Article Hepatopulmonary syndrome increases the postoperative mortality rate following liver transplantation: a prospective study in 90 patients SCHIFFER, Eduardo, et al. Abstract Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of patients with end-stage liver diseases. HPS is diagnosed by hypoxemia and pulmonary vascular dilatation and is an independent risk factor of mortality. Orthotopic liver transplantation (OLT) is the only factor that modifies the natural course of HPS. Once patients with HPS have been transplanted, their long-term survival rate is similar to transplanted patients without HPS. Consequently, HPS is an indication of OLT whatever the severity of hypoxemia. However, besides the favorable long-term survival of HPS patients with OLT, a high postoperative mortality (mostly within 6 months) has been suggested. The aim of our study was to analyze the incidence of HPS and postoperative outcome after OLT in 90 consecutive patients. All patients were prospectively included and had blood gas analysis to detect HPS. Patients with hypoxemia had contrast echocardiography to confirm HPS. Nine patients had HPS with a 50 Reference SCHIFFER, Eduardo, et al. Hepatopulmonary syndrome increases the postoperative mortality rate following liver transplantation: a prospective study in 90 patients. American Journal of Transplantation, 2006, vol. 6, no. 6, p. 1430-7 DOI : 10.1111/j.1600-6143.2006.01334.x PMID : 16686767 Available at: http://archive-ouverte.unige.ch/unige:36995 Disclaimer: layout of this document may differ from the published version.
American Journal of Transplantation 2006; 6: 1430 1437 Blackwell Munksgaard C 2006 The Authors Journal compilation C 2006 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/j.1600-6143.2006.01334.x Hepatopulmonary Syndrome Increases the Postoperative Mortality Rate Following Liver Transplantation: A Prospective Study in 90 Patients E. Schiffer a,c,, P. Majno b, G. Mentha b, E. Giostra c, H. Burri d, C. E. Klopfenstein a, M. Beaussier e, P. Morel b, A. Hadengue c and C. M. Pastor c a Service d Anesthésiologie, Département APSI, b Unité de Transplantation, Département de Chirurgie, c Laboratoire de physiopathologie hépatique et imagerie moléculaire and d Service de Cardiologie, Hôpitaux Universitaires de Genève, 1205 Geneva, Switzerland e Département d Anesthésie et Soins Intensifs, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, 75012 Paris, France Corresponding author: Eduardo Schiffer, eduardo.schiffer@hcuge.ch Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of patients with end-stage liver diseases. HPS is diagnosed by hypoxemia and pulmonary vascular dilatation and is an independent risk factor of mortality. Orthotopic liver transplantation (OLT) is the only factor that modifies the natural course of HPS. Once patients with HPS have been transplanted, their long-term survival rate is similar to transplanted patients without HPS. Consequently, HPS is an indication of OLT whatever the severity of hypoxemia. However, besides the favorable long-term survival of HPS patients with OLT, a high postoperative mortality (mostly within 6 months) has been suggested. The aim of our study was to analyze the incidence of HPS and postoperative outcome after OLT in 90 consecutive patients. All patients were prospectively included and had blood gas analysis to detect HPS. Patients with hypoxemia had contrast echocardiography to confirm HPS. Nine patients had HPS with a 50 PaO 2 70 mmhg. Among them 3 (33%) died while the mortality rate was 9.2% in the group without HPS (7 over 76 patients). In the HPS patients who survived, the syndrome completely recovered within 6 months. In conclusion, our study shows a high postoperative mortality rate following OLT even though the preoperative PaO 2 was >50 mmhg in all HPS patients transplanted. Key words: Hepatopulmonary syndrome, liver