Original Article
Preoperative pulmonary artery pressure and mortality after lung transplantation
Asian Cardiovascular & Thoracic Annals 21(3) 326–330 ß The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492312459972 aan.sagepub.com
Takashi Ohtsuka, Kevin R Flaherty, Jules Lin, Vibha N Lama, Rishindra M Reddy, Mark B Orringer, Kevin M Chan and Andrew C Chang
Abstract Background: The purpose of this study was to determine the influence of changes in pulmonary artery pressure during the waiting period on survival after lung transplantation for pulmonary fibrosis. Methods: We identified 65 patients with pulmonary fibrosis who underwent lung transplantation from 2003 to 2010. Pulmonary artery pressure determined at listing was compared with intraoperative pressure. The primary outcome was overall survival. Co-variates included type of transplantation (single or bilateral), ischemic time, recipient and donor age and sex. Results: The median age of the 65 patients undergoing transplantation was 58 years, and 27 (43%) underwent bilateral sequential transplantation. Twenty-two (35%) patients presented at transplantation with a mean pulmonary artery pressure increased by at least 10% compared to the initial pressure at the time of listing. Rising pulmonary artery pressure at transplantation was associated with increased mortality (p = 0.022). Other factors including type of operation, ischemic time, age, and sex, were not significantly associated with mortality. Post-transplantation survival was worse among recipients who had pulmonary artery pressure increased by at least 10% at transplantation (p = 0.003, logrank). Conclusions: Increasing pulmonary artery pressure while awaiting lung transplantation is associated with worse longterm survival following transplantation, and is a sign of progressively worsening disease for which greater urgency of donor organ allocation should be considered.
Keywords Hypertension, pulmonary, lung transplantation, pulmonary fibrosis, survival analysis
Introduction Idiopathic pulmonary fibrosis (IPF) is the most common adult form of diffuse parenchymal lung diseases of unknown origin.1 Although lung transplantation has been shown to be a viable option in these patients, the survival benefit of lung transplantation in IPF is still complicated by significant early mortality, especially within the first year.2 The 10-year survival rate after lung transplantation is worse with IPF than with other diseases such as idiopathic pulmonary arterial hypertension, cystic fibrosis, and a1-anti-trypsindeficiency emphysema.3 Elevated mean pulmonary arterial pressure (mPAP) in patients with IPF has been associated with decreased exercise capacity and a poor outcome.4,5 Higher mPAP is also associated with increased 90-day mortality after lung transplantation, as determined in an International Society for Heart and
Lung Transplantation registry study.6 One possible explanation for the relationship between pulmonary arterial hypertension (PH) and early mortality after lung transplantation is primary graft dysfunction, an acute lung injury that is responsible for significant morbidity and mortality. The purpose of this study was to determine the influence of changes in mPAP during the transplant waiting period on survival after lung transplantation. Departments of Surgery and Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA Corresponding author: Andrew C Chang, MD, Section of General Thoracic Surgery, University of Michigan Health System, TC2120G/5344, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. Email: [email protected]
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Patients and methods We performed a retrospective review of all patients with IPF who underwent lung transplantation at our medical center from 2003 to 2010 and in whom serial right heart catheterizations were available. This retrospective review was approved by our local institutional review board. All 63 adult patients who underwent lung transplantation from January 2003 to January 2010 with a diagnosis of IPF were eligible for inclusion. Patient characteristics are shown in Table 1. All patients had a diagnosis of IPF. The median age at transplantation was 58.1 years, and 27 (43%) patients underwent bilateral sequential transplantation. PH was defined as mPAP > 25 mmHg. The mPAP from the patients’ initial transplant evaluation was defined