Hepatopulmonary syndrome: Favorable outcomes in the MELD exception era

Authors


  • Potential conflict of interest: Nothing to report.

Abstract

Hepatopulmonary syndrome (HPS) is a pulmonary vascular disorder occurring as a consequence of advanced liver disease, characterized by hypoxemia due to intrapulmonary vascular dilatations. HPS independently increases mortality, regardless of the cause or severity of liver disease. Liver transplantation (LT) improves survival in HPS. We present the largest consecutive series of HPS patients specifically addressing long-term survival relative to the degree of hypoxemia and the era in which LT was conducted. We evaluated 106 HPS patients at the Mayo Clinic from 1986 through 2010. Survival was assessed using Kaplan-Meier methodology. LT was accomplished in 49 HPS patients. Post-LT survival (1, 3, 5, and 10 years) did not differ between groups based on baseline partial pressure of arterial oxygen (PaO2) obtained at the time of HPS diagnosis. Improvements in overall survival at 1, 3, and 5 years post-LT in those HPS patients transplanted after January 1 2002 (n = 28) (92%, 88%, and 88%, respectively) as compared with those transplanted prior to that time (n = 21) (71%, 67%, and 67%, respectively) did not reach statistical significance (5-year P = 0.09). Model for Endstage Liver Disease (MELD) exception to facilitate LT was granted to 21 patients since January 1 2002 with post-LT survival of 19/21 patients and one wait-list death. Conclusion: Long-term outcome after LT in HPS is favorable, with a trend towards improved survival in the MELD exception era since 2002 as compared to earlier HPS transplants. Survival after LT was not associated with PaO2 levels at the time of HPS diagnosis. (HEPATOLOGY 2012)

Hepatopulmonary syndrome (HPS) is a pulmonary vascular disorder characterized by a clinical triad of hepatic dysfunction (usually with portal hypertension), arterial hypoxemia, and intrapulmonary vascular dilatations. HPS is not uncommon and affects between 5%-32% of individuals being assessed for liver transplantation (LT), depending on the criteria used to define arterial hypoxemia.1

LT is the only therapy that has been shown to consistently and significantly improve or resolve HPS. Mortality associated with HPS, however, can be significant and not necessarily related to the severity of liver disease as measured by MELD (Model for Endstage Liver Disease) or CTP (Child-Turcotte-Pugh) scores. For those HPS patients with partial pressure of arterial oxygen (PaO2) <60 mmHg, a MELD exception has been granted in an attempt to improve survival for those with no other contraindications to LT.2

In the pre-MELD exception era (up to 2002), we had previously shown that HPS has a poor prognosis, with a 5-year survival of 23% without LT as compared to a 76% survival with LT.3

In this report we present additional and extended 10-year survival data for our cohort of 106 patients with HPS, including 49 patients who underwent LT since the inception of our LT program. We aimed to further define the role of arterial hypoxemia as measured by baseline PaO2 (at the time of HPS diagnosis) in determining post-LT survival, as well as describe outcome by the era in which LT was accomplished. Reasons for not accomplishing LT were also reviewed, along with revisiting the prognostic importance of baseline technetium macroaggregated albumin (99mTcMAA) lung-brain perfusion scan used to quantify the severity of HPS.

Materials and Methods

The study was carried out at the Mayo Clinic in Rochester, Minnesota, approved by the Institutional Review Board (IRB), and only included subjects who had provided research authorization. Institutional and divisional funds were used for the purposes of data collection and statistical analysis. There were no commercial interests involved with the study and the authors do not have any conflicts of interest to disclose with regard to this study. All subjects diagnosed with HPS (defined below) and seen at the Mayo Clinic Liver Transplantation program from 1986 through 2010 were included in this cohort.

Diagnostic Criteria for HPS.

HPS was diagnosed using the following criteria: (1) hepatic dysfunction manifesting as chronic liver disease (usually cirrhosis) and/or clinical manifestations of portal hypertension (esophagogastric varices, ascites, splenomegaly); (2) abnormal arterial oxygenation (PaO2 ≤70 mmHg) in the upright position breathing room air; and (3) contrast-enhanced transthoracic echocardiography using agitated saline “positive” for the presence of intrapulmonary shunting. A “positive” echocardiogram was evidenced by the appearance of bubbles in the left atria 4-6 cardiac cycles after their first appearance in the right atrium. Coexistent pulmonary conditions were documented, but were not a reason to exclude from this analysis as long as HPS criteria were met and 99mTcMAA lung perfusion scanning demonstrated abnormal uptake over the brain.