transplantation, perioperative mortality Received 12 December 2005, revised 3 February 2006 and accepted for publication 21 February 2006 Introduction The hepatopulmonary syndrome (HPS) occurs in 4 19% of patients with cirrhosis and portal hypertension (1 4). The syndrome associates hypoxemia and increased alveolararterial O 2 gradient, pulmonary vascular dilatation and redistribution of pulmonary blood flow toward lungs areas with low ventilation/perfusion (VA/Q) ratios (5,6). The redistribution of VA/Q ratios is further increased in the upright position (5) and during exercise (7,8). A decrease in vascular pulmonary reactivity and in the response to hypoxia explains the pulmonary blood flow redistribution within lung zones (6). One of the mediators responsible for pulmonary vascular dilatation is nitric oxide (NO). Increased exhaled NO has been found in patients with HPS (9 11) and exhaled NO decreased with the disappearance of HPS following orthotopic liver transplantation (OLT) (12,13). HPS in patients with end-stage liver disease is mainly diagnosed by hypoxemia and pulmonary vascular dilatation which are evidenced by contrast echocardiography or lung perfusion scanning with radioactive albumin (14). Studies that determined the long-term survival and outcome of patients with end-stage liver disease showed that HPS is an independent risk factor for mortality. In the absence of OLT, the long-term mortality is increased in cirrhotic patients with HPS in comparison to cirrhotic patients without HPS (4,15). Moreover, the 5-year mortality rate in HPS patients with OLT is 24% versus 77% in HPS patients who do not undergo OLT (15). Interestingly, following OLT, the long-term mortality is similar in patients with or without HPS (15). This conclusion is true even when the preoperative PaO 2 is 50 mmhg (15). Thus, considering a long-term period, OLT is the only factor that modifies the natural course of HPS and once patients with HPS have been transplanted, their long-term mortality rate is similar to transplanted patients without HPS (15). Consequently, in the absence of comorbidities, HPS is now an indication of OLT whatever the severity of HPS or hypoxemia (16,17). However, besides the favorable survival of HPS patients with OLT, a high postoperative mortality (mostly within 6 months) has been suggested (15,18,19). Because the immediate postoperative mortality rate has not been previously compared prospectively in patients with and 1430
HPS Increases Postoperative Mortality Rate Following LT without HPS, we analyzed the outcome of 90 consecutive patients with and without HPS transplanted in our institution. Methods Patient selection Ninety patients [70 males, 20 females, median age 53 years (range: 26 69)] were prospectively included in the study over a period of 4 years and followed for 6 months after OLT. The protocol was approved by the institutional ethics committee of the University of Geneva and written informed consent was obtained from each patient at the time of inclusion in the waiting list for OLT. Diagnostic criteria for HPS HPS was diagnosed when the following criteria were fulfilled: (1) presence of chronic liver disease (Child Turcotte Pugh score 6) and/or portal hypertension; (2) alveolar-arterial difference for the partial pressure of oxygen (AaDO 2 ) 15 mmhg (normal range, 4 8 mmhg) (20) associated with hypoxemia 70 mmhg in upright position while breathing room air; (3) intrapulmonary vascular dilatation detected by transthoracic two-dimensional contrast echocardiography and (4) absence of primary cardiac or pulmonary disease, according to history, electrocardiogram and echocardiography including Doppler measurements and chest X-ray. Figure 1: Illustration of a positive contrast-enhanced echocardiography. (A) Normal four-chamber view without contrast medium. (B) After one heartbeat, no microbubbles are present in the left cardiac chambers. (C) Four heartbeats after contrast medium injection, microbubbles are detectable in the right atrium and in the right ventricle of the heart. (D) Five heartbeats after injection, microbubbles also appear in the left cardiac chambers. (E) After 10 heartbeats, the left chambers are filled with microbubbles. (F) After 22 heartbeats, microbubbles are progressively disappearing. American Journal of Transplantation 2006; 6: 1430 1437 1431