as baseline mPAP. The baseline mPAP was obtained via right heart catheterization performed under local anesthesia. The second mPAP recording was obtained from right heart catheterization carried out at the time of lung transplantation with the patient supine and under general anesthesia. The mPAP was calculated according to the formula: mPAP = 0.61 systolic PAP þ 2 mmHg.7 We adhered to general selection criteria for suitable cadaveric donor organs. No patient received either a living-related lung transplant or organs obtained from non-beating heart donors. Ice-cold extracellular lowpotassium colloid solution (Perfadex, Vitrolife, Inc., Englewood, CO, USA) was administered for antegrade and retrograde pulmoplegia. The operative technique varied with the operating surgeon. Generally, singlelung transplantation was carried out via a posterolateral thoracotomy. Bilateral lung transplantation was performed via a bilateral anterolateral thoracotomy with or without a transverse sternotomy. Selective use of inhaled nitric oxide intra- and postoperatively and intraoperative cardiopulmonary bypass were utilized for patients with pulmonary hypertension or hypoxemia. For bilateral lung transplantation, total ischemic time indicates time to reperfusion of the second lung. Perioperative antibacterial agents consisted of vancomycin and ceftazidime for the first 48 h after transplant, adjusted according to intraoperative bronchial cultures. Patients at risk of cytomegaly virus infection were treated with postoperative ganciclovir for 21 days. Pneumocystis carinii prophylaxis was achieved with trimethoprim and sulfamethoxazole or dapsone. Patients received preoperative azathioprine or mycophenolate mofetil. Postoperatively, sublingual tacrolimus was given, starting at 0.05 mgkg1 twice daily. Azathioprine therapy with 2 mgkg1 intravenously or orally daily was initiated in the immediate postoperative period, adjusting doses for leukopenia (white blood cell count 10% mPAP (n = 22) (n = 41) p value
Age at transplant (years)
58.1 7.6
56.8 9.4
56.6 6.5
Sex (female)
25.3%
22.3%
24.30%
Variable
0.94
Procedure Single Bilateral Waiting time (days)
36 (57%)
13 (59%)
23(56%)
0.08
27 (43%) 261 248
9 (41%) 299 313
18(44%) 241 208
0.38
PAP at listing Systolic (mmHg)
35 13
43 15
0.04
Diastolic (mmHg) 16 7
41 14
14 6
18 7
0.02
Mean (mmHg)
24 8
28 9
0.04
43 16
48 17
41 15
0.09
Diastolic (mmHg) 19 7 Mean (mmHg) 28 10
21 6 31 11
17 7 26 10
0.03 0.07
359 92
317 89
0.08
27 9
PAP at transplant Systolic (mmHg)
Ischemic time (min)
332 92
Donor variables (n = 63) Donor age (years) 35.7 15.9 30.7 15.4
38.4 15.7 0.07
Sex (female)
36.6%
31.7%
22.7%
0.08
mPAP: mean pulmonary artery pressure; PAP: pulmonary artery pressure.
twice daily to 20 mg per day. The mean duration of follow-up was 865 days. Cox regression models were used to provide estimates of the hazard ratio and 95% confidence interval for outcomes. Cox regression was also used in a multivariable fashion to explore the association between outcomes and variables. Continuous data are presented as mean standard deviation. Categorical data are given as frequency and percentage. All statistical analyses were performed using PASW Statistics (SPSS, Inc., Chicago, IL, USA).
Results The mean baseline mPAP was 27 9 mmHg at the time of listing. The baseline prevalence of PH with IPF in our population was 52.4%. The distribution of mPAP at the 2 time intervals is shown in Figure 1. Thirty-day mortality occurred in 7 (11%) patients, due to multiorgan failure in 4, massive hemorrhage in 2, and sepsis in one. Survival (Kaplan-Meier) at 1, 3, and 5 years for the entire cohort was 83.6%, 71.1%, and 55.0%, respectively (Figure 2). Twenty-two (35%) patients presented at transplantation with mPAP increased by at least 10% compared to baseline mPAP. Univariate analysis showed that patients
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Asian Cardiovascular & Thoracic Annals 21(3) Table 2. Univariate analysis of factors associated with increased perioperative mortality. Variables
Hazard ratio (95%CI)
p value
Male sex Donor age mPAP >10% Recipient age Ischemic time Waiting days Bilateral
1.009 (0.185–5.562) 0.978 (0.943–1.015) 1.013 (1.002–1.025) 0.972 (0.896–1.056) 1.001(0.995–1.034)) 1.001 (0.998–1.003) 0.832 (0.181–3.823)
0.987 0.242 0.018 0.504 0.570 0.728 0.814
CI: confidence interval; mPAP: mean pulmonary artery pressure.
