LIVER TRANSPLANTATION 16:348-356, 2010 ORIGINAL ARTICLE Acute and Long-Term Effects of Inhaled Iloprost in Portopulmonary Hypertension Maria Teresa Melgosa,1,3 Giovanni L. Ricci,4 Juan Carlos Garcı́a-Pagan,2,5 Isabel Blanco,1,3 Pilar Escribano,6 Juan G. Abraldes,2,5 Josep Roca,1,3 Jaume Bosch,2,5 and Joan Albert Barberà1,3 1 Department of Pulmonary Medicine and 2Hemodynamic Laboratory, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; 3Network Center for Biomedical Research in Respiratory Diseases, Barcelona, Spain; 4Department of Clinical Sciences, Sapienza University of Rome, Rome, Italy; 5Network Center for Biomedical Research in Hepatic and Digestive Diseases, Barcelona, Spain; and 6Department of Cardiology, Hospital 12 de Octubre, Madrid, Spain Portopulmonary hypertension (PoPH) is a serious condition without an established treatment. Drugs used to treat pulmonary hypertension may have detrimental effects on portal hypertension. This study was designed to assess in patients with PoPH the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics and to evaluate the clinical outcome after 12 months of treatment. We conducted 2 separate studies. In the first one, 21 patients with PoPH were acutely tested with 2.8 lg of iILO. Pulmonary and hepatic hemodynamics were assessed at the baseline and through 60 minutes after iILO. In the second one, we retrospectively evaluated 12 patients treated with iILO (30 lg/day) for more than 1 year. The 6-minute walk distance (6MWD), functional class (FC), and echocardiogram were analyzed at the baseline and after 12 months of treatment. In the acute study, iILO rapidly reduced pulmonary artery pressure (PAP; 16% 6 8%, P < 0.001) and pulmonary vascular resistance ( 18% 6 14%, P < 0.001). The cardiac output did not change initially but decreased after 30 minutes. The hepatic venous pressure gradient (HVPG) and hepatic blood flow did not vary through the study. Pulmonary vasodilation induced by iILO was inversely related to HVPG. In the long-term evaluation, iILO improved FC by 1 or more in 7 patients (P ¼ 0.04) and increased 6MWD by 67 6 59 m at 12 months (P < 0.001). No change in systolic PAP was observed. Two patients died because of hepatic complications, and 4 additional patients presented clinically significant events that were related to hepatic disease in 2 and worsening of pulmonary hypertension in 2. We conclude that in patients with PoPH, iILO produces rapid and selective pulmonary vasodilation without altering the hepatic hemodynamics. Its long-term use may provide sustained improvements in symptoms and exercise tolerance in some patients with PoPH. A randomized, controlled trial is warranted to establish its clinical role in this serious condition. Liver Transpl 16:348-356, 2010. V 2010 AASLD. C Received July 20, 2009; accepted November 22, 2009. Portopulmonary hypertension (PoPH), the association of pulmonary arterial hypertension (PAH) and portal hypertension, accounts for 10% of cases with PAH1 and is present in 3.5% to 5% of patients with endstage liver cirrhosis.2,3 Patients with PoPH have a high mortality rate,4,5 especially if they are left Abbreviations: 6MWD, 6-minute walk distance; CI, cardiac index; CVP, central venous pressure; DLCO, diffusion capacity of the lung for carbon monoxide; FC, functional class; FEV1, forced expiratory volume in the first second; HBF, hepatic blood flow; HBV, hepatitis B virus; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; iILO, inhaled iloprost; MELD, Model for EndStage Liver Disease; OLT, orthotopic liver transplantation; PAH, pulmonary arterial hypertension; PAOP, pulmonary artery occlusion pressure; PAP, pulmonary artery pressure; PoPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; TIPS, transjugular intrahepatic portosystemic shunt. This study was supported by a research grant from the Catalan Society of Pneumology (Catalan Foundation of Pneumology) and by an unrestricted grant from Bayer-Schering (Madrid, Spain). Giovanni L. Ricci was supported by grants from the Ministry of Education, Universities, and Research/Athenaeum Foundation of the Sapienza University of Rome (8111.69.7 and 8111.4.9) and by a research grant from the Eleonora Spencer Lorillard Cenci Foundation. The Network Center for Biomedical Research in Respiratory Diseases and the Network