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Lung transplantation in children with idiopathic pulmonary arterial hypertension: An 18-year experience
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Lung transplantation in children with idiopathic pulmonary arterial hypertension: An 18-year experience Brian S. Goldstein, MD,a Stuart C. Sweet, MD,a Jingnan Mao, MS,a Charles B. Huddleston, MD,b and R. Mark Grady, MDa From the Departments of aPediatrics and bSurgery, Washington University School of Medicine, St. Louis, Missouri.
KEYWORDS: pediatric; lung transplantation; idiopathic pulmonary hypertension
BACKGROUND: The natural history of idiopathic pulmonary arterial hypertension (IPAH) in patients of all ages is one of relentless progression. For those who fail medical therapy, lung transplantation remains the ultimate palliation. In the USA, IPAH is the second leading indication for lung transplantation in children and first for children 1 to 5 years of age. In this study, we report our 18-year experience with lung transplantation in children with IPAH. METHODS: We performed a retrospective chart review of children with IPAH listed for lung transplant at our center between 1991 and 2009. Our data reflect a total of 26 children ranging in age from 1.6 to 18.9 years. Nineteen were transplanted and 7 died while waiting (27%). The impact of a number of pre-transplant variables on survival was evaluated. RESULTS: Median survival for those transplanted was 5.8 years, with 1- and 5-year survival rates of 95% and 61%, respectively. Survival was independent of pre-transplant considerations such as age, weight, need for intravenous (IV) inotropes, use of IV pulmonary vasodilators, year of transplant and severity of right-sided cardiac pressures. There was 1 hospital death. Compared with the transplanted group, children who died waiting had a significantly higher incidence of supra-systemic right heart pressures (p ⫽ 0.02) and hemoptysis (p ⫽ 0.01). CONCLUSIONS: Our study is the largest to date to look at outcomes for lung transplantation in children with IPAH. Their median survival compares favorably with that of all pediatric lung transplant recipients, 5.8 years vs 4.5 years, respectively. We did not identify any pre-transplant variables that presaged a poorer outcome. Thus, survival seemed more related to factors that influence long-term outcomes in all transplant recipients such as rejection and infection. Lung transplantation remains a viable option for children with IPAH, especially for those with supra-systemic right heart pressures despite maximal medical therapy. J Heart Lung Transplant 2011;30:1148 –52 © 2011 International Society for Heart and Lung Transplantation. All rights reserved.
Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease that primarily afflicts young adult women.1,2 Its natural history is one of relentless progression with ⬍50% living 3 years from the time of their diagnosis. Within the last 10 years, however, with increased awareness, specialized treatment centers, and the advent of pulmonary vasospecific dilators, there has been a dramatic increase in overall survival with ⬎60% of patients now living beyond 5 years from the time of diagnosis.3 Although the data are less Reprint requests: R. Mark Grady, MD, Department of Pediatrics, Washington University, 1 Children’s Place, Campus Box 8116 NWT, St. Louis, MO 63110. Telephone: 314-454-6095. Fax: 314-454-2561. E-mail address: [email protected]
prevalent, similar results are seen in children with IPAH. Without therapy, the natural history in children appears even worse than that of adults, while, in the current era of treatment, 5-year survival has been reported to be as high as 72%.4,5 Despite these improvements in outcomes, however, current treatment remains palliative and most patients will eventually die from their disease. For those IPAH patients failing medical therapy, lung transplantation remains the ultimate palliation. In the USA, IPAH is the second leading indication for lung transplantation in children and number one for children between 1 and 5 years of age.6 Despite the relatively frequent use of lung transplantation in children with IPAH, there have been no long-term studies published
1053-2498/$ -see front matter © 2011 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2011.04.009
Goldstein et al.
Pediatric Lung Transplantation for IPAH
1149
regarding their survival. In this report, we describe our nearly 20-year experience with lung transplantation in children diagnosed with IPAH and assess the impact of pre- and peri-operative variables upon survival.
pressures greater than systemic (left ventricular) pressures; or (2) right ventricular pressures less than or equal to systemic pressures. Transplantation techniques, immunosuppression protocols and post-transplant care have been described previously.7 Type of operation was bilateral lung (n ⫽ 13), single lung (n ⫽ 2), heart– bilateral lung (n ⫽ 3) or bilateral living-donor lobar transplant. Two of the 3 patients who underwent coincident heart transplant were believed to have irreversible right heart failure, whereas the third had developed significant mitral valve disease and sub-aortic stenosis. None of the 3 had left ventricular failure. Major postoperative complications were considered to be cardiopulmonary failure requiring extracorporeal membrane oxygenation (ECMO), bleeding that required surgical re-exploration or residual anatomic defects requiring either surgical or catheter-based intervention. Survival was based on death or lung re-transplantation (1 patient). Late deaths (after initial hospital discharge) were due to infection, bronchiolitis obliterans or heart failure.
