Lung Transplantation for Primary and Secondary Pulmonary Hypertension

Transcription

1 Lung Transplantation for Primary and Secondary Pulmonary Hypertension John V. Conte, MD, Marvin J. Borja, BS, Chandrahas B. Patel, BS, Steven C. Yang, MD, Rajiv M. Jhaveri, MD, and Jonathan B. Orens, MD Departments of Surgery, Anesthesia, and Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland Background. Single lung transplantation (SLT) and bilateral lung transplantation (BLT) are routinely performed in patients with primary pulmonary hypertension (PPH) and secondary pulmonary hypertension (SPH). It is unclear which procedure is preferable. We reviewed our experience with lung transplants for PPH and SPH to determine if any advantage exists with SLT or BLT for either PPH or SPH. Methods. We reviewed the outcomes of all lung transplants performed for PPH or SPH for 4.5 years (July 1995 to January 2000). Survival was reported by the Kaplan- Meier method, and log rank analysis was used to determine significance. Statistical analyses of clinical data were performed using analysis of variance and 2 analysis. Results. A total of 57 recipients met criteria for pulmonary hypertension with a mean pulmonary artery pressure of greater than or equal to 30 mm Hg. There were 15 patients with PPH and 40 patients with SPH. There were 6 patients who had SLTs and 9 patients who had BLTs in the PPH group; and there were 9 patients who had SLTs and 21 patients who had BLTs in the SPH group. We found a survival advantage for PPH patients who underwent BLTs at all time points up to 4 years (100% vs 67%; p < 0.02). There was no clear advantage to SLTs or BLTs for SPH. At 4 years there was a trend toward improved survival with SLTs (91% vs 75%) in SPH patients with a mean pulmonary artery pressure less than or equal to 40 mm Hg (p < 0.11) with equivalent survival (80%) in patients with a mean pulmonary artery pressure greater than or equal to 40 mm Hg. There was also a trend toward improved survival in patients with a mean pulmonary artery pressure greater than or equal to 40 mm Hg (PPH and SPH) with BLTs (88% vs 62%; p 0.19). The incidence of rejection, infection, and other complications was comparable between SLTs and BLTs in each group. Conclusions. We believe that BLT is the procedure of choice for PPH. The procedure of choice is less clear for SPH. Patients with SPH and a mean pulmonary artery pressure greater than 40 mm Hg may benefit from a BLT and those with a mean pulmonary artery pressure less than or equal to 40 mm Hg may do better with an SLT; however, no clear advantage is seen. (Ann Thorac Surg 2001;72: ) 2001 by The Society of Thoracic Surgeons Lung transplantation (LT) in patients with pulmonary hypertension (PHTN) has been performed since the first successful combined heart-lung transplant (HLTx) nearly 20 years ago in 1981 [1]. Procedures currently being performed include single lung transplantation (SLT), bilateral lung transplantation (BLT), and combined heart-lung transplantation (HLT). Although HLT was the first successful procedure for PHTN, and is still preferred at many centers, over the last decade the majority of lung transplant programs have changed to either SLTs or BLTs for PHTN [2 10]. This shift was multifactorial. Results with SLT or BLT for PHTN are comparable to or better than those for HLT. Right heart dysfunction is improved by SLT or BLT, and ethical and pragmatic concerns centered on donor shortages and organ distribution have encouraged this shift [2 12]. The current literature on LT for PHTN is largely Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9 11, Address reprint requests to Dr Conte, Division of Cardiac Surgery, Johns Hopkins Hospital, Blalock 618, 600 N Wolfe St, Baltimore, MD 21287; jconte@jhmi.edu. composed of single center studies that focus on outcomes comparing the procedures performed at that institution [2 10]. A large number of studies do not differentiate between PPH and SPH when assessing outcomes, and many studies only include SPH due to pulmonary vascular disease. Few studies consider patients who have SPH due to pulmonary parenchymal or systemic diseases who had transplants for their primary disease despite meeting the definition of PHTN [13, 14]. Most studies do not consider the severity of the PHTN once patients have met some threshold criteria of PHTN, and many do not