Long-Term Outcome of Lung and Heart-Lung Transplantation for ...

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Long-Term Outcome of Lung and Heart-Lung Transplantation for Idiopathic Pulmonary Arterial Hypertension Yoshiya Toyoda, MD, PhD, Jnanesh Thacker, MD, Ricardo Santos, MD, Duc Nguyen, MD, Jay Bhama, MD, Christian Bermudez, MD, Robert Kormos, MD, Bruce Johnson, MD, Maria Crespo, MD, Joseph Pilewski, MD, Jeffrey Teuteberg, MD, Rene Alvarez, MD, Michael Mathier, MD, Dennis McNamara, MD, Kenneth McCurry, MD, Marco Zenati, MD, and Brack Hattler, MD, PhD Departments of Surgery and Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Background. The survival after lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension has been reportedly the lowest among the major diagnostic categories of lung transplant recipients. Methods. Retrospective analysis was performed for lung and heart-lung transplant recipients for idiopathic pulmonary arterial hypertension from 1982 to 2006. The patients were divided into 2 groups, based on the era; group 1: 1982 to 1993, and group 2: 1994 to 2006. Since 1994, we have introduced our current protocols including prostaglandin E1 and nitroglycerin for donor lung preservation, and lung protection with cold and terminal warm blood pneumoplegia as well as immunosuppression with alemtuzumab induction. These modifications were introduced in different years over a wide span of time (1994 to 2003). Results. Group 1 had 59 patients (35 ⴞ 1 years old, ranging 15 to 53, 20 male and 39 female) with 7 single

lung, 11 double lung, and 41 heart-lung, whereas group 2 had 30 (43 ⴞ 2 years old, ranging 17 to 65, 9 male and 21 female) with 2 single, 20 double, and 8 heart-lung transplantations. The recipient age was significantly (p ⴝ 0.004) higher in group 2, and group 2 had significantly older (35 ⴞ 3 vs 26 ⴞ 1, p ⴝ 0.002) and more female donors (73% vs 41%, p ⴝ 0.007) compared with group 1. The actuarial survival was significantly (p ⴝ 0.004) better in group 2 with 86% at 1 year, 75% at 5 years, and 66% at 10 years compared with group 1 with 58% at 1 year, 39% at 5 years, and 27% at 10 years. Conclusions. With our current pulmonary protection and immunosuppression, the long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension is excellent.

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purpose of this study was to evaluate the long-term outcome of lung and heart-lung transplantation for IPAH at a single center over 25 years and to compare the contemporary outcome with previous years.

he survival after lung and combined heart-lung transplantation for idiopathic pulmonary arterial hypertension (IPAH) and Eisenmenger syndrome has been reported to be the lowest among all lung transplant recipients [1]. The updated International Heart and Lung Transplantation Registry based on the data from January of 1994 to June of 2004 shows that IPAH still has the lowest survival rate at 1 year among all lung transplant recipients, and the second lowest at 5 years following idiopathic pulmonary fibrosis, and that the actuarial survival after lung transplantation for IPAH is 66% at 1 year, 47% at 5 years, and 27% at 10 years [2]. Previously, we have reported the short- and medium-term outcome of lung and heart-lung transplantation for primary and secondary pulmonary hypertension [3, 4]. However, the long-term outcome of lung and heart-lung transplantation specifically for IPAH was unknown. Therefore, the Accepted for publication May 15, 2008. Address correspondence to Dr Toyoda, Cardiothoracic Transplantation, University of Pittsburgh Medical Center, 200 Lothrop Street, C-900 PUH, Pittsburgh, PA 15213; e-mail: [email protected].

© 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2008;86:1116 –22) © 2008 by The Society of Thoracic Surgeons

Patients and Methods The University of Pittsburgh Medical Center (UPMC) lung and heart-lung transplant evaluation and recipient research registry is approved by the University of Pittsburgh Institutional Review Board for the use of patient management, quality assurance reports, and clinical research. Individual consent to act as a subject in a research study was obtained for each patient. Data were prospectively collected into the Web-based Transplant Patient Management System, and the data were retrospectively reviewed to evaluate the long-term outcome of lung and heart-lung transplantation for IPAH, performed at UPMC Presbyterian Hospital from 1982 to 2006. Patients at the UPMC Children’s Hospital were excluded. To compare the contemporary outcomes with previous 0003-4975/08/$34.00 doi:10.1016/j.athoracsur.2008.05.049