Methods Patients We performed a retrospective chart review of patients diagnosed with IPAH who were listed for lung transplantation. Our data reflect a total of 26 pediatric patients listed for transplantation at St. Louis Children’s Hospital between 1991 and 2009. Ages of the 19 children who underwent transplantation ranged from 1.6 to 18.9 years. Seven children died while waiting for a transplant. The diagnosis of IPAH implies elevated pulmonary artery pressures in the absence of any definable cause. Excluded therefore were children with significant obstructive congenital heart disease (pulmonary vein stenosis) or with unrestrictive systemic to pulmonary shunts (e.g., large ventricular septal defect or patent ductus arteriosus). Eight children had trivial to small atrial-level shunts, and 1 child had a small-to-moderate primum atrial septal defect (nonTrisomy 21). Children diagnosed with persistent pulmonary hypertension of the newborn were also excluded. All patients were classified as World health Organization (WHO) Functional Class IV and were listed for transplantation for progressive symptoms. Time on the transplant list includes both active (accepting viable organ offers) days and inactive (not accepting organ offers but maintaining “transplant” status) days. Only 1 patient had a history of previous cardiothoracic surgery (ventricular septal defect closure before the age of 2 years). Nine children had native atrial-level shunts as described earlier, and 3 children underwent static balloon atrial septostomy via cardiac catheterization for symptoms secondary to low cardiac output. Intravenous (IV) pulmonary vasodilator therapy consisted of epoprostenol or treprostenol. IV inotropic support involved milrinone, dopamine or dobutamine. Oral pulmonary vasodilators utilized were sildenafil, bosentan or both. Oral heart failure medications include digoxin, diuretics or both. Anti-coagulation consisted of aspirin or warfarin. Echocardiographic and catheterization data were utilized to categorize children as having: (1) right ventricular
Table 1
Statistics Descriptive analysis was used to describe the mean and standard deviation for the variables assessed. The Cox proportional hazard regression model with maximum-likelihood estimates was used to analyze the effect of risk factors on death or re-transplantation. Hazard ratios and 95% confidence intervals were reported. Wilcoxon’s rank sum, chi-square and Fisher’s exact tests were used for comparison analyses between groups. Kaplan–Meier survival analysis was used to estimate survival time. p ⬍ 0.05 was considered statistically significant. Data analysis was performed using SAS (version 9.1) software (SAS, Inc., Cary, NC).
Results Pre-transplantation data Age at the time of operation for the 19 children successfully transplanted varied widely from 1.6 to 18.9 years of age, with weights ranging from 9.1 to 75 kg (Table 1). Twelve (63%) were girls and all were considered to be WHO Functional Class IV for patients with pulmonary hypertension. Sixteen children (84%) were treated for right heart
Demographic Characteristics and Pre-transplantation Data
Age at transplant (years)a Weight (kg)a Gender (females) Hemoptysis Oral heart failure medication Oral pulmonary vasodilators IV inotropes IV pulmonary vasodilators Supra-systemic RV pressure Time on transplant wait list (days)a
Transplanted (n ⫽ 19)
Died waiting (n ⫽ 7)
p-valueb
12.3 ⫾ 4.8 38.0 ⫾ 21 12 (63%) 3 (16%) 14 (74%) 2 (11%) 10 (53%) 13 (68%) 9 (47%) 402 ⫾ 664
13.2 ⫾ 1.9 43.1 ⫾ 11 6 (86%) 5 (71%) 6 (86%) 3 (43%) 4 (57%) 3 (43%) 7 (100%) 434 ⫾ 331
0.9 0.5 0.4 0.01 0.9 0.1 0.9 0.4 0.02 0.3
IV, intravenous; RV, right ventricular. a Expressed as mean ⫾ standard deviation. b Compares those transplanted vs those who died waiting.
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failure, 10 (53%) with intravenous inotropes. Nine children (47%) developed supra-systemic right-sided cardiac pressures. IV prostacyclins were utilized in 13 (63%) children. The 6 patients who did not receive prostacyclins were transplanted before 1997, a time prior to our consistent use of this medication in children with IPAH. Similarly, because 14 of the 19 children (74%) were transplanted before 2000, only 2 were treated with the relatively newer oral pulmonary-specific vasodilators bosentan, sildenafil or both. Three children underwent atrial septostomies for symptoms of low cardiac output, whereas 9 had native atrial level shunts ranging in size from trivial to moderate (1 patient). Despite the severity of disease, only 2 children required intensive care at the time of transplant with just 1 needing mechanical ventilation. The average wait time on the transplant list was 402 days (⬃1.1 years), with a wide range of 16 days to ⬎8 years. Seven of the 26 children listed for transplantation (⬃27%) died while waiting for a suitable donor. They were comparable to the transplanted group with regard to age, size and time on the transplant waiting list (Table 1). Furthermore, there was no difference between the two groups in their use of heart failure medications or pulmonary-specific vasodilators. What was significantly different in the children who died waiting for transplant was evidence of supra-systemic right-sided cardiac pressures (died waiting: 100%; transplanted: 47%; p ⫽ 0.02) and the presence of hemoptysis either at presentation or later in their disease course (died waiting: 71%; transplanted: 16%; p ⫽ 0.01).
Operative and post-operative data Thirteen of the 19 (68%) children underwent a bilateral lung transplant, whereas the others had either a single-lung, heart–lung or living-related donor transplant. Ischemic time for the transplanted organs averaged 245 minutes with a range of 87 to 313 minutes (Table 2). The shortest ischemic time involved the 1 child who underwent a living-related donor transplant. Total bypass time averaged 179 minutes. Average time spent in the intensive care unit after transplant was 14 days, with a range of 4 to 34 days. Four patients (21%) had a major post-operative complication: 3 developed cardiopulmonary failure requiring placement on ECMO, and 1 needed re-exploration for bleeding and stenting of a pulmo-
Table 2
Operative and Post-operative Data
ICU at time of transplant Type of transplant (BLTx) Ischemic time (min)a Bypass time (min)a ICU time (days)a Major post-operative complications In-hospital deaths
2 (11%) 13 (68%) 246 ⫾ 61 179 ⫾ 50 14 ⫾ 10 4 (21%) 1 (5%)
BLTx, bilateral lung transplant; ICU, intensive care unit. a Data expressed as mean ⫾ standard deviation.
