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Keywords:

  • Hepatopulmonary syndrome;
  • liver transplantation;
  • living donor;
  • transplantation;
  • posttransplant complications

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Hepatopulmonary syndrome (HPS) is present in 10–32% of chronic liver disease patients, carries a poor prognosis and is treatable by liver transplantation (LT). Previous reports have shown high LT mortality in HPS and severe HPS (arterial oxygen (PaO2) ≤50 mmHg). We reviewed outcomes in HPS patients who received LT between 2002 and 2008 at two transplant centers supported by a dedicated HPS clinic. We assessed mortality, complications and gas exchange in 21 HPS patients (mean age 51 years, MELD score 14), including 11/21 (52%) with severe HPS and 5/21 (24%) with living donor LT (median follow-up 20.2 months after LT). Overall mortality was 1/21 (5%); mortality in severe HPS was 1/11 (9%). Peritransplant hypoxemic respiratory failure occurred in 5/21 (24%), biliary complications in 8/21 (38%) and bleeding or vascular complications in 6/21 (29%). Oxygenation improved in all 19 patients in whom PaO2 or SaO2 were recorded. PaO2 increased from 52.2 ± 13.2 to 90.3 ± 11.5 mmHg (room air) (p < 0.0001) (12 patients); a higher baseline macroaggregated albumin shunt fraction predicted a lower rate of postoperative improvement (p = 0.045) (7 patients). Liver transplant survival in HPS and severe HPS was higher than previously demonstrated. Severity of HPS should not be the basis for transplant refusal.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

The hepatopulmonary syndrome (HPS) is defined by a triad of (1) liver dysfunction or portal hypertension (2), intrapulmonary vascular dilatations (IPVDs) and (3) abnormal gas exchange (1). Among cirrhotic subjects awaiting liver transplantation (LT), approximately 10–32% have HPS (2–5). This disease carries a very poor prognosis, with a risk of death which is approximately double that of patients without HPS having a similar severity of liver disease (6), and a median survival of less than 1 year (4). This high mortality correlates with the severity of hypoxemia (4,7).

Liver transplantation is the only known effective therapy for HPS. Although most survivors have an improvement in oxygenation within 1 year of transplantation (8), available evidence suggests that HPS patients have an elevated postoperative mortality (7–10), and this risk increases significantly in those with severe HPS, defined by a preoperative room air PaO2 of ≤50 mmHg (7,9). These results may have an important influence on both referrals and considerations regarding candidacy for transplantation in patients with severe HPS. However, they are based only on the four largest series (reporting on 16–24 adult patients with significant HPS) (7–10) and one literature review (reviewing 81 adult and pediatric reports) (11) currently available, all of which reported results of deceased donor liver transplantation (DDLT) only, with the majority of transplants performed in the 1990s.

We sought to add to the existing literature by reporting our more recent experience with overall LT survival and LT survival in severe HPS at two large Canadian centers. Also, both DDLT and living donor liver transplant (LDLT) were performed at these centers, and patients were managed in a specialized HPS clinic before and after transplantation. We also sought to detail the postoperative course, long-term outcomes and postoperative changes in gas exchange in these patients.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Patient selection

We retrospectively analyzed a cohort of 21 patients with HPS who underwent LT and 12 patients who were diagnosed with HPS over the study period but did not receive LT, at either the University of Toronto (University Health Network) or Université de Montréal (Hôpital St-Luc). Patients were identified among those seen by the liver transplant assessment team and a detailed chart review was completed in patients with an objective diagnosis of HPS. The period of retrospective review at each institution was based on the availability of data to confirm an objective diagnosis of HPS (November, 2000 at Université de Montréal and June, 2004 at University of Toronto, to July, 2008). Research ethics board approval was received at each institution prior to commencement of the study.

Diagnostic criteria for HPS

On the basis of history, examination and test results, any patient in whom the treating physician had a clinical suspicion of HPS was sent for confirmatory testing. The diagnosis of HPS was based on (1) clinical and radiographic evidence of liver dysfunction and/or portal hypertension (2), evidence of intrapulmonary vascular dilatation (IPVD) (by contrast echocardiography or macroaggregated albumin (MAA) perfusion scanning (12) and (3) evidence of abnormal gas exchange (partial pressure of arterial oxygen (PaO2) <70 mmHg or alveolar-arterial oxygen gradient >20 mmHg on room air) (8,13).

