ORIGINAL ARTICLES: CARDIOVASCULAR

Heart-Lung Transplantation for Primary Pulmonary Hypertension Richard I. Whyte, MD, Robert C. Robbins, MD, Julie Altinger, MS, Clifford W. Barlow, MB, PhD, Ramona Doyle, MD, James Theodore, MD, and Bruce A. Reitz, MD Department of Cardiothoracic Surgery, and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, California

Background. The operation of choice for primary pulmonary hypertension remains controversial, as heartlung transplantation, single-lung transplantation, and double-lung transplantation have all been advocated. Methods. We reviewed our institution’s experience with heart-lung transplantation for primary pulmonary hypertension. Results. Thirty-nine patients had heart-lung transplantation for primary pulmonary hypertension. Operative mortality rate was 18%, and actuarial survival was 72% at 1 year, 67% at 2 years, and 42% at 5 years. Freedom from obliterative bronchiolitis was 91% at 1 year, 83% at 2 years, and 70% at 5 years. Freedom from obliterative bronchiolitis-related death was 100% at 1 year, 90% at 2

years, and 87% at 5 years. Freedom from accelerated graft coronary disease was 92% at 5 years. The most frequent causes of death were infection, obliterative bronchiolitis, and accelerated graft coronary disease. Conclusions. Heart-lung transplantation results in survival comparable to that reported for single or double lung transplantation. Obliterative bronchiolitis is a significant cause of late death but seems to occur less frequently with heart-lung transplantation than with lung transplantation alone. Accelerated coronary graft disease is rare in the first 5 years after transplantation.

P

Patients and Methods

rimary pulmonary hypertension (PPH) is a rare and progressive disease that has no cure [1]. Although medical therapy has progressed over the past 2 decades, particularly with the increasing availability of continuous infusion of the prostaglandin inhibitor, Epoprostenol (prostacyclin), overall survival rates remain low with the median length of survival after diagnosis being only 2.5 years [2]. Transplantation is used as a treatment for PPH but there has been controversy as to whether single-lung transplantation (SLT), double-lung transplantation (DLT), or heart-lung transplantation (HLT) provides the best outcome in terms of survival, waiting time, and organ utilization [3– 6]. For many reasons, a prospective, randomized trial of the three procedures for this single diagnosis would be nearly impossible to conduct. As a result, the answer about which procedure is optimal will best be made by examining different series and retrospectively comparing the results. We reviewed our institution’s records of HLT for PPH, looking specifically at overall survival and its relationship with the development of chronic allograft rejection.

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26 –28, 1998. Address reprint requests to Dr Whyte, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305; e-mail: [email protected].

© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

(Ann Thorac Surg 1999;67:937– 42) © 1999 by The Society of Thoracic Surgeons

The records of all patients who had HLT for PPH at Stanford University Medical Center were reviewed. Data were obtained from medical records and from the thoracic transplant database wherein data have been accumulated prospectively since 1981. Follow-up is 100% complete through August 1997. Between March 1981 and July 1995, 39 patients met the study criteria. There were 25 female and 14 male patients; the average age was 32 years (range, 11 to 49 years). The diagnosis of PPH was made on the basis of right heart catheterization (with mean pulmonary artery pressure greater than 30 mm Hg), echocardiographic exclusion of concomitant anatomic heart disease, radiographic exclusion of significant pulmonary parenchymal disease, and radionuclide scanning to exclude chronic pulmonary thromboembolic disease. The major criterion for listing for lung or HLT was the presence of New York Heart Association class III or IV heart failure symptoms. Before September 1989 all transplants for PPH were heart-lung transplants (n 5 26). After that date, 5 patients had SLT for PPH, 2 patients had DLT for PPH, and 13 patients had HLT for PPH. The SLT and DLT results were not included in the following analysis. The decision whether to list patients for lung transplant (either single or double) versus heart-lung transplant was based on the presence of severe right ventricular enlargement or dysfunction, as determined by qualitative echocardiographic assessment; patients 0003-4975/99/$20.00 PII S0003-4975(99)00176-9

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with a severely impaired right ventricle were listed for HLT.

Operative Technique Before 1987, organ donors were transported to Stanford for organ procurement. Since 1987, distant organ procurement has been done with a pulmonary artery flush of Euro-Collins solution in conjunction with prostaglandin infusion, cold crystalloid cardioplegia, and topical cooling. The recipient operation was done through a median sternotomy in the manner described by Reitz [7].