Abbreviations

CTP, Child-Turcotte-Pugh; HPS, hepatopulmonary syndrome; LT, liver transplantation; MELD, Model for Endstage Liver Disease; PaO2, partial pressure of arterial oxygen.

Severity of Liver Disease.

MELD score and CTP classifications were determined to characterize the severity of liver disease. For the nontransplanted HPS patients, these data were determined at the time of HPS diagnosis. For those who underwent transplantation, data reported were those determined at the time of transplant listing.

Technetium Macroaggregated Albumin Lung Perfusion Scan (99m TcMAA).

Simultaneous 99mTcMAA lung and brain perfusion scanning was performed to quantify the degree of intrapulmonary vascular dilatation by way of measuring subsequent brain uptake. The procedure was performed with the use of 2 mCi of 99mTcMAA injected intravenously in the standing position and quantitative brain imaging, which was subsequently obtained in the supine position. Brain uptake/shunt fraction was calculated assuming a constant 13% blood flow to the brain. A fractional brain uptake greater than 5% was considered abnormal. The formula used for this purpose is as below,2 (GMT = geometric mean counts):

equation image

Pulmonary Function Studies.

All pulmonary function tests were performed at the Mayo Clinic and complied with the existing American Thoracic Society standards for acceptability and reproducibility at the time the study was performed. Expiratory airflow obstruction was defined as FEV1/FVC <70% (forced expiratory volume in one second/forced vital capacity). Restrictive physiology was defined as a TLC (total lung capacity) <80% predicted. Single breath diffusing capacity for carbon monoxide (DLCO), corrected for hemoglobin as a measure of gas exchange efficiency, was abnormal if <80% predicted.

Arterial Blood Gases (ABGs).

All subjects underwent ABGs in the upright position, breathing room air (FIO2 21%). ABGs were accomplished by way of a radial artery single stick in the Mayo Clinic Outpatient Pulmonary Function Laboratory (Radiometer ABL 725, Westlake, OH). PaO2 values reported were from the time of initial HPS diagnosis (baseline PaO2).

Post-LT Intensive Care Unit (ICU) Management Protocol.

All patients undergoing LT in this report followed a standardized post-LT management protocol for both ICU and post-ICU care (Fig. 1). All HPS patients undergoing LT arrived in the ICU intubated without any attempt to extubate in the operating room. During the ICU stay, the intensivist and ICU team were primarily in charge of management, with input from the transplant team. All patients underwent a liver ultrasound with Doppler assessment within the first 2 hours of arrival in the ICU. Periodic laboratory assessment by way of protocol included TEG, PT, PTT, Fibrinogen, and CBC assessment every few hours post-LT for the first 6-12 hours. Patients were extubated once the liver ultrasound was reported normal and vitals were stable. Initially, patients were given a closed face mask (nonrebreather) with Fi02 in the 0.5 to 1.0 range. For patients with increased work of breathing or persistent hypoxemia, noninvasive ventilation or high flow nasal oxygen (Optiflow) were the preferred options. Inhaled nitric oxide (NO) or alprostadil were also available but only rarely used and only in cases of refractory hypoxemia not responsive to standard measures described above. Reintubation was avoided as far as possible and only used when all the above measures failed to correct hypoxemia and respiratory distress. Every patient followed bundle strategies to prevent ventilator-associated pneumonia. Patients were also encouraged to ambulate early and participate in incentive spirometry to prevent atelectasis.

Figure 1.

Post-LT flow chart of ICU management protocol.

Statistical Analysis.

Survival and time to event estimates were obtained using Kaplan-Meier methodology and compared using the log rank test. Univariate Cox proportional hazards models were used to assess associations with the outcomes of liver transplant and mortality. Having a liver transplant was also considered a time-dependent covariate for the mortality outcome post-HPS diagnosis. Subsequent landmark Kaplan-Meier curves were constructed at 1, 3, 5, and 10 years post-HPS diagnosis, comparing those with and without a transplant at those times.4 Hazard ratios (HR) with 95% confidence intervals (CI) are provided for all Cox models. Statistical significance was assessed at the 5% level using two-sided tests.

Results

Patient Characteristics.