even define their threshold. The difficulty in studying LT for SPH is underscored by the fact that the largest database of LT, The Registry of the International Society of Heart and Lung Transplantation, does not track SPH and only recognizes PPH and congenital heart disease as those diagnoses which have PHTN [15]. We undertook this study in an attempt to learn if there was a difference in outcome between patients with PPH and SPH after SLT or BLT, including those patients with SPH due to parenchymal or systemic lung disease and not pulmonary vascular disease. We secondarily sought 2001 by The Society of Thoracic Surgeons /01/$20.00 Published by Elsevier Science Inc PII S (01)

2 1674 CONTE ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR PULMONARY HYPERTENSION 2001;72: to stratify patients by the degree of their pulmonary hypertension and the etiology of their disease to see if these factors had an impact on patient survival. Material and Methods We reviewed the records of all patients who underwent LT in our program over a year period (July 1995 to January 2000). All patients with a mean pulmonary arterial pressure (PAM) of greater than or equal to 30 mm Hg at the time of transplantation were included in the study. Patients who received HLTs were excluded from analyses. Patients were separated into two groups. Group A consisted of patients with PPH, and group B consisted of patients with SPH. Within each group the patients were then categorized into those who received SLT and those who received BLT. They were then subcategorized further into those who had a PAM more than 40 mm Hg or less than or equal to 40 mm Hg. Patients in the SPH group were also grouped into four categories based on the etiology of their primary lung disease: (1) congenital cardiac disease (Eisenmenger), (2) systemic (PHTN secondary to a systemic disease), (3) parenchymal (PHTN secondary to parenchymal lung disease), and (4) other etiologies. All patients met widely accepted criteria based on their primary lung disease and were believed to be suitable candidates for LT [16]. Although the determination of PHTN was made ahead of time with nearly all patients, the final diagnosis and pulmonary artery pressures (PAPs) used for data purposes were obtained by pulmonary artery catheterization the night of transplantation. Standard surgical techniques were used, and our protocol postoperative care was given to all patients including immunosuppressive drugs, antibiotics, and transbronchial biopsies at designated time intervals. Infection was defined as any episode suspicious for an infection with positive cultures and supporting laboratory evidence and was treated with a course of antimicrobial therapy. Acute rejection was determined by transbronchial biopsy and graded by The Registry of the International Society of Heart and Lung Transplantation criteria. Grades greater than or equal to A2 were considered significant. Bronchiolitis Obliterans Syndrome (BOS) was graded by The Registry of the International Society of Heart and Lung Transplantation criteria. Data are presented as mean standard error of the mean (median) unless noted. The survival curves were generated using the Kaplan-Meier method, and log rank analysis was used to determine significance. Measured clinical data were compared using analysis of variance and 2 analysis. A p value of less than or equal to 0.05 was considered significant. Results Demographics A total of 138 lung transplantation procedures were performed during the study period. Fifty-seven of them Table 1. Demographics of Patients With Primary Pulmonary Hypertension Group A (Primary Pulmonary Hypertension) n 15 Group B (Secondary Pulmonary Hypertension) n 40 Age Sex (% male) a 20% (3 of 15) 60% (24 of 40) PGI2 a 15 (100%) 6 (15%) New York Heart Association Class a Class 4 13 (87%) 26 (63%) Class 3 2 (13%) 14 (37%) Inotropic agents a 6 (40%) 2 (5%) Two agents 2 (13%) 0 Atrial septostomy 2 (13%) 0 Ventilator 0 2 (5%) Follow-up Group 558 months 637 months Patient a (32.9) (11.7) a p PGI2 Prostaglandin I 2. met the criteria for PHTN. Two patients who received heart-lung transplants were excluded. There were 15 patients in group A (PPH) and 40 patients in group B (SPH). There were 6 single lung transplant patients and 9 bilateral lung transplant patients in group A; and there were 19 single lung transplant patients