Immunosuppression Immunosuppression techniques have changed during the period encompassed by this study. Although the core of the immunosuppressive regimen has always included cyclosporine and steroids, the long-term immunosuppressive regimen has included azathioprine since 1987. Early in the series, patients received preoperative loading doses of cyclosporine and were maintained early at high serum levels. We currently do not administer a preoperative loading dose, and a cyclosporine infusion is started in the immediate postoperative setting with the aim of attaining a trough serum concentration of 150 to 250 ng/mL (as measured by fluorometric polarization assay, Abbott Laboratories, North Chicago, IL). Patients are converted to oral cyclosporine as quickly as possible. Azathioprine is currently started in the immediate postoperative period at a dose of 2 mg/kg per day. The dose is adjusted downward in the event of leukopenia (white blood cell count less than 5000/mm3), or thrombocytopenia (platelet count, 100,000/mm3). Early in the series, azathioprine was given for only 2 weeks after transplantation then discontinued. Currently azathioprine is continued indefinitely. Steroids are started intraoperatively with a 500-mg dose of methylprednisolone given at the conclusion of cardiopulmonary bypass. Three additional postoperative doses are given (5 mg/kg every 8 hours for 24 hours) and are then withheld for 2 weeks, assuming this would decrease the incidence of bronchial anastomotic complications. After 2 weeks, steroids are reinstituted with prednisone at a daily oral dose of 0.6 mg/kg, tapering to 0.1 to 0.2 mg/kg over several weeks. Induction therapy with antibody preparations has been used routinely since 1988. Since 1992, polyclonal rabbit antithymocyte globulin has been used exclusively, but between 1988 and 1992, either rabbit antithymocyte globulin or a murine monoclonal antibody preparation, OKT3, was used, with the choice based on availability. After an initial test dose on the first postoperative day, a dose of 0.1 mg/kg is administered daily for 14 days after transplantation.

Surveillance and Treatment of Rejection Surveillance techniques to monitor rejection have changed markedly over the years. Early in the experience, endomyocardial biopsies were done weekly and as clinically indicated for suspected rejection. After it was recognized that the cardiac and pulmonary allografts

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might reject asynchronously, periodic surveillance bronchoscopy with transbronchial biopsy and bronchoalveolar lavage was added. For the past several years, after it was recognized that cardiac rejection alone was uncommon in these patients, the number of heart biopsies has decreased. Currently, patients have one or two early endomyocardial biopsies, an annual endomyocardial biopsy, and a coronary arteriogram at odd-numbered annual anniversaries of their transplant (years 1, 3, 5, etc). The surveillance bronchoscopy schedule also has become less stringent with routine bronchoscopy now being done at 2, 4, 6, and 12 months and annually thereafter. Either endomyocardial or lung biopsies are obtained when clinically indicated by signs of rejection. Patients are followed up in the Lung Transplant Clinic where they have pulmonary functions tests (flow volume loop) at least every 2 months. Moderate or severe rejection has been treated with intravenous methylprednisolone (1 g/day for 3 days), followed by a 2-week tapering course of prednisone. Persistent rejection has been treated with an additional course of steroids followed by antithymocyte globulin, OKT3, or by total lymphoid irradiation.

Cytomegalovirus and Protozoal Prophylaxis Gancyclovir has been used routinely since its initial availability in all transplants except those where both donor and recipient were seronegative for cytomegalovirus. Trimethoprim-sulfamethoxazole has been given to all patients (except those allergic to sulfa preparations) as prophylaxis against Pneumocystis carinii infection.

Definition of Chronic Lung Allograft Rejection Patients were considered to have obliterative bronchiolitis (OB) if they met the criteria for obliterative bronchiolitis syndrome, including a 20% drop in forced expiratory volume in 1 second, with a temporally associated bronchoscopy (including transbronchial biopsy and bronchoalveolar lavage) showing no evidence of active acute rejection or infection. Biopsy confirmation of OB was not necessary to make the diagnosis.

Statistics Survival, event-free survival, and development of OB were plotted using life-table analysis by the CutlerEderer method [8]. Waiting times for organs are reported as mean, range, and standard deviation (SD).