Center for Biomedical Research in Hepatic and Digestive Diseases are funded by the Carlos III Institute of Health (Spanish Ministry of Science and Innovation). Address reprint requests to Joan Albert Barberà, M.D., Servei de Pneumologia, Hospital Clı́nic, Villarroel 170, 08036 Barcelona, Spain. Telephone: þ3493-2275747; FAX: þ3493-2275455; E-mail: jbarbera@clinic.ub.es DOI 10.1002/lt.21997 Published online in Wiley InterScience (www.interscience.wiley.com). C 2010 American Association for the Study of Liver Diseases. V ILOPROST IN PORTOPULMONARY HYPERTENSION 349 untreated,6 death being caused equally by cardiopulmonary and hepatic complications.5 Furthermore, PAH entails a high mortality risk after orthotopic liver transplantation (OLT). For this reason, patients with PoPH are not considered for this procedure unless pulmonary hemodynamics are within an acceptable range.3 A retrospective analysis of 74 patients showed that the treatment of PAH, followed or not followed by OLT, improves the outcome of PoPH.6 However, the optimal treatment approach remains unsettled because these patients have usually been excluded from the pivotal trials of current PAH treatments.7 Currently, 3 classes of drugs are used for the treatment of PAH: prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors.8 Intravenous epoprostenol (synthetic prostacyclin) has been used in PoPH with beneficial effects.9,10 However, endogenous prostacyclins are already increased in patients with liver cirrhosis,11,12 and their exogenous administration may enhance the hyperdynamic circulation13 and potentially produce excessively high cardiac output and progressive splenomegaly.14 Furthermore, the intravenous administration of epoprostenol is cumbersome, particularly in patients with advanced cirrhosis, who are more prone to septic shock. Endothelin receptor antagonists are not recommended in patients with advanced liver disease because of the risk of hepatotoxicity.15 Phosphodiesterase-5 inhibitors have been used in PoPH with beneficial results,16-18 although the effects on hepatic circulation have not yet been assessed. There is concern that phosphodiesterase-5 inhibitors may increase splanchnic circulation and portal pressure.19-21 We hypothesized that the use of the prostacyclin analogue iloprost, which is given by inhalation,22 might exert a selective effect on the pulmonary circulation without altering the hepatic circulation. Accordingly, we first assessed the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics in patients with PoPH. The results of this study showed that iILO did not exert detrimental effects on hepatic circulation. For this reason and in order to obtain further insight into the potential applicability of iILO for this condition, we retrospectively evaluated the clinical outcome of a cohort of 12 patients with PoPH who were treated with iILO for more than 1 year. PATIENTS AND METHODS Assessment of Acute Hemodynamic Effects Twenty-two consecutive patients (12 men and 10 women) with an established diagnosis of PoPH3,5 were studied. Before entering the study, all patients underwent an extensive evaluation including transthoracic Doppler echocardiography, lung function testing, arterial blood gas analysis, lung scintigraphy, and abdominal ultrasound examination. The clinical characteristics of the patients and their underlying liver TABLE 1. Characteristics of the Patients Assessed for the Acute and Long-Term Effects of Inhaled Iloprost Acute Long-Term Effects Effects Number 22 12* Gender, male/female 12/10 8/4 Age, years 47 6 12 51 6 11 Functional class, I-II/III-IV 7/15 3/9 Forced vital capacity, 92 6 10 95 6 10 % predicted FEV1, % predicted 88 6 13 89 6 11 DLCO, % predicted 52 6 15 58 6 14 Systolic PAP 73 6 15 77 6 18 (echocardiogram), mm Hg Mean PAP, mm Hg 49 6 13 55 6 10 PAOP, mm Hg 865 11 6 6# CVP, mm Hg 865 864 CI, L minute 1 m 2 3.84 6 1.09 2.87 6 0.84 564 6 282 802 6 313 PVR, dyn second cm 5 15.0 6 2.5 11.1 6 5.3 MELD scorey Liver diseasez HBV/HCV cirrhosis 3/13 1/4 Alcoholic cirrhosis 5 2 Primary biliary cirrhosis 1 2 Portal thrombosis 1 1 3k Other 3§ Ascites 10 7 Patients with a portosystemic shunt¶ TIPS 5 1 Surgical 1 2 NOTE: Values are given as means and standard deviations. *Six patients also participated in the acute study. y The MELD score was calculated