and 21 bilateral lung transplant patients in group B. There were five right single lung transplants and one left single lung transplant performed in group A; and there were 10 right single lung transplants and 9 left single lung transplants performed in group B. Cardiopulmonary bypass was used in all PPH patients, all SPH patients with a PAM greater than 40 mm Hg, and 50% (11 of 22) of those patients with a PAM less than or equal to 40 mm Hg. Those patients who did not require cardiopulmonary bypass were given a combination of inotropic agents, intravenous nitroglycerine, and inhaled nitric oxide (n 6) to avoid bypass. There were 27 male patients (3 PPH) and 28 female patients (12 PPH), (p 0.01). The mean age was years for group A and for group B, (p not significant). There was a total of 558 months of follow-up in group A and 637 in group B. The mean follow-up per patient was (median value, 33) in group A and (median value, 12) in group B(p 0.001) (Table 1). There were 13 patients (87%) who were in New York Heart Association class IV, and 2 patients who were in class III (13%) were in group A. In group B 26 patients were class IV (63%) and 14 patients were class III (37%) (p 0.05). All patients in group A were receiving continuous intravenous prostaglandin I 2 (PGI2); and 8 patients (20%) in group B were receiving PGI2 (p 0.05). There were 7 patients (47%) hospitalized at the time of transplantation in group A and 6 patients (15%) in group B

3 Ann Thorac Surg CONTE ET AL 2001;72: LUNG TRANSPLANTATION FOR PULMONARY HYPERTENSION 1675 Table 2. Secondary Pulmonary Hypertension: Patient Diagnoses and Pressure Groupings a Mean Pulmonary Artery Pressure 40 mm Hg Single Lung Transplants Bilateral Lung Transplants Mean Pulmonary Artery Pressure 40 mm Hg Single Lung Transplants Bilateral Lung Transplants Total patients (40) Parenchymal (26) Pulmonary Fibrosis (11) COPD (9) Cystic Fibrosis (6) Systemic (8) Scleroderma (5) Sarcoidosis (3) Congenital (2) Eisenmenger (2) Other (4) Thromboembolic (2) Bronchiectasis (1) Bronchial dysplasia (1) PAM 40 mm Hg 18 PAM 40 mm Hg a Patients in the secondary pulmonary hypertension group categorized by etiology of secondary pulmonary hypertension, type of procedure performed, and PAM. COPD chronic obstructive pulmonary disease; PAM mean pulmonary artery pressure. (p 0.05). Inotropic agents were required in 6 patients (40%) and two inotropic agents were required in 2 patients (13%) in group A. In group B, 2 patients (5%) required inotropic agents (p 0.05). An atrial septostomy was used in 2 patients (13%) in group A and none in group B. There were 2 patients on mechanical ventilation in group B and none in group A. Patients with SPH were categorized by the etiology of their SPH into parenchymal, systemic, congenital, or other etiologies groups. The patients were further stratified by their PAMs. Those patients whose PAM measurement was less than or equal to 40 mm Hg at the time of their transplantation were grouped together as were those with a PAM of more than 40 mm Hg. This categorization is used for later subgroup analyses (Table 2). Pulmonary Artery Pressures Pulmonary artery pressures were elevated in both groups with significantly higher pressures in the PPH group than the SPH group. The pulmonary artery systolic pressure (PAS) was (90) mm Hg versus (50) mm Hg (p 0.002) and the mean pulmonary artery pressure (PAM) was (52) mm Hg versus (33) mm Hg for the PPH and SPH groups (p 0.003). In the SPH group there were no differences in PAPs between any subgroups. Although the PAPs were gener- Table 3. Pulmonary Artery Pressure a Preoperative Postoperative % Decrease Overall % Decrease Bilateral Lung Transplant % Decrease Single Lung Transplant Group A (primary pulmonary hypertension) Systolic (PAS) (90) b (43) 58.5 c 60.5 c 50.1 Mean (PAM) (52) b (29) 49.5 c 54.0 c 31.5 Group B (secondary pulmonary hypertension) Systolic (PAS) (50) b (37.5) Mean (PAM) (33) b (25) a Preoperative and postoperative pulmonary artery pressures in primary pulmonary hypertension and secondary pulmonary hypertension groups. Data presented as mean standard error (median). b p for preoperative and postoperative pressures in both groups. c p 0.01 in the percent decrease of pulmonary artery pressures between primary and secondary pulmonary hypertension. PAM mean pulmonary artery pressure; PAS pulmonary artery.