Assessment routine

All patients with clinically suspected HPS had MAA shunt testing and/or contrast echocardiography. Patients with HPS were followed in a specialized HPS clinic (pre- and post-LT) at the University of Toronto (as of January, 2005, held every 1–2 weeks) and at Université de Montréal (as of January, 2007, held every 3–6 weeks) by two pulmonologists with a clinical and research interest in HPS (SG and MEF). Preoperatively, patients had standard pulmonary function testing (14) and thoracic CT scan, and received optimization of any concurrent lung disease. They were followed at ≤3-month intervals with an arterial blood gas (ABG) and standard 6-min-walk test (6MWT) (14) at each visit. Patients with a saturation <88% at rest or on 6MWT also received oxygen titration to maintain a saturation of ≥88% (oxygen therapy was either initiated or the dose of existing oxygen therapy was increased). Newly diagnosed patients, patients who had a drop in PaO2 of ≥5 mmHg relative to the last visit and patients who required a change in their resting and/or exercise oxygen dose were retested at 6-week intervals until these parameters stabilized. Any changes in respiratory status were communicated directly to the LT team. These pulmonologists also participated in postoperative care through frequent contact with LT and ICU care teams, particularly in cases of refractory hypoxemia. All patients had regular follow-up for clinical assessments and laboratory testing until death or until August 31, 2008.

Statistical analysis

Data are expressed as proportions (percentages), means and standard deviations or medians and minimum and maximum values, as appropriate. All continuous variables were tested for normality. Comparisons between groups were performed with two-sample t-tests for normally distributed continuous variables and with Fisher's exact test for categorical variables. Pre- and posttransplant values were compared with paired t-tests. Relationships between normally distributed continuous variables were assessed with Pearson's coefficient. Rates of preoperative decline and postoperative increase in PaO2 were calculated using the least squares regression technique. Univariate regression analyses were performed to determine the effect of various variables on the duration of mechanical ventilation, the rate of postoperative improvement in PaO2 (using linear regression), the likelihood of severe postoperative hypoxemia and the likelihood of biliary complications (using logistic regression). A p-value of less than 0.05 was considered statistically significant. All data were analyzed using the SAS system for Windows (v. 8.02).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Baseline patient characteristics

A total of 33 patients were diagnosed with HPS over the study period. Twenty-one patients (63.6%) received LT between November, 2002 and July, 2008 (7/21 University of Toronto, 14/21 Université de Montréal) (9/21, 43% female) (Table 1). Twelve patients (36.4%) did not receive LT because they were either refused for LT (4/33, 12.1%) or died while awaiting LT (8/33, 24.2%) (3/12, 25% female) (Table 2).

Table 1.  Demographics and baseline characteristics of HPS patients receiving LT
Patient no.Age1 (years)EtiologyCP class/ scoreMELD scoreTLC (% predicted)FEV1/FVC ratio (%)Preoperative CT ScanCoexisting lung disease
  1. 1Age at time of transplant; gender was omitted to protect patient identities.

  2. 2Plethysmography demonstrated increased lung volumes as a variant of normal (14).

  3. 3No clinical suspicion of COPD, methacholine challenge test negative for asthma, ratio normalized to 75% after LT.

  4. HCV = hepatitis C virus; NASH = nonalcoholic steatohepatitis; FNH = focal nodular hyperplasia (diffuse); PBC = primary biliary cirrhosis; NRH = nodular regenerative hyperplasia; NSAIDs = nonsteroidal antiinflammatories; CP = Child's-Pugh; MELD = model for end-stage liver disease; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; CT = computerized tomography; IS = interstitial; LLL = left lower lobe; RML = right middle lobe; LN = lymph node; LUL = left upper lobe; RUL = right upper lobe; COPD = chronic obstructive pulmonary disease; ILD = interstitial lung disease.