Results Mortality Perioperative (30-day and in-hospital) mortality for HLT was 18% (seven deaths of 39 operations). The major causes of early death were hemorrhage and neurologic deficit, although there was also one case of early nonspecific graft failure. There was no relationship between early mortality risk and date of transplant. Actuarial survival is shown in Figure 1. Survival was 72% at 1 year, 67% at 2 years, and 42% at 5 years. Causes

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Table 1. Causes of Late Mortality After Heart-Lung Transplantation for Primary Pulmonary Hypertension Cause of Death Infection Viral Bacterial Fungal Obliterative bronchiolitis Accelerated graft coronary disease Nonlymphoid malignancy Nonspecific graft failure Adult respiratory distress syndrome Trauma

No. 5 2 2 1 4 4 1 1 1 2

of death after the first month are listed in Table 1 with the most frequent being infection (n 5 5), obliterative bronchiolitis (n 5 4), and accelerated graft coronary disease (n 5 4). Of the 14 patients currently alive, 11 are in New York Heart Association heart failure class I (no symptoms), and 3 are in class II (symptoms with heavy activity). No patients have either class II or IV heart failure symptoms.

Obliterative Bronchiolitis and Accelerated Graft Coronary Disease The time course for the development of obliterative bronchiolitis is shown in Figure 2. At 1 year, 91% of patients were free of OB; by 2 years, this had decreased to 83%, and by 5 years, 70% of survivors were free of OB. Death directly related to OB occurred in 4 patients, with its time-related incidence shown in Figure 3. There were no OB-related deaths within 1 year of transplantation, and the freedom from OB-related death was 90% at 2 years and 87% at 5 years. Actuarial freedom from accelerated graft coronary disease was 96% at 1 year, 96% at 2 years, and 92% at 5 years (Fig 4).

Fig 1. Survival after heart-lung transplantation for primary pulmonary hypertension.

Fig 2. Freedom from obliterative bronchiolitis (OB) after heart-lung transplantation for primary pulmonary hypertension.

Comment Although the overall outlook for patients with PPH is improving, thoracic organ transplantation remains a commonly desired option for treatment. One major recent advance has been the increasing availability of continuously infused Epoprostenol (prostacyclin), which results in dramatic symptomatic improvement and reduction in pulmonary artery pressures in some patients. In other patients, however, the drug is ineffective, and even for the ones that benefit from it, the duration of benefit is highly variable. The major effect of this drug, in the long-term, might be to delay the need for transplantation, thereby increasing the number of candidates that survive the waiting period. Despite the efficacy of Epoprostenol, thoracic organ transplantation remains a mainstay of therapy for patients with PPH. It is clear that SLT, DLT, and HLT are all viable options, and there are both theoretic and practical advantages of each. The data from the Registry of the International Society for Heart and Lung Transplantation

Fig 3. Freedom from death caused by obliterative bronchiolitis (OB) after heart-lung transplantation for primary pulmonary hypertension.

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Fig 4. Freedom from accelerated graft coronary disease (AGCD) after heart-lung transplantation for primary pulmonary hypertension.

show that all three operations are being done in substantial numbers: 30% of HLTs were done for PPH, and 7.5% of SLTs and 11% of all DLTs were done for PPH [9]. To decide which operation, SLT, DLT, or HLT, is appropriate for PPH, one must look at several ways to measure outcome. Mortality and function are the most commonly measured criteria for outcome, but transplantation is unusual in that efficiency of organ utilization and death while awaiting transplantation must also be considered. Obviously, a dramatic difference in mortality rates between two operations would render one operation inappropriate, but when the differences are slight, the other measures of outcome (organ utilization and waiting time) might be decisive. Single and double lung transplants are favored over HLT because of the potential for increased use of scarce donor organs. If a single lung suffices, the other lung and heart (if usable) can be used in other recipients. The effect of this is to increase organ utilization, diminish waiting time, and decrease mortality rates for patients awaiting transplantation. It has been reported that, in the setting of pulmonary hypertension, DLT results in both greater hemodynamic improvements and shorter duration of postoperative mechanical ventilation than SLT [3]. One postulated reason for this is that DLT provides a larger pulmonary vascular bed and avoids the problem of unequal blood flow to the two lungs. Conversely, DLT is a longer operation than SLT, and there is an increased ischemic time, at least to one of the two transplanted lungs. Furthermore, wound-related and anastomosis-related complications would be expected to be higher after DLT than SLT. Double-lung transplantation has the potential advantage, over HLT, of avoiding complications related to a tracheal anastomosis. In terms of long-term mortality rate, the results of SLT versus DLT for PPH are similar. The International Society for Heart and Lung Transplantation database indicates a 12-month survival rate of 64% after SLT and 65% with DLT [4]. A study at the University of Pittsburgh, in a