Figure 1. Distribution of mean pulmonary artery pressure (mPAP) at baseline and at transplant (n = 63). R = 0.75. Table 3. Multivariate analysis of factors associated with increased perioperative mortality. Variables
Hazard ratio (95%CI)
p value
mPAP >10% Recipient age Ischemic time Waiting time Bilateral
1.015 1.003 1.004 1.000 0.832
0.022 0.402 0.9 0.152 0.756
(1.001–1.030) (0.933–1.079) (0.999–1.010) (1.000–1.000) (0.178–3.880)
CI: confidence interval; mPAP: mean pulmonary artery pressure.
Figure 2. Post-transplant survival. Thirty-day mortality occurred in 7 (11%) patients. Survival (Kaplan-Meier) at 1, 3, and 5 years for the entire cohort was 83.6%, 71.1%, and 55.0%, respectively.
whose mean mPAP increased by at least 10% had worse 30-day survival (p = 0.018, Table 2). There were no significant correlations noted between 30-day mortality and other variables including sex, age, type of transplantation (single or bilateral), ischemic time, and time on the waiting list. Multivariate analysis showed that an increase in mPAP at the time of transplantation was associated with an increased risk of death (hazard ratio = 1.015 for each percentile increase in mPAP; 95% confidence interval: 1.001–1.030, p = 0.022). Other factors including type of operation, total ischemic time, recipient or donor age and sex, were not significantly associated with mortality (Table 3). Posttransplantation survival was significantly worse (p = 0.003, logrank) among recipients who had at
Figure 3. Post-transplant Kaplan-Meier survival analysis based on the rate of change of mean pulmonary artery pressure (mPAP). Survival was significantly worse among recipients who had at least a 10% increase during the time from listing to transplantation (p = 0.03).
least a 10% increase in mPAP during the time from listing to transplantation (Figure 3).
Discussion Secondary PH is relatively common in IPF patients, and may contribute to worse functional status, quality of life, morbidity, and mortality.8 PH has been reported
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to occur in 32% to 85% of patients with IPF, and more frequently in advanced disease.8 Although several studies have noted that PH affects the prognosis of patients with IPF, the impact of serial changes in PH during the waiting period prior to lung transplantation has not been reported.5,9,10 Our study showed that rising mPAP while awaiting lung transplantation, rather than waiting list time alone, was associated with worse long-term survival following transplantation, and was a sign of progressively worsening disease. PH in IPF patients at the time of listing has been implicated as a significant risk factor for worse early outcomes after lung transplantation.11 The mechanism of the association between PH and high mortality after lung transplantation in IPF is uncertain. Right ventricle hypertrophy secondary to chronically elevated afterload may increase pulmonary edema in ischemic reperfusion injury through markedly elevated reperfusion pressures after vascular reanastomosis.12,13 One of the issues that our study raises is whether or how patients with IPF should be monitored for the development of PH. There are a number of potential reasons for the development of PH in IPF patients. Pathologic vascular findings in IPF consist of changes in the arteries, arterioles, and venules, as well as destruction of the capillary bed.4 Adventitial thickening around the pulmonary vessels reflects an increase in connective tissue. Smooth muscle cell hypertrophy and proliferation, accumulation of collagen and elastin in the media of the small muscular pulmonary arteries, and muscularization of the distal pulmonary arterioles have all been reported.4 Both hypoxia and thromboembolic disease appear to be contributing factors in the development of PH in IPF patients.14–16 The cytokine milieu may play a significant role in the histopathologic vascular changes. Endothelin-1, serotonin, and platelet-derived growth factor, as well as other mediators, have been shown to affect the medial layer of large pulmonary arteries, and may incite PH.17,18 Better understanding of these processes may lead to identification of reversible factors, which might help to delay disease progression in this population, even while awaiting pulmonary transplantation. Whether PH associated with IPF should be treated pharmacologically with agents that have been proven to be effective for other forms of PH has yet to be determined. The consideration of pulmonary vasodilator therapy for IPF-associated PH is attractive. Sildenafil and iloprost have both been studied as therapies for patients with IPF-associated PH, with possible efficacy.19,20 Ghofrani and colleagues19 found that after administration of oral sildenafil in patients with PH and pulmonary fibrosis, pulmonary hemodynamics improved while preserving shunt fraction, work of breathing, and mean systemic arterial pressure.