Schiffer et al. Arterial blood gas analysis Arterial blood gas samples were obtained by percutaneous radial artery puncture, both in the upright (patients being seated in an armchair) and the supine position while breathing room air. Arterial blood gas analysis was performed with an analyzer (Stat Profile Ultra, Nova Biomedical, Waltham, MA, USA) calibrated hourly. Arterial PO 2, partial pressure of arterial carbon dioxide (PaCO 2 ), arterial base excess, bicarbonate concentration, ph and AaDO 2 were measured or calculated, according to the standard formula as previously described (15,20,21), using daily barometric pressure (P B ), water vapor pressure at 37 C (47 mmhg), FIO 2 at room air (0.21) and assuming a ventilation/perfusion ratio 0.8: and PAO 2 = [0.21 (P B 47)] (PaCO 2 /0.8) AaDO 2 = PAO 2 PaO 2 (mmhg). Pulmonary hemodynamics To exclude pulmonary hypertension, pulmonary hemodynamics were measured during a right heart catheterization in steady conditions in all patients via a pulmonary artery catheter (Swan-Ganz catheter, Baxter Healthcare, Irvine, CA, USA). Measurements included mean pulmonary artery pressure (MPAP, mmhg), mean right atrial pressure (RAP, mmhg), cardiac output (L/min, using the thermodilution method), cardiac index (L/min/m 2 ) and pulmonary capillary wedge pressure (PCWP, mmhg). Pulmonary vascular resistances (PVRI, dyne s/cm 5 m 2 ) were calculated. Transhepatic pressure gradient was also measured using free hepatic vein pressure and wedged hepatic vein pressure as previously described (22). Pulmonary function tests Vital capacity and forced expiratory volume in 1 second (FEV1) were obtained by a computerized spirometer (Autobox 6200, Sensor Medics, Yorba Linda, CA, USA) using standard procedures. Total lung capacity was measured by a body plethysmograph (Autobox 6200, Sensor Medics, Yorba Linda, CA, USA) and diffusing capacity for carbon monoxide (DLCO) was calculated by either the single-breath technique corrected for serum hemoglobin or the steady-state technique and reported with reference to standard predicted percentages (23). Enhanced contrast echocardiography Contrast medium was obtained by agitation of saline solution, which creates a stream of microbubbles after intravenous injection. Transthoracic two-dimensional echocardiography was performed after the iv injection of the contrast medium (5 ml) in a peripheral vein. Echocardiography was performed by an experienced cardiologist using two-dimensional apical fourchamber views (Figure 1). Positive contrast echocardiography for intrapulmonary shunt was defined by the appearance of microbubbles in the left side of the heart chambers within 6 but not before 4 heartbeats after the appearance in the right side of the heart. Thus, microbubbles (diameter: 60 90 lm) opacify the left heart chambers only when they pass through the pulmonary capillaries (24). The distinction between intrapulmonary or intracardiac shunt is made by the time of appearance in the left heart chambers. When intracardiac shunt exists, microbubbles appear within 3 heartbeats in the left heart chambers. In contrast, with intrapulmonary shunts, microbubbles appear within 4 6 heart beats after the initial appearance in the right side of the heart (4,25). Data analysis Comparisons between groups were performed by the Mann-Whitney U test for non-parametric data and the v 2 test when appropriate. Statistical significance was