4 1676 CONTE ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR PULMONARY HYPERTENSION 2001;72: ally lower in the SPH group, all four subgroups had patients with PAPs equal to the PPH group. There were significant reductions in PAS and PAM postoperatively in both the PPH and SPH groups (p 0.003). Overall there was a greater percentage decrease in PAP in the PPH group; PAS 58.5% versus 30.1% and PAM 49.5% versus 24.1% (p 0.014). In the PPH group, patients undergoing BLT experienced a greater drop in PAS (60.5% vs 24.8%) and PAM (54.0% vs 30.2%) (p 0.004) than that seen in the SPH group. Bilateral lung transplantation provided a greater reduction in PAP than SLT in the PPH group, but the difference did not reach statistical significance (p 0.07) (Table 3). Infection There were clinically significant infections in 20% of the PPH patients (3 of 15) and 28% of the SPH patients (11 of 40) in the first 30 days (p 0.13) and 13% of each group (2 of 15 PPH) and (5 of 40 SPH) between 31 and 60 days (p 0.49). There was no significant difference in the overall incidence of infection or that of bacterial, fungal, or viral infections between the PPH and SPH groups or between SLT and BLT within groups. Bacterial infections were the most common in each group, comprising 54% of the PPH and 57% of the SPH infections, with the remainder of infections equally split between fungal and viral in each group. Bacterial pneumonias were the most common infection overall. Rejection There was no significant difference in the overall incidence of rejection between the PPH and SPH groups. The incidence of acute rejection in the first 30 days posttransplantation was 7% (1 of 15) in the PPH group and 10% (4 of 40) in the SPH group (p 0.66). Between 31 and 60 days the incidences were 7% and 13%, respectively for the PPH and SPH groups (p 0.56). The overall incidence of acute cellular rejection (any grade) was episodes per patient per month of survival in the PPH group and 0.07 in the SPH group (p 0.12). The incidence of obliterative bronchiolitis syndrome was low and equivalent in both groups with no predilection for SLTs or BLTs; there were 3 patients in the PPH group and 7 patients in the SPH group. Ventilation The duration of mechanical ventilation was longer in the PPH group overall: days (median, 8 days) versus days (median, 4 days) (p 0.46). In both groups the duration of mechanical ventilation was greater in the BLT groups but did not reach significance. In the PPH group the duration of mechanical ventilation was days (median, 7 days) for SLTs and days (median, 9 days) for BLTs (p 0.39). In the SPH group the duration of mechanical ventilation was days (median, 3 days) and days (median, 5 days) for SLTs and BLTs, respectively (p 0.84). Between groups the duration of mechanical ventilation with BLT was significantly lower in the PPH group (p 0.04). In the Fig 1. Kaplan-Meier survival curves for primary pulmonary hypertension group based on procedure performed. (ALL acute lymphocytic leukemia; BLT bilateral lung transplantations; SLT single lung transplantations.) SPH group there was no difference in the high or low pressure groups. Length of Hospitalization and Intensive Care Unit Length of Stay The overall length of hospitalization was greater in the PPH group ( days; 33 days versus days; median, 24 days) but did not reach significance overall or between SLT recipients (p 0.41). The BLT patients in the PPH group had the longest overall length of hospitalization ( days; median, 30 days), whereas in the SPH group it was days (median, 22 days) (p 0.001). The length of hospitalization for SLT recipients was days (median, 38 days) and days (median, 19 days) for PPH and SPH patients, respectively (p 0.53). In the SPH group there was no difference in the high or low pressure groups. The intensive care unit length of stay was higher in the PPH group overall, days (median, 18 days) versus days (median, 7 days) but did not reach significance (p 0.25). The intensive care unit stay was longer in the PPH BLT group ( days; median, 22 days versus days; median, 9 days) for the SPH BLT group (p 0.005). There was no difference between SLT or BLT in the SPH group or between the high or low pressure groups. Survival There were 2 early deaths ( 30 days) in the PPH group and 3 in the SPH group. In the PPH group 2 SLT recipients died of multisystem organ failure after courses marked by reperfusion injury and infection. In the SPH group 2 BLT recipients died of acute graft failure, one SLT died of multisystem organ failure (MSOF) and one of sepsis. Two late deaths ( 30 days) occurred in the PPH group due to posttransplant lymphoproliferative disease and obliterative bronchiolitis. In the SPH group two late deaths were due to obliterative bronchiolitis and two to sepsis and MSOF. The actuarial survival was evaluated in several ways. The overall 4-year actuarial survival was very similar