on the United Network for Organ Sharing Web site. z Three patients in the acute study and 1 patient in the long-term study had mixed etiologies. § HCV chronic hepatitis (1), alcoholic hepatopathy (1), and myeloid metaplasia (1). k HCV chronic hepatitis (2) and hemochromatosis (1). ¶ Patients had undergone shunting in order to lower the portal pressure at least 6 months before entering the study. # Two patients had a PAOP of 19 mm Hg with elevated PVR (444 and 778 dyn second cm 5, respectively). disorders are shown in Table 1. The diagnosis of portal hypertension either was clinical or was based on previous hemodynamic measurements. At least 6 months before entering the study, 6 patients had received either a portocaval shunt (n ¼ 1) or a transjugular intrahepatic portosystemic shunt (TIPS; n ¼ 5) in order to lower portal pressure because of repeated upper gastrointestinal tract bleeding. All patients were already in follow-up at the Hospital Clinic of Barcelona for at least 3 months. The study was approved by the internal review board, and all patients gave written informed consent before the study. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases 350 MELGOSA ET AL. Procedures All patients underwent right heart catheterization, and 11 patients underwent simultaneous catheterization of the hepatic veins. Vasodilator drugs had been discontinued for at least 48 hours before the study. A 7-Fr triple-lumen Swan-Ganz catheter (Baxter, Irvine, CA) was placed in the pulmonary artery under fluoroscopic control as previously reported.23 Catheterization of the hepatic veins was performed via a second jugular insertion with a balloon occluding catheter (OB-Medi-Tech, Boston Scientific Cork, Ltd., Cork, Ireland) for the measurement of the free and wedged hepatic venous pressures and determination of the hepatic venous pressure gradient (HVPG).24 In 7 patients, the hepatic blood flow (HBF) was determined during a continuous infusion of indocyanine green.25 The cardiac output was determined in triplicate by the thermodilution technique (M1012A, Hewlett-Packard). The cardiac index (CI), pulmonary vascular resistance (PVR), and systemic vascular resistance were computed. After a duplicate set of baseline measurements taken more than 20 minutes apart, iloprost (Ilomedin, Bayer-Schering Pharma, Madrid, Spain), diluted in physiological saline to a concentration of 11 lg/mL, was delivered with an ultrasonic nebulizer (Halolite, Medic-Aid, Ltd., Bognor Regis, United Kingdom) for a total inhaled dose of 2.8 lg.26,27 Subsequently, the pulmonary hemodynamics and cardiac output were measured 5, 15, 30, 45, and 60 minutes after iloprost inhalation. Changes in the hepatic vein pressures and HBF were evaluated 30 and 60 minutes after iILO. Long-Term Outcome We retrospectively evaluated 12 patients (8 from the Hospital Clinic, Barcelona, Spain, and 4 from Hospital 12 de Octubre, Madrid, Spain) with an established diagnosis of PoPH (8 men and 4 women) who were treated with iILO for at least 1 year between 2002 and 2008. Six patients had also participated in the assessment of the acute effects of iILO. The characteristics of the patients and their underlying liver diseases and pulmonary hemodynamics at diagnosis are shown in Table 1. All patients received iloprost (Ventavis, Bayer-Schering Pharma) at a dose of 5 lg per inhalation with 6 inhalations per day for a total daily dose of 30 lg. For 9 patients, iILO was initiated as the first treatment, whereas for 3 patients who were already receiving 125 mg of bosentan twice daily, it was used as add-on therapy. Assessments of the functional class (FC) and 6-minute walk distance (6MWD), transthoracic Doppler echocardiography, laboratory tests, and an assessment of the Model for End-Stage Liver Disease score were performed at the baseline and 6 and 12 months after the initiation of iILO. Survival and clinically significant events (hospital admission due to worsening of pulmonary hypertension or liver disease or the need for additional medication for pulmonary hypertension) were recorded. Statistics In the acute study, baseline measurements were expressed as the means of duplicate measurements. Changes in hemodynamic parameters from the baseline were assessed with the Student t test. Correlations between variables were assessed with