Summaries of baseline characteristics and their associations with LT are shown in Table 1. On univariate analysis, higher MELD scores and bilirubin values at time of HPS diagnosis were associated with increased likelihood of LT.

Table 1. Baseline Characteristics at Time of HPS Diagnosis and Associations with Liver Transplantation
 NOverall HPS cohort (n=106)HR (95% CI)P-value
Age (median, range)10653 (12-70)0.98 (0.96, 1.00)0.11
Female sex (%)10645 (42%)1.12 (0.64, 1.96)0.69
Pa02 mm Hg (median, range)10650 (31-70)1.02 (0.99, 1.05)0.18
Pa02 ≤ 50 mm (%)10658 (55%)0.64 (0.37, 1.13)0.12
Pa02 ≤ 60 mm (%)10682 (77%)0.72 (0.38, 1.33)0.29
Aa Gradient mm Hg (median, range)10258 (25-89)0.99 (0.97, 1.01)0.27
DLCO (% predicted) (median, range)4946 (15-94)1.00 (0.98, 1.02)0.79
99mTc MAA (%) (median, range)8518 (1-83)1.01 (0.99, 1.02)0.41
99mTc MAA > 20%8536 (42%)1.09 (0.59, 2.02)0.79
99mTc MAA > 30%8521 (25%)1.09 (0.54, 2.22)0.81
MELD (median, range7814 (6-30)1.13 (1.05, 1.23)0.002
INR (median, range)791.3 (0.9-2.7)1.50 (0.66, 3.39)0.33
Creatinine (median, range)790.9 (0.4-1.6)1.78 (0.48, 6.58)0.39
Bilirubin (median, range)792.8 (0.2-36.5)1.15 (1.08, 1.24)<0.001

The median follow-up time for the 106 HPS patients was 7 years. There were 49 deaths overall, with 15 deaths after transplant. The median follow-up time after transplant was 6.5 years and the median time to transplant after HPS diagnosis was 2.6 years using Kaplan-Meier methodology for all HPS patients. Among patients listed prior to 2002, the median time from listing to LT was 9 months, whereas it was 6 months for those listed in the MELD exception era (P = 0.27).

Primary causes of liver disease in the LT group were cryptogenic cirrhosis (n = 14), alcoholic cirrhosis (n = 9), and hepatitis C (n = 6); others included nonalcoholic steatohepatitis (NASH) (n = 4), autoimmune cirrhosis (n = 3), primary biliary cirrhosis (PBC) (n = 3), biliary atresia (n = 2), nodular regenerative hyperplasia (NRH) (n = 2), Abernethy malformation, ZZ antitrypsin deficiency, sarcoid, hemochromatosis, primary sclerosing cholangitis, and hepatitis B. Major diagnoses in the non-LT group included alcoholic cirrhosis (n = 22), hepatitis C (n = 12), cryptogenic cirrhosis (n = 7), autoimmune disorders (n = 4), NASH (n = 3), and PBC (n = 3), as well as others including combined variable immune deficiency (n = 2), NRH (n = 2), and Wilson's disease (n = 1). Hepatocellular carcinoma was present in three patients in the LT group and two patients in the non-LT group.

Pulmonary angiograms were performed in 27 subjects with the identification of discrete pulmonary arteriovenous communication (by way of chest CT scanning) in three subjects who underwent coil embolization without subsequent improvement in oxygenation. Pulmonary function testing was conducted in 53 patients. The median DLCO was 47% predicted. Spirometry patterns were: normal (n = 22, 42%); nonspecific pattern (n = 12, 23%); expiratory airflow obstruction (n = 10, 20%), and restrictive lung physiology (n = 9, 17%).

Post-HPS Survival.

LT was performed in 49 subjects (23 females) with a median age of 53 years. From the time of HPS diagnosis, survival in the LT cohort tended to be better (without achieving statistical significance) at various time intervals (1, 3, 5, and 10 years) than in those who did not receive LT (HR 0.52, CI 0.26-1.05, P = 0.067) (Fig. 2A-D).

Figure 2.

Landmark survival analyses for HPS patients (LT versus No LT group) at 1, 3, 5, and 10-year landmark points (A-D). This figure utilizes the landmark time-to-event analysis to highlight the survival difference between the LT and non-LT cohorts at different timepoints after initial HPS diagnosis.

Association of HPS Diagnosis with Post-LT Survival.