designated as p < 0.05. The Kaplan Meier method was Table 1: Drop-outs from the waiting list (n = 21) Causes of exclusion Death 8 Severe cardiac disease 1 Pulmonary hypertension 1 (MPAP > 35 mmhg or PVR 2 > 250 dyne s/cm 5 ) Absence of alcohol abstinence 1 Extensive neoplasm 1 Evolving liver carcinoma 7 Portal vein thrombosis 1 1 Pulmonary hypertension occurred in two patients on the waiting list. used to determine patient survival and the log-rank test to compare survival between groups. Statistical analysis was performed with SPSS (Release 11, SPSS Inc., Chicago, IL, USA). Results Prevalence of HPS We included 90 patients transplanted at a single transplantation center (Hôpitaux Universitaires de Genève, Geneva, Switzerland) between January 1999 and December 2003. Twenty-one additional patients listed during the same period had to be excluded from OLT for various reasons that are explained in Table 1. An overview algorithm that characterizes the patients in terms of HPS assessment and outcome after OLT is provided in Figure 2. Among the 90 patients of the study, blood gas analysis was performed according to the investigation protocol and 18 were suspected to have HPS. Among these 18 patients, 13 had transthoracic contrast echocardiography, which confirmed the syndrome in 9. Thus, 10% of the patients had confirmation of HPS. However, higher percentage of patients with HPS should be expected since among the 5 patients suspected to have HPS based on blood gas analysis and who had no transthoracic contrast echocardiography, 3 4 patients (70% of suspected patients had HPS confirmation) should have HPS. Considering the uncertainty on their clinical status, these 5 patients were finally excluded from the statistical analysis. Thirteen living donor liver transplantations were performed during the study, but none of these patients had HPS. Of note the criteria for HPS was more severe than the one highlighted recently by the European Respiratory Society that considers the threshold value of hypoxemia to be 80 mmhg when we chose a PaO 2 70 mmhg (16,17). Because all HPS patients had 52 PaO 2 70 mmhg, we classified the syndrome between moderate and severe according to recent guidelines (16). No patient had a PaO 2 50 mmhg value that classifies HPS as very severe (16). Clinical characteristics of patients The clinical characteristics of the 9 patients who fulfilled the criteria for HPS diagnosis were compared to those of patients without HPS (Table 2). Mean age, sex and cause n 1432 American Journal of Transplantation 2006; 6: 1430 1437
HPS Increases Postoperative Mortality Rate Following LT Figure 2: Overview algorithm of the study patients listed for OLT. OLT = orthotopic liver transplantation; HPS = hepatopulmonary syndrome. White boxes represent HPS patients, gray boxes non-hps patients. Table 2: Clinical characteristics of patients (n = 85). Patients were considered HPS+ only when contrast echocardiography was positive (n = 9) With Without HPS HPS (n = 9) (n = 76) p-value Age (years) ± SD 56 ± 8 53 ± 10 NS Male (%) 89 71 NS Cause of cirrhosis (%) Alcohol 11.1 32.9 NS Hepatitis C virus 88.9 34.1 NS Hepatitis B virus 0 13.2 Biliary cirrhosis 0 6.8 Autoimmune hepatitis 0 2.6 Amyloidosis 0 2.6 Metabolic inherited disease 0 2.6 Others 0 5.2 Child Pugh class (%) A 33.3 22.4 NS B 22.2 40.8 NS C 44.4 36.8 NS Child Pugh score 8.9 ± 2.8 8.8 ± 2.4 NS MELD score 17.2 ± 6.1 15.1 ± 6.4 NS Serum creatinine (lmol/l) 124 ± 35 108 ± 43 NS Total bilirubin (lmol/l) 50 ± 25 46 ± 28 NS Albumin (g/l) 29 ± 6 30 ± 4 NS Prothrombin time (INR) 1.5 ± 0.3 1.5 ± 0.3 NS FEV 1 (% predicted) 89 ± 25 84 ± 15 NS FEV 1 /vital capacity (%) 73 ± 11 72 ± 6 NS PaO 2 (mmhg) 60 ± 6 86 ± 12 <0.00001 AaDO 2 (mmhg) 52 ± 10 25 ± 14 <0.00001 of cirrhosis were similar in both groups. More importantly, the severity of liver diseases assessed by Child Pugh and model of end-stage liver