Pearson’s 2-tailed test. The different responses of pulmonary artery pressure (PAP) in patients with no correction of portal hypertension and in patients with a TIPS or shunt were evaluated with a generalized linear model for repeated measurements at different time points (STATA, Stata Corp., College Station, TX). In the longterm study, the overall survival and event-free status were analyzed with the Kaplan-Meier method. For patients with more than 1 clinically significant event, only the first event was used in the analysis. Longitudinal data were analyzed by means of a general linear model accounting for the intra-individual variability; the baseline value was used as a covariate, and all treated subjects were included. Missing values after dropout (2 deaths and 1 treatment change) were handled considering the worst case value of the imputation scale, which in our study was coincident with the last observation carried forward approach. A global assessment of factors and comparisons from the baseline were performed by means of a nonparametric approach with a rank transformation. Results were expressed as estimated marginal means and 95% confidence intervals for each follow-up time (SPSS 15.0 package, SPSS, Inc., Chicago, IL). RESULTS Acute Effects of iILO The administration of iILO resulted in a significant drop of PAP, which was observed throughout the whole 60-minute observation period (Fig. 1). The maximal effect was reached at 15 minutes with an average decrease of 16% 6 8% from the baseline (Table 2). Eight patients showed a PAP decrease > 20% from the baseline, and in 7 patients, the PAP value decreased from above 35 mm Hg to below 35 mm Hg, the current limit for OLT listing.3 The systemic arterial pressure did not change during the study. No changes were observed in CI at 15 minutes when PAP reached its lowest value (Table 2). However, 30 minutes after iILO, CI decreased progressively (Fig. 1). PVR decreased by 18% 6 14% at 15 minutes (Table 2), with a change > 20% in 12 patients, and returned progressively to baseline values thereafter (Fig. 1). Seven patients (32% of the whole series) fulfilled the criteria of the European Respiratory Society-American Thoracic Society Task Force on Pulmonary-Hepatic LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases ILOPROST IN PORTOPULMONARY HYPERTENSION 351 TABLE 2. Acute Hemodynamic Effects of Inhaled Iloprost 15 Minutes Mean PAP, mm Hg PAOP, mm Hg Cardiac index, L/minute/m2 Total PVR, dyn second cm 5 Right atrial pressure, mm Hg SVR, dyn second cm 5 Baseline After Iloprost 49.2 6 12.8 8.2 6 5.1 3.84 6 1.09 42.0 6 13.5* 8.4 6 5.5 3.84 6 1.29 564 6 282 471 6 266* 7.7 6 5.0 7.3 6 4.6 1089 6 475 1019 6 334 NOTE: Values are given as deviations. *P < 0.001 versus the baseline. means and standard Measurements of hepatic vein pressures and HBF were repeated after iILO administration in 8 and 7 patients, respectively. No significant changes from the baseline were observed in either HVPG or HBF at 30 and 60 minutes post-iILO (Fig. 2). Relationships Between Pulmonary and Portal Hemodynamics Figure 1. Acute effects of inhaled iloprost: changes from the baseline in PAP, CI, and PVR during the 60-minute observation period. Values are means and 95% confidence intervals. *P < 0.05 versus the baseline. Vascular Disorders for a significant vasodilator response (20% decrease from the baseline in both PAP and PVR with no decrease in cardiac output).3 Measurements of hepatic vein pressures at the baseline were performed in 11 patients with cirrhosis. One patient with a human immunodeficiency virus infection and hepatis C virus chronic hepatitis was excluded from further analysis because she did not have sinusoidal portal hypertension (HVPG, 2.5 mm Hg). In the remaining 10 patients, the mean wedged hepatic venous pressure was 23.4 6 5.5 mm Hg. Two patients with portal hypertension had mild increases in HVPG. One with primary biliary cirrhosis had an HVPG of 7 mm Hg, and another with alcoholic cirrhosis had an HVPG of 5.5 mm Hg; in both cases, the central venous pressure was relatively high (10 and 14 mm Hg, respectively). All the remaining patients had HVPG > 10 mm Hg. The effects of iILO on pulmonary hemodynamics in these 10 patients did not differ from the effects in the whole series: at 15 minutes, PAP decreased by 9% 6 