Ann Thorac Surg 2003;76:843-847
© 2003 The Society of Thoracic Surgeons
Original article: cardiovascular
Long-term survival after pediatric cardiac transplantation and postoperative ECMO support
Kathleen N. Fenton, MDa*,
Steven A. Webber, MDb,
David A. Danford, MDa,
Sanjiv K. Gandhi, MDb,
Jayson Periera, MDb,
Frank A. Pigula, MDb
a Children’s Hospital, Omaha, Nebraska, USA
b Children’s Hospital, Pittsburgh, Pennsylvania, USA
* Address reprint requests to Dr Fenton, Cardiothoracic Surgery, Children’s Hospital, 8200 Dodge St, Omaha, NE 68114
e-mail: kfenton{at}chsomaha.org
Presented at the Forty-ninth Annual Meeting of the Southern Thoracic Surgical Association, Miami Beach, FL, Nov 7–9, 2002.
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Abstract
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BACKGROUND: Graft failure after cardiac transplantation in children can be managed acutely with mechanical support, most commonly extracorporeal membrane oxygenation (ECMO). The purpose of this study was to evaluation the long-term outcome of ECMO support early and late after pediatric cardiac transplantation.
METHODS: From February 1982 through October 2002, 168 patients underwent isolated cardiac transplantation. Twenty patients (11.9%) required mechanical support early or late after transplantation. Inpatient and outpatient records of these were reviewed.
RESULTS: Indication for transplantation was complex congenital heart disease in 12, cardiomyopathy in 7, and graft failure (retransplant) in 1. One patient was also on ECMO preoperatively. Fifteen patients required circulatory support immediately or shortly (less than 6 weeks) after transplantation. The remaining 5 patients were placed on ECMO for ventricular dysfunction late (3 months to 7 years) after transplantation. In the perioperative ECMO group, 8 (53%) were successfully decannulated and subsequently discharged. Three of 5 (60%) patients placed on ECMO late were successfully decannulated, 1 of whom died in hospital 10 days later and 2 of whom are still alive.
CONCLUSIONS: Mechanical circulatory support using ECMO can be a useful strategy is the management of graft dysfunction after pediatric cardiac transplantation both early and late postoperatively. The mortality rate is acceptable in this very high risk group of patients and long-term outcome is good.
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Introduction
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Mechanical circulatory support is now commonly used in both children and adults to permit recovery from ischemic injury or cardiac surgery, to support the circulation in patients with cardiomyopathy, and as a "bridge" to transplantation. Circulatory support for infants and children is most often provided using extracorporeal membrane oxygenation (ECMO). The reported survival of children supported with ECMO for cardiac indications is about 50% [1, 2] although results are greatly affected by selection criteria. After heart transplantation ECMO has traditionally been used as a bridge to a second transplant. Some recent studies in adults [3–5] and in children [6–9] have evaluated the role of circulatory support after transplant. We hypothesized that ECMO would provide time for recovery of cardiac function early and late after transplantation and would allow long-term survival.
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Patients and methods
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From February 1982 through October 2002, 168 infants and children (aged 18 years or younger) underwent isolated orthotopic cardiac transplantation. Patients with early or late graft failure, pulmonary failure, or circulatory collapse were placed on ECMO at the discretion of the cardiac surgeon and transplant cardiologist, if recovery was expected. Patients placed on ECMO acutely posttransplant were cannulated through the chest; late after transplant, cannulation was through the neck or groin depending on the patient’s size. No patients received other forms of mechanical support after heart transplant. Patients with late graft dysfunction requiring ECMO were treated empirically for rejection. Twenty patients (11.9%) were supported with ECMO early or late after transplantation; these patients form the study population.
The study was reviewed and approved by the Institutional Review Board of the Children’s Hospital, Pittsburgh. Patients were identified from the hospital’s cardiac transplant and ECMO databases. Inpatient, outpatient, and autopsy records were reviewed. Data were collected retrospectively. Variables examined included cardiac and noncardiac diagnoses, age at operation, duration of time from transplant to ECMO use, indication for ECMO, year, and number of days ECMO support. End points included death on ECMO, survival to decannulation, and death after decannulation. Statistics were performed for categorical variables using contingency table analysis, for continuous variables using a Student t test, and for the relationship between survival and year using logistic regression analysis.
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Results
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The ages for all transplanted patients ranged from 1 day to 18 years (mean 7.3 years; Table 1).