disease (MELD) scores was not related to HPS presence. Accordingly, total bilirubin, albumin and creatinine concentrations in serum and prothrombin time were not different in patients with or without HPS. There was no significant difference in lung function parameters. Hepatic and systemic hemodynamic parameters Table 3: Hepatic and systemic hemodynamic parameters HPS Non-HPS patients patients (n = 9) (n = 76) p HVPG (mmhg) 15.9 ± 3.7 15.8 ± 6.0 0.92 MPAP (mmhg) 13.8 ± 5.4 15.3 ± 5.1 0.34 PCWP (mmhg) 8.4 ± 4.9 8.6 ± 4.1 0.88 Cardiac index (L/m 2 ) 3.5 ± 0.9 3.5 ± 1.2 0.84 PVRI (dyne s/cm 5 m 2 ) 125 ± 32 162 ± 90 0.22 HVPG = hepatic venous pressure gradient; MPAP = mean pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; PVRI = pulmonary vascular resistance index. were also similar in both groups (Table 3). As expected, PaO 2 was significantly reduced and AaDO 2 was significantly increased in patients with HPS. However, all patients with HPS had a 50 PaO 2 70 mmhg (Table 4). The PaO 2 ranges for non-hps patients were 71 104 mmhg and the AaDO 2 ranges were 3 31 mmhg. All patients with HPS documented by positive contrast echocardiography had deceased-donor OLT and were followed for 6 months. Median time from HPS diagnosis to OLT was 10.3 months in the 9 patients with HPS. At OLT time, PaO 2 had deteriorated in all but 2 patients. Individual clinical details of the 18 patients having blood gas analysis suggesting HPS are also presented in Table 5. Postoperative mortality rate The mortality rate was compared between the 76 patients who had no HPS and the 9 patients who had a positive echocardiography. The 5 patients suspected to have HPS without confirmation by contrast transthoracic echocardiography were excluded from the statistics to avoid speculation on their clinical status. Mean survival rates at 6 months were significantly different (p = 0.0012, log-rank test, Figure 3). The mortality rate in patients with HPS was 33% while the mortality rate of patients without HPS was 9.2%. At 6 months, the overall mortality of patients with and American Journal of Transplantation 2006; 6: 1430 1437 1433
Schiffer et al. Table 4: Patients with HPS confirmed by positive echocardiography Age Child Pugh Child Pugh MELD PaO 2 PCO 2 AaDO 2 Patient Sex (years) Etiology class score score (mmhg) (mmhg) (mmhg) Outcome 1 1 M 60 HCV C 12 20 54 33 58 Alive 2 F 69 HCV A 6 11 63 29 54 Alive 3 M 63 HCV A 6 11 56 29 62 Alive 4 M 51 HCV C 12 23 62 33 50 Dead 5 M 48 HCV B 8 13 59 32 55 Alive 6 M 52 Alcohol C 12 28 68 40 35 Dead 7 M 65 HCV A 6 12 55 29 62 Alive 8 M 53 HCV B 9 18 52 38 54 Alive 9 M 51 HCV C 10 19 70 37 38 Dead HCV = hepatitis C virus; MELD = model for end-stage liver disease. 1 Six-month follow-up. Table 5: Patients with blood gas analysis suggesting HPS Supine upright difference Positive Cause Child Supine Upright Supine Upright Supine in contrast Outcome of Pugh MELD PaO 2 PaO 2 PaCO 2 PaCO 2 AaDO 2 AaDO 2 echocar- DLCO post Patient Age Sex cirrhosis score score (mmhg) (mmhg) (mmhg) (mmhg) (mmhg) (mmhg) diography % LT 1 1 42 M HCV B8 12 61 59 29 28 56 3.4 NA 47 Dead 2 53 M HCV A6 7 56 57 30 29 60 0.2 96 Alive 3 60 M HCV C12 20 54 52 33 28 58 8.8 + 41 Alive 4 69 F HCV A6 11 63 54 29 27 54 11.8 + 73 Alive 5 63 M HCV A6 11 56 53 29 25 62 7.7 + 82 Alive 6 42 M Alcohol C10 18 61 63 29 30 56 3.3 NA Alive 7 51 M HCV C12 23 62 63 33 33 50 0.7 + 55 Dead 8 48 M HCV B8 13 59 59 32 32 55 0.7 + NA Alive 9 60 M Alcohol A5 6 60 54 30 27 56 10.1 NA 94 Alive 10 45 M HCV B9 19 62 53 33 30 51 12.8 NA NA Alive 11 52 M Alcohol C12 28 68 59 40 29 35 23.8 + NA Dead 12 50 M Alcohol C12 24 61 60 29 30 56 0.2 46 Alive 13 65 M HCV A6 12 55 52 29 25 62 8.6 + 85 Alive 14 52 M Alcohol B8 13 55 56 33 33 57 1.5 NA 94 Alive 15 59 F Alcohol C14 25 56 59 32 32 58 3.9 64 Alive 16 53 M HCV B9 18 52 51 38 38 54 1.7 + 67 Alive 17 51 M HCV C10 19 70 64 37 30 38 14.4 + 96 Dead 18 35 M Metabolic B9 14 56 56 25 30 67 7.3 NA 38 Alive HCV = hepatitis C virus; NA = non-available; MELD = model for end-stage liver disease. 