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a Department of Cardiovascular and Thoracic Surgery, Loma Linda University Children's Hospital, Loma Linda, California
b Department of Pediatrics, Loma Linda University Children's Hospital, Loma Linda, California
Accepted for publication March 20, 2009.
* Address correspondence to Dr Bailey, Loma Linda University Children's Hospital, 11234 Anderson St, Loma Linda, CA 92354 (Email: lbailey{at}llu.edu).
Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Methods: For the study group institutional and UNOS databases (July 2000 to December 2008) were reviewed to examine outcomes of pediatric heart transplantation using donor hearts that had been previously refused one or more times because of organ quality. Variation between outcomes of this cohort and recipients who received primarily offered heart grafts in a single institution was analyzed.
Results: In 29 recipients, transplantation or retransplantation was with heart grafts previously declined on the basis of quality. Recovery distances (p < 0.002) and graft cold ischemic times (p < 0.001) were significantly longer for declined hearts. Operative survival was 93% ± 5.0% (27 of 29). Seven-year actuarial survival was 74% ± 10.5%. At the present time, 24 of the 29 recipients (83%) are alive. These results do not vary statistically from those experienced by 84 recipients of 86 primarily offered donor organs during the same time.
Conclusions: Despite longer distance recovery (ie, longer graft cold ischemic times), outcomes of pediatric heart transplantation using donor heart grafts refused on the basis of organ quality are highly competitive. Pediatric donor hearts should seldom be declined on the basis of organ quality (UNOS code 830).
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Although attempting to increase the absolute number of pediatric donors is laudable and must be encouraged, it is equally vital for transplant center personnel to use as many of the organs as possible that do become available. Yet, this does not always appear to be the case in the United States, a point highlighted by UNOS data. Of 6000 potential pediatric donor hearts offered to transplant centers for consideration between July 2000 and November 2008, 3943 (65.7%) were actually used (Fig 1). It is this gap between donor hearts that are made available to centers and those that are actually used for transplantation that is the subject of this report. Why are these donor hearts unacceptable? What are the recipient outcomes of transplantation using previously declined donor organs? The present study was designed to help answer this second question in an attempt to shed some light, if indirectly, on the first.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Three markers of potential graft morbidity listed under code 830 that might regularly apply to infants and children were assessed. These variables included (1) cause of death, (2) cardiac arrest with cardiopulmonary resuscitation (CPR), and (3) use of high-dose vasopressors. For the purposes of this report, high-dose pressors were defined as dopamine or dobutamine, or both, exceeding 5 µg/kg/min; epinephrine or norepinephrine, or both, exceeding 0.05 µg/kg/min, or any combination of two or more of these pressor agents. Also evaluated were graft-specific data, including percentage of fractional shortening, ejection fraction, graft cold ischemic time (minutes), and donor point of origin (local vs nonlocal organ procurement organization [OPO]). Fractional shortening and ejection fraction data were the most recent values obtained before organ recovery.
Recipients were divided into two groups. Group A consisted of those who had initial or repeat transplantation with donor hearts offered primarily. Group B recipients were those whose donor hearts were accepted and used after being refused by one or more transplantation centers on the basis of UNOS code 830. Recipient outcomes for both groups were evaluated and compared in terms of need for mechanical circulatory support, need for a temporary or permanent pacemaker, postoperative days of mechanical ventilation, days in the hospital, operative death from primary graft failure, operative death from all other causes, late death from all causes, and survival. In addition, donor hearts primarily offered to the LLU pediatric transplant program and then refused on the basis of organ quality (code 830) during the study were evaluated in terms of number, ultimate OPO disposition, and final outcomes.
Pertinent Transplantation Techniques
Recipient primary and repeat transplantation procedures were facilitated by the use of systemic hypothermia (20°C) and reduced bypass flow rates (20 to 40 mL/kg/min). Cavocaval attachments were used in all but the neonates and smallest infants. Graft reperfusion and the recipient rewarming process were extended, in every instance, to a minimum of 60 minutes before separation from extracorporeal circulation.
Donors (depending on size) were given 10 to 25 mg/kg of intravenous methylprednisolone and 5 to 20 mL of 50% dextrose intravenously every 15 minutes until actual graft recovery. Donor heart recovery was enabled by the use of a single dose of cold crystalloid cardioplegia. Modified Roe's solution (Table 1) was used, delivering (by gravity) approximately 250 mL through infant grafts and 500 mL through hearts obtained from older children and adolescents. Hearts were transported in ice-cold 5% dextrose in normal saline. No additional coronary perfusion was used until completion of the aortic anastomosis and release of the aortic cross-clamp.