Figure 1 Survival of children with idiopathic pulmonary hypertension after lung transplantation. Median survival was 5.8 years.
nary vein. All children but 1 (95%) were successfully discharged from the hospital after transplant. The 1 in-house death was secondary to a nosocomial para-influenza infection.
Survival Median survival for the entire group was 5.8 years with 1and 5-year survival of 95% and 61%, respectively (Figure 1). Six of the 19 patients are still alive with our longest survivor ⬎18 years post-transplant. Late deaths (and 1 retransplantation) were due to either infection or bronchiolitis obliterans. We assessed a number of pre- and peri-operative variables with regard to their impact on survival (Table 3).
Table 3 Risk Factors for Death After Transplant or Retransplantation
Pre-transplantation data Age at transplant Weight Gender (female) Use of IV inotropes Use of IV pulmonary vasodilator Suprasystemic RV pressure Presence of ASD Time on transplant wait list Date of transplant Operative and post-operative data Type of transplant (BLTx) Ischemic time of organs Bypass time Major post-operative complication
HR
95% CI
p-value
1.0 1.0 1.8 1.3 2.2 0.9 1.5 1.0 1.0
0.9–1.1 1.0–1.0 0.6–6.1 0.4–3.8 0.8–6.9 0.3–2.7 0.5–4.6 1.0–1.0 1.0–1.0
0.4 0.8 0.3 0.2 0.1 0.8 0.5 0.2 0.3
0.5 1.0 1.0 2.6
0.1–2.0 1.0–1.0 1.0–1.0 0.7–9.5
0.4 0.7 0.7 0.1
ASD, atrial septal defect; BLTx, bilateral lung transplant; CI, confidence interval; HR, hazard ratio; IV, intravenous; RV, right ventricular.
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Gender, size and age of child did not influence survival. Thus, the 9-kg toddler had the same outcome as the 75-kg teenager. Patients with evidence of right heart failure requiring IV inotropes had no worse outcomes. Similarly, children with supra-systemic right ventricular pressures had a survival comparable to those with lower pressures. Thus, the data suggest that children who had evidence of being “sicker,” with worse right heart dysfunction at the time of transplant, had no worse survival after transplant. However, as noted by other investigators and by our pre-transplant deaths, poor right heart mechanics in children with IPAH increases the risk of dying from the disease.3 Presence or absence of an atrial-level shunt, which theoretically benefits patients with more advanced disease, did not influence posttransplant survival. Similarly, children treated with pulmonary-specific vasodilators also had no long-term advantage. Time spent on the transplant list did not influence survival. Interestingly, and perhaps disappointingly, although our first child was transplanted almost 20 years ago, we found that survival was not influenced by year of transplant. Type of transplant, ischemic time of the transplanted organs and total bypass time also did not correlate with outcome. Surprisingly, a major post-operative complication did not significantly influence long-term survival.
intensive care prior to transplant and only 1 needed mechanical ventilation. Nonetheless, 10 children received IV inotropes for evidence of right heart failure and 9 had developed supra-systemic right-sided cardiac pressures. Despite these signs of worsening disease, however, neither presaged a poorer outcome post-transplant. Still, worsening hemodynamics and right heart failure together are an ominous prognostic sign for patients with IPAH.2,3 Thus, perhaps not surprisingly, the children in our series who died while waiting for transplant all had supra-systemic right-sided cardiac pressures. A caveat to this discussion is the child with IPAH who progresses to catastrophic right heart failure and requires full mechanical cardiopulmonary support, specifically ECMO. Our dismal experience in transplanting children requiring ECMO has led us to currently consider it a contraindication to lung transplantation.10 Newer technologies, however, such as extracorporeal membrane ventilators (e.g., Novalung), may alter transplant consideration and management of children with critical end-stage lung disease.11 We recently managed a young child with severe IPAH who presented in shock from acute right heart failure.12 He was initially stabilized with ECMO but was then transitioned to the Novalung. Aggressive pulmonary vasodilator therapy was begun and he was listed for lung transplantation. Fortunately, his symptoms improved dramatically allowing for his eventual discharge home on medical therapy, which obviated, for the time, the need for transplant. A relatively rare complication of IPAH is hemoptysis. The significance of this symptom in IPAH patients is unclear from any published data and possibly reflects more advanced disease. To that end, we found that ⬃70% of the children who died waiting for transplant in our study exhibited hemoptysis compared with only ⬃16% of those successfully transplanted. Therefore, children with IPAH and supra-systemic right-sided cardiac pressures who develop hemoptysis should be given additional priority in the lung allocation system. With the advent of powerful pulmonary-specific vasodilators, beginning with IV prostacyclins in the mid-1990s, coupled with the increasingly sophisticated management of IPAH in general, overall survival for IPAH patients has improved dramatically.3,5 This relative success in treating IPAH has allowed many patients to delay consideration of lung transplantation. Indeed, in our series, nearly 75% of the children were transplanted prior to 2000, with only 1 transplant since 2005. IV prostacyclins currently appear to be the most effective medical therapy for IPAH, both in adults and children.13,14 In our study, 12 children were receiving prostacyclins at the time of transplant. The 7 who did not were transplanted before 1997, prior to our routine use of prostacyclins in children with IPAH. Interestingly, utilization of prostacyclins had no impact, positive or negative, upon post-transplant survival. Nonetheless, given its apparent efficacy, we currently would not consider lung transplantation in a child with IPAH who has not had a trial of prostacyclin therapy.
