LIVER TRANSPLANTATION 20:182–190, 2014

ORIGINAL ARTICLE

Defining and Characterizing Severe Hypoxemia After Liver Transplantation in Hepatopulmonary Syndrome Dhruv Nayyar,1 H. S. Jeffrey Man,3,4 John Granton,3,4 and Samir Gupta1,2,3 Li Ka Shing Knowledge Institute, Department of Medicine, St. Michael’s Hospital, Toronto, Canada; 2 Division of Respirology, Department of Medicine, St. Michael’s Hospital, Toronto, Canada; 3Department of Medicine, University of Toronto, Toronto, Canada; and 4Division of Respirology and Interdepartmental Division of Critical Care, Department of Medicine, University Health Network, Toronto, Canada

1

Hepatopulmonary syndrome is defined as a triad of liver disease, intrapulmonary vascular dilatations, and abnormal gas exchange, and it carries a poor prognosis. Liver transplantation is the only known cure for this syndrome. Severe hypoxemia in the early postoperative period has been reported to be a major complication and often leads to death in this population, but it has been poorly characterized. We sought to propose an objective definition for this complication and to describe its risk factors, incidence, and outcomes. We performed a systematic literature search and reviewed our single-center experience to characterize this complication. On the basis of the most commonly applied definition in 27 identified studies, we objectively defined severe postoperative hypoxemia as hypoxemia requiring a 100% fraction of inhaled oxygen to maintain a saturation  85% and out of proportion to any concurrent lung process. Nineteen of the 27 reports (70%) fulfilled this definition, as did 4 of the 21 patients (19%) at our center. We determined the prevalence and mortality of this complication from reports including 10 or more consecutive patients and providing sufficient postoperative details to determine whether this complication had occurred. In these reports, the prevalence of this complication was 12% (25/209). For the 11 cases with reported outcomes, the posttransplant mortality rate was 45% (5/11). There was a trend toward an increased risk of developing this complication in patients with very severe preoperative hypoxemia, defined as a partial pressure of arterial oxygen  50 mm Hg (8/41 with very severe hypoxemia versus 3/49 without severe hypoxemia, P 5 0.053), and there was a significantly increased risk for patients with anatomic shunting  20% (7/25 with anatomic shunting  20% versus 1/25 without anatomic shunting  20%, P 5 0.049). In conclusion, increased preoperative vigilance for this common complication is required among high-risk patients, and further research is C 2013 AASLD. required to identify the best management strategies. Liver Transpl 20:182-190, 2014. V Received July 28, 2013; accepted October 16, 2013. Hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10% to 32% of patients with cirrhosis and is defined by the triad of (1) liver dysfunction or portal hypertension, (2) intra-

pulmonary vascular dilatations, and (3) abnormal gas exchange.1-4 Liver transplantation (LT) is the only known cure for HPS. Although the majority of patients who survive the postoperative period have a

Abbreviations: APRV, airway pressure release ventilation; CT, computed tomography; FEV1, forced expiratory volume in 1 second; FiO2, fraction of inhaled oxygen; FVC, forced vital capacity; HCV, hepatitis C virus; HFJV, high-frequency jet ventilation; HFOV, high-frequency oscillatory ventilation; HPS, hepatopulmonary syndrome; iNO, inhaled nitric oxide; LT, liver transplantation; MAA, macroaggregated albumin; MELD, Model for End-Stage Liver Disease; MeSH, Medical Subject Heading; N/A, not available; PaO2, partial pressure of arterial oxygen; PCO2, partial pressure of carbon dioxide; P/F, partial pressure of arterial oxygen/fraction of inhaled oxygen; POD, postoperative day; VAP, ventilator-associated pneumonia; VQ, ventilation-perfusion. Dhruv Nayyar was supported by the Keenan Research Centre through the Li Ka Shing Knowledge Institute Summer Student Program. John Granton is a member of the scientific steering committee for a clinical trial sponsored by Ikaria. Address reprint requests to Samir Gupta, M.D., F.R.C.P.C., M.Sc., St. Michael’s Hospital, 30 Bond Street, Suite 6044, Bond Wing, Toronto, Ontario, Canada M5B 1W8. Telephone: 416-864-6060, extension 2252; FAX: 416-864-5649; E-mail: [email protected] DOI 10.1002/lt.23776 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2013 American Association for the Study of Liver Diseases. V