8%, and PVR decreased by 16% 6 9%. The severity of portal hypertension, as measured by HVPG, correlated directly with cardiac output (r ¼ 0.77, P ¼ 0.009) and inversely with PVR (r ¼ 0.57, P ¼ 0.09; Fig. 3). Patients with a higher HVPG tended to have a hyperdynamic circulation with lesser pulmonary hemodynamic impairment. Changes induced by iILO also correlated with the severity of portal hypertension. The magnitude of the decrease in PVR at minute 15 was inversely related to the baseline HVPG (r ¼ 0.82, P ¼ 0.004); the greater the HVPG was, the lesser the pulmonary vasodilation was (Fig. 3). Indeed, the change in cardiac output 15 minutes after iILO was inversely correlated with the baseline HVPG (r ¼ 0.70, P ¼ 0.025; Fig. 3). Patients treated with TIPS or shunt (n ¼ 6) to correct portal hypertension had greater CI at the baseline than the remaining patients (4.78 6 0.92 versus 3.49 6 0.95 L minute 1 m 2, P ¼ 0.007); interestingly, the vasodilator effect of iILO was more prolonged in the former group (Fig. 4). Long-Term Treatment with iILO The characteristics of the patients who underwent chronic treatment with iILO are shown in Table 1. On average, the group of patients treated over the long term with iILO showed higher PAP, lower CI, and greater PVR than those in the acute study, even though 6 of them had also participated in the latter study (Table 1). Before starting the iILO treatment, 3 patients were in FC II, and 9 were in FC III. The LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases 352 MELGOSA ET AL. Figure 2. Individual changes in the hepatic venous pressure gradient and hepatic blood flow at the baseline and 30 and 60 minutes after iloprost inhalation. The short lines indicate the mean value at each time point. Figure 4. Influence of the correction of portal hypertension on the effects of inhaled iloprost on PAP. Changes in PAP after iloprost in 6 patients with a TIPS or a surgical portocaval shunt and in 15 patients with uncorrected portal hypertension are shown. Values are means and 95% confidence intervals. The difference between the 2 curves was evaluated with a generalized linear model for repeated measurements in each individual at different time points. P 5 0.002 for the comparison between the 2 groups. Figure 3. Relationships between HVPG and CI and PVR at the baseline (upper panels) and changes induced by inhaled iloprost in these measurements (lower panels). distance covered in the 6-minute walk test was 396 6 97 m (Table 3). Two patients died after starting iILO: one at 4 months because of hepatorenal syndrome and the other at 9 months because of progressive liver failure. Both patients suffered from alcoholic cirrhosis, were in Child class B at the baseline, and had severe pulmonary hypertension (PAP, 69 and 71 mm Hg, respectively). The other 10 patients completed the 1-year follow-up. The overall survival estimates were 91% and 83% at 6 and 12 months, respectively. Four of these 10 patients presented a clinically significant event during the follow-up: worsening of pulmonary hypertension in 2, variceal bleeding requiring hospital admission in 1, and hepatic encephalopathy in 1. All patients continued on iILO therapy during the observation period, and only in 1 case was sildenafil treatment added at 6 months because of deterioration of pulmonary hypertension. The event-free survival rate in this cohort was 50% with an estimated mean event-free survival of 271 days (95% confidence interval, 208-333 days). During the observation period, FC improved by at least 1 in 7 patients, remained unchanged in 3, and worsened in 2 (P ¼ 0.04 for the global effect; Table 3). The estimated increase in 6MWD was 37 6 66 m at 6 months (P ¼ 0.04) and 67 6 59 m at 12 months (P < 0.001; Table 3 and Fig. 5). In contrast, systolic PAP, measured by Doppler echocardiography, remained essentially unchanged through the 12-month observation period (Table 3). The clinical outcomes of the 6 patients who underwent both acute and long-term iILO studies were similar to those of the whole group, and we could not find any statistically significant association between the acute and long-term responses to iILO; this was likely due to the reduced number of patients in this particular subgroup. In the 10 patients completing the 1-year observation period, the Model for