TOYODA ET AL LUNG AND HEART-LUNG TRANSPLANT FOR IPAH

Table 1. University of Pittsburgh Medical Center Presbyterian Protocol: Pulmonary Protection During Donor and Recipient Surgery Year Introduced Donor lung procurement: Adequate venting of the left atrium Topical cooling with ice slush Prostaglandin E1 bolus injection before cross-clamp Prostaglandin E1 in the first bag of preservation solution Nitroglycerin in the first bag of preservation solution Retrograde flush Preservation solution: Perfadex Recipient Surgery: Topical cooling with ice slush Cold blood pneumoplegia Terminal warm blood pneumoplegia Methylprednisolone bolus injection before reperfusion

1994 1994

1998 2001

1996 1996

Table 2. University of Pittsburgh Medical Center Presbyterian Protocol: Postoperative Management Year Introduced

PEEP ⫽ positive end-expiratory pressure.

Table 3. Composition of Pneumoplegia Dextrose (50%) Insulin (regular) Glutamate-aspartate Lidocaine Adenosine Nitroglycerin Verapamil Deferoxamine Ascorbic acid Hematocrit

5 gm/L 20 units/L 0.92 M 100 mg/L 3 mg/L 2.5 mg/L 2.5 mg/L 125 mg/L 250 mg/L 20 ⫾ 5%

1997

years, the patients were divided into two groups solely based on the era. Group 1 represents the first half from 1982 to 1993 and group 2 the second half from 1994 to September of 2006. Our current UPMC protocols for lung transplantation are shown in Tables 1 and 2. For donor lung procurement, we give a bolus injection of prostaglandin E1 500mcg into the main pulmonary artery immediately

Ventilator management: Low tidal volume: 6 cc/kg of the donor body weight PEEP 10–15 cm H2O Immunosuppression: Induction (before reperfusion) Methylprednisolone 1 g Alemtuzumab 30 mg Maintenance Tacrolimus: Goal: 12–15 ng/mL Mycophenolate mofetil: 750 mg twice a day Prednisolone: 5 mg once a day Infection prophylaxis: Cytomegalovirus valganciclovir for 6 months Fungus, yeast voriconazole for 4 months Clostridium difficile metronidazole during hospitalization Pneumocystis carinii trimethoprim/sulfamethoxazole

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2000 2000

2003 1990 1997

2003 2003

before cross-clamp and add additional prostaglandin E1 500 mcg in the first bag of the preservation solution, which was started in 1994. We started to add nitroglycerin 50 mg in the first bag in 1997. We introduced retrograde flush with preservation solution from the pulmonary veins at the donor back table in 1998. We switched the preservation solution from Euro-Collins to Perfadex (Vitrolife AB, Gothenburg, Germany) in 2001. We give 70 cc/kg of Perfadex antegradely through the main pulmonary artery in the operative field and 1 liter of Perfadex for each lung retrogradely through the pulmonary veins at the back table. During the recipient surgery, we give cold blood pneumoplegia and terminal warm blood pneumoplegia, which was started in 1996. The composition of our pneumoplegia is shown in Table 3. Since 2000, we do ventilatory management with low tidal volume (6 cc/kg of the donor body weight) and high positive end-expiratory pressure (PEEP). For immunosuppression, we give 30 mg of alemtuzumab (Campath 1-H; Genzyme Corporation, Cambridge, MA) before reperfusion as an immunosuppressive induction, which was started in 2003. For maintenance immunosuppression, we use tacrolimus and started to use mycophenolate mofetil in 1997. We use mycophenolate mofetil in half dose (750 mg twice daily) and minimize steroid (5 mg once daily). Because of alemtuzumab induction that causes profound T-cell depletion for 6 months, we give valganciclovir for cytomegalovirus prophylaxis for 6 months and voriconazole against fungus and yeast for 4 months.

Statistical Analysis Statistical analysis was performed using SPSS version 14.0 (SPSS Inc. Chicago, IL). Data are shown as mean plus or minus standard error of the mean. The unpaired, two-tailed t test was used to compare independent continuous variables between the two groups. The Fisher exact test was used to determine if there are nonrandom associations between two categoric variables. KaplanMeier analysis was used to calculate actuarial survival and the log-rank test was used to test the null hypothesis that there is no difference in Kaplan-Meier survival curve between the groups. Univariate and multivariate analysis was performed using logistic regression to identify risk factors contributing to mortality. All factors with a value

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Table 4. Patient Demographics: Recipient and Donor Factors

Variables

Fig 1. Heart-lung versus lung transplantation. Kaplan-Meier survival after lung and combined heart-lung transplantation (Tx) for primary pulmonary hypertension from 1982 to 2006. (— ⫽ heartlung Tx; - - - ⫽ lung Tx.)

of p ⬍ 0.05 by univariate analysis were included in the multivariate analysis.