 153AlcoholicB710130276N/ANone
 241Chronic Budd-ChiariA610106 85NormalNone
 350AlcoholicA6139276Lingular bronchiectasisLingular bronchectasis
 464HCVA612103 80N/ANone
 557NASHC1220106 73Upper lobe emphysema, mild subpleural IS markingsMild COPD, mild ILD
 660CryptogenicB8158677Mild emphysemaMild COPD
 729NASHB917101 727mm LLL noduleNone
 856AlcoholicC112396795mm RML noduleNone
 937FNHB715114 75NormalMild asthma
1053PBCC1122103 74Upper lobe emphysema, mild basilar subpleural IS markings, mild mediastinal LN enlargementMild COPD, mild ILD
1141HCV, alcoholicA6 6119 78NormalMild asthma
1260FNHA5118873Prominent vasculatureNone
1356NASHB714103 71Apical emphysema, fine reticular changes in LULMild COPD, mild asthma
1430NRHA6119279NormalNone
1554HCVB91293 663NormalNone
1655HCVC1022116 80NormalNone
1750CryptogenicB713117 706mm nodule RULNone
1852Alcoholic, NSAIDsC10138778NormalNone
1962AlcoholicB914101 81NormalMild COPD
2059AlcoholicB917113 73CardiomegalyNone
2150HCVA611N/A79NormalNone
SummaryMean: 50.9 SD: 10.2A–33% B–43% C–24%Mean: 14.1 SD: 4.6Mean: 103 SD: 12Mean: 76 SD: 4
Table 2.  Demographics, baseline characteristics, reasons for LT denial, and causes of death in HPS patients not receiving LT
Patient no.Age (years)1EtiologyCP class/ scoreMELD scorePaO2 (mmHg)Coexisting lung diseaseReason for LT denialCause of death
  1. 1Age at time of diagnosis of HPS; gender was omitted to protect patient identities.

  2. HBV = hepatitis B virus; HCV = hepatitis C virus; NASH = nonalcoholic steatohepatitis; CP = Child's-Pugh; MELD = model for end-stage liver disease; ILD = interstitial lung disease; POPH = portopulmonary hypertension; LT liver transplant; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; CT = computerized tomography; IS = interstitial; LLL = left lower lobe; RML = right middle lobe; LD = lymph node; LUL = left upper lobe; RUL = right upper lobe; ILD = interstitial lung disease; COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; DVT = deep venous thrombosis; PE = pulmonary embolism; ARDS = adult respiratory distress syndrome.

 173AlcoholicA5938Emphysema, mild ILDAgeHypoxemic respiratory failure
 269AlcoholicA51043NoneAgeAlive
 352AlcoholicC122466NoneDied on waiting listGI sepsis
 460HBVB7882Mild ILDDelisted because of improved liver diseaseAlive
 557AlcoholicB82753POPHPsychologically unstableAlive
 644AlcoholicC111872Mild COPDDied on waiting listDVT/PE
 765AlcoholicB81352Moderate COPDDied on waiting listGI sepsis, hypoxemic respiratory failure
 855HCVC101688NoneDied on waiting listLiver failure
 953AlcoholicB91658Mild COPDDied on waiting listARDS
1064NASHB81482NoneDied on waiting listMetastatic hepaoma
1151HCVB91078NoneDied on waiting listSepsis (source unknown)
1260AlcoholicB8968NoneDied on waiting listPelvic fracture, septic arthritis, sepsis
SummaryMean: 58.6 SD: 8.3A–17% B–58% C–25%Mean: 14.5 SD: 6.1Mean: 65.0 SD: 16.3

Baseline HPS evaluation

Pretransplant ABGs were performed within 6 months of transplant in the majority of patients (18/21). Eleven patients (52.4%) had severe hypoxemia (PaO2≤50 mmHg) and 18 (85.7%) were on oxygen therapy at the time of transplant. Among 20 patients with echocardiographic assessment, none had an estimated right ventricular systolic pressure >50 mmHg or systolic dysfunction. Contrast echocardiography was positive in 18/18 patients and the remaining patients (patients 1, 7 and 8) had elevated MAA shunt fractions (Table 3).

Table 3.  Baseline HPS evaluation and type of liver transplant
Patient no.PaO2 (RA) (mmHg)AaDO2 (mmHg)PaO2 (100%) (mmHg)OSR (%)MAA shunt (%)DLCO (% predicted)ClubbingFIO2 (L/min)1Type of LT
  1. 1Preoperative oxygen requirements with exertion.

  2. 2This patient had MAA shunt testing only, without a confirmatory echocardiogram. However, oxygenation improved postoperatively with a concurrent improvement in the MAA shunt fraction from 40% to 8%.

  3. 3Total body MAA shunt calculated, as original images were not available for recalculation of brain uptake.