End-Stage Liver Disease score did not change significantly under iILO treatment. Furthermore, the platelet count, albumin, bilirubin, creatinine, prothrombin time, aspartate aminotransferase, and alanine aminotransferase remained unaltered during the follow-up (data not shown). In 2 patients in whom OLT was initially contraindicated because of the presence of PAH, the procedure LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases ILOPROST IN PORTOPULMONARY HYPERTENSION 353 TABLE 3. Changes Induced by Long-Term Treatment with Inhaled Iloprost Estimated Differences from Mean (95% the Baseline Follow-Up Confidence Interval) Functional class Baseline 2.8 (2.5-3.0) 6 months 2.4 (2.0-2.8) 12 months 2.3 (1.8-2.7) 6-minute walk distance, m Baseline 396 (385-406) 6 months 433 (399-466) 12 months 463 (434-492) Systolic PAP, mm Hgy Baseline 76.7 (76.2-77.2) 6 months 78.7 (74.4-83.0) 12 months 71.4 (58.3-84.5) (Standard P Error) Value* 0.33 (0.27) 0.5 (0.32) 0.15 0.04 36.6 (19.1) 0.04 67.5 (17.0) <0.001 2.0 (2.2) 5.3 (6.7) 0.43 0.48 Figure 5. Evolution of the distance covered in the 6-minute walk test in 11 patients treated with inhaled iloprost. Triangles indicate values at the baseline and at 6 months for 2 patients who did not complete the 12-month observation period (1 death and 1 treatment change). *Versus the baseline. y Measured by Doppler echocardiography. could be subsequently performed under iILO treatment. In 1 patient, mean PAP decreased from 40 to 32 mm Hg after 5 months of treatment, and the patient underwent transplantation in month 11. In the other, mean PAP decreased from 39 to 28 mm Hg in month 18, and the patient underwent transplantation after 20 months of treatment. Both patients were alive 16 and 84 months after OLT with specific therapy (iloprost and bosentan, respectively) due to persistent PAH after transplantation. DISCUSSION This is the first study reporting the concomitant effects of a specific PAH drug on the pulmonary and hepatic circulations in patients with PoPH. The results of the acute hemodynamic study show that in these patients the administration of iILO produces selective pulmonary vasodilation without exerting detrimental effects on portal pressure. Furthermore, the retrospective analysis indicates that 12 months of treatment with iILO provided clinical improvement and increased exercise capacity. Acute Effects of iILO We hypothesized that the delivery of the prostacyclin analogue iloprost by inhalation could overcome the unwanted effects of prostanoids on splanchnic circulation.14 The results of the acute study, in which hepatic hemodynamics were assessed simultaneously with cardiopulmonary hemodynamics, confirm this hypothesis and show that iILO produced significant decreases in PAP and PVR without altering portal pressure or HBF (Table 2 and Figs. 1 and 2). The effects of iILO on pulmonary circulation in our series concur with the results of previous studies showing maximal vasodilation 5 to 15 minutes after administration, with a progressive return to the baseline until the practical disappearance of the effect after 60 minutes.28,29 The mechanisms by which the intermittent administration of iILO provides clinical benefit in PAH are not fully understood. Conceivably, this could be related to effects that go beyond vasodilation because prostacyclins, modulating the action of growth factors and regulating the cell cycle, also exert antiproliferative effects.30,31 The effects of iILO on hepatic hemodynamics differ from the effects of other drugs used in PAH treatment. Calcium channel blockers, which are used in the subset of patients with a vasospastic component, may increase portal pressure.32 Intravenous prostacyclins decrease systemic vascular resistance, increase cardiac output33 and HBF,13 and may produce progressive splenomegaly.14 Phosphodiesterase-5 inhibitors may increase mesenteric blood flow and portal venous pressure.19-21 Accordingly, because some drugs used for the treatment of PAH entail the potential risk of worsening hepatic hemodynamics, their effects on portal pressure should be carefully assessed before their clinical use is extended to the subgroup of patients with PoPH. As for the use of iILO for acute vasoreactivity testing in PoPH, the current data agree with the previous observation that prostanoids