Over the same time period, there were 1,816 LTs performed (excluding HPS patients) in our center with 1, 3, 5, and 10-year post-LT survival of 91%, 85%, 81%, and 68%, respectively (582 total deaths). Post-LT survivals in those with HPS were 83%, 78%, 78%, and 64% at 1, 3, 5, and 10 years (15 total deaths). No significant survival differences were noted between HPS versus non-HPS transplants (P = 0.37).

Post-LT Survival Based on Hypoxemia Severity, MELD, and 99mTcMAA Scanning.

Survival at 1, 3, and 5 years after LT was not dependent on baseline PaO2 (obtained at the time of HPS diagnosis) (Fig. 3). For example, post-LT survival at 1, 3, and 5 years for PaO2 >50 mmHg (84%, 80%, and 80%) was not significantly different from survival at similar timepoints for PaO2 ≤50 mmHg (82%, 76%, and 76%) (P = 0.86 and P = 0.68 for cutoffs of 50 and 60 mmHg, respectively, considering all follow-up times). Using a univariate Cox proportional hazards model, there was no relationship between post-LT survival and baseline PaO2 (HR 0.98, CI 0.92-1.03, P = 0.39), MELD score (HR 1.05, CI 0.92-1.19, P = 0.48), and 99mTcMAA brain uptake quantifications (HR 1.01, 0.98-1.03, P = 0.53). Multivariate modeling was performed but not reported due to missing values and low number of events. We also noted that in the MELD exception era there was no significant difference between PaO2 at the time of HPS diagnosis and PaO2 subsequently obtained weeks prior to LT (data not shown).

Figure 3.

Post-LT survival based on baseline PaO2 values. The graphs shown are for PaO2 ≤50 mmHg, >50 mmHg, ≤60 mmHg, and >60 mmHg.

Post-LT Survival in LT Subjects in the MELD Exception Era.

Survival after LT in the MELD exception era (after January 1 2002) did seem to improve as compared to the pre-MELD era, but this did not reach statistical significance. Patients undergoing LT in the MELD exception era (n = 28) had 1, 3, and 5-year survival rates of 92%, 88%, and 88%, respectively, as compared to 71%, 67%, and 67% in those transplanted prior to January 1 2002 (pre-MELD era, n = 21) (P = 0.06, 0.09, 0.09, respectively, for 1, 3, and 5-year survival (Fig. 4).

Figure 4.

Post-LT survival by MELD era (MELD exception for HPS began in 2002). There were 28 HPS transplanted patients from 2002 onward.

There were 21 HPS patients considered LT candidates and given MELD exception (pre-LT PaO2 <60 mmHg) beginning in January of 2002 and of these 20 were successfully transplanted. There were two post-LT deaths in this group. Cause of death included an Aspergillus pulmonary infection day 144 days post-LT and a presumed massive myocardial infarction 1,526 days after LT. There was one HPS patient granted exception who died on the wait list due to peritonitis and sepsis.

Syndrome Resolution Post-LT.

Of all the HPS patients undergoing LT, only one did not normalize their PaO2 posttransplant. That patient had concomitant pulmonary fibrosis (pre-LT TLC of 62% predicted with abnormal high-resolution chest computed tomography [CT] scans), improved the PaO2 (54 to 66 mmHg), and brain uptake of 99mTcMAA (24% to 12%), but had progressive pulmonary fibrosis necessitating successful double lung transplant 19 months after his liver transplant.

Reasons for Not Accomplishing LT.

The reasons for LT refusal/nonaccomplishment in the initial cohort of 61 subjects have been described.3 Table 2 shows the reasons for not accomplishing LT in the subsequent 24 patients evaluated since 2002; six HPS patients (five with MELD exception) were awaiting LT at the time of data analysis. No patients were rejected for LT based solely on severity of HPS or the degree of hypoxemia.

Table 2. Reasons for Not Accomplishing Liver Transplantation (LT) in HPS Patients Evaluated Since 2002 (n= 24)
ReasonNComments
  • *

    These patients evolved into portopulmonary hypertension (POPH) and were denied LT until pulmonary hemodynamics could be improved.

  • CVID = common variable immune deficiency; ETOH= alcohol use; HCC= hepatocellular carcinoma; ARDS= adult respiratory distress syndrome.