Results Long-Term Outcome From 1982 to 2006 From May of 1982 to September of 2006, 949 patients received lung and heart-lung transplants including 444 single lung, 384 double lung, and 121 combined heartlung transplants at UPMC Presbyterian Hospital. Idiopathic pulmonary arterial hypertension was the indication for lung and heart-lung transplantation in 10% of our recipients, but IPAH was the most common indication for combined heart-lung transplantation in 45% of our heartlung transplant recipients. Eighty-nine patients underwent lung and heart-lung transplants for IPAH. Three redo-lung transplants and 1 combined heart-lung-liver transplant were excluded from this study. The mean age

Fig 2. Heart-lung versus double lung versus single lung transplantation (Tx). Kaplan-Meier survival after lung and combined heartlung transplantation for primary pulmonary hypertension from 1982 to 2006. (— ⫽ double lung Tx; - - - ⫽ single lung Tx; – – – ⫽ heart-lung Tx.)

Recipient: Age (years) Age (range, years) Gender, male BMI sPAP (mm Hg) PCWP (mm Hg) CI (L/min/m2) TPG (mm Hg) PVR (Wood unit) LVEF IT, right lung (min) IT, left lung (min) CPB time (min) Donor: Age (years) Age (range, years) Gender, male

Group 1 1982–1993 (n ⫽ 59)

Group 2 1994–2006 (n ⫽ 30)

35 ⫾ 1 15–53 20 (34%) 25 ⫾ 1 94 ⫾ 4 10 ⫾ 1 2.2 ⫾ 0.1 52 ⫾ 3 14 ⫾ 1 0.59 ⫾ 0.05 294 ⫾ 35 301 ⫾ 22 200 ⫾ 8

43 ⫾ 2 17–65 9 (30%) 26 ⫾ 1 88 ⫾ 3 8⫾1 2.3 ⫾ 0.1 48 ⫾ 2 13 ⫾ 1 0.60 ⫾ 0.01 320 ⫾ 19 283 ⫾ 16 216 ⫾ 12

26 ⫾ 1 12–55 34 (58%)

35 ⫾ 3 9–58 8 (27%)

p Value 0.004 0.81 0.60 0.20 0.14 0.40 0.26 0.69 0.88 0.48 0.50 0.28 0.002 0.007

BMI ⫽ body mass index; CI ⫽ cardiac index; CPB ⫽ cardiopulmonary bypass; IT ⫽ ischemic time; LVEF ⫽ left ventricular ejection fraction; PCWP ⫽ pulmonary capillary wedge pressure; PVR ⫽ pulmonary vascular resistance; sPAP ⫽ systolic pulmonary artery pressure; TPG ⫽ transpulmonary gradient.

was 38 ⫾ 1 years, ranging 15 to 65. There were 29 males and 60 females. The actuarial survival for combined heart-lung transplantation was 61% at 1 year, 40% at 5 years, 33% at 10 years, 23% at 15 years, and 19% at 20 years; it was 74% at 1 year, 62% at 5 years, and 39% at 10 years for lung transplantation (Fig 1). There was no statistical difference (p ⫽ 0.367) in overall survival between combined heart-lung and lung transplantation. Similarly, there was no significant difference (p ⫽ 0.655) in overall survival among heart-lung versus double lung (77% at 1 year, 64% at 5 years, and 40% at 10 years) versus single lung (67% at

Fig 3. Kaplan-Meier survival after lung and combined heart-lung transplantation for primary pulmonary hypertension (1982 to 1993 vs 1994 to 2006). (— ⫽ 1982 to 1993; – – – ⫽ 1994 to 2006.)


Table 5. Survival After Lung Transplantation for Primary Pulmonary Hypertension

UPMC Presbyterian 1994–2006 ISHLT 23rd Report 1994–2004

1 Year (%)

5 Years (%)

10 Years (%)

86 66

75 47

66 27

ISHLT ⫽ International Society of Heart and Lung Transplantation; UPMC ⫽ University of Pittsburgh Medical Center.

1 year, 56% at 5 years, and 33% at 10 years) transplantation (Fig 2).