The indication for transplantation was cardiomyopathy in 88 (52%), congenital heart disease in 71 (42%), graft failure (retransplant) in 7 (4.1%), and Kawasaki disease and tumor in 1 each. In the ECMO group the ages ranged from 1 day to 15 years (mean 4.3 years) and the indication for transplantation was complex congenital heart disease in 12 (60%), cardiomyopathy in 7 (35%), and graft failure (retransplant) in 1 (5%). Thus transplanted patients who underwent ECMO were younger (p = 0.02), with a trend (p = 0.08) toward a higher incidence of congenital heart disease. One patient in the postoperative ECMO group was also on ECMO preoperatively. Fifteen patients required circulatory support immediately or shortly (less than 1.5 months) after transplantation (Table 2).
The remaining 5 patients were placed on ECMO for ventricular dysfunction late (3 months to 7 years) after transplantation. Patients spent an average of 6 days (range, 11 hours to 24 days) on ECMO. The mean duration of ECMO support was 5 days (range, 1 to 11) for survivors and 7 days (range, 11 hours to 24 days, p = not significant) for nonsurvivors.
In the perioperative ECMO group, 8 patients (53%) were successfully decannulated. Six of these children are still alive, now 5.6 months to 9.8 years later. One patient in the perioperative group was retransplanted 3 days later, again failed to wean from bypass apparently owing to elevated pulmonary vascular resistance, and died. No other patients have been retransplanted. Three of 5 patients (60%) placed on ECMO late were successfully decannulated, 1 of whom died 10 days later (Fig 1).
The other 2 patients are still alive: 1 is alive 3 months after ECMO and 3 years after transplant, and the other is alive 4 years after ECMO and 11 years after transplant. Of the 9 patients discharged alive, 1 died 21 months later and the remaining 8 are still alive with a mean follow-up of 45 months.
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Fig 1. Early and late use of extracorporeal membrane oxygenation (ECMO) after pediatric cardiac transplant (slashed bars = total number of patients placed in ECMO in each group; open bars = decannulated; solid bars = discharged).
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The indications for ECMO were primary graft failure (failure to wean from bypass) in 6, rejection in 4, pulmonary failure in 3, pulmonary hypertension in 3, sepsis or multiorgan failure in 2, and unexpected in-hospital arrest in 2. Patients placed on ECMO early were most likely to have primary graft failure or elevated pulmonary vascular resistance as indications, whereas patients placed on ECMO late had various indications (Fig 2).
Long-term survival was related to the indication for ECMO: 83% for primary graft failure, 100% for rejection, and 50% for patients who arrested suddenly. One patient with respiratory failure and posttransplant lymphoproliferative disease was successfully decannulated but died in hospital. There were no hospital survivors among patients placed on ECMO for pulmonary hypertension, pulmonary failure, or multiorgan failure/sepsis. Age at transplant was unrelated to the chance of surviving to decannulation. The chance of surviving ECMO improved over time: logistic regression analysis yielded an odds ratio of survival per each increasing year of 1.36 (p = 0.037; Fig 3).
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Fig 2. Indications for extracorporeal membrane oxygenation in early (shaded bars) and late (slashed bars) groups. (ACR = acute cellular rejection; Arrest = sudden cardiac arrest; GF = graft failure; MOF = multiorgan failure; Pulm = pulmonary failure; PVR = elevated pulmonary vascular resistance.)
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Fig 3. Effect of date on extracorporeal membrane oxygenation (ECMO) use and survival (solid bars = number treated; slashed bars = number of patients undergoing ECMO; open bars = survivors).
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Comment
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Cardiac transplantation has become the final common pathway for many infants and children with end-stage heart disease resulting from cardiomyopathy and congenital heart defects. The reported survival after pediatric heart transplant is about 80% at 1 year [7, 10, 11] and 70% at 5 years [11] but survival has improved with time. Long-term survival may be somewhat better for young infants [12, 13].
Mechanical circulatory support has been used for more than 20 years to allow the heart and lungs to recover from ischemia, injury, or myocarditis. At our institution [1], 68 children were placed on ECMO for cardiac support with 9 of 14 successfully bridged to transplantation and an overall survival of 38%. Similarly Kirshbom [8] recently reported a 39% rate of successful bridge to cardiac transplantation. These study results are in line with other reported results of cardiac ECMO; in general the survival is not as good as that for neonatal ECMO for respiratory indications (primary pulmonary hypertension of the newborn or meconium aspiration).