Discussion Our study is the largest to date looking at survival after lung transplantation in children diagnosed with IPAH. The 19 children transplanted over an 18-year period (from 1991 to 2009) ranged in age from 1.6 to 18.9 years and had a median survival of 5.8 years. This compares favorably with a median survival of 4.5 years for all pediatric patients undergoing lung transplantation (cystic fibrosis being the leading indication).6 Children who underwent lung transplantation at our institution with associated congenital heart disease, such as pulmonary vein stenosis or Eisenmenger syndrome, fared slightly better than children with IPAH, with a median survival of 6.1 and 6.4 years, respectively.8 Our median survival rate of 5.8 years is remarkably similar to that seen in adults who undergo lung transplantation for IPAH, who have a median survival of 5.6 years.9 We assessed a number or pre-transplant variables for their impact on post-transplant outcomes. Interestingly, we found that neither age nor size influenced survival despite ages ranging from 1.6 to 18.9 years and weights from 9.1 to 75 kg. This finding is consistent with our previous observation that showed a similar survival post–lung transplant in children with pulmonary vein stenosis (mainly infants) vs those with Eisenmenger syndrome (mainly teenagers).8 Thus, age or size of a child should not be a barrier to consideration of lung transplantation for IPAH. We assessed whether children who had worse hemodynamics and/or signs of right heart failure fared more poorly after transplant, especially in the immediate post-operative period. Although all 19 children transplanted in our study were considered WHO Functional Class IV, only 2 were in
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According to the 2009 annual report from the International Society for Heart and Lung Transplantation, adults undergoing lung transplant for IPAH had the worst 3-month survival rate for any pre-transplant diagnosis, an outcome attributed primarily to early post-operative graft dysfunction.9 In our series, we had only 1 in-hospital death secondary to a nosocomial para-influenza infection. Thus, our in-house mortality was 5%, with all other children living beyond 1 year (1-year survival of 95%). These outcomes were unaffected by the type of transplant. In the past, concern for irreversible right ventricular dysfunction posttransplant led to several of our children receiving heart transplants in addition to bilateral lungs. However, we found that children who needed intravenous inotropes for right heart failure or had supra-systemic right heart pressures prior to transplant had survival rates similar to those who did not. Furthermore, none of the children post-transplant died of right heart failure. Thus, the significant right heart dysfunction seen pre-transplant improves substantially post-transplant, a finding observed in adult series as well.15 Unfortunately, our data are insufficient to specifically address the important question of whether one can predict, pre-transplant, the “recoverability” of right heart function post-surgery. Currently, we favor bilateral lung transplant alone for children with IPAH and reserve heart– bilateral lung transplant for those children with concomitant left heart failure. Our study is the largest to date to assess outcomes for lung transplantation in children with IPAH. We found a median survival of 5.8 years with 1-, 3- and 5-year survival of 95%, 73% and 61%, respectively. We did not identify any pre-transplant or operative variables that affected survival, thus outcome in our series seemed more related to those factors that influence long-term survival in all transplants, such as rejection and infection. With the advent of newer treatment strategies for IPAH, prognosis continues to improve, making timing of transplant a challenge. In our study, approximately 25% of the children listed for transplant died while waiting, all with evidence of supra-systemic right-sided cardiac pressures. Thus, it seems reasonable to consider transplant in those children who develop such unfavorable hemodynamics despite maximal therapy, including IV prostacyclins.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Chin K, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol 2008;51:1527-38. 2. D’Alonzo G, Barst R, Ayres S, et al. Survival in patients with primary pulmonary hypertension. Ann Intern Med 1991;115:343-9. 3. Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 2010;35:1079-87. 4. Rashid A, Ivy D. Pulmonary hypertension in children. Curr Paediat 2006;16:237-47. 5. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006. Heart 2009;95:312-7. 6. Aurora, P, Edwards LB, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric lung and heart/lung transplantation report—2009. J Heart Lung Transplant 2009;28:1023-30. 7. Mendeloff EN, Meyers BF, Sundt TM, et al. Lung transplantation for pulmonary vascular disease. Ann Thorac Surg 2002;73:209-19. 8. Grady RM, Gandhi S, Sweet SC, et al. Dismal lung transplant outcomes in children with tetralogy of Fallot with pulmonary atresia compared to Eisenmenger syndrome or pulmonary vein stenosis. J Heart Lung Transplant 2010;28:1221-5. 9. Christie JD, Edwards LB, Aurora P, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-sixth official adult lung and heart–lung transplantation report—2009. J Heart Lung Transplant 2009;28:1031-49. 10. Puri V, Epstein D, Raithel SC, et al. Extracorporeal membrane oxygenation in pediatric lung transplantation. J Thorac Cadiovasc Surg 2010;140:427-31. 11. Strueber M, Hoeper MM, Fischer S, et al. Bridge to thoracic organ transplantation in patients with pulmonary arterial hypertension using a pumpless lung assist device. Am J Transplant 2009;9:853-7. 12. Gazit AZ, Sweet SC, Grady RM, et al. First experience with a paracorporeal artificial lung in a small child with pulmonary hypertension. J Thorac Cardiovasc Surg (epub ahead of print). 13. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82. 14. Lammers AE, Hislop AA, Flynn Y, et al. Epoprostenol treatment in children with severe pulmonary hypertension. Heart 2007;93:739-43. 15. Saggar R, Lynch JP, Belperio JA, et al. Pulmonary arterial hypertension and lung transplantation. Sem Respir Crit Care Med 2010; 31:147-60.