  4. 4100% FIO2, patient was intubated prior to LT.

  5. 550% FIO2 by face mask.

  6. PaO2= partial pressure of arterial oxygen; RA = room air; AaDO2= alveolar-arterial oxygen gradient; OSR = oximetric shunt ratio; MAA = maccroaggregated albumin; DLCO = diffusion lung capacity for carbon monoxide; FIO2= fraction of inspired oxygen; LT = liver transplant; DDLT = deceased donor liver transplant; LDLT = living donor liver transplant.

 1263624301340356No2.5DDLT
 25364462125966Yes5DDLT
 34673416143427Yes6DDLT
 464N/A4911214350No3DDLT
 5712540015640No3DDLT
 65958N/AN/A25340Yes4DDLT
 74365N/AN/A6640Yes6DDLT
 85257N/AN/A2644Yes12DDLT
 94968N/AN/A3045Yes4DDLT
104483208301135Yes6DDLT
11565853182962Yes3DDLT
12485730318N/A43Yes5DDLT
136346N/AN/A1348Yes0DDLT
14437143513N/A43Yes6LDLT
15288434017N/A40Yes100%4DDLT
164263N/AN/AN/A62Yes50%5LDLT
1733935239N/A47Yes6DDLT
1866555806N/A62No0DDLT
196448N/AN/AN/A48Yes0LDLT
203867N/AN/AN/A50Yes10LDLT
21405956872142Yes3.5LDLT
Mean (SD)50.7 (11.8)62.8 (14.7)437.5 (107.6)13 (6)28.7 (17.9)47.1 (9.9)

There was no correlation between baseline PaO2 and MELD score. PaO2 was not correlated with MAA (p = 0.20) or diffusion capacity (DLCO) (p = 0.31). MAA was not correlated with DLCO (p = 0.31).

Sequential change in PaO2 pretransplant

Sequential ABGs were acquired in 15 patients awaiting transplant, once a diagnosis of HPS was suspected (median 5 ABGs/person). Over 1.5 to 45.5 months (mean 13 months), 13/15 patients (87%) had a decline in PaO2 from 59.9 ± 13.2 to 50.3 ± 12.3 mmHg. Mean rate of decline in PaO2 was 13.5 ± 16.5 mmHg per year (1.1 ± 1.4 mmHg per month).

Postoperative mortality

Patients were followed for a median of 20.2 (range 1.8–70.1) months after transplant; mortality was 1/21 (5%) overall and 1/11 (9%) in subjects with severe hypoxemia (Table 4). The only death observed during the study period occurred 9 months after transplant (Table 5). Five patients (24%) had LDLT and all survived the transplant hospitalization and are currently alive (median follow-up 7.7, range 1.8–38.2 months).

Table 4.  Post liver transplant mortality
StudyOverall mortalityMortality in severe HPSFollow-up period
  1. 1This was a review summarizing 78 previously reported cases and three new cases.

  2. 2Six out of seven deaths occurred within 6 months of LT.

  3. 3These three series reported overlapping outcomes from at least one common center (Mayo Clinic, Rochester, MN) between 1996 and 2001.

  4. 4This study included 16 adults and 16 children.

  5. 5This study did not provide the median follow-up period. Given that all deaths occurred within 6 months of LT, we calculated the 6-month mortality by assuming that all other study patients had also been followed for a minimum of 6 months. Actual mortality rates are higher, as some patients were followed for <6 months (these numbers were not available).

  6. N/A = not available.

Current study1/21 (5%)1/11 (9%)20 months (median)
0/20 (0%)0/11 (0%)Transplant hospitalization
0/19 (0%)0/9 (0%)3 months
0/18 (0%)0/9 (0%)6 months
1/14 (7%)1/7 (14%)12 months
Krowka et al. (11)113/81 (16%)7/23 (30%)3 months
Taille et al. (10)7/23 (30%)N/A17 months (median)2
Arguedas et al. (9)37/24 (29%)6/9 (67%)Transplant hospitalization and 12 months
Krowka et al. (8)3,45/321 (16%)N/ATransplant hospitalization
Swanson et al. (7)3≥5/24 (21%)5≥4/10 (40%)56 months5
Table 5.  Postoperative course
Patient no.Preoperative PaO2 (RA) (mmHg)Duration of intubation/ tracheostomy (days)Duration of MV (days)Duration in ICU (days)Duration of hospital stay (days)Time to cessation of oxygen (days)Current survival at study end (days)
  1. 1Required tracheostomy for difficulty weaning (patients 5, 15 and 16) or for secretion management (patient 8), on postoperative days 21, 9, 30 and 15, respectively.