5 Ann Thorac Surg CONTE ET AL 2001;72: LUNG TRANSPLANTATION FOR PULMONARY HYPERTENSION 1677 Fig 2. Kaplan-Meier survival curve for secondary pulmonary hypertension group based on procedure performed. (ALL acute lymphocytic leukemia; BLT bilateral lung transplantations; n.s. not significant; SLT single lung transplantations.) between the PPH and SPH groups as a whole encompassing both SLT and BLT, 80% versus 73% (p 0.75). When the groups were evaluated based on the type of procedure performed differences emerged. In the PPH group the survival for BLT at all time points up to 4 years was 100% versus 67% at 30 days and 50% at 4 years for the SLT recipients (p 0.001) (Fig 1). In the SPH group there was a slight survival advantage with the SLT at 30 days, 94% versus 82%, and at 4 years it was 76% versus 71%, which was not significant (p 0.93) (Fig 2). When the SPH patients were broken down into groups based on a greater than or less than 40 mm Hg there was a nonsignificant survival advantage seen at 30 days for SLTs in the group with a PAM more than 40 mm Hg, 100% versus 80% (p 0.31). This difference was equalized by 1 year and remained the same up to 4 years posttransplantation. In the PAM less than or equal to 40 mm Hg group, survival was 100% for both SLT and BLT at 30 days, but by one year an insignificant advantage was seen for SLT 91% versus 75% which was maintained out to 4 years (p 0.81) (Fig 3). When all patients with a PAM greater than 40 mm Hg were looked at together (15 PPHs and 18 SPHs) and Fig 3. Kaplan-Meier survival curves for secondary pulmonary hypertension group based on mean pulmonary arterial pressure and transplant type. (BLT bilateral lung transplantations; n.s. not significant; pts patients; SLT single lung transplantations.) Fig 4. Kaplan-Meier survival curve for all patients with mean pulmonary arterial pressure (PAM) more than 40 mm Hg based on transplant type. (BLT bilateral lung transplantations; SLT single lung transplantations.) compared with those patients with a PAM less than or equal to 40 mm Hg (12 SPHs) some differences were seen. There was a small survival advantage at 30 days (87% versus 82%) for BLT that increased by 1 year (87% versus 62%) and this was maintained to 4 years but never reached statistical significance (p 0.19) (Fig 4). Comment The optimal LT procedure for PHTN is not known and likely never will be agreed upon by all practitioners. The three procedures that are currently being used include SLT, BLT, and HLT, and each procedure has its own advocates [13]. Proponents of SLT have argued that SLT is an easier procedure to perform, has less morbidity and mortality associated with it than BLT or HLT, results in less ischemic time, therefore an SLT has better early graft function, requires less bypass time, has improved early survival associated with it, and will allow more patients to receive lung transplants. Proponents of BLT have argued that bilateral lung transplants result in less ventilation perfusion (V/Q) mismatches, are easier to care for in the perioperative period, will enable more marginal lungs to be utilized, will provide better overall lung function, are protective against the physiologic manifestations of obliterative bronchiolitis, and have a better long-term survival. Both procedures have been accepted by practitioners and likely will be acceptable for the foreseeable future. Heart-lung transplantion probably will never reassume the large role it once had in LT for PHTN because of the donor organ shortage and the reality of the organ allocation system in the United States. The aim of this study was to identify whether a survival advantage existed between SLT and BLT in two groups of patients (PPH and SPH groups). Many articles have been written about LT for PHTN, but relatively few have been written about SPH with an effort to look at this group in detail [14]. In fact most articles have ignored the large group of patients with SPH due to nonvascular etiologies. We were intentionally inclusive and tried to dissect this group of patients to elucidate any differences between

6 1678 CONTE ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR PULMONARY HYPERTENSION 2001;72: them and the PPH group, and to find the best procedure for each group. We specifically selected a mean PAP of 30 mm Hg as the threshold level to define PHTN. This pressure is above generally accepted criteria for PHTN and has been used commonly in peer reviewed literature on LT for PHTN [3 5, 14, 15]. In one of the first articles dealing with LT for PHTN, Pasque and colleagues [2] reported on 34 patients with PHTN and 24 patients with PPH. They described a 91% 30-day survival with 1-year, 2-year, and 3-year survivals of 78%, 66%, and 61% with SLT, respectively. Most survivors (91%) were in New York Heart Association class I or II. The subgroup of PPH patients did slightly better than the overall group with a 30-day survival of 96%, and 1-year, 2-year, and 