Prostacyclin analogues used via inhalation could maintain ventilation perfusion matching. Inhaled iloprost decreased mPAP in patients with PH secondary to lung fibrosis, with maintenance of gas exchange and systemic arterial pressure.21 Studies of therapies directed at preventing the development of PH in IPF should be encouraged because these might delay the progression of PH in IPF patients. There are a number of limitations of our study, including the relatively small number of patients and the retrospective nature of its design. The wide range in time between mPAP measurements is also a potential confounder. Although our measures of mPAP were via right heart catheterization, they were performed under different circumstances, specifically, in the cardiac catheterization laboratory at the time of listing or while under general anesthesia at the time of transplantation. As mPAP decreases on induction of general anesthesia, we would expect that the actual change in measured mPAP would be greater than the differences observed in our study cohort.22 Despite these limitations, this study demonstrates that increasing mPAP while awaiting lung transplantation is associated with worse longterm survival following transplantation. Increasing mPAP is a sign of progressively worsening disease, for which greater urgency of donor organ allocation should be considered. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement None declared. Presented in part as a poster at the 47th Annual Meeting of the Society of Thoracic Surgeons, San Diego, CA, USA, January 30, 2011.
References 1. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: 646–664. 2. McCurry KR, Shearon TH, Edwards LB, Chan KM, Sweet SC, Valapour M, et al. Lung transplantation in the United States, 1998-2007. Am J Transplant 2009; 9: 942–958. 3. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Aurora P, Christie J, et al. Registry of the International Society for Heart and Lung Transplantation: twentyfourth official adult heart transplant report—2007. J Heart Lung Transplant 2007; 26: 769–781.
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4. Patel NM, Lederer DJ, Borczuk AC and Kawut SM. Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest 2007; 132: 998–1006. 5. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S and Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129: 746–752. 6. Whelan TP, Dunitz JM, Kelly RF, Edwards LB, Herrington CS, Hertz MI, et al. Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant 2005; 24: 1269–1274. 7. Chemla D, Castelain V, Humbert M, He´bert JL, Simonneau G, Lecarpentier Y, et al. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest 2004; 126: 1313–1317. 8. Nathan SD, Noble PW and Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med 2007; 175: 875–880. 9. Harari S, Simonneau G, De Juli E, Brenot F, Cerrina J, Colombo P, et al. Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation. J Heart Lung Transplant 1997; 16: 460–463. 10. King TE Jr, Tooze JA, Schwarz MI, Brown KR and Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001; 164: 1171–1181. 11. Davis RD Jr, Trulock EP, Manley J, Pasque MK, Sundaresan S, Cooper JD, et al. Differences in early results after single-lung transplantation. Washington University Lung Transplant Group. Ann Thorac Surg 1994; 58: 1327–1334. 12. Bhabra MS, Hopkinson DN, Shaw TE, Onwu N and Hooper TL. Controlled reperfusion protects lung grafts during a transient early increase in permeability. Ann Thorac Surg 1998; 65: 187–192. 13. Fiser SM, Kron IL, Long SM, Kaza AK, Kern JA, Cassada DC, et al. Controlled perfusion decreases