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normalization of oxygenation within 1 year of transplantation, previous reports have noted a high rate of postoperative complications in these patients.5-8 In particular, severe posttransplant hypoxemia is a major complication that has been reported as a cause of death in this population.6,8-10 We reviewed the existing literature and our own experience in order to identify an objective definition for this complication, to describe risk factors for its occurrence, and to describe its incidence and outcomes.

PATIENTS AND METHODS Literature Search We identified articles through a MEDLINE search (from its inception to week 1 of October 2013) of English language studies involving human subjects with the Medical Subject Headings (MeSHs) hepatopulmonary syndrome and liver transplantation. We then performed a manual search of reference lists from all retrieved articles. We defined HPS as described previously (see above), and we searched for any reports describing severe posttransplant hypoxemia. We initially defined severe hypoxemia broadly in order to capture all possible cases, including all cases for which special maneuvers or medications were used to treat hypoxemia and/or for which authors used any qualifier suggesting that hypoxemia was severe. We included all case series that described post-LT complications in patients with HPS in sufficient detail to determine whether severe posttransplant hypoxemia occurred and all case reports that specifically described the occurrence of this complication. One of the authors (D.N.) reviewed all abstracts and categorized them as definitely, possibly, or definitely not meeting the inclusion criteria. Two of the authors (D.N. and S.G.) then reviewed full manuscripts for all abstracts definitely or possibly meeting the inclusion criteria and all citations of interest from the reference lists of the retrieved articles to determine whether they should be included (any differences were settled by discussion, which led to consensus).

Analysis We reviewed the definitions of severe postoperative hypoxemia used by the authors of all the included articles, and we proposed an objective definition for this complication based on these reports. Further analyses were performed with this objective definition. We used case series of 10 or more consecutive patients to estimate the prevalence of this complication and its mortality rate and to determine whether patients with very severe HPS [partial pressure of arterial oxygen (PaO2)  50 mm Hg]11 and/or patients with an elevated macroaggregated albumin (MAA) shunt fraction (20%)9 were at increased risk for this complication. We used the chi-square test or Fisher’s exact test (whatever was appropriate) to compare proportions (SAS 9.3).

NAYYAR ET AL. 183

Case Series We retrospectively reviewed the charts of all 21 patients with HPS who underwent LT at the University of Toronto (University Health Network) between June 2004 and October 2012. HPS was defined as liver disease, intrapulmonary vascular dilatation on contrast echocardiography, and a PaO2 < 70 mm Hg or an alveolar-arterial oxygen gradient >20 mm Hg on room air.6 We recorded baseline PaO2 and MAA shunt fraction values, and we identified any patient who developed severe posttransplant hypoxemia according to our objective definition. Using a standardized data collection sheet to capture details of the postoperative course of each such patient, we conducted a careful chart review. Approval from the research ethics board was received before the commencement of the study.

RESULTS Literature Search We retrieved 379 citations with the MeSH term hepatopulmonary syndrome, 32,938 citations with the MeSH term liver transplantation, and 154 citations with both. Two of these citations were duplicates, 6 met the inclusion criteria, 37 possibly met the inclusion criteria, and 109 did not meet the inclusion criteria. After a full manuscript review, only 5 of the 37 citations initially classified as possibly meeting the inclusion criteria were found to actually meet them. We identified another 34 citations of interest from a manual search of reference lists, and 16 of these citations were found to meet the inclusion criteria after a full manuscript review. Therefore, 27 reports met the inclusion criteria.