3-year survivals of 87%, 76%, and 68%, respectively. The SPH patients in that series consisted of 7 patients with congenital cardiac abnormalities, 5 patients of whom had concomitant repairs, and 3 patients with other fibrotic diseases. The differences in survival between PPH and SPH patients were not statistically significant. This study did not include BLT and included only a small percentage of SPH patients who were not well characterized because this was not the aim of the article. The University of Pittsburgh has extensive experience in LT for PHTN and many of the most informative articles in recent years have come from their group. Early articles from this group supported BLT or HLT [4, 5]. The most recent article by Gammie and colleagues [3] updated their experience reviewing 58 LT procedures over 7 years from 1989 to 1996 (19 PPH and 39 SPH) [17]. The SPH patients consisted of 29 with Eisenmenger s syndrome, 3 patients each with scleroderma, thromboembolic PHTN, and 4 patients with other diagnoses. They found similar 30-day survivals with SLT and BLT of 84% and 81%, respectively, and identical 1-year and 4-year survivals of 67% and 57%. Similar to our article, the MPAPs were modestly higher after transplantation in the SLT recipients compared with the BLT recipients, and the BLT patients had somewhat longer intensive care unit stays (p not significant), ventilation, and hospital stays. They noted no difference in New York Heart Association functional status, and in the incidence of obliterative bronchiolitis, although other authors have made an association between PHTN and the development of obliterative bronchiolitis in SLT recipients [18]. Unlike our patients, their SLT and BLT patients had marked preoperative similarity...(pg 400). Our PPH patients were clearly more ill and this may have contributed to the improved survival with BLT. The authors concluded that because of the high mortality of patients with PHTN on the lung transplantation waiting list they support cautious preferential application of SLT for PHTN. They will avoid SLT if the donor is undersized...(pg402) or if the donor lung is less than pristine [3]. A recent study from the University of Vienna reviewed 16 BLT patients with PPH [9], Eisenmenger [4], and chronic pulmonary thromboemboli [3]. They found universally excellent hemodynamic outcomes, resolution of echocardiographic cardiac abnormalities, and survivals approaching 80% at 4 years with BLT. They concluded that BLT should be the preferential method of treating end stage PHTN with HLT reserved for special indications such as patients with Eisenmenger s syndrome caused by complex congenital heart disease (pg 2894) [7]. This is similar to the recommendation from the University of Michigan [19]. Heart-lung transplantation has lost the primary position it once held in the field of LT for PHTN, but contemporary reports on the outcomes with HLT are available. The Stanford group recently looked at HLT for PPH in They reported an 18% operative mortality, 72% 1-year and 42% five-year survival [8]. The group at the Alfred hospital in Victoria, Australia found 2-year survivals of approximately 65% for both HLT and BLT in patients with PPH and Eisenmenger s syndrome [10]. These articles were consistent with earlier reports for HLT including the 1994 article by Bando and colleagues [5] which described a hospital survival of 88% with HLTx and a 1-year survival of 70% for PPH and Eisenmenger s syndrome patients. The survival was 82% and 80%, respectively for the BLT patients in that series. The extensive Harefield experience of 186 HLTs for PHTN due to PPH (1 of 3) and SPH (2 of 3) from 1983 through 1996 resulted in a 30-day survival of 78%, and 1-year, 5-year, and 10-year survivals of 60%, 44%, and 35% [9]. Lower survivals have been noted, however, including 2-year and 4-year survivals of 49% and 41%, with HLT for 21 patients reported by Chapelier and colleagues [6]. The only other recent article that has attempted to look at the impact of PHTN on survival came from the University of Colorado. In this article the authors looked at the impact of PHTN (PAM 30 mm Hg) on survival of SLTs in patients with and without SPH. They excluded patients with PPH and SPH due to Eisenmenger s syndrome. The institutional preference is to perform SLTs for PHTN. They found no difference in survival between the SPH patients and the controls. However, it is important to point out that the degree of PHTN was lower than in our SPH group. The PAM was mm Hg; no patients had a PAM more than 40 mm Hg, and no patients required cardiopulmonary bypass or inhaled nitric oxide to perform the LT. However, their results do agree with our findings that patients with a PAM of between 30 to 40 mm Hg do equally as well with SLT as BLT. Limited numbers and a heterogeneous population hampered the interpretation of our results. This may be the reason that several findings did not reach statistical significance. We did not have enough patients to evaluate the benefits of SLT versus BLT based on the etiology of their SPH. The patients who underwent BLT in both groups were clearly more ill than the patients who underwent SLT, as was the PPH group overall. Perhaps this obscured several issues. What we were able to do was review a group of contemporary patients whose PHTN has been treated with the full medical armamentarium known to date, including PGI2 and inhaled nitric oxide, over a short time period; this is something that most articles on the subject have not done. Our ability to