1 Six-month follow-up. without HPS (n = 90) was 13%. Characteristics of HPS patients who died are shown in Table 6. Child Pugh score was similar in those who died in comparison to those who survived but MELD score was higher (Table 6). Surprisingly, PaO 2 was significantly higher and AaDO 2 significantly lower in the HPS patients who died. However, the small number of HPS patients precludes extrapolating these findings to larger groups of patients. Evolution of HPS after OLT Blood gas analysis was performed at 6 months in the 6 patients with HPS who survived and showed complete resolution of hypoxemia in all patients as revealed by normalization of the AaDO 2 gradient (Figure 4). Mean PaO 2 after OLT was significantly higher than the pre-olt value: 92.6 mmhg (72 102 mmhg) versus 57 mmhg (52 63 mmhg). Causes of death in the patients with HPS are listed in Table 7. Three patients died within the first 35 days after OLT of either septic (2) or hemorrhagic shock (1) having never improved blood gas exchange. Discussion Our prospective study shows that the postoperative mortality rate following OLT in patients with moderate-tosevere HPS (50 PaO 2 70 mmhg) is much higher than the postoperative mortality rate of patients without HPS. The reasons for such high mortality remain puzzling. 1434 American Journal of Transplantation 2006; 6: 1430 1437
HPS Increases Postoperative Mortality Rate Following LT % cumulative survival 100 80 60 40 20 HPS- (n = 76) HPS+ (n = 9) P = 0.0012 0 0 3 6 9 12 15 18 21 24 27 Weeks after OLT Figure 3: Cumulative survival rate of patients screened for HPS who underwent OLT over a 6-month follow-up period. Upper continuous line represents patients without HPS (n = 76) and lower continuous line represents patients with proven HPS (n = 9). Survival was significantly different between patients with or without documented HPS (log-rank test). Table 6: Demographic and clinical characteristics of patients with HPS Alive Dead (n = 6) (n = 3) p Age 59 ± 8 52 ± 1 0.158 Child Pugh score 7.7 ± 2.6 11.3 ± 1.2 0.056 MELD score 14.0 ± 4.0 23.4 ± 4.5 0.015 PaO 2 (kpa) 53 ± 3 62 ± 3 0.006 AaDO 2 (kpa) 58 ± 4 41 ± 8 0.003 Liver disease Alcohol 0 1 0.33 Hepatitis 6 2 However, the syndrome completely recovered within 6 months in patients who survived. Thus, although the favorable long-term survival of HPS patients with OLT may prompt centers to transplant all HPS patients whatever the preoperative hypoxemia, the immediate postoperative mortality rate remains high in this group of patients. Postoperative mortality Previous studies have determined that HPS is an independent risk factor of long-term mortality in cirrhosis. In the absence of OLT, the long-term mortality is increased in cirrhotic patients with HPS in comparison to cirrhotic patients without HPS (4,15). Moreover, the 5-year mortality rate in HPS patients who had OLT is 24% versus 77% in HPS patients who do not undergo OLT (15). Following OLT, the long-term mortality is similar in patients with or without HPS (15). This conclusion is true even when preoperative PaO 2 was 50 mmhg (15). Thus, considering a long-term period, OLT is the only factor that modifies the mortality rate in patients with HPS and once patients with HPS have been transplanted, their long-term mortality rate is similar AaDO 2 (mmhg) PaO 2 (mmhg) 70 60 50 40 30 20 10 0 110 100 90 80 70 60 50 40 Pre OLT 6 months post OLT Figure 4: Alveolar-arterial difference for the partial pressure of oxygen AaDO 2 (mmhg) and PaO 2 (mmhg) before and 6 months after OLT (n = 6). Table 7: Causes of death in patients with HPS Delay between Causes OLT Correction of and death of Patient 1 death (days) hypoxemia 7 Septic shock (ARDS) 15 11 Septic shock (ARDS) 34 17 Multiple organ failure 4 ARDS = acute respiratory distress syndrome. 