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reperfusion injury after high-flow reperfusion. J Heart Lung Transplant 2002; 21: 687–691. Tuder RM, Yun JH, Bhunia A and Fijalkowska I. Hypoxia and chronic lung disease. J Mol Med (Berl) 2007; 85: 1317–1324. Grigg A, Buchanan M and Whitford H. Late-onset pulmonary arterial hypertension in association with graft-versus-host disease after allogeneic stem-cell transplantation. Am J Hematol 2005; 80: 38–42. Skoro-Sajer N, Hack N, Sadushi-Kolici R, et al. Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension: a pilot study. Circulation 2009; 119: 298–305. Keane MP, Arenberg DA, Lynch JP 3rd, Whyte RI, Iannettoni MD, Burdick MD, et al. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol 1997; 159: 1437–1443. Kovacs EJ and DiPietro LA. Fibrogenic cytokines and connective tissue production. FASEB J 1994; 8: 854–861. Ghofrani HA, Wiedemann R, Rose F, Weissmann N, Schermuly RT, Quanz K, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360: 895–900. Minai OA, Sahoo D, Chapman JT and Mehta AC. Vasoactive therapy can improve 6-min walk distance in patients with pulmonary hypertension and fibrotic interstitial lung disease. Respir Med 2008; 102: 1015–1020. Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld-Wollbruck B, Grimminger F, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 1999; 160: 600–607. But AK, Ozgul U, Erdil F, Gulhas N, Toprak HI, Durmus M, et al. The effects of pre-operative dexmedetomidine infusion on hemodynamics in patients with pulmonary hypertension undergoing mitral valve replacement surgery. Acta Anaesth Scand 2006; 50: 1207–1212.
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Preoperative pulmonary artery pressure and mortality after lung transplantation
Asian Cardiovascular & Thoracic Annals 21(3) 326–330 ß The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492312459972 aan.sagepub.com
Takashi Ohtsuka, Kevin R Flaherty, Jules Lin, Vibha N Lama, Rishindra M Reddy, Mark B Orringer, Kevin M Chan and Andrew C Chang
Abstract Background: The purpose of this study was to determine the influence of changes in pulmonary artery pressure during the waiting period on survival after lung transplantation for pulmonary fibrosis. Methods: We identified 65 patients with pulmonary fibrosis who underwent lung transplantation from 2003 to 2010. Pulmonary artery pressure determined at listing was compared with intraoperative pressure. The primary outcome was overall survival. Co-variates included type of transplantation (single or bilateral), ischemic time, recipient and donor age and sex. Results: The median age of the 65 patients undergoing transplantation was 58 years, and 27 (43%) underwent bilateral sequential transplantation. Twenty-two (35%) patients presented at transplantation with a mean pulmonary artery pressure increased by at least 10% compared to the initial pressure at the time of listing. Rising pulmonary artery pressure at transplantation was associated with increased mortality (p = 0.022). Other factors including type of operation, ischemic time, age, and sex, were not significantly associated with mortality. Post-transplantation survival was worse among recipients who had pulmonary artery pressure increased by at least 10% at transplantation (p = 0.003, logrank). Conclusions: Increasing pulmonary artery pressure while awaiting lung transplantation is associated with worse longterm survival following transplantation, and is a sign of progressively worsening disease for which greater urgency of donor organ allocation should be considered.