Mechanical circulatory support has on occasion been used after heart or lung transplant. It has most commonly been done as a bridge to a second transplant but recent studies in adults and children have suggested that circulatory support may be useful in selected transplant patients as a "bridge to recovery." Tenderich and associates [5] reported a series of 25 adults who had undergone orthotopic heart transplantation and required mechanical assist devices postoperatively. Eighteen of these (72%) died of multiple organ failure, 5 (20%) were successfully weaned, and 2 were retransplanted. Mitchell and coworkers [9] reported a series of 14 infants placed on ECMO after transplant; 10 (71%) were successfully decannulated and 8 (57%) were discharged alive. Most recently Kirshbom and coworkers [8] reported 12 pediatric heart transplant patients who received postoperative ECMO with 33% surviving to discharge. These studies demonstrate that mechanical support can be used successfully in some adults and children after cardiac transplantation.
Our data confirm that ECMO can be a useful adjunct to the management of patients with cardiopulmonary compromise after cardiac transplantation. We have shown that ECMO can salvage a significant number of pediatric patients with cardiorespiratory failure both early (less than 1.5 months) and late (up to 7 years) after heart transplant (Fig 1). We have similar short- and long-term survival early and late after transplant in our small series. The results of ECMO for both respiratory and cardiac indications are significantly affected by patient selection criteria. We have attempted to examine outcomes based on the initial indication for circulatory support. The reason for ECMO was classified as primary graft failure, rejection, elevated pulmonary vascular resistance, pulmonary failure, multiorgan failure (with or without sepsis), or sudden cardiac arrest. Outcomes were examined by group (Fig 4). All 10 patients with a cardiac indication for ECMO (primary graft failure or rejection) survived to decannulation, and long-term survival was 63%. This result compares favorably with the results of ECMO for other cardiac indications. Patients with pulmonary indications for ECMO after heart transplantation (elevated pulmonary vascular resistance or pulmonary failure from infection) did not survive in our study. We found that the outcome of ECMO after transplant is related more to the indication for ECMO than to its timing (early or late).
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Fig 4. Effect of extracorporeal membrane oxygenation (ECMO) indication on outcome (slashed bars = total; solid bars = decannulated; dotted bars = discharged; open bars = alive 5.6 months to 9.8 years after ECMO). (ACR = acute cellular rejection; Arrest = sudden cardiac arrest; GF = graft failure; MOF = multiorgan failure; Pulm = pulmonary failure; PVR = elevated pulmonary vascular resistance.)
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The ECMO results have improved with time in most series including our own. Patient selection is likely the primary reason for this improvement but many small technical changes probably contribute as well. We currently use heparin-bonded circuits when ECMO is instituted perioperatively for example, allowing us to run the patient at a lower activated clotting time and thus cutting down on bleeding. Similarly we have learned the importance of decompressing the left atrium when there is significant left ventricular dyskinesia. Finally weaning patients with marginal function is also a learning experience. We have observed for example that patients supported with a vortex pump may seem to fail weaning at low flows but do better with the circuit clamped. These small changes in individual patients may add up to a significant improvement in outcome over the years.
There are several potential explanations for the trend toward a higher incidence of ECMO use in patients transplanted for congenital heart disease. These patients are more likely to have been transfused before transplant and thus more likely sensitized. Also they often have more complex operations and are more likely to have some element of pulmonary vascular disease.
Limitations of our study include its retrospective nature and the lack of clearly defined criteria for the use of ECMO after heart transplantation. We hope that the study itself has helped us to determine which patients will benefit from the use of circulatory support after heart transplantation. Patients with cardiac failure due to primary graft failure or acute rejection recover function with treatment and are thus good candidates for ECMO support. They include patients who develop acute rejection late after transplant. Extracorporeal membrane oxygenation is not helpful for pulmonary failure after heart transplantation and may not be useful for posttransplant pulmonary hypertension. We currently use ECMO to support patients with primary graft dysfunction and rejection. Patients with pulmonary hypertension are also supported with ECMO in the perioperative period. Extracorporeal membrane oxygenation is not offered to patients with multiorgan dysfunction.
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Discussion
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DR VINCENT K. H. TAM (Ft. Worth, TX): Kathleen, let me first congratulate you on an excellent presentation. I also thank you for allowing my access to the manuscript before our meeting. Your paper provides useful information regarding management of the pediatric post–heart transplant patient. In your institution’s experience, EMCO support after transplant gave better than expected results. I would, however, caution that some of your conclusions are drawn on the basis of a few patients. I have a few questions.
First, why did you choose one month to distinguish between the early and late group? I would have thought maybe a week would have captured all of the perioperative graft failure patients.
Second, the experience from Children’s Hospital in Philadelphia reported recently by Kirshbom et al showed favorable survival with ECMO support in the post–lung transplant patients. Can you comment on why the post–heart transplant patients with "pulmonary failure" did so poorly?