Comparison of Contemporary Outcomes With Previous Years Group 1 (1982 to 1993) had 59 patients including 41 heart-lung, 11 double lung, and 7 single lung transplants, and group 2 (1994 to 2006) had 30 patients including 8 heart-lung, 20 double lung, and 2 single lung transplants. The recipients’ age was significantly (p ⫽ 0.004) higher up to 65 years in group 2 and group 2 had significantly older (p ⫽ 0.002) and more (p ⫽ 0.007) female donors compared with group 1. There was no significant difference in preoperative hemodynamics, ischemic time, or cardiopulmonary bypass time between the groups (Table 4). The actuarial survival was significantly (p ⫽ 0.004) better in group 2 with 86% at 1 year, 75% at 5 years, and 66% at 10 years compared with group 1 with 58% at 1 year, 39% at 5 years, and 27% at 10 years (Fig 3). The survival rates of our patients are approximately 20% to 40% better than the most recent ISHLT registry data, the 23rd official report from the registry of the International Society of Heart and Lung Transplantation (Table 5). With our current UPMC protocols altogether since 2003, all patients are surviving 6 heart-lung transplants and 7 double lung transplants (actuarial survival: 100% at 2 years).

Cause of Death In group 1, 49 patients died due to the following: chronic rejection (n ⫽ 22), infection (n ⫽ 9), primary graft failure (n ⫽ 4), technical/bleeding (n ⫽ 4), malignancy (n ⫽ 2), multiple organ failure (n ⫽ 2), aortic aneurysm (n ⫽ 1), and others (n ⫽ 5). In group 2, 7 patients died due to

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infection (n ⫽ 4), primary graft failure (n ⫽ 2), and others (n ⫽ 1). In group 1, 25 patients died within 1 year due to infection (n ⫽ 6), primary graft failure (n ⫽ 4), bleeding (n ⫽ 4), rejection (n ⫽ 3), and others (n ⫽ 8); in group 1, 4 patients died within 1 year due to primary graft failure (n ⫽ 2), infection (n ⫽ 1), and unknown (n ⫽ 1). The incidence of histologic bronchiolitis obliterans per patient was significantly higher (p ⬍ 0.01) in group 1 versus group 2 (1.6 episodes per patient vs 0.5), and the incidence of histologic bronchiolitis obliterans per biopsy was also significantly higher (p ⬍ 0.01) in group 1 versus group 2 (0.2 episode per biopsy vs 0.06) (Fig 4).

Logistic Regression The univariate analysis identified use of prostaglandin E1 injection (odds ratio: 16.1; confidence interval: 5.4 to 47. 7, p ⬍ 0.01), donor retrograde flush at the back table (odds ratio: 15.6; confidence interval: 4.6 to 53.2, p ⬍ 0.01), use of Perfadex (odds ratio: 25.4; confidence interval: 5.3 to 122, p ⬍ 0.01), use of pneumoplegia during recipient surgery (odds ratio: 10.8; confidence interval: 3.7 to 31.0, p ⬍ 0.01), and postoperative ventilator management (odds ratio: 18.8, confidence interval: 4.9 to 72.3, p ⬍ 0.01) as significant predictors of survival. The multivariate analysis showed use of prostaglandin E1 injection (odds ratio: 9.8; confidence interval: 1.8 to 52.4, p ⫽ 0.007), use of pneumoplegia during recipient surgery (odds ratio: 3.8; confidence interval: 1.1 to 12.7, p ⫽ 0.03), and postoperative ventilatory management (odds ratio: 21.3; confidence interval: 5.1 to 89.4, p ⬍ 0.01) as significant predictors of survival.

Comment The 23rd official report from the registry of the ISHLT shows that IPAH had the highest perioperative mortality rate among the major diagnostic categories of lung transplant recipients, the lowest survival rate at 1 year, and the second lowest at 5 years [2]. This suggests that the outcome of lung and heart-lung transplantation for IPAH has been suboptimal, and because of that and possibly due to recent advancement of medical treatment for pulmonary artery hypertension, it is possible that pulmonologists and cardiologists hesitate to list the patients on

Fig 4. Incidence of histologic evidence of bronchiolitis obliterans. (A) Episode per patient. (B) Episode per biopsy.