Keywords Hypertension, pulmonary, lung transplantation, pulmonary fibrosis, survival analysis
Introduction Idiopathic pulmonary fibrosis (IPF) is the most common adult form of diffuse parenchymal lung diseases of unknown origin.1 Although lung transplantation has been shown to be a viable option in these patients, the survival benefit of lung transplantation in IPF is still complicated by significant early mortality, especially within the first year.2 The 10-year survival rate after lung transplantation is worse with IPF than with other diseases such as idiopathic pulmonary arterial hypertension, cystic fibrosis, and a1-anti-trypsindeficiency emphysema.3 Elevated mean pulmonary arterial pressure (mPAP) in patients with IPF has been associated with decreased exercise capacity and a poor outcome.4,5 Higher mPAP is also associated with increased 90-day mortality after lung transplantation, as determined in an International Society for Heart and
Lung Transplantation registry study.6 One possible explanation for the relationship between pulmonary arterial hypertension (PH) and early mortality after lung transplantation is primary graft dysfunction, an acute lung injury that is responsible for significant morbidity and mortality. The purpose of this study was to determine the influence of changes in mPAP during the transplant waiting period on survival after lung transplantation. Departments of Surgery and Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA Corresponding author: Andrew C Chang, MD, Section of General Thoracic Surgery, University of Michigan Health System, TC2120G/5344, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. Email: [email protected]
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Patients and methods We performed a retrospective review of all patients with IPF who underwent lung transplantation at our medical center from 2003 to 2010 and in whom serial right heart catheterizations were available. This retrospective review was approved by our local institutional review board. All 63 adult patients who underwent lung transplantation from January 2003 to January 2010 with a diagnosis of IPF were eligible for inclusion. Patient characteristics are shown in Table 1. All patients had a diagnosis of IPF. The median age at transplantation was 58.1 years, and 27 (43%) patients underwent bilateral sequential transplantation. PH was defined as mPAP > 25 mmHg. The mPAP from the patients’ initial transplant evaluation was defined as baseline mPAP. The baseline mPAP was obtained via right heart catheterization performed under local anesthesia. The second mPAP recording was obtained from right heart catheterization carried out at the time of lung transplantation with the patient supine and under general anesthesia. The mPAP was calculated according to the formula: mPAP = 0.61 systolic PAP þ 2 mmHg.7 We adhered to general selection criteria for suitable cadaveric donor organs. No patient received either a living-related lung transplant or organs obtained from non-beating heart donors. Ice-cold extracellular lowpotassium colloid solution (Perfadex, Vitrolife, Inc., Englewood, CO, USA) was administered for antegrade and retrograde pulmoplegia. The operative technique varied with the operating surgeon. Generally, singlelung transplantation was carried out via a posterolateral thoracotomy. Bilateral lung transplantation was performed via a bilateral anterolateral thoracotomy with or without a transverse sternotomy. Selective use of inhaled nitric oxide intra- and postoperatively and intraoperative cardiopulmonary bypass were utilized for patients with pulmonary hypertension or hypoxemia. For bilateral lung transplantation, total ischemic time indicates time to reperfusion of the second lung. Perioperative antibacterial agents consisted of vancomycin and ceftazidime for the first 48 h after transplant, adjusted according to intraoperative bronchial cultures. Patients at risk of cytomegaly virus infection were treated with postoperative ganciclovir for 21 days. Pneumocystis carinii prophylaxis was achieved with trimethoprim and sulfamethoxazole or dapsone. Patients received preoperative azathioprine or mycophenolate mofetil. Postoperatively, sublingual tacrolimus was given, starting at 0.05 mgkg1 twice daily. Azathioprine therapy with 2 mgkg1 intravenously or orally daily was initiated in the immediate postoperative period, adjusting doses for leukopenia (white blood cell count 10% mPAP (n = 22) (n = 41) p value
Age at transplant (years)
58.1 7.6
56.8 9.4
56.6 6.5
Sex (female)
25.3%
22.3%
24.30%
Variable
0.94
Procedure Single Bilateral Waiting time (days)
36 (57%)
13 (59%)
23(56%)
0.08
27 (43%) 261 248
9 (41%) 299 313
18(44%) 241 208
0.38
PAP at listing Systolic (mmHg)
35 13
43 15
0.04
Diastolic (mmHg) 16 7
41 14
14 6
18 7
0.02
Mean (mmHg)
24 8
28 9
0.04
43 16
48 17
41 15
0.09
Diastolic (mmHg) 19 7 Mean (mmHg) 28 10
21 6 31 11
17 7 26 10
0.03 0.07
359 92
317 89
0.08
27 9
PAP at transplant Systolic (mmHg)
Ischemic time (min)
332 92
Donor variables (n = 63) Donor age (years) 35.7 15.9 30.7 15.4
38.4 15.7 0.07
Sex (female)
36.6%
31.7%
22.7%
0.08
mPAP: mean pulmonary artery pressure; PAP: pulmonary artery pressure.