elicit significant vasodilator responses in a substantial number of patients with PoPH.34 It remains to be settled whether or not the LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases 354 MELGOSA ET AL. acute response to iILO predicts the long-term outcome in PoPH, as it has been shown in PAH.35 Modulation of the Response by Hepatic Hemodynamics The results of the present study reveal that, under the name of PoPH, we may include patients with a heterogeneous pathophysiological condition with respect to the degree of portal hypertension and pulmonary hemodynamics.2,3 Indeed, HVPG correlated with cardiac output and was inversely related to PVR; this points to greater cardiopulmonary impairment in patients with less severe portal hypertension (Fig. 3). The effects of iILO on pulmonary circulation in this group of patients differed from those seen in idiopathic PAH.35 Although in PoPH iILO resulted in a rapid and significant decrease in PAP, it also produced a delayed and progressive reduction of cardiac output (Fig. 1). Six of the patients had undergone correction of portal hypertension with a TIPS or surgical shunt. Interestingly, the reduction of PAP was more consistent and prolonged in this subgroup of patients than in the other ones (Fig. 4). Furthermore, the analysis of the relationships between HVPG and changes in pulmonary hemodynamics induced by iILO indicates that patients with more severe portal hypertension showed less change in PVR and were those in whom cardiac output decreased (Fig. 3). Altogether, we believe that the presence of severe portal hypertension might represent an impediment to the expected increase in venous return that should result from the pulmonary vasodilator effect of iILO, which likely accounts for a decrease in right ventricular filling and hence in cardiac output. The present study also illustrates how abnormalities in hepatic hemodynamics can influence the response to PAH therapy. Accordingly, we consider acute pulmonary vasodilator testing and the assessment of portal pressure to be essential steps for fully characterizing patients with suspected PoPH. Long-Term Treatment Long-term treatment with iILO provided acceptable 12-month survival and improvements of both FC and exercise tolerance (Table 3 and Fig. 5). Treatment with iILO resulted in an improvement of exercise tolerance, which was already apparent in the majority of patients at 6 months and increased further at 12 months (Table 3 and Fig. 5). The increase in 6MWD was similar to that reported in patients with idiopathic PAH treated with iILO for 1 year35 and greater than that shown in patients with PAH treated for 3 months with a double-blind design.22 It is tempting to speculate that compared with other forms of PAH, prolonged treatment with iILO might result in a greater increase in exercise tolerance for patients with PoPH; this effect is likely related to the lesser cardiac impairment in this subgroup of patients.36 iILO also resulted in an improvement of FC in the majority of patients. Conversely, no changes in sys- tolic PAP were observed during treatment. A lack of change in mean PAP, which was measured by right heart catheterization, was also reported in patients with PAH treated with iILO, despite a reduction in PVR.22 In our series, Doppler echocardiography conceivably was not sensitive enough to reflect the changes in PVR and cardiac output produced by iILO. Six patients presented clinical deterioration during the 1-year follow-up: right ventricular failure in 2 cases, with one of them requiring additional medication (sildenafil), and complications of the liver disease in 4 cases, which resulted in death in 2 cases. Before iILO treatment was started, among the 4 patients developing hepatic complications, 2 were in ChildPugh class B, and 2 were in class C. We believe that clinical worsening due to hepatic complications, which in some cases resulted in death, was more likely related to the severity of the liver disease at entry rather than to an effect of iILO, although this contention must be evaluated in a controlled clinical trial. It is interesting to note that 2 patients treated with iILO underwent successful OLT and were in good clinical condition 16 months and 6 years after the procedure, and this is in agreement with the observation that