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series of lung transplants for both PPH and secondary pulmonary hypertension, found a 1-year survival rate of 67% with no difference between SLT and DLT recipients. These data are comparable to the 1- and 2-year survival rates of 72% and 67%, respectively, in the present series. Furthermore, the 1997 Report of the International Society of Heart and Lung Transplantation showed no significant differences in survival between SLT, DLT, and HLT for PPH [10]. The results of HLT for the present series are comparable to those of both Madden and colleagues [11] and Bolman and colleagues [12], although both those series and our own prior report included a number of different diagnoses in addition to PPH [13]. Furthermore, our 5-year survival rate of 42% is similar to the 44% rate reported by Mikhail and associates [14] and the 38% reported by Hosenpud and associates [9]. In terms of functional capacity (as measured by the New York Heart Association heart failure classification), most surviving HLT patients do extremely well. In this series most were in New York Heart Association class I and none were in classes III or IV. The Pittsburgh series of SLT and DLT for pulmonary hypertension had similar results, with 91% of survivors having either class I or class II symptoms at the time of censoring, and there being no difference between SLT and DLT recipients [4]. Another issue to be considered is waiting time. United Network for Organ Sharing allocation rules mandate that heart-lung blocks be offered before either the lungs or hearts alone, except for status I hearts. In areas of the country where there is a high concentration of status I heart recipients, it is unlikely that a heart-lung block will become available and the waiting time for HLT recipients will be prohibitively long. In reviewing waiting time data for this center (for operations done between September 1990 and January 1996), the average waiting time for HLT was 454 days (range, 2 to 999 days; SD, 360 days), whereas it was 297 days (range, 8 to 844 days; SD, 250 days) for all lung-only recipients. The issue of death while awaiting transplantation has been highlighted by Gammie and associates [4] in their description of the University of Pittsburgh’s experience. In that series, 58 patients with pulmonary hypertension died while awaiting transplantation while another 58 patients had either SLT or DLT for the same diagnosis. If overall mortality rate is to be improved, waiting time must be minimized. The observed incidence of OB in the present series of patients was lower than has commonly been reported after either SLT or DLT [15, 16]. Although it is difficult to compare the rates of OB using the life-table method used in this report with the quartile method used by the Washington University group [15], the Washington University group reported an incidence of OB of 10% in patients followed up for 4 to 17 months, 38% in those followed up for 18 to 31 months, and 67% in patients followed up for 32 to 45 months. Our group has reported 1-, 2-, and 5-year freedom from OB rates of 72%, 51%, and 44%, respectively, in a combination of HLT and lung transplant recipients, but there were no significant differences between the lung and heart-lung groups. It is

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possible that the lower-than-expected rate of OB in the present series is a result of differing statistical methods, definitions, surveillance strategies, or immunosuppressive regimens. However, it is also possible that concomitant heart transplantation confers a degree of immunologic protection to the lungs. Although we did not have ready access to late postoperative hemodynamic data, the absence of late heartfailure symptoms suggest that recurrent pulmonary hypertension is rarely a problem. Although few studies have been published on this issue, Mikhail and colleagues [14] claim that recurrent pulmonary hypertension developed in none of 186 patients who had HLT for pulmonary hypertension in over 13 years of follow-up. The major problem facing survivors of heart-lung and lung transplantation remains chronic allograft rejection, ie, OB and accelerated graft coronary disease. In the present series, these diseases accounted for over 50% of the late deaths. At the present time, treatment for these diseases is both empiric and marginally successful. This is likely to remain the case until the basic biologic mechanisms of chronic rejection are better understood.

References 1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111–7. 2. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–9. 3. Bando K, Armitage JM, Paradis IL, et al. Indications for and results of single, bilateral, and heart-lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1994; 108:1056– 65. 4. Gammie JS, Keenan RJ, Pham SM, et al. Single- versus double-lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1998;115:397– 403.