  2. 2Patient died (while still on oxygen).

  3. 3Patient still admitted at time of analysis.

  4. 4Not on O2 preoperatively.

  5. 5Patient still on O2, <2 months posttransplant.

  6. 6Median time to cessation of oxygen in patients who were on oxygen preoperatively and were followed for ≥3 months posttransplant.

  7. RA = room air; MV = mechanical ventilation; ICU = intensive care unit.

 1631113 37602104 
 25311290185 561
 34657157 66 98N/A2 2752
 46411470180 1539 
 57111323700 1618 
 6591112 39601405 
 74311666120 653
 85223111 27 4747682
 94911214144 444
1044114219324
115611320148 288
124811741123 274
13631818 28 N/A3534134
144311122130 1147 
152833114 15 58145 1078 
164278160 62 8178895
173322126275 682
186611112 64738
1964111 8 54230
203811113N/A5 55
214011141N/A5 60
Median49114391306607

Postoperative course and complications

Details of the immediate postoperative course and time to cessation of oxygen are provided in Table 5. In univariate analyses, the duration of postoperative mechanical ventilation was not predicted by baseline MAA (p = 0.65), baseline PaO2 (p = 0.17) or type of transplant (LDLT vs. DDLT) (p = 0.53).

Early respiratory complications:  Five of 21 patients (23.8%) developed hypoxemic respiratory failure in the posttransplant period, requiring 100% inspired oxygen for a prolonged period (range 11–31 days). Four of these five patients also had severe preoperative hypoxemia. Trendelenburg positioning was used in two patients, inhaled nitric oxide (NO) was administered in one patient and high-frequency oscillator ventilation was used in one patient; all of these techniques improved oxygenation.

Late respiratory events:  Patient 3 suffered postoperative respiratory failure, ventilator-associated pneumonia and sepsis. After 98 days in hospital, he was discharged on 2 L oxygen by nasal prongs (was on 6 L preoperatively). Four months later, he developed respiratory failure from sirolimus pulmonary toxicity, requiring intubation and a 31-day hospital admission. Less than 1 week later, he developed pneumonia with subsequent acute respiratory distress syndrome (ARDS) requiring intubation. He died of respiratory failure a few days later (275 days posttransplant). His death was not directly related to his original HPS that had improved significantly by the end of his transplant hospitalization. However, his prolonged posttransplant recovery may have rendered him more susceptible to future complications.

Patient 5, who had mild interstitial lung disease (ILD) and emphysema before transplantation, did not suffer any respiratory complications during the transplant hospitalization, but developed progressive ILD after transplant. Initially, his HPS improved and oxygen was successfully discontinued. Approximately 6 months later, he developed progressive hypoxemia and a CT scan showed progression of his ILD (diagnosis unknown). Recurrent HPS was ruled out by three negative contrast echocardiographies and a repeat MAA shunt fraction of 6.2%. He currently requires 4 L oxygen by nasal prongs.

Nonrespiratory complications:  A number of complications were observed during the early and late postoperative periods. Six of 21 (29%) patients had bleeding or vascular complications and 6/16 DDLT (38%) and 2/5 LDLT (40%) recipients had biliary complications (excluding cholestasis alone). A detailed complication report is provided in Supporting Table S2.

In univariate analyses, neither the occurrence of hypoxemic respiratory failure nor the occurrence of biliary complications were predicted by baseline MAA (p = 0.18 and 0.94, respectively), baseline PaO2 (p = 0.19 and 0.47, respectively) or type of transplant (LDLT/DDLT) (p = 1.0 and 1.0, respectively).