twice daily to 20 mg per day. The mean duration of follow-up was 865 days. Cox regression models were used to provide estimates of the hazard ratio and 95% confidence interval for outcomes. Cox regression was also used in a multivariable fashion to explore the association between outcomes and variables. Continuous data are presented as mean standard deviation. Categorical data are given as frequency and percentage. All statistical analyses were performed using PASW Statistics (SPSS, Inc., Chicago, IL, USA).
Results The mean baseline mPAP was 27 9 mmHg at the time of listing. The baseline prevalence of PH with IPF in our population was 52.4%. The distribution of mPAP at the 2 time intervals is shown in Figure 1. Thirty-day mortality occurred in 7 (11%) patients, due to multiorgan failure in 4, massive hemorrhage in 2, and sepsis in one. Survival (Kaplan-Meier) at 1, 3, and 5 years for the entire cohort was 83.6%, 71.1%, and 55.0%, respectively (Figure 2). Twenty-two (35%) patients presented at transplantation with mPAP increased by at least 10% compared to baseline mPAP. Univariate analysis showed that patients
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Asian Cardiovascular & Thoracic Annals 21(3) Table 2. Univariate analysis of factors associated with increased perioperative mortality. Variables
Hazard ratio (95%CI)
p value
Male sex Donor age mPAP >10% Recipient age Ischemic time Waiting days Bilateral
1.009 (0.185–5.562) 0.978 (0.943–1.015) 1.013 (1.002–1.025) 0.972 (0.896–1.056) 1.001(0.995–1.034)) 1.001 (0.998–1.003) 0.832 (0.181–3.823)
0.987 0.242 0.018 0.504 0.570 0.728 0.814
CI: confidence interval; mPAP: mean pulmonary artery pressure.
Figure 1. Distribution of mean pulmonary artery pressure (mPAP) at baseline and at transplant (n = 63). R = 0.75. Table 3. Multivariate analysis of factors associated with increased perioperative mortality. Variables
Hazard ratio (95%CI)
p value
mPAP >10% Recipient age Ischemic time Waiting time Bilateral
1.015 1.003 1.004 1.000 0.832
0.022 0.402 0.9 0.152 0.756
(1.001–1.030) (0.933–1.079) (0.999–1.010) (1.000–1.000) (0.178–3.880)
CI: confidence interval; mPAP: mean pulmonary artery pressure.
Figure 2. Post-transplant survival. Thirty-day mortality occurred in 7 (11%) patients. Survival (Kaplan-Meier) at 1, 3, and 5 years for the entire cohort was 83.6%, 71.1%, and 55.0%, respectively.
whose mean mPAP increased by at least 10% had worse 30-day survival (p = 0.018, Table 2). There were no significant correlations noted between 30-day mortality and other variables including sex, age, type of transplantation (single or bilateral), ischemic time, and time on the waiting list. Multivariate analysis showed that an increase in mPAP at the time of transplantation was associated with an increased risk of death (hazard ratio = 1.015 for each percentile increase in mPAP; 95% confidence interval: 1.001–1.030, p = 0.022). Other factors including type of operation, total ischemic time, recipient or donor age and sex, were not significantly associated with mortality (Table 3). Posttransplantation survival was significantly worse (p = 0.003, logrank) among recipients who had at
Figure 3. Post-transplant Kaplan-Meier survival analysis based on the rate of change of mean pulmonary artery pressure (mPAP). Survival was significantly worse among recipients who had at least a 10% increase during the time from listing to transplantation (p = 0.03).
least a 10% increase in mPAP during the time from listing to transplantation (Figure 3).