Objective Definition We reviewed these 27 articles to identify the definitions used by the authors when they were describing cases of severe hypoxemia. We did not find a standard definition, but 19 of the 27 studies (70%) set a threshold requirement of a 100% fraction of inhaled oxygen (FiO2) to consider this a complication meriting description. This was the most consistently used definition. Seventeen of these 19 studies (89%) further qualified the definition (either explicitly or implicitly) to include a need for a 100% FiO2 to maintain adequate oxygen saturation. The reported descriptions used for this complication included a need for prolonged ventilatory support after LT (2/27 or 7%), a low PaO2 value despite a high FiO2 value (2/27 or 7%), the development of respiratory distress (1/27 or 4%), persistent hypoxemia and orthodeoxia (1/27 or 4%), impressive hypoxemia (1/27 or 4%), and severe hypoxemia (1/27 or 4%). The authors also noted that this complication was report-worthy because the severity of hypoxemia was out of keeping with any other concurrent acute or chronic lung disease. On the basis of these data, we defined severe posttransplant hypoxemia in HPS as hypoxemia requiring

60/female 4

*The last value available before LT. None implies normal results for spirometry, lung volume testing, and a CT scan of the thorax. HPS was confirmed by a finding of late shunting on contrast echocardiography in each patient. ‡ Analyzed with the Abrams technique.13 § The patient’s CT scan of the thorax showed a bilateral, diffuse, upper lobe–predominant micronodular pattern that was consistent with sarcoidosis and that had not changed from the previous year when her gas exchange was normal. Pulmonary function tests demonstrated mild obstruction with an FEV1 of 1.8 L (75% of the predicted value), an FVC of 3.1 L (107% of the predicted value), an FEV1/FVC ratio of 0.58, and a total lung capacity of 4.07 L (85% of the predicted value). †

Died (POD19) VAP (POD7) Immediate 31 13

Mild pulmonary sarcoidosis§

41

POD1 22 41 None 10 58/female 3

Therapies

iNO, HFOV Epoprostenol, iNO, HFOV iNO, epoprostenol HFOV, epoprostenol, iNO, HFJV, methylene blue VAP (POD2) VAP (POD5, POD36, POD60) VAP (POD3) POD1 Immediate N/A 41 42 33 None None 22 13

HCV cirrhosis Cryptogenic cirrhosis Cryptogenic cirrhosis HCV cirrhosis 54/female 54/male

Other Post-LT

Hypoxemia (%)*‡ (mm Hg)* Score* Liver Disease (Years)/Sex Number

A 54-year-old woman with hepatitis C virus (HCV) cirrhosis–related HPS (baseline PaO2 5 42 mm Hg) was

Patient

Patient 1

Age

University of Toronto Case Series Four of the 21 patients (19%) met the inclusion criteria and were included in the chart review (Table 1). A low tidal volume ventilation strategy and a positive end-expiratory pressure for optimizing gas exchange were used for all patients during mechanical ventilation.

Disease†

Onset of Severe Post-LT MAA Shunt Fraction PaO2 Concurrent Lung MELD

On the basis of reports including at least 10 consecutive HPS patients, the prevalence of severe posttransplant hypoxemia was 12% (25/209). For the 11 cases with reported outcomes, the peritransplant mortality was 45% (5/11). This complication was also associated with 17 of the 25 reported peritransplant deaths (68%; Table 2). Data from smaller case series and case reports describing this complication are presented in Table 3. There were 16 reports describing the timing of the onset of severe posttransplant hypoxemia, and 13 of these (81%) reported postoperative day 3 (POD3) as the latest time of onset; this included 7 of the 16 studies (44%) reporting immediate postoperative onset. On the basis of the 4 reports (Gupta et al.,6  et al.,8 Iyer et al.,14 and current series) providTaille ing precise data on the prevalence of this complication according to the baseline gas exchange (90 patients), we found a prevalence of 20% (8/41) for patients with very severe HPS (PaO2  50 mm Hg) and a prevalence of 6% (3/49) for patients with a PaO2 > 50 mm Hg (P 5 0.053). Standardized MAA shunt fractions were also available for 3 of these studies (Gupta et al.,6 Iyer et al.,14 and current series; 50 patients). We found a prevalence of this complication of 28% (7/25) for patients with an MAA shunt fraction  20% and a prevalence of 4% (1/25) for patients with an MAA shunt fraction < 20% (P 5 0.049).