Evolution of HPS after LT

Follow-up room air assessment of oxygenation was available in 19/21 patients after LT (ABG in 15 patients, room air saturation only in four patients). We compared the last preoperative to the most recent postoperative measures in all patients with minimum 3-month posttransplant follow-up data (17 patients). All patients had an increase in PaO2 or saturation (17/17) (Figure 1A) and a decrease in AaDO2 (12/12) (Figure 1C). PaO2 increased from 52.2 ± 13.2 to 90.3 ± 11.5 mmHg (room air) (p < 0.0001) and AaDO2 decreased from 61.9 ± 16.3 to 15.0 ± 12.4 mmHg (p < 0.0001) (room air) (12 patients) (Figure 1B,D). Nine of 11 patients (82%) had a normal room air PaO2 (≥80 mmHg) by 6 months posttransplant, and 12/12 patients (100%) by 12 months posttransplant. Among patients with a minimum 3-month follow-up, 15/16 (93.8%) who were on ambulatory oxygen preoperatively were able to discontinue oxygen therapy at a median of 130 (range 9–700) days postoperatively, and 12/16 (75%) were off oxygen by 6 months posttransplant. Serial individual oxygenation data are provided in the supporting Table S1.

image

Figure 1. Changes in gas exchange after liver transplant. All first points represent the last pre-liver transplant (LT) value and all second points represent the most recent post-LT value, performed a minimum of 3 months post-LT (between 4 months to 2.6 years post-LT). Error bars represent the standard error of the mean. (A) Pre- and post-LT partial pressure of arterial oxygen (PaO2) or oxygen saturation (saturation in dotted lines) (17 patients), (B) mean pre- and post-LT PaO2 (12 patients), (C) pre- and post-LT alveolar-arterial oxygen gradient (AaDO2) (12 patients) and (D) mean pre- and post-LT AaDO2 (12 patients).

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To determine the rate of postoperative improvement in PaO2, we considered only those patients whose first postoperative ABG demonstrated a PaO2 value that was below normal (seven patients), given that patients whose gas exchange had already normalized by the time of first measurement would not be expected to improve further. Over 3–22 months of observation, all patients had an increase in PaO2, from a mean of 65.1 ± 9.4 to 90.9 ± 8.0 mmHg (room air). The mean rate of increase was 3.1 ± 2.3 mmHg/month. In univariate analyses, a higher baseline MAA predicted a lower rate of postoperative improvement in PaO2 (p = 0.045), but neither the baseline PaO2 (p = 0.51) nor the preoperative rate of decline of PaO2 (p = 0.74) were significant predictors. It should be noted that the rate of postoperative improvement in PaO2 is not a pertinent concept in the small subgroup of patients who experience a rapid recovery in PaO2, within 1–2 months of transplantation (one of seven patients had a rapid recovery in our series; please see Supporting Table S1).

In all 10 patients who had repeat posttransplant contrast echocardiography (range 1–18, median 5 months posttransplant), the degree of left atrial opacification was less than that seen in the pretransplant study, indicating improvement. Five patients had complete resolution of intrapulmonary shunt (range 4.5–18, median 11 months posttransplant).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

In this report, we have shown a 100% peritransplant and 6-month survival, and a 93% 1-year survival for LT in HPS. Although comparisons are limited by the fact that this is a single, small series, these data are similar to recent overall survival statistics for both DDLT and LDLT in the United States (15).

Three particular findings are of potential importance and will be explored. First, overall survival and survival in patients with severe HPS were higher than those reported previously. Second, this is the largest report of adult-to-adult LDLT in HPS, and the only report of LDLT in adults with severe HPS; this appeared to be effective in our patients. Third, biliary and vascular complications were more frequent than those reported in routine LT, implying the need for increased vigilance and strategies to minimize these complications.

Survival

Our results differ from those reported by other major centers in the four largest comparable HPS transplant series (reporting at least 15 cases) (7–10) and one literature review (11) published to date (Table 4). Mortality differences were particularly pronounced in subjects with severe hypoxemia. One-year mortality in severe HPS was 14% in our series, compared to a mortality of 67% within the transplant hospitalization (9), 30% at 3 months (11) and ≥40% at 6 months posttransplant (7). Existing data may have (1) discouraged physicians from referring patients with severe HPS for LT, (2) discouraged patients with severe HPS from pursuing LT and (3) formed the basis for transplant refusal in certain severe cases. In this context, our results may have important implications for current practice.