Pending LT65/6 given HPS MELD exception
1/6 HCC MELD exception
Denied LT due to:12CVID (2)
Interstitial lung disease (1)
Advanced emphysema (1)
HPS → POPH (4)*
Continued ETOH use (2)
Aortic stenosis/age>70 (1)
Metastatic HCC (1)
Died on waitlist from:3Renal abscess/sepsis (1)
Peritonitis/sepsis (1)
Pneumonia/ ARDS (1)
Lost to follow-up3Never completed transplant evaluation

Peritransplant Morbidity and Mortality.

Full perioperative details including odds ratio (OR) and ICU management of ventilation, oxygenation, fluid balance, transfusions, and length of stay in the ICU and hospital were available for 32 patients undergoing LT and are described in Table 3. The median ICU length of stay for these patients was 2 days (range 1-15 days) with a median hospital stay of 14 days (range 5-65 days) (Table 3). Intubation and mechanical ventilation post-LT occurred for a median of 10 hours (range 1-230 hours). Baseline PaO2 <50 mmHg was noted in 13/28 (46%). Of the 28/49 patients transplanted in the MELD exception era; no patient required a tracheostomy.

Table 3. Perioperative Details Including Oxygenation, Ventilation, Fluid Balance, and Length of Stay for LT Subjects
NumberLast statusAge/sexPre LT Pa02/shunt fraction (%)ICU LOS (days)Hosp LOS (days)Initial OR Fi02Highest OR Fi02Highest ICU Fi02 & vent settingsHighest post extubation O2 settingsHighest ICU PEEP (cm/H20)ICU Intubation (post LT) (hours)RBC (intraoperative) (ml) (excluding cell saver)Fluid balance (first 24 hrs post LT) (liters)
  1. Comments: Patient # 1 received 40ppm of Nitric oxide (NO) for 1 day. Patients # 2 received alprostadil at a dose of 40 mcg/hr for 2 days and patient # 6 received the same dose for 4 hrs. Patient # 4 underwent bilateral lung transplantation for lung fibrosis 19 months after LT. Patient # 30 underwent retransplantation after 6 days for primary graft dysfunction.

1Alive41/F47/1921160%100%60% SIMV70% CFM55150013.4
2Deceased56/F67/-2666%95%60% SIMV40% CFM5911007.2
3Alive44/F48/2861466%91%80% A/C100% Optiflow106808.9
4Alive57/M46/2461660%100%80% A/CCFM 40%12.596200012.3
5Alive37/F40/4921360%60%50% CPAP +PSCFM 70%7.5735010.6
6Alive63/M46/921545%90%50% CPAP +PS40% CFM7.5308.4
7Alive25/F48/3772740%80%100% A/C100% CFM151569000.35
8Deceased53/M47/182860%70%50% SIMV50% CFM5104108.7
9Alive64/F62/632345%90%60% SIMV50% CFM51123303.2
10Alive60M67/621355%60%40% A/C40% CFM5823008.4
11Deceased23/M57/2621355%85%35% CPAP + PS4L NC556609.6
12Alive65/F47/1721665%87%50% A/C40% BIPAP5607.6
13Deceased67/M69/221656%95%35% CPAP +PS35% CFM5204.1
14Alive16/M66/81760%60%45% CPAP +PS35% CFM51104.1
15Alive65/M63/111955%55%50% SIMV40% CFM5122258.8
16Alive23/M51/8316565%90%60% CPAP +PS100% CFM5308.4
17Alive54/M55/-112655%90%70% A/C50% CFM7230480020
18Deceased48/M69/622050%80%60% SIMV2L NC51918509.7
19Deceased68/M62/1871055%100%100% A/C70% CFM10180320023
20Alive55/M44/25152380%60%60% SIMV3L NC524298013.5
21Alive60/M51/911060%60%60% CPAP +PS50% CFM5170013.1
22Alive46/F57/482660%100%60% SIMV100% CFM540353053.2
23Alive52/M43/3032995%55%70% AC100% CFM5706.5
24Alive23/M45/201855%55%60% SIMV50% CFM5809.6
25Alive56/M67/31560%100%40% CPAP +PS40% CFM51012.2
26Alive18/F47/6652560%60%65% SIMV35% CFM5243006.1
27Deceased56/F52/2521560%90%70% CPAP +PS70% CFM-93009.7
28Alive59/F67/3115406060% CPAP +PSN/A54150012
29Alive65/M54/101106010050% CPAP +PSN/A5208.3
30Deceased58/F58/720653510060% SIMV70% CFM7.5450455022.6
31Alive58/F70/7110606060% SIMV2L NC51507.4
32Alive52/M45/17314559560% CPAP + PS100% CFM51605.6