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Results |
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Donor causes of death included anoxia in 21, cerebrovascular in 7, brain tumor in 1, head trauma in 50, and other causes in 7. CPR was required in 30 donors (36%), and 37 (43%) were being managed with one or more high-dose vasopressors when the offer to LLU was made. Graft cold ischemic time averaged 289 minutes (range, 98 to 627 minutes). One Legacy (Los Angeles/Inland Empire, CA) OPO recovered 28 donor hearts, and the rest were from other OPOs from as far away as Florida and Pennsylvania.
Four recipients required postoperative ECMO of variable duration. Each of these 4 donor grafts exhibited normal function by echocardiography before recovery. This recipient group spent a median 1 day (range, 0 to 85 days) on mechanical ventilation and a median 13 days (range, 2 to 85 days) in the hospital after the transplantation.
Group B
One recipient initially underwent transplantation as a member of group A, but then had repeat transplantation as a group B member. The median age of recipients was 1.5 years (range, 17 days to 17.5 years), and median weight was 8.7 kg (range, 3.3 to 84 kg). The median donor-recipient age ratio was 1.3 (range, 0.02 to 7.8), and the weight ratio was 1.3 (range, 0.8 to 1.9). Median time waiting for transplantation was 25 days (range, 1 to 317 days). UNOS status was 1A in 14 (48%), 1B in 6 (21%), and 2 in 9 (31%). ECMO support was required in 1 of the 14 status 1A recipients (7%), and despite a donor graft with normal prerecovery function, was continued postoperatively until pulmonary edema cleared.
The causes of donor death included anoxia in 14, brain tumor in 1, head trauma in 9, and other causes in 5. Cardiac arrest resulting in CPR occurred in 13 donors (45%). High-dose vasopressors were in use at the time of donor offer among 12 (41%). One of the donor hearts was recovered through One Legacy OPO, and 28 were recovered through other OPOs from as far as New Jersey and North Carolina. Donor hearts used in group B recipients had been refused by other transplant centers on the basis of UNOS code 830 an average 3.2 times (range, 1 to 29). Graft cold ischemic time averaged 384 minutes (range, 195 to 624 minutes). Recipients required a median 1 day (range, 0 to 34 days) of mechanical ventilation and the median postoperative stay in the hospital was 14 days (range, 7 to 45 days).
There was no significant difference in operative or late survival between the two recipient groups (Fig 3). The 30-day survival was 93% (78 of 84) for group A compared with 93% (27 of 29) for group B. Actuarial patient survival at 7 years was 78.5% ± 4.9% for group A and 74.1% ± 10.5% for group B. Currently, 67 recipients (78%) in group A and 24 (83%) in group B are alive.
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During the study period, 9 donor hearts offered to the LLU team were declined on the basis of organ quality (code 830), of which 5 (56%) were adult donors with a mean age of 32.6 years, (range, 18 to 48 years). These 5 hearts were offered for children aged 13 to 15 years. Of the remaining 4 declined donors, echocardiographic assessment suggested mild-to-moderate mitral valve regurgitation in 2, 1 of whom experienced 53 minutes of CPR, and the other was 4 years younger than the 16-year-old intended recipient. The LLU potential recipients for these 2 donors were status 2. A newborn donor was declined on the basis of age (size) and a positive screen for cocaine and troponin. Finally, a 13-year-old donor was declined because of prolonged Q-T interval on repeated electrocardiographic assessment, and the heart was never used for transplantation. Eight of the 9 hearts refused by LLU were, however, used for transplantation in other centers, 7 for adult recipients. Operative survival was 100%, and late survival thus far has ranged from 90 to 2214 days.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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The major difference between the two groups of recipients in the present study was the donor graft designation as a primary offer or as a heart offered after being previously declined on the basis of UNOS code 830 or its historic equivalent. Code 830 is designed to capture data from all age groups relating to quality of the heart graft. Hence, refusal of a pediatric heart offer based on code 830 likely indicates that the graft itself was considered by the transplant center as being unsuitable for transplantation, at least in the specific recipient.
Outcomes of the present study suggest that the indicators included under code 830, such as high-dose vasopressors, cardiac arrest and CPR, and cause of donor death are simply too "soft" to be useful by themselves in the decision-making process. There is little, if any, objective evidence in the pediatric literature to suggest that any of these three elements should necessarily contraindicate use of a heart graft, and it seems evident from the present study that caution should be used when refusing hearts solely on the basis of issues contained in code 830.
In defense of code 830, it is designed to provide UNOS with a mechanism for grouping various graft-related reasons that transplant centers provide to the OPOs for refusing the donor offers given to them. Code 830 has never been promoted by UNOS as a list of evidence-based contraindications to using a heart graft, and, indeed, should not be used in this manner.
Nor should pediatric heart grafts that fall into the categories listed in code 830 be considered marginalized or alternate-risk grafts. Although the aim of the present study did not include a comparison of outcomes based solely on the presence or absence of the three code 830 donor variables examined (many donors in both study groups exhibited one or more of these features), there is little to suggest that these variables, in and of themselves, contributed to a worsening of immediate or late outcomes. Hence, it is the policy of this center to approach each donor offer affirmatively, unless or until a less-disputed contraindication becomes apparent.