At our centers, there was no apparent selection bias favoring patients with less severe HPS for transplantation, as nontransplanted patients had a higher mean PaO2 than the transplanted cohort. Differences in the severity of HPS also could not account for the improved survival compared to other reports, as our series contained the largest proportion of patients with severe HPS and had the lowest mean PaO2 (51 mmHg). There were no evident differences in demographic or baseline characteristics related to survival, compared to other series (16). Our mean cohort age (51 years) was the highest, and distribution of recipient liver disease was similar to that in the other series, with the exception of a higher and lower prevalence of alcoholic cirrhosis in Taille et al. (52%) and Swanson et al. (8%), respectively, and a higher prevalence of biliary atresia in Krowka et al. (given a large number of pediatric cases), none of which would be expected to alter transplant outcomes significantly (16). The severity of liver disease in our study was similar to that in three of the four other series with which it could be compared (no data on severity of liver disease was available from Krowka et al.). Our patients had a similar mean MELD score (14) to that in Swanson et al.'s study (MELD 13) (7). Although none of the other series reported MELD scores, the proportion of patients in Child's-Pugh (CP) class A was comparable to ours (33%) in Taille et al.'s study (30%) (10) and in Krowka et al.'s 2004 study (24%) (8). Only Arguedas et al. (9) had a much lower percentage of CP class A patients (12%). However, this study noted identical mean CP scores in survivors (9 ± 2) and nonsurvivors (9 ± 1) (9), suggesting no significant relationship between CP class and mortality in this population—a finding confirmed by Swanson et al. (7). Although the MELD scoring system for organ allocation was widely introduced in 2002, this system was not adopted at either of our centers and therefore did influence our results.

Improved survival in this series was seen despite comparable rates of postoperative complications to those in other reporting series. Several factors may account for this. First, our patients may have benefited from medical and technological advances in care. Prior series included transplants performed as remotely as 1968 (11), 1985 (7), 1991 (10) and 1996 (8,9), with most performed in the 1990s and none later than 2002. In contrast, 20/21 transplants in our series were performed in 2004 or later and 15/21 in 2006 or later. Modern advances include changes in LT practices including experience, techniques, surgical materials, perioperative anesthetic care (17,18) and ICU care (19). Accordingly, overall LT survival has improved significantly between 1997 and 2005 (15). Furthermore, improvements in the management of certain particularly common complications in HPS patients may have impacted survival. For example, the widespread use and availability of endosopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography may have improved the early diagnosis and management of biliary complications, which were the cause of death in four of five patients in Krowka et al.'s series (8). Also, manipulation of conventional ventilator settings is generally ineffective in the management of severe postoperative hypoxemia in HPS (10), but high-frequency oscillator ventilation has also only recently been used in adult patients (20). This technology was lifesaving in one case of respiratory failure in our series, and respiratory failure accounted for all perioperative mortalities in Taille et al.'s report (10), and for the majority of overall deaths in Arguedas et al.'s report (9) and in Krowka et al.'s review (11).

Second, patients may have benefited from pre- and perioperative care by a specialized HPS clinic and team. Preoperatively, important features may have included optimization of concurrent lung disease and frequent follow-up for oxygen titration. Our data demonstrated a rapid preoperative rate of decline in PaO2 and a high variability in this rate between patients. Given that there are no established clinical predictors of this rate, frequent oxygen titration was used to match increasing oxygen demands with appropriate oxygen therapy to preserve functional status and muscle mass, and to prevent deconditioning. Given that functional status is a significant predictor of surgical survival (16), this may have contributed to favorable outcomes. Other possible consequences of suboptimal pre- and perioperative oxygen delivery that may have been minimized include delayed wound healing, decreased resistance to bacterial infection, biliary and vascular anastamotic ischemia and depressed immune function (10,21–23). Postoperatively, availability of HPS specialists working in conjunction with ICU and transplant specialists may also have been beneficial, as it led to the early use of HPS-specific strategies such as inhaled NO and Trendelenberg positioning for management of refractory postoperative hypoxemia (10,24–27). The key elements of this specialized care model which might be transferable to other centers were: (1) frequent follow-up with oxygen titration and (2) knowledge of HPS-specific strategies to address refractory hypoxemia in the postoperative period, which could be protocolized.