TABLE 1. Characteristics of Case Report Patients

Characteristics of Severe Postoperative Hypoxemia

Complications

Attempted

Outcome

100% FiO2 to maintain a saturation  85% and out of proportion to any other concurrent lung process. Although FiO2 is usually titrated to a saturation  88%, we considered an adequate saturation to be 85% because most HPS patients have physiological adaptations to chronic hypoxemia.12 Previous authors have also recommended tolerating a lower saturation threshold before considering aggressive therapies for these patients, and have demonstrated adequate liver graft function under severely hypoxic conditions.12 Nineteen reports, including 8 case series and 11 case reports, met this definition and were included in the analysis. Twelve reports described children, 5 described adults only, and 2 described both (Tables 2 and 3).

Survived Died (POD77) Survived

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1 2

184 NAYYAR ET AL.

55.4 49.6 50.5 8.6§ 50.4 44.2 23.2# —

Mean

50.3 54.9 53.6 55§ 54.5 50.8 52.9# —

Preoperative PaO2 (mm Hg)

Prevalence of

4/21 (19) 2/32 (6) 3/14 (21) 2/14 (14) 4/24 (17)k 2/23 (9) 8/81 (10)k 25/209 (12)

Severe Postoperative Hypoxemia [n/N (%)] 4/12 (33) 1/13 (8) 2/6 (33) N/A 4/9 (44)k 1/10 (10) 3/33 (9)k 15/83 (18)

Hypoxemia in Very Severe HPS [n/N (%)]*

Severe Postoperative

2/4 (50) N/A 0/3 (0) 1/2 (50) N/A 2/2 (100) N/A 5/11 (45)

Hypoxemia [n/N (%)]†

Postoperative

Mortality in Severe

Proportion of

2/2 (100) N/A N/A 1/1 (100) 4/7 (57) 2/2 (100) 8/13 (62) 17/25 (68)

Hypoxemia [n/N (%)]†

Postoperative

Deaths Associated With Severe

Overall Postoperative

†

*Among patients with severe baseline HPS, which was defined as a PaO2  50 mm Hg.11 All deaths occurred during the transplant hospitalization and/or within 30 days of transplantation. ‡ The original study reported 21 patients from our center and the University of Montreal; for this table, we removed the 7 patients who overlapped with the current report from our center, leaving only patients from the University of Montreal. § Means were reported for all 18 patients, 14 of whom underwent transplantation (individual patient data not reported). k Only causes of death were reported, so this was considered the minimum number of patients who developed the complication (rates of mortality from the complication could not be calculated). ¶ This is a review summarizing 78 previously reported cases and 3 new cases of LT in HPS, and it is thus subject to publication bias (relevant cases are detailed individually in Table 3). #Data were not reported for all patients in the series (means were calculated on the basis of available patient data).

Current report Iyer et al.14 (2013) Gupta et al.6 (2010)‡ Al-Hussaini et al.5 (2010) Arguedas et al.9 (2003) Taill e et al.8 (2003) Krowka et al.10 (1997)¶ Cumulative

Study

Mean Age (Years)

Prevalence of

TABLE 2. Reported Prevalence of and Mortality Due to Severe Hypoxemia After LT in HPS

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TABLE 3. Summary of Small Case Series and Individual Case Reports Describing Severe Hypoxemia After LT in HPS Preoperative

MAA

Patients

Age

(n)

(Years)

(mm Hg)

Underlying Liver Disease

Fraction

Outcome*

Mews et al. (1990) McCloskey et al.16 (1991)† Laberge et al.17 (1992)† Schwarzenberg et al.18 (1993)†

1 1 1 1

12 18 12 16

48 41 42 35

50% 30% 35% Large

Died Survived Survived Survived

Hobeika et al.19 (1994)†

3

9‡

51§

30%§

Died (3/3)

Durand et al.20 (1998) Meyers et al.21 (1998) Taniai et al.22 (2002) Saad et al.23 (2007) Fleming et al.24 (2008) Roma et al.25 (2010) Schiller et al.26 (2010) Urahashi et al.27 (2011)