Less-disputed pediatric donor contraindications have changed little in the last 20 years, and include (1) cardiac shortening fraction of less than 20% on serial echocardiographic studies accomplished over 24 to 36 hours in donors that are properly preloaded and supported, (2) complex congenital heart disease, (3) untreated or uncontrolled sepsis, and (4) malignancy other than primary brain tumors. Refusal of a donor offer for reasons other than these four may be valid in relation to a specific donor-recipient pair, but should occur infrequently if recipient listing data are accurately updated. Elevated troponin or cardiac enzymes (when these assays are available) may factor in the decision for or against a donor, but should rarely trigger the decision. In addition, the LLU program has neither encountered nor used a donor heart with a history of important atrial or ventricular dysrhythmia.
The one confounding variable listed under UNOS code 830 is donor age, which may or may not relate directly to donor heart quality. This variable is undoubtedly meant to capture refusals relating to elderly organs that might be considered unacceptable because of advanced age. But, age alone may also relate to perfectly good organs that may be poorly matched by age to pediatric recipients. This was the case for 5 of the 9 donor offers declined by the LLU team during the study period. It would be helpful in future analyses if UNOS would give donor age a separate refusal code number.
Adult heart transplant teams, encouraged by reports from the Oregon Cardiac Transplant Program and from the University of California at Los Angeles (UCLA) group [2–4], among others, have ventured to expand the use of potential donors by establishing protocols that use so-called marginal donors for status 1 and elderly recipients. Marginal donors have included those of advanced age, use of high-dose vasopressors, known coronary artery disease, and protracted CPR. Although outcomes have been mixed in some series [5, 6], others, including the UCLA, Oregon, and London, Ontario, groups, have found recipient outcomes to be unaffected by this choice in donor strategy [7–10]. Whether or not one agrees that code 830 indicators should marginalize a pediatric donor, results of this present study parallel the favorable outcomes reported in adult series of recipients in whom so-called marginal hearts were used.
An additional perceived barrier to the use of donors whose graft history includes elements of code 830 is geographic distance, expressed as graft cold ischemic time. Prolonged graft cold ischemic times have been studied by Kawauchi [11, 12] and Scheule [13] and their colleagues based on LLU data, and by Mitropoulos and colleagues [14] representing the UCLA adult heart transplant experience. These authors could identify no important outcomes difference between donor hearts that required 5 or more hours of cold preservation compared with those that had less than 5 hours of ischemic time. Other authors have related similar outcomes [10, 15, 16]. Some relate these satisfactory outcomes to specific graft preservation techniques, cardioplegic solutions, and method of graft reperfusion [17–21].
The approach used for recipients in the present series is outlined under Methods in this report and is notable for its simplicity. The LLU group has yet to identify a geographic limitation to pediatric heart graft recovery in North America, Hawaii, and Puerto Rico. Graft cold ischemic time has, therefore, generally been considered a nonissue in the decision for organ recovery. Geographic distance, reflected as graft cold ischemia, had no significant effect in the outcomes comparison of declined vs primarily offered donor hearts.
One point deserves emphasis. A single echocardiographic assessment of the donor heart can be misleading, particularly if it is timed poorly in relation to the acute events surrounding brain death. This issue is emphasized by authors of the "Consensus Conference Report on Maximizing Use Of Organs Recovered From Cadaveric Donors" [22]. This report was aimed at cardiac recommendations for adult donors, but the echocardiographic observations are relevant to infants and children. The message here is to insist on serial echocardiography for any potential donor whose initial functional measures are suboptimal.
Finally, as the ultimate test of donor heart quality (viability), and in an effort to actually expand the number of potential pediatric donors, Boucek and colleagues [23] in Denver, studied the clinical use of non-heart-beating cardiac graft donors. Transplantations were done in 3 infant recipients with heart grafts obtained acutely from these unique donors, and all 3 survived the experience.
Critics of this study were not focused so much on the concept of this approach to donor recovery as on the specific amount of time that transpired between cardiac arrest and organ recovery. Both experimental and clinical evidence now suggests that potential pediatric donors may die of cardiac arrest, experience graft resuscitation in either the donor (prerecovery) or the recipient (postrecovery), yet still produce satisfactory clinical outcomes of cardiac transplantation. In the animal model, time between cardiac arrest and heart recovery has been stretched to 30 minutes with reliable acute graft recovery in recipients [24, 25].
With regard to UNOS code 830, both clinical and laboratory findings challenge the use of donor cardiac arrest and resuscitation as a reason to decline a heart offer [2–4, 7–9, 22–26]. As the strategy illustrated by Boucek and colleagues [23] matures, some of the fear about injured hearts will be assuaged, leading to an absolute increase in available heart donors.