And then last, were there any factors which predicted the need for postoperative ECMO support in the donor, the recipient or in the transplant process itself? How many of these patients were considered high–risk transplant candidates?
I thank the Association for the opportunity to discuss this paper.
DR FENTON: I based that on two things. First of all, there was a nice split in my data at around the time of 1 month. Secondly, the only definition I could find in the literature of early graft failure was actually defined at 1 month; this was in a paper by Wagner in Circulation 2001. So I decided to go with that definition.
I did not really look at the issue of how many patients were high risk or whether or not groups of patients were at an increased risk of graft failure. I do not really have any data to even make a guess other than the fact that there was no difference in the use of preoperative ECMO in the patients. What I did not look at, which probably would have been helpful, was how sick they were, for example whether they were status I or status II.
I think the inherent difference in lung versus heart transplants is probably the reason that patients are able to recover or to come off ECMO and do well in the long term. This is basically a matter of being able to predict whether or not they have a recoverable injury. We did not have enough lung transplant patients in Pittsburgh who had been placed on ECMO for me to separately look at those, but I think that to place a lung transplant patient with lung failure on ECMO either for rejection or for a preservation-related injury is probably something that is more recoverable. In contrast, the heart transplant patients with pulmonary failure were kids who a lot of times had chronic pulmonary disease or had, at least in one case that I can think of, a viral pulmonary infection, which is probably not a recoverable lung injury. I think that is where the difference is.
DR MICHAEL H. HINES (Winston-Salem, NC): I think this is excellent data. People outside the ECMO community when they look at ECMO numbers frequently see 50% survival and see that as bad, and certainly if you were doing Ross procedures and had a 50% survival, you would have to really look closely at it. But you have to remember that this is a population of patients who otherwise have a 100% mortality, and to borrow from the heart surgeons’ handbook, given the choice between slim and none, most patients prefer slim.
And my question to you is given that, and that many of us in the ECMO community that do a lot of that are willing to go for it for most patients, so which patients specifically would you not offer ECMO outside of pulmonary hypertension, and with the patients with pulmonary hypertension, you say you would use your discretion, but which patients would you not put on, particularly in light of Flolan and nitric oxide and time that can help as well?
DR FENTON: One thing that I did not really mention in the talk that I meant to mention is that looking at ECMO survival data can be very confusing, because ECMO survival data are probably more based on patient selection than on anything else. When you have an ECMO team who are more willing to place higher risk patients on ECMO or more willing to kind of place everyone on ECMO, you are going to have worse results but you may have more patients surviving in the end. I think that it is important to look at that when you think about the results of ECMO.
You were asking about pulmonary hypertension. My recommendation based on the data would probably be to take someone who has early graft failure or someone you can’t wean off bypass. Even if you think that the primary problem is pulmonary hypertension, it is probably worth trying it, especially now that we have the adjunctive therapy to treat the pulmonary hypertension.
There was actually one child out of the three patients with pulmonary hypertension who failed to wean off bypass, was thought to have pulmonary hypertension, was listed for another transplant, got another heart 3 or 4 days later and still couldn’t wean off bypass, and she died. So I think that is probably not a preservation injury two times in a row. It is probably a real pulmonary hypertension problem.
It is going to be hard to sort that out, and I think in the short term probably the patients who we should turn down are the multiple organ failure patients, the patients with viral infections, and the patients who are far out from their transplant who have sort of long-standing pulmonary hypertension that is probably not going to get better. Probably the early patients or the patients with a more acute issue have a better chance of getting better and it is therefore worth trying it.
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References
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- Aharon A.S., Drinkwater D.C., Jr, Churchwell K.B., et al. Extracorporeal membrane oxygenation in children after repair of congenital cardiac lesions. Ann Thorac Surg 2001;72:2095-2102.[Abstract/Free Full Text]
- Albes J.M., Eckstein F.S., Heinemann M.K., Ziemer G. Successful weaning of a transplanted heart from biventricular assist device. Ann Thorac Surg 2000;70:277-278.[Abstract/Free Full Text]
- Hetzer R, Hennig E, Schiessler A, Friedel N, Warnecke H, Adt M. Mechanical circulatory support and heart transplantation. J Heart Lung Transplant 1992;11:S175–81
- Tenderich G., Koerner M.M., Stuettgen B., et al. Mechanical circulatory support after orthotopic heart transplantation. Int J Artif Organs 1998;21:414-416.[Medline]
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- Mitchell M.B., Campbell D.N., Bielefeld M.R., Doremus T. Utility of extracorporeal membrane oxygenation for early graft failure following heart transplantation in infancy. J Heart Lung Transplant 2000;19:834-839.[Medline]
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Abstract
Introduction