Lung transplantation in children with idiopathic pulmonary arterial hypertension: An 18-year experience Brian S. Goldstein, MD,a Stuart C. Sweet, MD,a Jingnan Mao, MS,a Charles B. Huddleston, MD,b and R. Mark Grady, MDa From the Departments of aPediatrics and bSurgery, Washington University School of Medicine, St. Louis, Missouri.
KEYWORDS: pediatric; lung transplantation; idiopathic pulmonary hypertension
BACKGROUND: The natural history of idiopathic pulmonary arterial hypertension (IPAH) in patients of all ages is one of relentless progression. For those who fail medical therapy, lung transplantation remains the ultimate palliation. In the USA, IPAH is the second leading indication for lung transplantation in children and first for children 1 to 5 years of age. In this study, we report our 18-year experience with lung transplantation in children with IPAH. METHODS: We performed a retrospective chart review of children with IPAH listed for lung transplant at our center between 1991 and 2009. Our data reflect a total of 26 children ranging in age from 1.6 to 18.9 years. Nineteen were transplanted and 7 died while waiting (27%). The impact of a number of pre-transplant variables on survival was evaluated. RESULTS: Median survival for those transplanted was 5.8 years, with 1- and 5-year survival rates of 95% and 61%, respectively. Survival was independent of pre-transplant considerations such as age, weight, need for intravenous (IV) inotropes, use of IV pulmonary vasodilators, year of transplant and severity of right-sided cardiac pressures. There was 1 hospital death. Compared with the transplanted group, children who died waiting had a significantly higher incidence of supra-systemic right heart pressures (p ⫽ 0.02) and hemoptysis (p ⫽ 0.01). CONCLUSIONS: Our study is the largest to date to look at outcomes for lung transplantation in children with IPAH. Their median survival compares favorably with that of all pediatric lung transplant recipients, 5.8 years vs 4.5 years, respectively. We did not identify any pre-transplant variables that presaged a poorer outcome. Thus, survival seemed more related to factors that influence long-term outcomes in all transplant recipients such as rejection and infection. Lung transplantation remains a viable option for children with IPAH, especially for those with supra-systemic right heart pressures despite maximal medical therapy. J Heart Lung Transplant 2011;30:1148 –52 © 2011 International Society for Heart and Lung Transplantation. All rights reserved.
Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease that primarily afflicts young adult women.1,2 Its natural history is one of relentless progression with ⬍50% living 3 years from the time of their diagnosis. Within the last 10 years, however, with increased awareness, specialized treatment centers, and the advent of pulmonary vasospecific dilators, there has been a dramatic increase in overall survival with ⬎60% of patients now living beyond 5 years from the time of diagnosis.3 Although the data are less Reprint requests: R. Mark Grady, MD, Department of Pediatrics, Washington University, 1 Children’s Place, Campus Box 8116 NWT, St. Louis, MO 63110. Telephone: 314-454-6095. Fax: 314-454-2561. E-mail address: [email protected]
prevalent, similar results are seen in children with IPAH. Without therapy, the natural history in children appears even worse than that of adults, while, in the current era of treatment, 5-year survival has been reported to be as high as 72%.4,5 Despite these improvements in outcomes, however, current treatment remains palliative and most patients will eventually die from their disease. For those IPAH patients failing medical therapy, lung transplantation remains the ultimate palliation. In the USA, IPAH is the second leading indication for lung transplantation in children and number one for children between 1 and 5 years of age.6 Despite the relatively frequent use of lung transplantation in children with IPAH, there have been no long-term studies published
1053-2498/$ -see front matter © 2011 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2011.04.009
Goldstein et al.
Pediatric Lung Transplantation for IPAH
1149
regarding their survival. In this report, we describe our nearly 20-year experience with lung transplantation in children diagnosed with IPAH and assess the impact of pre- and peri-operative variables upon survival.
pressures greater than systemic (left ventricular) pressures; or (2) right ventricular pressures less than or equal to systemic pressures. Transplantation techniques, immunosuppression protocols and post-transplant care have been described previously.7 Type of operation was bilateral lung (n ⫽ 13), single lung (n ⫽ 2), heart– bilateral lung (n ⫽ 3) or bilateral living-donor lobar transplant. Two of the 3 patients who underwent coincident heart transplant were believed to have irreversible right heart failure, whereas the third had developed significant mitral valve disease and sub-aortic stenosis. None of the 3 had left ventricular failure. Major postoperative complications were considered to be cardiopulmonary failure requiring extracorporeal membrane oxygenation (ECMO), bleeding that required surgical re-exploration or residual anatomic defects requiring either surgical or catheter-based intervention. Survival was based on death or lung re-transplantation (1 patient). Late deaths (after initial hospital discharge) were due to infection, bronchiolitis obliterans or heart failure.