7 Ann Thorac Surg CONTE ET AL 2001;72: LUNG TRANSPLANTATION FOR PULMONARY HYPERTENSION 1679 stratify patients based on the degree of PHTN was enlightening, even if we could not show statistical significance in some outcomes. Our finding that patients with higher PAPs may have a survival advantage with BLT, regardless of the etiology, is illustrative of just that point. We did not address several issues. Among them were the importance of the degree of reduction in PAPs. It is generally accepted that BLT will reduce PAP, and more importantly, pulmonary vascular resistance to a greater degree; therefore, we did not explore this issue to a large extent. In reality, it is unclear how important this issue is in terms of its impact on survival. The issues of HLT versus BLT and cardiac repair are complex and incompletely evaluated to date [19]. An evaluation that takes into account the complexity of the defect and the severity of the PHTN needs to be undertaken before the correct answer will be known. Our program s belief is that all patients with severe PHTN (PAM 40 mm Hg) are best treated with BLT. We based this partly on our findings in this study and partly on our observations indicating that these patients are subjectively more difficult to take care of postoperatively. Patients with lesser degrees of PHTN can be treated with either BLT or SLT. Early- and mid-survival may be equivalent but there may be a long-term advantage to BLT. However, donor organ availability is the ultimate adjudicator, and as we and others have shown, acceptable (if not equivalent) survival is achievable with SLT with any degree of PHTN. References 1. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982;306: Pasque MK, Trulock EP, Cooper JD, et al. Single lung transplantation for pulmonary hypertension: single institution experience in 34 patients. Circulation 1995;92: Gammie JS, Keenan RJ, Pham SM, et al. Single versus double lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1998;115: Bando K, Keenan RJ, Paradis IL, et al. Impact of pulmonary hypertension on outcome after single lung transplantation. Ann Thorac Surg 1994;58: 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: Chapelier A, Vouhe P, Macchiarini P, et al. Comparative outcome of heart-lung and lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1993;106: Birsan T, Zuckerman Z, Artermiou O, et al. Bilateral lung transplantation for pulmonary hypertension. Transplant Proc 1997;29: Whyte RI, Robbins RC, Altinger J, et al. Heart-lung transplantation for primary pulmonary hypertension. Ann Thorac Surg 1999;67: Mikhail G, Al-Kattan K, Banner N, et al. Long-term results of heart lung transplantation for pulmonary hypertension. Transplant Proc 1997;29: Ueno T, Smith JA, Snell GI, et al. Bilateral sequential single lung transplantation for pulmonary hypertension and Eisenmenger s syndrome. Ann Thorac Surgery 2000;2: Kramer MR, Valantine HA, Marshall SE, Starnes VA, Theodore J. Recovery of the right ventricle after single lung transplantation in pulmonary hypertension. Am J Cardiol 1994;73: Schulman LL, Leibowitz DW, Anandarangam T, et al. Variability of right ventricular functional recovery after lung transplantation. Transplantation 1996;15: Hosenpud JD, Bennett LE, Keck BM, et al. The Registry of the International Society of Heart and Lung Transplantation: seventeenth official report. J Heart Lung Transplant 2000: Huerd SS, Hodges TN, Grover FL, et al. Secondary pulmonary hypertension does not adversely affect outcome after single lung transplantation. J Thorac Cardiovasc Surg 2000; 119: McLaughlin VV, Rich S. Pulmonary hypertension: advances in medical and surgical interventions. J Heart Lung Transplant 1998;17: Maurer JR, Frost AE, Estenne M, et al. International guidelines for the selection of lung transplant candidates. Transplant 1998;66: Park SJ, Savitt MA, Bolman RM. Single or double lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1999;117: Kshettry VR, Kroshus TJ, Savik K, et al. Primary pulmonary hypertension as a risk factor for the development of obliterative bronchiolitis in lung allograft recipients. Chest 1996; 110: Lupinetti FM, Bolling SF, Bove EL, et al. Selective lung or heart-lung transplantation for pulmonary hypertension associated with congenital cardiac anomalies. Ann Thorac Surg 1994;57: DISCUSSION