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the lung and heart-lung transplant waiting list before the patients become critically sick. Klepetko and colleagues [5] have suggested that as medical therapies have improved, recipient selection criteria has extended to its limit in many patients before transplantation, and in such a situation, potential recipients can be transformed into high-risk or unacceptable candidates for transplantation and the opportunity for transplantation can be lost. However, it is also possible that recent advancements in surgical techniques of donor and recipient surgery, organ preservation, and perioperative management including immunosuppression and infection prophylaxis and treatment improve the outcome of lung and heart-lung transplant for IPAH, and if that is the case, it becomes reasonable for pulmonologists and cardiologists to list patients for transplantation earlier rather than too late. In this study, we show dramatic improvements in both short- and long-term outcomes in lung and heart-lung transplantation for IPAH. Since 1994, the survival rate after lung and heart-lung transplantation is 86% at 1 year, 75% at 5 years, and 66% at 10 years, which is better by approximately 20% to 40% compared with the most recent ISHLT data, which are 66% at 1 year, 39% at 5 years, and 27% at 10 years (Table 5). Given our previous survival rate from 1982 to 1993 that was 58% at 1 year, 39% at 5 years, and 27% at 10 years, similar to the current ISHLT data, it is reasonable to speculate that changes made after 1994 have improved the outcome. This speculation is further supported by our most recent outcome, in which with our current protocols altogether since 2003, all recipients including 6 combined heart-lung and 7 double lung transplants are surviving with actuarial survival of 100% at 2 years. As shown in Tables 1 and 2, we made several important changes in our donor lung procurement protocols such as bolus injection of prostaglandin E1 before cross-clamp, addition of prostaglandin E1 and nitroglycerin in the first bag of Perfadex, and retrograde flush with Perfadex from the pulmonary veins at the back table. Naka and colleagues [6] have reported that prostaglandin E1 is beneficial to the lung through not only a vasodilating effect of the pulmonary vasculature but also nonvasodilating effects such as decreased graft neutrophil infiltration, vascular permeability, and platelet deposition by increasing cyclic adenosine monophosphate levels [6]. The nitric oxide donor, nitroglycerin, has also been shown to maintain pulmonary vascular homeostatic properties, reducing neutrophil and platelet accumulation and modulating vasomotor tone, and to have additive protective effects to Perfadex [7, 8]. Perfadex, that is a 5% dextran-based, lightly buffered extra-cellular low K⫹ electrolyte solution, is reported to protect the lung better than other types of solutions such as University of Wisconsin or Euro-Collins [8, 9]. It has been shown to have effects against edema formation and alveolar epithelial damage [10]. Retrograde flush of preservation solution from the pulmonary veins can perfuse both pulmonary artery and bronchial artery circulation and achieve more homogeneous distribution of preservation solution regardless of pulmonary artery vasoconstriction compared with antegrade pulmo-


nary artery flush only [11]. In addition, we often see thrombi and emboli coming out from the pulmonary artery during the retrograde flush. Clearing the pulmonary emboli is certainly beneficial for the oxygenation as well as the reduction of afterload to the right ventricle after transplantation. Use of prostaglandin E1, Perfadex, and retrograde flush was identified as significant predictors of survival by the univariate analysis and of these the use of prostaglandin remained significant with multivariate analysis. For recipient surgery, we give cold blood pneumoplegia and terminal warm blood pneumoplegia to protect the lungs from ischemia-reperfusion injury. Oxygenderived free radicals are shown to be involved in mechanisms of pulmonary reperfusion injury [12]. Efficacy of glutamate-aspartate for cardioprotection is well documented by Rosenkranz and colleagues [13] who have shown it improves metabolic and functional recovery of cardiac myocytes, and glutamate-aspartate is also shown to decrease incidence of lung ischemia-reperfusion injury [14]. Lidocaine is also reported to reduce reperfusion injury in lung allografts by inhibiting neutrophil adhesion and migration to the lung allograft [15]. Previously, we have shown that adenosine enhances cardioprotection through antistunning, antiinfarct, and antiapoptotic effects against ischemia-reperfusion injury by adenosine receptors and ATP sensitive potassium channels [16 –18]. Adenosine is also shown to reduce inflammation and preserve pulmonary function in an in vivo model of lung transplantation through adenosine A2A receptor activation [19]. Verapamil, a calcium antagonist, would prevent Ca2⫹ overload and is shown to reduce myocardial infarct size by prostacyclin pathway [20]. Iron chelation with deferoxamine is an oxygen free radical scavenger and is shown to improve lung preservation, resulting in increased oxygenation and decreased pulmonary vascular resistance [21]. These mechanisms are in agreement with the result of the multivariate analysis, which demonstrated pneumoplegia as a significant predictor of survival. Since the Acute Respiratory Distress Syndrome Network demonstrated that mechanical ventilation with a lower tidal volume resulted in decreased mortality and increased the number of days without ventilator use [22], we have maintained the tidal volume low at 6 cc/kg of the donor body weight to prevent barotraumas. We also use higher PEEP ranging from 10 to 15 cm H2O in order to decrease the fraction of inspired oxygen that would decrease oxygen-derived free radical injury caused by ischemia-reperfusion. This postoperative ventilatory management is also identified as a significant predictor of survival by multivariate analysis. For immunosuppression for lung and combined heartlung transplantation, we started alemtuzumab induction with steroid minimization in 2003 [23]. Since then, early outcome after transplantation has improved with fewer episodes of acute rejections [23]. In group 1 (1982 to 1993), 37% (22 of 59) of recipients died of chronic rejection whereas no (0 of 30) recipient died of chronic rejection in group 2 (1994 to 2006) at this point of time. Of course,

