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Ann Thorac Surg 1998;66:199-204
© 1998 The Society of Thoracic Surgeons

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Original articles: general thoracic

Lung retransplantation in children

^a Divisions of Cardiothoracic Surgery, Pediatric Allergy, Pulmonary Medicine, and Pediatric Cardiology, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, Missouri, USA

Address reprint requests to Dr Huddleston, Children’s Hospital, #1 Children’s Place, Suite 5W 24, St. Louis, MO 63110
e-mail: (huddleston_ c{at}a1.kids.wustl.edu)

Presented at the Forty-fourth Annual Meeting of the Southern Thoracic Surgical Association, Naples, FL, Nov 6–8, 1997.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Early primary graft failure due to reperfusion injury may occur in up to 10% of all patients undergoing lung transplantation. Late graft failure in the form of bronchiolitis obliterans progressively increases in frequency as posttransplantation follow-up increases. In both situations, the degree of pulmonary dysfunction may worsen and result in the death of the recipient. The only treatment in many instances is retransplantation. The results in adults are reasonably well established.

Methods. We reviewed our experience in children. Of the 136 transplant procedures performed to date in children, 14 have been retransplantations. Six patients required retransplantation for early primary graft failure and 8 underwent retransplantation for bronchiolitis obliterans.

Results. There were three early and three late deaths. The actuarial survival at 2 years is 58%. The retransplant procedures were more complex than the primary transplant operations as evidenced by the longer time on cardiopulmonary bypass (199 ± 71 versus 150 ± 41 minutes; p < 0.01) and the greater volume of blood transfused (1,303 ± 936 versus 570 ± 300 mL; p < 0.01). Two of the long-term survivors who received transplants for bronchiolitis obliterans have subsequently had development of this same condition and 1 died secondary to this. In four instances living related donors were used for the retransplant procedure. The most striking difference in these procedures compared with those transplantations performed with cadaveric donors was the shorter donor lung ischemic times (99.5 and 123.3 minutes for the two lungs for living related donors and 251 and 293 minutes for the first and second lung for the cadaveric donors; p < 0.01).

Conclusions. We believe that lung retransplantation in children is a reasonable therapy to offer in the circumstance of severe graft dysfunction. In the older child, the option of living donor transplantation offers advantages that might offset of the overall higher risk of this procedure.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
There are certain forms of acute or chronic graft failure after lung transplantation for which there is no therapy other than repeat lung transplantation. However, as patient referrals have greatly exceeded donor availability, the waiting lists for initial transplantation and the incidence of death while awaiting lung transplantation have increased; 385 patients died while on the lung transplant waiting list in 1996 [1]. Retransplantation (retx) of the lungs is complicated further because of higher morbidity and lower survival rates compared to primary transplants [2], a theme consistent with the practice of retx of other solid organs [1, 2]. All of those involved in organ transplantation have an obligation to make the most economical use of the available donor organ pool, yet in many lung transplant patients progressive graft dysfunction refractory to medical therapy will develop, for which retx is the only viable option.

Most previously reported series of pulmonary retx deal exclusively with adults [3–6]. Novick and colleagues [7–10] have established an international registry of patients undergoing pulmonary retx to which we send data concerning our patients. However, the great bulk of this registry is of adult patients. Children with acute or chronic lung graft failure may be a more reasonable group for this procedure. Because of their smaller size the waiting list for cadaveric organs is shorter [1]. In addition, for older children who compete with small adults for the same organ donor pool, living donor lung transplantation [11] provides an alternative to cadaveric donors that might otherwise be used for a first-time recipient.

We reviewed our experience to compare outcomes of retx in children to those undergoing primary transplantation. In addition, we also evaluated our experience with lung retx using living donor to compare the results in those few patients with those undergoing retx from cadaveric donors.