patients with PoPH treated with specific PAH therapy and OLT are those who show better clinical outcome.6 Nevertheless, pulmonary hypertension persisted after transplantation, and both patients are still undergoing PAH therapy. Few studies have evaluated the efficacy of specific PAH therapy in PoPH.16-18,37,38 These studies have been conducted in small series of patients with an open-label design, as in the present investigation. Hoeper et al.37 showed improvements in symptoms (FC decrease  1, 45% of patients) and exercise tolerance (change in 6MWD, 78 m) in 11 patients with Child A cirrhosis after 1 year of treatment with bosentan (a dual endothelin receptor antagonist) that were similar to those in the present series. A more recent retrospective analysis38 comparing patients treated with bosentan (n ¼ 18) and iILO (n ¼ 13) showed better survival with bosentan at 1 and 3 years as well as better clinical and hemodynamic outcomes. One-year survival in the current study was intermediate between that reported in patients treated with bosentan (94%) and that reported in patients treated with iILO (77%) in that series.38 Differences in mortality between bosentan and iILO might be explained, at least in part, by the different severities of liver disease in the 2 groups, as patients to be treated with bosentan were selected from those with lesser hepatic dysfunction (Child-Pugh class A). Reichenberger et al.16 evaluated the effect of sildenafil in 14 patients with PoPH. One-year survival was 86%, FC improved by 0.5 classes, and 6MWD increased by 95 m; these changes are comparable to those observed in our series (Table 3). Sildenafil treatment produced a marked decrease in PVR but no change in mean PAP,16 and this is in keeping with the lack of change in systolic PAP observed in the present study. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases ILOPROST IN PORTOPULMONARY HYPERTENSION 355 Overall, it can be concluded that long-term treatment of PoPH patients with iILO may provide clinical improvements similar to those shown with other specific PAH drugs, which have a less established safety profile for hepatic function and portal hemodynamics. Our study had several limitations. First, in the acute study, hepatic hemodynamics were not assessed in all patients: some of them had portal hypertension already corrected by means of a TIPS or portocaval shunt, and for others, there were technical reasons. Nevertheless, the pulmonary hemodynamics at the baseline and the effects of iILO on the pulmonary circulation in the subset of patients who underwent double catheterism did not differ from those of the whole group. Second, the long-term analysis was retrospective and uncontrolled and was conducted in a reduced number of patients, and we cannot disregard that variables which were not measured could influence the results. Accordingly, no firm conclusions can be drawn at present; further investigations are needed. Finally, there were 3 patients who did not complete the 1-year follow-up because of death (2 cases) or a need for additional specific PAH therapy (1 case). To overcome this situation, missing values after dropout were handled with a last observation carried forward approach, which in our series represented the worst case value of the imputation scale. Subsequent analyses were conducted for all treated subjects and not only for those who completed the 12-month observation period in order to get a more informative assessment of treatment effects. In summary, in patients with PoPH, iILO has a rapid and selective vasodilator effect on the pulmonary circulation without altering hepatic hemodynamics. Long-term treatment with iILO provided sustained effects on clinical symptoms and exercise tolerance in a group of patients with PoPH. Accordingly, iILO may be a suitable option for the acute and long-term management of PoPH. A multicenter, controlled trial is warranted to establish its clinical role in this sizeable group of patients. ACKNOWLEDGMENTS The authors are indebted to F. Burgos, J. L. Valera, J. A. Rodrı́guez, M. A. Baringo, L. Rocabert, and R. Saez for their contributions to the hemodynamic studies and to J. Rios for statistical advice. REFERENCES 1. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. 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