Methods Patients We performed a retrospective chart review of patients diagnosed with IPAH who were listed for lung transplantation. Our data reflect a total of 26 pediatric patients listed for transplantation at St. Louis Children’s Hospital between 1991 and 2009. Ages of the 19 children who underwent transplantation ranged from 1.6 to 18.9 years. Seven children died while waiting for a transplant. The diagnosis of IPAH implies elevated pulmonary artery pressures in the absence of any definable cause. Excluded therefore were children with significant obstructive congenital heart disease (pulmonary vein stenosis) or with unrestrictive systemic to pulmonary shunts (e.g., large ventricular septal defect or patent ductus arteriosus). Eight children had trivial to small atrial-level shunts, and 1 child had a small-to-moderate primum atrial septal defect (nonTrisomy 21). Children diagnosed with persistent pulmonary hypertension of the newborn were also excluded. All patients were classified as World health Organization (WHO) Functional Class IV and were listed for transplantation for progressive symptoms. Time on the transplant list includes both active (accepting viable organ offers) days and inactive (not accepting organ offers but maintaining “transplant” status) days. Only 1 patient had a history of previous cardiothoracic surgery (ventricular septal defect closure before the age of 2 years). Nine children had native atrial-level shunts as described earlier, and 3 children underwent static balloon atrial septostomy via cardiac catheterization for symptoms secondary to low cardiac output. Intravenous (IV) pulmonary vasodilator therapy consisted of epoprostenol or treprostenol. IV inotropic support involved milrinone, dopamine or dobutamine. Oral pulmonary vasodilators utilized were sildenafil, bosentan or both. Oral heart failure medications include digoxin, diuretics or both. Anti-coagulation consisted of aspirin or warfarin. Echocardiographic and catheterization data were utilized to categorize children as having: (1) right ventricular
Table 1
Statistics Descriptive analysis was used to describe the mean and standard deviation for the variables assessed. The Cox proportional hazard regression model with maximum-likelihood estimates was used to analyze the effect of risk factors on death or re-transplantation. Hazard ratios and 95% confidence intervals were reported. Wilcoxon’s rank sum, chi-square and Fisher’s exact tests were used for comparison analyses between groups. Kaplan–Meier survival analysis was used to estimate survival time. p ⬍ 0.05 was considered statistically significant. Data analysis was performed using SAS (version 9.1) software (SAS, Inc., Cary, NC).
Results Pre-transplantation data Age at the time of operation for the 19 children successfully transplanted varied widely from 1.6 to 18.9 years of age, with weights ranging from 9.1 to 75 kg (Table 1). Twelve (63%) were girls and all were considered to be WHO Functional Class IV for patients with pulmonary hypertension. Sixteen children (84%) were treated for right heart
Demographic Characteristics and Pre-transplantation Data
Age at transplant (years)a Weight (kg)a Gender (females) Hemoptysis Oral heart failure medication Oral pulmonary vasodilators IV inotropes IV pulmonary vasodilators Supra-systemic RV pressure Time on transplant wait list (days)a
Transplanted (n ⫽ 19)
Died waiting (n ⫽ 7)
p-valueb
12.3 ⫾ 4.8 38.0 ⫾ 21 12 (63%) 3 (16%) 14 (74%) 2 (11%) 10 (53%) 13 (68%) 9 (47%) 402 ⫾ 664
13.2 ⫾ 1.9 43.1 ⫾ 11 6 (86%) 5 (71%) 6 (86%) 3 (43%) 4 (57%) 3 (43%) 7 (100%) 434 ⫾ 331
0.9 0.5 0.4 0.01 0.9 0.1 0.9 0.4 0.02 0.3
IV, intravenous; RV, right ventricular. a Expressed as mean ⫾ standard deviation. b Compares those transplanted vs those who died waiting.
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The Journal of Heart and Lung Transplantation, Vol 30, No 10, October 2011
failure, 10 (53%) with intravenous inotropes. Nine children (47%) developed supra-systemic right-sided cardiac pressures. IV prostacyclins were utilized in 13 (63%) children. The 6 patients who did not receive prostacyclins were transplanted before 1997, a time prior to our consistent use of this medication in children with IPAH. Similarly, because 14 of the 19 children (74%) were transplanted before 2000, only 2 were treated with the relatively newer oral pulmonary-specific vasodilators bosentan, sildenafil or both. Three children underwent atrial septostomies for symptoms of low cardiac output, whereas 9 had native atrial level shunts ranging in size from trivial to moderate (1 patient). Despite the severity of disease, only 2 children required intensive care at the time of transplant with just 1 needing mechanical ventilation. The average wait time on the transplant list was 402 days (⬃1.1 years), with a wide range of 16 days to ⬎8 years. Seven of the 26 children listed for transplantation (⬃27%) died while waiting for a suitable donor. They were comparable to the transplanted group with regard to age, size and time on the transplant waiting list (Table 1). Furthermore, there was no difference between the two groups in their use of heart failure medications or pulmonary-specific vasodilators. What was significantly different in the children who died waiting for transplant was evidence of supra-systemic right-sided cardiac pressures (died waiting: 100%; transplanted: 47%; p ⫽ 0.02) and the presence of hemoptysis either at presentation or later in their disease course (died waiting: 71%; transplanted: 16%; p ⫽ 0.01).
Operative and post-operative data Thirteen of the 19 (68%) children underwent a bilateral lung transplant, whereas the others had either a single-lung, heart–lung or living-related donor transplant. Ischemic time for the transplanted organs averaged 245 minutes with a range of 87 to 313 minutes (Table 2). The shortest ischemic time involved the 1 child who underwent a living-related donor transplant. Total bypass time averaged 179 minutes. Average time spent in the intensive care unit after transplant was 14 days, with a range of 4 to 34 days. Four patients (21%) had a major post-operative complication: 3 developed cardiopulmonary failure requiring placement on ECMO, and 1 needed re-exploration for bleeding and stenting of a pulmo-
Table 2
Operative and Post-operative Data
ICU at time of transplant Type of transplant (BLTx) Ischemic time (min)a Bypass time (min)a ICU time (days)a Major post-operative complications In-hospital deaths
2 (11%) 13 (68%) 246 ⫾ 61 179 ⫾ 50 14 ⫾ 10 4 (21%) 1 (5%)
BLTx, bilateral lung transplant; ICU, intensive care unit. a Data expressed as mean ⫾ standard deviation.