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5. Pasque MK, Kaiser LR, Dresler CM, et al. Single lung transplantation for pulmonary hypertension. Technical aspects and immediate hemodynamic results. J Thorac Cardiovasc Surg 1992;103:475– 82. 6. Levine SM, Gibbons WJ, Bryan CL, et al. Single lung transplantation for primary pulmonary hypertension. Chest 1990;98:1107–15. 7. Reitz BA. Heart-lung transplantation. In: Baumgartner WA, Reitz BA, Achuff SC, eds. Heart and heart-lung transplantation. Philadelphia: WB Saunders, 1990:319–36. 8. Cutler SJ, Ederer F. Maximum utilization of the life-table method in analyzing survival. J Chronic Dis 1958;8:699 – 712. 9. Hosenpud JD, Novick RJ, Bennett LE, et al. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official report—1996. J Heart Lung Transplant 1996;15:655–74. 10. Hosenpud JD, Bennett LE, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: fourteenth official report—1997. J Heart Lung Transplant 1997;16:691–712. 11. Madden B, Radley-Smith R, Hodson M, et al. Medium-term results of heart and lung transplantation. J Heart Lung Transplant 1992;11:S241–3. 12. Bolman RM, Shumway SJ, Estrin JA, Hertz MI. Lung and heart-lung transplantation. Evolution and new applications. Ann Surg 1991;214:456–70. 13. Sarris GE, Smith JA, Shumway NE, et al. Long-term results of combined heart-lung transplantation: the Stanford experience. J Heart Lung Transplant 1994;13:940–9. 14. Mikhail G, al-Kattan K, Banner N, et al. Long-term results of heart-lung transplantation for pulmonary hypertension. Transplant Proc 1997;29:633. 15. Sundaresan S, Trulock EP, Mohanakumar T, Cooper JD, Patterson GA, and The Washington University Lung Transplant Group. Prevalence and outcome of bronchiolitis obliterans syndrome after lung transplantation. Ann Thorac Surg 1995;60:1341–7. 16. Reichenspurner H, Girgis RE, Robbins RC, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg 1995;60:1845–53.

DISCUSSION DR BARTLEY P. GRIFFITH (Pittsburgh, PA): Thank you Dr Anderson, Dr Whyte. I think it is worth just a moment to emphasize the contributions of the Stanford group not only to heart-lung transplantation but to heart and lung transplantation as well. I remember visiting Stanford the spring morning, 4 days after Dr Reitz had completed the world’s first successful heartlung transplantation. That was a breakthrough event that changed my career forever. I would agree with most of Dr Whyte’s comments. He has demonstrated world leading rates for survival of heart-lung transplantation, which we have come to expect from Stanford. The Stanford group has demonstrated that patients who receive lung grafts as part of heart-lung blocks also have a lower rate of obliterative bronchiolitis than single- or double-lung recipients. And we hear that those who receive heart-lung blocks also have a lower incidence of obliterative coronary artery disease than recipients of cardiac grafts. Why is there any controversy over the appropriate transplant for primary pulmonary hypertension? Dr Whyte has indicated, and I agree, that it is an issue of supply and demand versus overall survival. If we can treat up to 3 patients with one donor as opposed to one recipient for one donor, then why not split the heart-lung block and treat more people?

I can show you with my first slide that at Pittsburgh, 125 heart-lung transplant patients treated for all indications, not just primary pulmonary hypertension, fared as well as 25 single-lung and 37 double-lung recipients with pulmonary hypertension. We believe that in the short-term to mid-term, survival rates were roughly equal. The survival curve is 13 years in the heart-lung group and about half as long in the single- and double-lung group. Although survival rates are similar, perhaps heart-lung transplantation is a little better in the Stanford series than in the single-lung or double-lung series in Pittsburgh. Does that small benefit make it reasonable then to withhold three recipients for one? I wish Dr Whyte had calculated his results with an intent-to-treat type of analysis. Once a patient is placed on the list, that patient at Stanford waits approximately a half a year longer for his transplant than a patient who received a double or single lung at that institution for the same indication. It would be interesting to know the results if the survival analysis begins with listing. Now lastly, I want to discuss obliterative bronchiolitis, which is less of a problem in heart-lung recipients. Why is it better? In Pittsburgh we ascribe it to a microchimerism paradigm for reducing the risk of chronic rejection. The more donor tissue