patients in group 1 have a longer follow-up period during which patients can be more likely to suffer from chronic rejection. Accordingly, the episode of histologic bronchiolitis obliterans per patient was significantly higher in group 1 compared with group 2. However, the episode of histologic bronchiolitis obliterans per biopsy demonstrated that the patients in group 2 had a significantly lower incidence of chronic rejection, suggesting that patients in recent years may really have less chronic rejection that could explain the better long-term outcome (Fig 4). Even in the recent literature [1, 2], the mechanisms of chronic rejection after lung transplantation are still unknown, but ischemia-reperfusion injury and acute rejection have been reported to contribute to the development of chronic rejection. With our current protocol, we have better protection against ischemia-reperfusion and better immunosuppressive protocol, at least against acute rejection [23], which may explain the lower incidence of chronic rejection. In our previous reports [3, 4] we have demonstrated that single lung transplant can provide similar short- and medium-term survival to double lung transplant for pulmonary hypertension, which is in agreement with the result in this study where there was no difference in overall long-term survival between single and double lung transplants, although single lung transplant recipients tend to have some disadvantages, such as less symptomatic improvements and longer intensive care unit stay [3]. Others reported similar findings [24] and suggested that we could utilize lung donors more efficiently with single lung transplant because two recipients can receive each lung from a donor instead of one recipient getting both lungs, and thus single lung transplant may be better for optimal use of limited donor organ supply [24]. However, we stopped doing a single lung transplant in 1998. There are three reasons. First, the long-term outcome tends to be better with double lung transplant especially for young patients, according to the ISHLT data [2]; patients with IPAH are young in general and in fact the mean age of our recipients with IPAH was 38 years. Second, postoperative management is safer and easier with double lung transplant as we and others have indicated [1, 25]. Third, from the donor resource standpoint, we do not think doing a single lung transplant for IPAH patients would save much of donor resources because, for a single lung transplant for IPAH, the donor lung has to be perfect due to the postoperative ventilation-perfusion mismatch, so we need to decline a marginal donor for this reason. Therefore, it may take a longer time for patients with IPAH to find a suitable donor for single lung transplant. If we do a double lung transplant, we can take marginal donors. In fact, we have aggressively extended the donor selection criteria and often take marginal donors that other centers decline [26]. With our strategy, it seems to be quicker to find a suitable double lung donor for IPAH recipients and we may be able to utilize donor resources more efficiently. We determine who receives heart-lung versus double lung transplant based on preoperative inotropic requirements. If a patient is chronically inotropic dependent, we


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perform a combined heart-lung transplant, and if not, a double lung transplant. Of course, even inotropicdependent patients may do well with double lung transplant alone as others suggest [1, 2], but our data suggest that our indication for combined heart-lung transplantation is reasonable from the outcome standpoint. However, if some of the patients with chronic inotropic therapy do well with double lung transplantation without heart, we need to figure out how much inotropic dependency is too much for double lung transplant. Double lung transplant is inevitably better than combined heartlung transplant from a donor resource standpoint. Major limitations of this study are twofold. First, this is a retrospective study. Second, this is a single center study. Therefore, a prospective, randomized, multicenter study is warranted to further clarify the factors influencing the improved outcome. In conclusion, this study shows significant improvement in the long-term survival of lung and combined heart-lung transplantation for IPAH in recent years as compared with previous years, and with our current pulmonary protection and immunosuppressive techniques, the contemporary outcome is excellent. Based on this current improved outcome of lung and combined heart-lung transplantation for IPAH, potential recipients should be listed before they develop refractory right heart failure and multiple organ dysfunctions such as liver and kidney.

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