Figure 1 Survival of children with idiopathic pulmonary hypertension after lung transplantation. Median survival was 5.8 years.
nary vein. All children but 1 (95%) were successfully discharged from the hospital after transplant. The 1 in-house death was secondary to a nosocomial para-influenza infection.
Survival Median survival for the entire group was 5.8 years with 1and 5-year survival of 95% and 61%, respectively (Figure 1). Six of the 19 patients are still alive with our longest survivor ⬎18 years post-transplant. Late deaths (and 1 retransplantation) were due to either infection or bronchiolitis obliterans. We assessed a number of pre- and peri-operative variables with regard to their impact on survival (Table 3).
Table 3 Risk Factors for Death After Transplant or Retransplantation
Pre-transplantation data Age at transplant Weight Gender (female) Use of IV inotropes Use of IV pulmonary vasodilator Suprasystemic RV pressure Presence of ASD Time on transplant wait list Date of transplant Operative and post-operative data Type of transplant (BLTx) Ischemic time of organs Bypass time Major post-operative complication
HR
95% CI
p-value
1.0 1.0 1.8 1.3 2.2 0.9 1.5 1.0 1.0
0.9–1.1 1.0–1.0 0.6–6.1 0.4–3.8 0.8–6.9 0.3–2.7 0.5–4.6 1.0–1.0 1.0–1.0
0.4 0.8 0.3 0.2 0.1 0.8 0.5 0.2 0.3
0.5 1.0 1.0 2.6
0.1–2.0 1.0–1.0 1.0–1.0 0.7–9.5
0.4 0.7 0.7 0.1
ASD, atrial septal defect; BLTx, bilateral lung transplant; CI, confidence interval; HR, hazard ratio; IV, intravenous; RV, right ventricular.
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Gender, size and age of child did not influence survival. Thus, the 9-kg toddler had the same outcome as the 75-kg teenager. Patients with evidence of right heart failure requiring IV inotropes had no worse outcomes. Similarly, children with supra-systemic right ventricular pressures had a survival comparable to those with lower pressures. Thus, the data suggest that children who had evidence of being “sicker,” with worse right heart dysfunction at the time of transplant, had no worse survival after transplant. However, as noted by other investigators and by our pre-transplant deaths, poor right heart mechanics in children with IPAH increases the risk of dying from the disease.3 Presence or absence of an atrial-level shunt, which theoretically benefits patients with more advanced disease, did not influence posttransplant survival. Similarly, children treated with pulmonary-specific vasodilators also had no long-term advantage. Time spent on the transplant list did not influence survival. Interestingly, and perhaps disappointingly, although our first child was transplanted almost 20 years ago, we found that survival was not influenced by year of transplant. Type of transplant, ischemic time of the transplanted organs and total bypass time also did not correlate with outcome. Surprisingly, a major post-operative complication did not significantly influence long-term survival.
intensive care prior to transplant and only 1 needed mechanical ventilation. Nonetheless, 10 children received IV inotropes for evidence of right heart failure and 9 had developed supra-systemic right-sided cardiac pressures. Despite these signs of worsening disease, however, neither presaged a poorer outcome post-transplant. Still, worsening hemodynamics and right heart failure together are an ominous prognostic sign for patients with IPAH.2,3 Thus, perhaps not surprisingly, the children in our series who died while waiting for transplant all had supra-systemic right-sided cardiac pressures. A caveat to this discussion is the child with IPAH who progresses to catastrophic right heart failure and requires full mechanical cardiopulmonary support, specifically ECMO. Our dismal experience in transplanting children requiring ECMO has led us to currently consider it a contraindication to lung transplantation.10 Newer technologies, however, such as extracorporeal membrane ventilators (e.g., Novalung), may alter transplant consideration and management of children with critical end-stage lung disease.11 We recently managed a young child with severe IPAH who presented in shock from acute right heart failure.12 He was initially stabilized with ECMO but was then transitioned to the Novalung. Aggressive pulmonary vasodilator therapy was begun and he was listed for lung transplantation. Fortunately, his symptoms improved dramatically allowing for his eventual discharge home on medical therapy, which obviated, for the time, the need for transplant. A relatively rare complication of IPAH is hemoptysis. The significance of this symptom in IPAH patients is unclear from any published data and possibly reflects more advanced disease. To that end, we found that ⬃70% of the children who died waiting for transplant in our study exhibited hemoptysis compared with only ⬃16% of those successfully transplanted. Therefore, children with IPAH and supra-systemic right-sided cardiac pressures who develop hemoptysis should be given additional priority in the lung allocation system. With the advent of powerful pulmonary-specific vasodilators, beginning with IV prostacyclins in the mid-1990s, coupled with the increasingly sophisticated management of IPAH in general, overall survival for IPAH patients has improved dramatically.3,5 This relative success in treating IPAH has allowed many patients to delay consideration of lung transplantation. Indeed, in our series, nearly 75% of the children were transplanted prior to 2000, with only 1 transplant since 2005. IV prostacyclins currently appear to be the most effective medical therapy for IPAH, both in adults and children.13,14 In our study, 12 children were receiving prostacyclins at the time of transplant. The 7 who did not were transplanted before 1997, prior to our routine use of prostacyclins in children with IPAH. Interestingly, utilization of prostacyclins had no impact, positive or negative, upon post-transplant survival. Nonetheless, given its apparent efficacy, we currently would not consider lung transplantation in a child with IPAH who has not had a trial of prostacyclin therapy.