	Material and methods

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Since the lung transplant program began at St. Louis Children’s Hospital in 1990, 136 transplantations have been performed in 122 patients. Thus, 14 patients have undergone retx and form the basis for this report (Table 1). The average age of the group was 9.9 ± 5.5 years at the time of the initial transplantation and 11.2 ± 5.5 at the time of retx. There were 8 girls and 6 boys. The pretransplantation diagnoses and indications for retx are listed in Table 1. The follow-up of all those surviving the early posttransplantation interval was 1.6 ± 1.1 years. The median time between the first and second transplantations for the entire group was 341 days, but this differed significantly depending on the indication for retx. For those with primary graft failure the median time was 63 days and for those with bronchiolitis obliterans (OB) the average time was 639 days (p < 0.01). The median time from listing to primary transplantation in this group was 132 days; the median time waiting on the list for the retx (excluding those receiving living donor transplants) was 32 days. These were not significantly different statistically. Over this same time, the average wait list time for all lung transplant recipients was more than 350 days [1].

The timing of retx for OB depends on the severity of the clinical picture and the perception of the transplant team as to whether the patient might be able to escape this dreaded complication after a second lung transplantation. In 2 patients the treatment of posttransplantation lymphoproliferative disease (PTLD) required reduction in immunosuppression and, we believe, led to subsequent development of OB. Once the patient was convincingly clear of any remnants of PTLD, retx was pursued as needed according to the clinical status of the patient. Another patient had repeated episodes of acute rejection in spite of aggressive treatment; she received retx at the point of worsening respiratory function under the assumption that there was a peculiar mismatch of this organ and that more compatible lungs could be obtained at retransplant. The others had no particular unusual episodes leading to OB but were motivated, very adherent patients who we believed were otherwise appropriate candidates. All these patients were on supplemental oxygen, 2 required in-hospital care, and 1 of those was on a ventilator. The average forced expiratory volume in 1 second of these patients on the last set of pulmonary function tests before retx was 19% ± 7% of predicted. Two underwent living donor lung transplantation and the other 6 had cadaveric donors.

All patients were treated with standard triple-drug immunosuppression consisting of cyclosporine, azathioprine, and prednisone. This is the same immunosuppressive regimen used after the primary transplantation in these patients. All patients are followed up continuously at our center. Surveillance bronchoscopy with transbronchial biopsies is performed at regular intervals. Pulmonary function tests are also performed at regular intervals. All patients receive a portable hand-held spirometer to measure pulmonary function on a daily basis at home. Acute rejection was treated with bolus doses of methylprednisolone (10 mg/kg) daily for 3 days.

Statistics
Results are expressed as mean ± standard deviation and as the median where appropriate. Survival results are expressed using the Kaplan-Meier method. Comparisons between primary transplantations and retxs in these patients were done with paired Student’s t tests. A p value of less than 0.05 was considered statistically significant.

	Results

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Operative characteristics
All patients except one underwent bilateral lung transplantation as their retx procedure; the other one had double-lung transplantation. The living donor lung transplantations were performed using the lower lobes from the donors. Cardiopulmonary bypass was used in all patients and the operative procedure was performed just as for primary transplantation. Typically, cardiopulmonary bypass was initiated as the recipient pneumonectomies were begun. The cardiopulmonary bypass time required for retx was 199.2 ± 71.2 minutes. For this same group of patients, the time on cardiopulmonary bypass for the initial transplantation was 150 ± 41.4 minutes. This difference was statistically significant (p = 0.008). The ischemic times to the lungs at the retx were 208 ± 87 minutes for the first and 254 ± 98 minutes for the second lung implantation. At the initial transplantation the times were 252 ± 38 and 304 ± 40 minutes. These differences between the initial and retx ischemic times were not significant (p = 0.09 for the first lung, initial versus retx; p = 0.06 for second lung, initial versus retx). The ischemic times are a reflection of the distance traveled for organ procurement in one group compared with another, as well as the impact of living donor transplantation used for 4 of the recipients at the time of retx. Thus, ischemic time is not necessarily indicative of the relative complexity of the procedure.