Overall, 5/49 patients died within 30 days of LT and none underwent an autopsy. These subjects were transplanted in the years 1989, 1995, 1996, 2000, and 2007. None had received MELD exception. Death causes were: pulmonary infection with cytomegalovirus (CMV) and pneumocystis; massive cerebrovascular bleed; myocardial infarction in the setting of suspected hypertrophic cardiomyopathy and pre-LT pacemaker insertion; portal vein thrombosis with decision to withdraw life support; ventricular fibrillation in the setting of a normal pre-LT dobutamine stress echocardiogram.

Overall, 15/49 transplanted HPS patients had died at the time of this analysis. Causes of death beyond 30 days from LT (n = 10) were documented as sudden death (1; etiology unknown), metastatic colon cancer (1), myocardial infarction (2), cerebrovascular accident (2), gastrointestinal sepsis (1), progressive graft dysfunction (2), and immunocompromised respiratory infection (1). In no circumstance did unresolved HPS appear to be a factor in mortality.

Discussion

Our data, the largest cohort of HPS patients reported from a single institution over a 25-year period, furthers HPS liver transplant knowledge in three areas: (1) the long-term survival in HPS patients with and without LT; (2) outcome of LT related to the severity of baseline arterial hypoxemia (at the time of HPS diagnosis) and brain uptake after 99mTcMAA lung perfusion scanning; and (3) HPS wait-list and LT outcome mortality in the era of MELD exception (since January 1 2002).

Long-Term Survival.

This series describes the longest follow-up of HPS patients (transplanted or not). At various times from the HPS diagnosis, those who were transplanted had significantly better survival than those not transplanted. The 10-year, 64% post-LT survival of HPS patients provides a unique benchmark.

For comparative purposes, our 30-day mortality post-LT (11%) is comparable to other series (N > 5 cases) reported by other investigators4-17 (Table 4). Importantly, no intraoperative deaths were noted in this or any other study. Unfortunately, posttransplant hospitalization death did occur, but we believe those events were not related to the pre-LT severity of HPS. We could not document severe hypoxemia as a direct contributing cause in terms of needing high-flow, supplemental oxygen, or intubation/mechanical ventilation due to unresolved HPS. These outcomes serve as a reminder that post-LT mortality in HPS patients may not be trivial and the causes are often multifactorial. For those not transplanted our outcome data may appear more favorable than those reported by Schenk et al.13; however, patients in that report had more severe liver disease (the majority were Childs C classification). It should be stressed that syndrome resolution post-LT in our cohort (as measured by arterial oxygenation) was almost universal and often preceded the events leading to death.

Table 4. Mortality Following Liver Transplant in HPS (Series with n > 5 Cases)
StudyNEarly MortalityLate MortalityPre-LT Pa02*
  • *

    Mean PaO2 mm Hg at time of diagnosis unless otherwise stated.

  • 30-day or during transplant hospitalization mortality.

  • Variable follow-up time periods from the time of transplant up to the month listed.

Scott (5)60%0%59
Hobieka (6)944%0%59
Fewtrell (7)813%0%83 (Hgb sat)
Barbe (8)1136%0%; 48 months f/u57
Egawa (9)2110%28%; 12 months f/u57
Collisson (10)60%50%; 28 months f/u52
Taille (11)239%22%; 72 months f/u52 (median)
Arguedas (12)2529%0%; 12 months f/u54
Schenk (13)70%43%; 24 months f/u75 (median)
Kim (14)138%0%; 90 days f/uNR
Krowka (15)3217%no f/u beyond Tx hosp51
Schiffer (16)932%0%; 6 months f/u60
Deberaldini (17)2532%8%; 48 months f/u75
Gupta (18)210%5%; 70 months f/u51
Current cohort4910%20%; 120 months f/u58 (median)

LT Outcome Related to Severity of Hypoxemia and 99mTcMAA Lung Perfusion Scanning.