Discussion Our study is the largest to date looking at survival after lung transplantation in children diagnosed with IPAH. The 19 children transplanted over an 18-year period (from 1991 to 2009) ranged in age from 1.6 to 18.9 years and had a median survival of 5.8 years. This compares favorably with a median survival of 4.5 years for all pediatric patients undergoing lung transplantation (cystic fibrosis being the leading indication).6 Children who underwent lung transplantation at our institution with associated congenital heart disease, such as pulmonary vein stenosis or Eisenmenger syndrome, fared slightly better than children with IPAH, with a median survival of 6.1 and 6.4 years, respectively.8 Our median survival rate of 5.8 years is remarkably similar to that seen in adults who undergo lung transplantation for IPAH, who have a median survival of 5.6 years.9 We assessed a number or pre-transplant variables for their impact on post-transplant outcomes. Interestingly, we found that neither age nor size influenced survival despite ages ranging from 1.6 to 18.9 years and weights from 9.1 to 75 kg. This finding is consistent with our previous observation that showed a similar survival post–lung transplant in children with pulmonary vein stenosis (mainly infants) vs those with Eisenmenger syndrome (mainly teenagers).8 Thus, age or size of a child should not be a barrier to consideration of lung transplantation for IPAH. We assessed whether children who had worse hemodynamics and/or signs of right heart failure fared more poorly after transplant, especially in the immediate post-operative period. Although all 19 children transplanted in our study were considered WHO Functional Class IV, only 2 were in
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According to the 2009 annual report from the International Society for Heart and Lung Transplantation, adults undergoing lung transplant for IPAH had the worst 3-month survival rate for any pre-transplant diagnosis, an outcome attributed primarily to early post-operative graft dysfunction.9 In our series, we had only 1 in-hospital death secondary to a nosocomial para-influenza infection. Thus, our in-house mortality was 5%, with all other children living beyond 1 year (1-year survival of 95%). These outcomes were unaffected by the type of transplant. In the past, concern for irreversible right ventricular dysfunction posttransplant led to several of our children receiving heart transplants in addition to bilateral lungs. However, we found that children who needed intravenous inotropes for right heart failure or had supra-systemic right heart pressures prior to transplant had survival rates similar to those who did not. Furthermore, none of the children post-transplant died of right heart failure. Thus, the significant right heart dysfunction seen pre-transplant improves substantially post-transplant, a finding observed in adult series as well.15 Unfortunately, our data are insufficient to specifically address the important question of whether one can predict, pre-transplant, the “recoverability” of right heart function post-surgery. Currently, we favor bilateral lung transplant alone for children with IPAH and reserve heart– bilateral lung transplant for those children with concomitant left heart failure. Our study is the largest to date to assess outcomes for lung transplantation in children with IPAH. We found a median survival of 5.8 years with 1-, 3- and 5-year survival of 95%, 73% and 61%, respectively. We did not identify any pre-transplant or operative variables that affected survival, thus outcome in our series seemed more related to those factors that influence long-term survival in all transplants, such as rejection and infection. With the advent of newer treatment strategies for IPAH, prognosis continues to improve, making timing of transplant a challenge. In our study, approximately 25% of the children listed for transplant died while waiting, all with evidence of supra-systemic right-sided cardiac pressures. Thus, it seems reasonable to consider transplant in those children who develop such unfavorable hemodynamics despite maximal therapy, including IV prostacyclins.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Chin K, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol 2008;51:1527-38. 2. D’Alonzo G, Barst R, Ayres S, et al. Survival in patients with primary pulmonary hypertension. Ann Intern Med 1991;115:343-9. 3. Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 2010;35:1079-87. 4. Rashid A, Ivy D. Pulmonary hypertension in children. Curr Paediat 2006;16:237-47. 5. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006. Heart 2009;95:312-7. 6. Aurora, P, Edwards LB, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric lung and heart/lung transplantation report—2009. J Heart Lung Transplant 2009;28:1023-30. 7. Mendeloff EN, Meyers BF, Sundt TM, et al. Lung transplantation for pulmonary vascular disease. Ann Thorac Surg 2002;73:209-19. 8. Grady RM, Gandhi S, Sweet SC, et al. Dismal lung transplant outcomes in children with tetralogy of Fallot with pulmonary atresia compared to Eisenmenger syndrome or pulmonary vein stenosis. J Heart Lung Transplant 2010;28:1221-5. 9. Christie JD, Edwards LB, Aurora P, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-sixth official adult lung and heart–lung transplantation report—2009. J Heart Lung Transplant 2009;28:1031-49. 10. Puri V, Epstein D, Raithel SC, et al. Extracorporeal membrane oxygenation in pediatric lung transplantation. J Thorac Cadiovasc Surg 2010;140:427-31. 11. Strueber M, Hoeper MM, Fischer S, et al. Bridge to thoracic organ transplantation in patients with pulmonary arterial hypertension using a pumpless lung assist device. Am J Transplant 2009;9:853-7. 12. Gazit AZ, Sweet SC, Grady RM, et al. First experience with a paracorporeal artificial lung in a small child with pulmonary hypertension. J Thorac Cardiovasc Surg (epub ahead of print). 13. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82. 14. Lammers AE, Hislop AA, Flynn Y, et al. Epoprostenol treatment in children with severe pulmonary hypertension. Heart 2007;93:739-43. 15. Saggar R, Lynch JP, Belperio JA, et al. Pulmonary arterial hypertension and lung transplantation. Sem Respir Crit Care Med 2010; 31:147-60.