1 Refers to patient number in Table 5. to transplanted patients without HPS (15). Consequently, in the absence of comorbidities, HPS is now an indication of OLT whatever the severity of HPS or hypoxemia (16). However, besides the good evolution of HPS patients with OLT over 5 years, a high postoperative mortality (mostly within 6 months) has been suggested. In their retrospective study, Swanson et al. (15) showed a 21% (5 over 24 patients) postoperative mortality rate in HPS patients. All 5 patients had a low preoperative PaO 2 ( 51 mmhg). Another retrospective analysis also found a 22% postoperative mortality rate in HPS patients (18) while in the prospective study by Arguedas et al. (19), the postoperative American Journal of Transplantation 2006; 6: 1430 1437 1435
Schiffer et al. mortality was 29%. Because the immediate postoperative mortality rate of patients with and without HPS has not been previously compared prospectively, we analyzed the outcome of 90 consecutive OLT patients. All patients with HPS were classified as having moderate-to-severe HPS according to recent guidelines, all patients having a PaO 2 between 52 and 70 mmhg (17). As suggested by previous studies, we confirmed that the postoperative mortality following OLT was significantly higher in patients with HPS (33%) than in patients without HPS (9.2%). The reasons for the increased postoperative mortality in HPS patients are puzzling. In their study, Taille et al. (18) found that the immediate postoperative mortality was not associated with the severity of HPS. In the 9 HPS patients, Child Pugh score was similar in those who died in comparison to those who survived but MELD score was higher (Table 6). Surprisingly, PaO 2 was significantly higher and AaDO 2 significantly lower in the HPS patients who died. However, the small number of HPS patients precludes extrapolating these findings to larger groups of patients. Although the severity of pulmonary shunt was not quantified by echocardiography in the preoperative period, we estimated the shunt in the operating room in patients breathing 100% FIO 2. No difference was found between the patients who survived (25 ± 3%) and those who died (27 ± 5%). Prevalence of HPS The reported prevalence of HPS in patients with liver disease varies from 4% to 19%, probably because various criteria and threshold values defining arterial deoxygenation have been used (2,21,26). Thus, in a study including 98 patients of whom 33 (34%) had a positive contrast echocardiography, the suspicion of HPS was higher when the AaDO 2 was >15 mmhg (32%), >20 mmhg (31%), and greater than age-related threshold (28%) than when a PaO 2 threshold was chosen <80 mmhg (19%), <70 mmhg (15%), and age-related threshold (15%) (26). Moreover, the techniques used to confirm the pulmonary vascular dilatation (contrast echocardiography vs. scintigraphic perfusion scanning) have also to be considered. The prevalence of HSP among OLT patients was 10% (9 over 90) in our study similarly to the retrospective study of Mohamed et al. (27), who found hypoxemia in 7% of the patients listed for OLT. However, in this study no shunt could be diagnosed either by echocardiography or by scintigraphy. In more recent studies, no prevalence of HSP in OLT candidates was mentioned (15,19,28). Thus, the prevalence of HSP in OLT candidates is difficult to assess because in most studies patients with severe hypoxemia have been excluded from OLT or patients with minimal shunt have not been diagnosed as having HPS. Additionally, considering that 70% (9/13) patients suspected to have HPS have confirmed the diagnosis with contrast echocardiography, the 5 patients suspected to have the syndrome without echocardiography confirmation might increase the prevalence to 14%. Clinical characteristics of HPS patients No specific clinical