Blood use in the perioperative period was significantly greater at the time of retx compared with the initial transplantation for each patient. The mean volume of packed red cell transfusion during and in the first 24 hours after retx was 1,304 ± 936 mL. This was a significantly larger amount than these patients required in the same time interval around their first transplantation (571 ± 300 mL, p = 0.01). Two patients required reexploration for bleeding after retx, whereas none of these patients required reexploration after their primary transplant.

Posttransplantation complications
In general, the post-retx hospital stay was more complicated than that after the first transplantation. For obvious reasons, those patients who underwent retx for early graft failure had quite complex, prolonged posttransplantation courses after their initial transplantation and do not provide a good comparison with the course after retx. Thus, for practical purposes the comparisons made here are for those undergoing retx for OB. The average time on mechanical ventilation was greater after the retx (6.2 ± 7.4 days versus 2.2 ± 1.2 days), but this difference did not achieve statistical significance (p = 0.19). The average time spent in the intensive care unit (90 days versus 4.8 days, p = 0.23) and total time in the hospital (17.2 days versus 15.2 days, p = 0.29) tended to be longer after the retx, but again did not achieve statistical significance.

Moderate stenosis in the left bronchial anastomosis developed in 1 of the patients after retx; this required a single balloon dilation for resolution. Other complications include unilateral diaphragm dysfunction in 3 patients, hoarseness due to vocal cord paralysis in 1 patient, renal failure requiring peritoneal dialysis in 1 patient, and seizures in 2 patients.

Two patients had recurrent OB in the retransplanted lungs, and 1 died secondary to this. For our entire group of lung transplant patients the incidence of bronchiolitis obliterans at 1, 2, and 3 years of follow-up is 25%, 40%, and 46% respectively. None of the patients who had retx have had posttransplantation lymphoproliferative disease.

Living donor retransplantation
Four of the patients who had retx received transplants from living donors. The decision to proceed with this option was based on the assumption that these children were too ill to wait on the list for a cadaveric donor. Three of the 4 were on mechanical ventilation, paralyzed, and sedated. The other was hospitalized on supplemental oxygen and unable to walk from the bed to the bathroom. One of these died 7 days after retx from multiple pulmonary emboli. The other 3 patients are doing well without respiratory symptoms at an average of 2 years after-transplant. The mortality for those undergoing retx with lungs from cadaveric donors was 50%. The donor ischemic times were considerably shorter compared with procedures using cadaveric donors: 99.5 ± 18.3 minutes and 123.3 ± 31.4 minutes for each lung versus 251.6 ± 58.8 minutes and 295.3 ± 63.6 minutes (p = 0.003 for both the first and second lung implantations).

Survival
There were three early deaths for an early posttransplantation mortality of 21%. There were three late deaths. Our longest current post-retx survivor is now 3.4 years after the second transplantation. The cause of death in two of the three early deaths was disseminated Aspergillus infection. The other patient died of multiple pulmonary emboli; she had been at bed rest for 3 weeks before her transplantation. The late deaths were attributable to recurrent OB in 1 patient and late graft failure of unclear cause in 2. The deaths were evenly divided between having retx for primary graft failure and OB. The actuarial survival was 58% at 1 year and has remained flat for the period of follow-up thus far. This is somewhat worse than the actuarial survival for all our lung transplantations, where the 1-, 2-, and 3-year survival is 80%, 71%, and 63% respectively (Fig 1).