Living donor liver transplantation

Previous English language reports of LDLT in HPS include a series of two adults with moderate HPS (PaO2 69 and 67 mmHg) (28), a report of one child with severe HPS (PaO2 40 mmHg) (29) and a report of one child with moderate HPS (PaO2 50–60 mmHg) (27); all patients demonstrated rapid improvement in oxygenation post-LT. Egawa et al. reported outcomes in 19 children and 2 adults with intrapulmonary shunting who received LDLT, however it is unclear how many of these patients had HPS (gas exchange data not reported). Although all survivors had an improvement in MAA shunt fraction, 1-year mortality was 38% in that series (21). In our series, all five LDLT patients survived the transplant hospitalization (four of five had severe HPS), and LDLT was not associated with an increase in complications. All three LDLT recipients who were followed for >3 months had a resolution in hypoxemia within 3–6 months, which was comparable to DDLT recipients. This suggests that the initially reduced liver mass and hepatic synthetic function in LDLT do not impede reversal of intrapulmonary shunting, and is congruent with previous observations that hepatic synthetic dysfunction is not correlated with baseline HPS severity or incidence (30,31).

Although a longer follow-up period and more patient data will be required, our results may suggest that LDLT is effective in adults with severe HPS. The main advantage of LDLT is that it usually reduces an individual's transplant waiting time. Given (1) the rapidly progressive hypoxemia in HPS (in our report and others (7)); (2) the increased pretransplant mortality in these patients (6), which correlates with the severity of hypoxemia (4,7) and (3) the current median liver transplant waiting time of nearly 1 year (15), LDLT may be a particularly important strategy to consider in HPS patients.

Postoperative complications

Two of five LDLT (40%) and 6/16 DDLT (38%) recipients had biliary complications (excluding cholestasis alone). These rates were higher than previously reported rates in non-HPS patients in both LDLT and DDLT (24–34% and 10–20%, respectively) (32,33). In patients with HPS, Taille et al. (10) did not report on all biliary complications, but did note a high rate of bile leaks (26%). Increased biliary complications such as anastomotic leaks and stenoses may result from exaggerated tissue hypoxia at the level of the anastamosis in patients with HPS, as has been suggested by other authors (8,21). Although preoperative PaO2 was not a significant predictor of biliary complications, this may have been due to small numbers. Vascular complications were seen in 29% of patients and included caval and hepatic artery anastamotic strictures, which may also have resulted from anastamotic hypoxia; a similarly elevated overall vascular complication rate of 22% was reported by Taille et al. (10).

Overall, these results suggest a need for increased vigilance and a lower threshold for investigation for biliary and vascular complications in the postoperative period. We speculate that strategies to maximize perioperative tissue oxygen delivery, including titrating inspired oxygen to achieve maximum hemoglobin saturation (100% where possible) and maintaining hemoglobin above 100 mg/L (34) might reduce the risk of these complications.

Limitations in this study include its small size, limiting our ability to draw statistically significant conclusions. Referrals to our centers may have been biased in favor of patients who were more likely to be candidates for liver transplant, with less comorbidities. It is unclear whether more severe HPS patients were more likely to be referred to our center given the existence of a specialized clinic and transplant expertise, or less likely to be referred given existing poor transplant outcomes reported in the literature. Within our centers, severe cases were more likely to be recognized and diagnosed with HPS by clinical suspicion. Although these factors prevent any generalization about the distribution of severity of HPS, they do not alter our conclusions about the potential benefits of LT in severe HPS. However, given expertise in LDLT and existence of a dedicated HPS clinic at our centers, generalization to all LT centers should be made with caution.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

In this series, we have shown higher survival post-LT in HPS, and in severe HPS in particular, compared to prior reports. Temporal improvement in care and/or a specialized HPS pulmonary care model may have had an impact on these outcomes, and the latter should be explored further. The major clinical implications of our study are that even the most severe HPS patients should be referred for transplant consideration, and when other comorbidities do not preclude transplantation, the severity of HPS should not be a basis for transplant refusal.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

The authors thank the entire liver transplant team, including hepatologists, transplant surgeons and intensivists at both Université de Montréal and University of Toronto, all of whom play an integral role in the care of these patients.

Funding sources: Dr. Gupta is supported by the Li Ka Shing Knowledge Institute of St. Michael's Hospital and the St. Michael's Hospital Research Institute. Dr. Faughnan is supported by the Nelson Arthur Hyland Foundation and the Li Ka Shing Knowledge Institute of St. Michael's Hospital. The views expressed in this paper are those of the authors, and no official endorsement by supporting agencies is intended or should be inferred.

Potential competing interests: None.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Table S1: Evolution of room air PaO2 (mmHg) or saturation after LT (in months)

Table S2: Postoperative complications

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AJT_2822_sm_TableS1-S2.doc138KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.