DR FREDERICK L. GLOVER (Denver, CO): Thank you for a very well presented and important article. We would agree that the literature is very confusing regarding transplantation for pulmonary hypertension because of mixing primary pulmonary hypertension patients with those with secondary pulmonary hypertension. For that reason, our group reported the University of Colorado experience at the American Association for Thoracic Surgery meeting in 1999 on secondary pulmonary hypertension patients only. Your results in many ways confirm the findings of our study. We had about 18 patients with secondary pulmonary hypertension, the majority being in the less severe category with a mean pulmonary artery pressure of 30 to 39 and found that our 1-, 2- and 4-year survival with single lung transplantation was 81%, 81%, and 61%, respectively. We had the disadvantage of not being able to compare results of double versus single lung transplantation because we have always performed single lung transplantation for this group of patients. Your report is very important because it does not show an advantage of double lung transplantation over single lung for moderate secondary pulmonary hypertension. There are still some groups that perfrom double lung transplantation for moderate secondary pulmonary hypertension, but hopefully your data will result in a more conservative approach, allowing for better organ allocation for the precious few donor lungs that are available. We have very seldom used cardiopulmonary bypass in this group of secondary pulmonary hypertension patients, and I am

8 1680 CONTE ET AL Ann Thorac Surg LUNG TRANSPLANTATION FOR PULMONARY HYPERTENSION 2001;72: curious as to whether you have done these with or without bypass. DR CONTE: We have actually done them both with and without bypass for those patients with mean pressures less than 40. In that group, approximately 65% of the patients still require bypass. For those that do not, we use inhaled nitric oxide as well as intravenous nitroglycerine to try and allow us to do it, and in fact, in that small group of patients, 2 patients had to be converted to bypass during the procedure, which can sometimes be difficult. So we are kind of up in the air whether we should try to apply bypass universally or whether to try and use nitric oxide, which is a very expensive alternative, and in fact is more expensive than using a bypass set-up for the operation. So I do not think we have an answer and I do not think anybody does, just because the numbers are too small. DR CURT G. TRIBBLE (Charlottesville, VA): John, I enjoyed your presentation and wanted to ask you one question. I did not have a chance to review this ahead of time and do not have any data like Fred did, but we too have been very discouraged with trying to use single lung transplantation for these patients with pulmonary hypertension despite some groups claims that you could do it. I have one specific question for you. We have had some patients where we are trying to push the envelope. Of course, everybody would love to do single lung transplants. They are quicker, they are less morbid, and you can transplant more patients. We have had a few people that we transplanted who were on the fringe, in that range where they probably ended up in the operating room with pulmonary pressures in the range of 40 to 50, mostly systolic and maybe even higher, some of which may have risen since the last study. Some of those people have had terrible postoperative pulmonary edema, such that we could hardly ventilate or oxygenate them. We salvaged a few of them with nitric oxide. You mentioned that you tried that in the operating room, so I wondered what your thoughts were about using it postoperatively if you get in this type of trouble. I am sure you have found yourself in that situation. DR CONTE: Unfortunately, I think all of us have. What we generally do is we are very aggressive about trying to prevent that, and the things that we do to try and prevent it are that we prime our pump with colloids only, whether it is fresh frozen plasma, albumin or blood. We aggressively diurese these patients postoperatively. We keep very low cyclosporine or FK levels postoperatively, and we use induction therapy, and we are also very aggressive about keeping the patient sedated and keeping high mean airway pressures. Patients will routinely come out of the operating room who have undergone operations for pulmonary hypertension with the positive end-expiratory pressure set at about 15 cm, and we believe that this really does help prevent the development of the pulmonary reperfusion injury. As far as using it postoperatively, we use it when we get into trouble. We have not found that it has a significant impact on preventing trouble, but it does absolutely make a big difference once you have gotten into trouble. We have had several patients who have gotten through probably only because they have.