Discussion Secondary PH is relatively common in IPF patients, and may contribute to worse functional status, quality of life, morbidity, and mortality.8 PH has been reported
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to occur in 32% to 85% of patients with IPF, and more frequently in advanced disease.8 Although several studies have noted that PH affects the prognosis of patients with IPF, the impact of serial changes in PH during the waiting period prior to lung transplantation has not been reported.5,9,10 Our study showed that rising mPAP while awaiting lung transplantation, rather than waiting list time alone, was associated with worse long-term survival following transplantation, and was a sign of progressively worsening disease. PH in IPF patients at the time of listing has been implicated as a significant risk factor for worse early outcomes after lung transplantation.11 The mechanism of the association between PH and high mortality after lung transplantation in IPF is uncertain. Right ventricle hypertrophy secondary to chronically elevated afterload may increase pulmonary edema in ischemic reperfusion injury through markedly elevated reperfusion pressures after vascular reanastomosis.12,13 One of the issues that our study raises is whether or how patients with IPF should be monitored for the development of PH. There are a number of potential reasons for the development of PH in IPF patients. Pathologic vascular findings in IPF consist of changes in the arteries, arterioles, and venules, as well as destruction of the capillary bed.4 Adventitial thickening around the pulmonary vessels reflects an increase in connective tissue. Smooth muscle cell hypertrophy and proliferation, accumulation of collagen and elastin in the media of the small muscular pulmonary arteries, and muscularization of the distal pulmonary arterioles have all been reported.4 Both hypoxia and thromboembolic disease appear to be contributing factors in the development of PH in IPF patients.14–16 The cytokine milieu may play a significant role in the histopathologic vascular changes. Endothelin-1, serotonin, and platelet-derived growth factor, as well as other mediators, have been shown to affect the medial layer of large pulmonary arteries, and may incite PH.17,18 Better understanding of these processes may lead to identification of reversible factors, which might help to delay disease progression in this population, even while awaiting pulmonary transplantation. Whether PH associated with IPF should be treated pharmacologically with agents that have been proven to be effective for other forms of PH has yet to be determined. The consideration of pulmonary vasodilator therapy for IPF-associated PH is attractive. Sildenafil and iloprost have both been studied as therapies for patients with IPF-associated PH, with possible efficacy.19,20 Ghofrani and colleagues19 found that after administration of oral sildenafil in patients with PH and pulmonary fibrosis, pulmonary hemodynamics improved while preserving shunt fraction, work of breathing, and mean systemic arterial pressure.
Prostacyclin analogues used via inhalation could maintain ventilation perfusion matching. Inhaled iloprost decreased mPAP in patients with PH secondary to lung fibrosis, with maintenance of gas exchange and systemic arterial pressure.21 Studies of therapies directed at preventing the development of PH in IPF should be encouraged because these might delay the progression of PH in IPF patients. There are a number of limitations of our study, including the relatively small number of patients and the retrospective nature of its design. The wide range in time between mPAP measurements is also a potential confounder. Although our measures of mPAP were via right heart catheterization, they were performed under different circumstances, specifically, in the cardiac catheterization laboratory at the time of listing or while under general anesthesia at the time of transplantation. As mPAP decreases on induction of general anesthesia, we would expect that the actual change in measured mPAP would be greater than the differences observed in our study cohort.22 Despite these limitations, this study demonstrates that increasing mPAP while awaiting lung transplantation is associated with worse longterm survival following transplantation. Increasing mPAP is a sign of progressively worsening disease, for which greater urgency of donor organ allocation should be considered. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement None declared. Presented in part as a poster at the 47th Annual Meeting of the Society of Thoracic Surgeons, San Diego, CA, USA, January 30, 2011.
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