View larger version (17K): [in this window] [in a new window]   Fig 1. Survival of the retransplantation group compared with all the other lung transplantations performed in our program. The survival is worse, but this difference did not reach statistical significance. (n = number at risk; ReTx = retransplantations; Tx = transplantations.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

The long-term survival, like that after first-time lung transplantations, will be linked directly to the incidence of OB. Thus far, OB has developed in 18% (2 of 11) of our patients surviving the immediate posttransplantation period. Both underwent retx for OB developing after their initial transplantation. There is now some suggestion again from the registry of Novick and associates [10] that OB may occur more commonly in those undergoing retx for OB than in those undergoing retx for other reasons. Should these findings hold up over longer follow-up, this would damper what little enthusiasm exists for retx for OB. Although one might argue that changing management strategies after the second lung transplantation might alter the incidence of OB, thus far there is no clear regimen that has such an effect. Some investigators [12] have proposed using cytolytic therapy once clinical evidence of OB is present. Other researchers [13] substitute methotrexate for azathioprine in the immunosuppressive regimen. A randomized, prospective trial from the group at Pittsburgh [14] comparing tacrolimus and cyclosporine in primary lung transplantation has shown some promise but no conclusive evidence that the incidence of OB might be less with tacrolimus. Mycophenolate mofetil has also shown some promise in stabilizing pulmonary function once the diagnosis of OB is made [15].

Complications in our series after retx represent much of what one might expect in the setting of transplantation when there has been a previous thoracic procedure. Bleeding indicated by the significantly greater volume of blood transfused in the retx operation compared with the primary transplantation was an obvious problem. We routinely used aprotinin for all retxs in an effort to prevent this complication. Other events in the early posttransplantation hospitalization occurred at a frequency similar to that seen with primary transplantation. Although there was a trend for longer time on the ventilator, longer stay in the intensive care unit, and longer hospitalization after retx, these differences did not reach statistical significance. Nonetheless, it is fair to predict that these patients will likely have a more complex posttransplantation course than a patient undergoing primary transplantation.

A consistent finding in the retransplant registry information compiled by Novick and coworkers [8–10] is that results in an experienced center are better than those performing a small number of retxs. Indeed, the 1-year survival for our first six retxs was 33% and for the next eight 75%. Over this interval our group obtained more experience in the management of lung transplant patients in general. One change that occurred over the course of this experience was in the management of patients colonized with Aspergillus organisms. We take a more aggressive approach in these patients, with the early institution of intravenous amphotericin B as well as the liberal use of aerosolized amphotericin B.

The use of living donors has made the conduct of the retx procedure safer. The ischemic time for the donated lungs is much shorter than with cadaveric organs. There are two reasons for this. One of these is obvious—there is no significant travel time involved in the ischemic time. The other issue concerns the actual conduct of the recipient operation. In the setting of cadaveric donor, we wait until the donor team has safely arrived back at our institution before beginning the recipient pneumonectomies. For the living donors, the recipient pneumonectomies are performed as the donor procedures are being carried out. Furthermore, the second donor lung is not harvested until the first transplantation is nearly completed, thus shortening the ischemic time for the second lung. Although our numbers are too small to provide meaningful comparisons, it is conceivable that the advantages conveyed by the use of living donors may offset the high-risk aspects of the retx procedure. As mentioned above, the use of living donors also eliminates the ethical considerations related to allocation of a scarce resource (cadaveric donors) to an ever-growing list of potential recipients. However, living donor lung transplantation has its own set of ethical dilemmas.

Selecting patients for retx is without question the most difficult part of the process involved in this procedure. Bronchiolitis obliterans occurs in increasing numbers of lung transplant patients as they are followed up for longer periods of time. Those followed up for more than 4 years after transplantation have an incidence of more than 50% [16]. Mortality is approximately 25% 1 year after establishment of the diagnosis of OB, and the earlier after transplantation that the diagnosis is made, the more rapid the progression to death [17]. It is impractical to perform retx in all those patients. As more experience accumulates, however, risk factors for OB are being recognized [19] and may help guide the selection of patients. Moreover, recognition of risk factors amenable to modification would allow for changes in management to prevent the development of OB.

In summary, lung retx in children can be performed successfully but has a higher early mortality than primary transplantation. Lesser competition for organs in this age group allows for a shorter wait time than would be seen in adults. The use of living donors would eliminate the obligatory waiting interval for teenage children. In addition, it may result in a safer operation and better early mortality than what has previously been experienced in retxs where cadaveric donors are used.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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