency of complications developing within other organ systems such as renal and respiratory failure as well as gastrointenstinal complications was similar.
At the current point in time we are at a crossroads in heart transplantation. A constant and progressive decline in donor organ availability is beginning to seriously curtail its viability as a treatment option for end-stage heart disease. If this disturbing trend continues, it will become increasingly difficult to extend this surgical treatment to patients with severe heart failure. This realization has led us to focus our efforts on evaluating and resuscitating the ‘borderline’ donor heart. We have already demonstrated that hearts with less than optimal function in the organ donor, can be resuscitated, procured and transplanted without a negative impact on mortality [3]. Our policy is to rely on data obtained through Swan-Ganz measurement of cardiac function and hemodynamics to aid us in determining whether an individual heart may be suitable for transplantation. A final decision on suitability is only made after the donor has been optimally resuscitated. Finally, the realization that cardiac arrest, provided that it is not excessively long, can be tolerated by the organ donor may have some important implications. Non-heart beating donors are a source of organs for hepatic, renal and more recently lung transplantation [17–19]. It has previously been assumed that due to cardiac arrest in the non-heart beating donor the heart would be unsuitable for transplantation. We have demonstrated that cardiac arrest in the organ donor can be tolerated. With this realization it is conceivable that under controlled circumstances and with appropriate resuscitation, cardiac donation from non-heart beating donors may be feasible. This may represent a means for increasing the number of donor hearts in the future.
In conclusion with careful case selection, there was no evidence that survival after cardiac transplantation was worse following a period of cardiac arrest in the organ donor. A history of cardiac arrest in the organ donor should not exclude an organ from being considered for transplantation.
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Appendix A
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Conference discussion
Dr G.V. Gonzalez-Stawinski (Cleveland, OH, USA): When you look at the literature, particularly in lung transplantation, and you read about Stein's experience associated to using non-beating-heart donors for lung transplantation, it is clear that one of the major hurdles to using that particular strategy was overcoming social and ethical barriers to that technique. I commend you on using this particular type of strategy in hopes of increasing the donor pool.
But my question has more to do with regards of the ethical or social barriers that you have encountered prior to instituting such a protocol. In our own state or region where we do transplantation it is considered a crime even to use organs from non-beating donors for lung transplantation. So you could imagine if we were to try this type of technique in our own region, we would actually be sued.
So, giving that little piece of introduction, what type of social and ethical barriers did you have to overcome and how did you overcome them prior to the institution of this particular protocol?
Dr Ali: Actually, these were not true asystolic donors; therefore, we did not encounter any of the ethical considerations that you would do with asystolic donors. These were brain stem dead cadaveric donors who had suffered cardiac arrest, either in relation to their terminal event or during their subsequent hospital management. Following cardiac arrest they were resuscitated and their hemodynamic parameters returned towards normal. So in terms of consent and related issues, we proceeded with the standard protocols for consent for brain-stem dead heart beating cadaveric donation. Of course, with regards to true asystolic donation, there would be considerable ethical issues regarding restoration of heart beat following asystole.
Dr A. Murday (Glasgow, United Kingdom): I wanted to ask about the issue of how long you could allow an arrest to happen to these donors and still accept the organ. Do you have data from those donors over that long period of time that has not been accepted, where the main reason has been because of a prolonged period of cardiac arrest?
And in the middle of night, you know how it is, there can be one of six surgeons, perhaps, accepting or declining an offer, and sometimes it will be a whole mixture of things, part of which will be the fact that the donor has had an arrest sometime in the preceding history. What is your feeling from all those organs that have been declined, and how much does arrest of the donor play a part in that decision?
Dr Ali: Unfortunately, I do not have information relating to how many organs we actually declined on the basis of cardiac arrest. I did try to look into that, but due to the retrospective nature of the data collection it was quite difficult to ascertain the exact cause of why an organ was not accepted in some reasons.
In terms of those that we do select, when we select an organ we do so based on invasive hemodynamic measurements following Swan-Ganz catheterization. So even if there is an arrest period of 25 or 30 min, if the consultant reviewing the donor offer feels that it is appropriate to assess the organ we would attend the donor. In our case of the 38 donors in our study, 27 of them had hemodynamic data which we eventually used to make the decision as to whether or not we should take the organ.
In terms of how long resuscitation can be allowed to go on, I think it is unclear, but past the half hour mark would certainly be concerning for most people. And it depends, of course, on the quality of resuscitation measures.
Dr D. Loisance (Creteil, France): Thank you for raising this issue, because actually your paper is extremely provocative. And at the Program Committee we have been wondering a lot about the opportunity to get the paper presented.
The reason is that, obviously, at Papworth, you are extremely careful in the donor selection. You are now clearly talking about hemodynamic data to make the difference between the good donor and the marginal donor. And, obviously, because of that, what you call a marginal donor because of cardiac arrest is not the marginal donor. So your paper, down the road, may be extremely confusing because your conclusion might be extrapolated to really bad and poor donors. So we have to be very careful.
And personally, I would love very much some change in your conclusion. You are saying with careful case selection you have to be much more precise and give really your feeling about your donor selection process, which is not accepted everywhere throughout the world.
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Footnotes
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\#9734; Presented at the joint 20th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 14th Annual Meeting of the European Society of Thoracic Surgeons, Stockholm, Sweden, September 10–13, 2006.
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Abstract
1. Introduction