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Discussion |
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Dr Bailey has analyzed the heart transplant experience at Loma Linda, where hearts refused by UNOS [United Network of Organ Sharing] code 830 and probably other reasons at other centers were transplanted at Loma Linda, and compared this group with hearts accepted primarily. As pointed out, the 830 refusal for quality includes high inotropic support, cardiac arrest and resuscitation, and causes of death, most commonly massive chest trauma, which many centers will out of hand turn down, as opposed to head trauma and asphyxia as a cause of death, which also at many centers with prolonged asphyxia will turn down. They have had excellent results in both groups, for which they should be commended, and they have shown that none of these factors affected their outcomes.
At UCLA [University of California, Los Angeles] we have performed 266 transplants in 244 patients from '84 to 2008 with a 30-day mortality of 4.9%. Our patients were older than the Loma Linda group, with a mean age of around 7 years, as opposed to the 2.1 years for Dr Bailey's primarily accepted group and 1.5 years for the refused hearts. We, too, have accepted hearts at a distance, and you can see here our ischemic times, with 52 hearts under 4 hours, 28 at 4 to 6 hours, most of them were over 5, and three at 6 to 8 hours, and 1 over 8 hours. We have had 3 other patients before this latest period who were also over 8 hours and a very low incidence of either ECMO [extracorporeal membrane oxygenation] or open chest for cardiac dysfunction.
In the adult population, where we have had many more marginal donors and recipients, we have created the alternate heart transplant list in order to increase the donor pool and also to increase the number of marginal or high-risk recipients who otherwise would be turned down. These high-risk recipients are then placed on an alternate list and are explained prospectively that they will get an alternate heart, but they may have the advantage of getting a heart quicker than those on the regular list, but they also may have a potential risk from some of these risk factors. In this group of patients, many of whom were in the 65- to 70-age group, we found no difference in outcomes. This was true up to 5 years. After 5 years in the older patients, we see an increasing incidence of cancer.
I would like to ask Dr Bailey several questions. First of all, how many of these patients actually did have mild or moderately impaired ventricular function with shortening fractions in the below 25% range and how many between 20 and 25? In our own experience, we have found that the combination of risk factors such as an impaired ventricular function together with a long ischemic time or a slight size mismatch where you have an 8-hour ischemia time, the recipient is the same size as the donor, or that the ejection fraction or shortening time is slightly impaired, we would turn that heart down. Have you also founded that additive factors should be avoided in trying to minimize the risk of these borderline recipients?
The second question is whether you think that in view of your experience, which is dominated by infants, the infant donor heart is much more amenable to prolonged periods of ischemia than the adult heart?
And thirdly, we have not applied the alternate heart list to our adult patients, because, like you, we accept pretty much most donors and everyone wants to do the most even for high-risk recipients as opposed to turning them down. However, the advantage of an alternate list is it provides some discipline and a framework under which a surgeon can accept these alternate hearts as well as the cardiologists. And one of the biggest problems in a program is that every time this comes up, individual surgeons very frequently turn a heart down because it is a beautiful child who is waiting at home and they don't want to take a risk, thus denying the total pool of donors for the total number of patients. But having a framework where you say, well, this is an increased-risk patient, accept it, might increase the utilization. So I would appreciate your comments on these subjects. Thank you.
I would like to thank the Society for the privilege of discussing the paper. Thank you.
DR BAILEY: Well, thank you, Dr Laks, for those comments. I have long admired your leadership in this area. Your first question had to do with whether these hearts had decreased function and whether additive features relating to the donor would affect our willingness to accept that donor and would it change the outcomes. I think the answer to that is there are very few hearts with shortening fractions above 20% at the time of offer (and at a reasonable time interval from brain death injury) that we would turn down. We do have a shortening fraction cutoff of 20%, particularly if that level of myocardial dysfunction persists in repeated echoes. If we can't get it above 20% with inotropic support, then we won't accept it. Now, that is about the only graft-related refusal indication we use. I don't know whether a cumulative effect makes a difference. It didn't appear to make a difference in this study.
It may be that infants tolerate prolonged ischemia better than older children or adults, although that hasn't been tested in our center. We never get the option to travel across the country for an adult heart and so we may never be able to test whether adult hearts will put up with the same amount of ischemic time used in pediatrics. We have had dozens and dozens of pediatric hearts out over 8 hours and up to more than 10 hours, and we have traveled all over North America, out to Puerto Rico, and up to Nova Scotia with excellent graft recovery and trivial need for temporary mechanical circulatory support. We would go to Hawaii if we had half a chance. We don't know the limits of cold ischemia. I think your idea, Dr Laks, of an alternate list, even for pediatrics, is just excellent. Thank you.
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Acknowledgments |
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