Using a univariate Cox proportional hazards model, we found that long-term survival after LT was not related to the degree of arterial hypoxemia before LT, to the brain shunt fraction using 99mTcMAA, or to the MELD score before LT. A multivariate model was not fitted, as discussed above. Specifically, we were unable to demonstrate that using a baseline PaO2 cutoff of either 50 or 60 mmHg made any difference to post-LT survival in HPS patients. In addition, changes in PaO2 from the time of diagnosis to the time of LT were varied and not statistically significant. Also, those receiving MELD exception had shorter wait times to LT and thus had a lesser likelihood of major changes in PaO2 compared to patients in the pre-MELD era.3

The recent experience by Gupta et al.18 demonstrates that transplanting HPS patients with severe hypoxemia (PaO2 <50 mmHg; 1/11 deaths) can result in minimal mortality, but perhaps increased morbidity. We would agree with such an aggressive transplant approach with continued clinical efforts to improve long-term outcomes.

The reasons for a lack of association between mortality post-LT and 99mTcMAA shunt fraction are unclear. One possible explanation may be the poor correlation between PaO2 and 99mTcMAA shunt fractions, which may reflect variability in true cardiac output to the brain (as opposed to an assumed fixed percent that was used in our shunt calculations).

MELD Exception: LT Outcome and HPS Wait-List Mortality.

We found a trend toward improved survival consistent over 5 years in HPS patients in the era since January 1 2002 (beginning with MELD exception) as compared to those transplanted prior to 2002. Current MELD exception guidelines provide an opportunity to minimize wait-list mortality, but more important, facilitate post-LT outcomes that minimize morbidity (especially prolonged intubation/mechanical ventilation and hepatic exposure to severe degrees of arterial hypoxemia). One of the 21 HPS patients in our cohort who received MELD exception died on the wait list (peritonitis/sepsis) and the two post-LT deaths were not related to hypoxemia. Indeed, MELD exception has been critically scrutinized with varied opinions.19 The success of LT in the setting of HPS and the data presented herein lend further credence to the validity of this approach.3 Certainly, continued critical evaluation of outcomes following MELD exception and adherence to rigorous HPS diagnostic criteria would be prudent.20 Not all HPS are appropriate for LT. Since our last report, an additional 24 subjects were denied/pending LT (Table 2), but we wish to emphasize that since the last report3 no subject was denied LT solely due to the severity of their HPS (degree of hypoxemia). Such decisions not to transplant potentially impact wait-list mortality and LT outcomes.

The fact that we could not demonstrate a difference in LT outcomes based on baseline PaO2 values should be interpreted carefully. Nearly 50% of the HPS patients who were transplanted (23/49) had a baseline PaO2 <50 mmHg, a level considered severe by any standard. Many perioperative factors are to be considered to optimize the LT management as centers transplant such patients.21 Despite such severe abnormal oxygenation, we pay particular attention to intraoperative blood products/fluid administration, intubation with mechanical ventilation using low tidal volumes and low positive end-expiratory pressure, early extubation (but relying on combined 100% oxygen by way of face mask and high flow nasal cannula oxygen), intermittent use of inhaled NO/alprostadil to favorably impact ventilation-perfusion postoperatively, and avoiding reintubation solely due to severe hypoxemia. All of these interventions, as well as implementing the MELD exception algorithm, may have contributed to the success in managing the most severe HPS patients

Limitations.

Several limitations in this analysis should be noted. First, the data herein represent an uncontrolled, single-institution experience that may have reflected selection bias for LT consideration based on institutional as opposed to national or multicenter experience. Second, over the years we have used a very stringent arterial hypoxemia criterion to diagnose HPS (PaO2 ≤70 mmHg in the upright position at rest). This may have led to a diagnostic bias by excluding the less severely hypoxemic HPS patients with abnormal alveolar oxygen gradients associated with positive contrast-enhanced echocardiograms. The intent of this analysis was not to study a cohort of those with minimal oxygenation abnormalities. Third, although no patients were denied LT solely due to severe hypoxemia, the decision not to transplant was usually due to multiple comorbidities. Subsequent management in these patients was not controlled in any manner and that may have affected long-term, non-LT outcomes.

In conclusion, we present a large, single-institution cohort of HPS patients diagnosed and managed over a 25-year period. Survival post-LT was not dependent on baseline PaO2 values obtained at the time of HPS diagnosis. We observed a trend (without reaching statistical significance) for better 5-year survival in the MELD exception era (since January 1 2002) as compared to earlier HPS transplants. Limited experience with HPS-MELD exception suggests a positive impact on survival and our data fully support HPS exception for LT.

Acknowledgements

No external or internal funding source used.

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