characteristics of HPS patients have been observed in our study. Gender, age and causes of liver disease are similar in patients with or without HPS (Table 2). Hepatic and pulmonary hemodynamic parameters were not different (Table 3). The severity of liver diseases is also identical in both groups of patients. These findings have already been reported in previous studies (2). FEV 1 and FEV 1 /CV did not change in patients with and without HPS and although several patients had a decreased DLCO, as observed in another study (29), this finding is not a prerequisite for the diagnosis of HPS. To document intrapulmonary vascular dilatation, we used contrast echocardiography and found nine positive examinations over the 13 patients who had blood gas abnormalities. An alternative to contrast echocardiography is scintigraphic perfusion scanning. Under normal conditions, 99m Tc albumin macroaggregates that exceed 20 lm in diameter are almost completely trapped in the pulmonary circulation. In the presence of cardiac right-to-left shunts or intrapulmonary vascular dilatation, the uptake of 99m Tc albumin macroaggregates can be visualized in other organs such as the brain or the spleen. Contrast echocardiography was shown to be more efficient than scintigraphic perfusion scanning to diagnose pulmonary vascular dilatation in cirrhotic patients with HPS (14). Guidelines on pulmonary hepatic vascular disorders recently highlighted echocardiography in the screening algorithm for HPS, scintigraphic scanning being inadequate to differentiate between pulmonary and intracardiac shunts (16). Evolution of HPS after OLT Besides the favorable long-term survival rate, another reason to perform OLT in patients with HPS is the recovery of a normal pulmonary function after OLT (18,27). In our study, correction of hypoxemia occurs as early as 6 months after OLT. The reversibility of HPS is also found within 10 months in other studies (18,30). However, the time of reversibility might be longer when HPS is more severe. An increased recovery time was observed when PaO 2 is 52 mmhg, AaDO 2 is 66 mmhg, age is >48 years, or if the etiology of liver disease is alcohol intoxication (18). A delayed resolution of HPS might favor complications in the postoperative period (19). Hypoxemia and outcome in patients with HPS In the absence of OLT, a PaO 2 60 mmhg significantly increases the long-term mortality rate of patients with HPS (4). In contrast, following OLT, the long-term mortality rate of HPS patients is not significantly modified by a PaO 2 50 mmhg, OLT interrupting the natural course of the syndrome (15). After the postoperative period, the recovery time of a normal PaO 2 might depend on the severity of HPS: the lower the PaO 2 in the preoperative period, the longer the delay of recovery. Finally, our study shows a high postoperative mortality rate following OLT in HPS 1436 American Journal of Transplantation 2006; 6: 1430 1437
HPS Increases Postoperative Mortality Rate Following LT patients, even though all patients with HPS had a PaO 2 50 mmhg. Identification of risk factors for early mortality is difficult considering the small number of patients with HPS. In conclusion, although the favorable long-term survival of HPS patients with OLT may prompt centers to transplant all HPS patients whatever the preoperative hypoxemia, the immediate postoperative mortality rate remains high in this group of patients. References 1. Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann Intern Med 1995; 122: 521 529. 2. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363: 1461 1468. 3. Fallon MB, Abrams GA. Pulmonary dysfunction in chronic liver disease. Hepatology 2000; 32: 859 865. 4. Schenk P, Schoniger-Hekele M, Fuhrmann V, Madl C, Silberhumer G, Muller C. Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis. 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