1 1 1 1 1 1 1 2

4 58 11 61 12 15 10.5 10¶

37-55 N/A 50-60 37 53 44 57%-65%k 50¶

Wilson’s disease Cryptogenic cirrhosis Biliary atresia Alpha-1-antitrypsin deficiency Biliary atresia, tyrosinemia, Budd-Chiari syndrome Biliary atresia Alcoholic cirrhosis Biliary atresia HCV Autoimmune hepatitis Autoimmune hepatitis Graft-versus-host disease Biliary atresia

14% N/A 38% N/A Elevated N/A >20% 31%

Survived Survived Survived Survived Survived Survived Survived Survived (2/2)

Study 15

†

PaO2

Shunt

*Within 3 months of transplantation and during transplant hospitalization. This individual report was also included in Krowka et al.’s study10 (see Table 2). ‡ The reported mean is for all 9 patients in this case series, although only 3 of the 9 patients developed severe posttransplant hypoxemia (individual patient data not reported). § The reported means are only for the 3 patients in this case series who developed severe posttransplant hypoxemia. k PaO2 data were N/A; the oxygen saturation is provided. ¶ The reported means are for all 3 patients presented in this case series, although only 2 of the 3 patients developed severe posttransplant hypoxemia. †

assessed for progressive dyspnea in January 2006 and underwent living donor LT in March 2006. After an uneventful operative course, her PaO2 was 71 mm Hg on an FiO2 of 0.6 [partial pressure of arterial oxygen/fraction of inhaled oxygen (P/F) ratio 5 118]. Later that day, her PaO2 had declined to 68 mm Hg on an FiO2 of 0.9 (P/F ratio 5 76). Inhaled nitric oxide (iNO) therapy was started at 20 ppm and resulted in an improvement in her PaO2 to 90 mm Hg (P/F ratio 5 100) after 2.5 hours and to 99 mm Hg (P/F ratio 5 110) after 4.5 hours. Despite ventilatorassociated pneumonia (VAP) on POD2, the patient’s oxygen requirements initially decreased before they climbed again on POD4. From POD4 to POD9, she remained on iNO, but she required an FIO2 between 0.8 and 1 to maintain a PaO2 of 60 mm Hg (P/F ratio 5 60-75). She was started on high-frequency oscillatory ventilation (HFOV; 5 Hz, mean airway pressure 5 34 cm H2O) on POD9, and this resulted in an improvement in her PaO2 from 59 to 117 mm Hg on an FiO2 of 1.0 (P/F ratio 5 59-117) 7 hours after she started HFOV. She had a tracheotomy on POD9. Between POD9 and POD23, she remained on iNO and HFOV but continued to require an FiO2 between 0.7 and 1.0 to maintain a PaO2 of 60 mm Hg (P/F ratio 5 60-86). She was switched to airway pressure release ventilation (APRV) on POD23, and this resulted in an improvement in her PaO2 from 75 mm Hg on an FiO2 of 0.7 and iNO at 8 ppm (P/F

ratio 5 107) to 89 mm Hg on an FiO2 of 0.6 and iNO at 20 ppm (P/F ratio 5 148) within 1 hour. Subsequently, she had decreasing FiO2 requirements and was weaned to pressure support ventilation by POD29, at which point iNO was also stopped. She was able to tolerate intermittent tracheotomy mask use as of POD42. She remained stable thereafter, with FIO2 requirements decreasing to room air by POD78.

Patient 2 A 52-year-old man with cryptogenic cirrhosis–related HPS (baseline PaO2 5 33 mm Hg) was assessed in December 2008 and underwent uneventful deceased donor LT in November 2010. Immediately after transplantation, he required an FiO2 of 1.0, but he was gradually weaned and extubated with a PaO2 of 56 mm Hg on an FiO2 of 0.6 (P/F ratio 5 93) before extubation on POD4. The patient developed VAP on POD5 (treated with antibiotics) and required reintubation on POD7 for respiratory distress with a PaO2 of 59 mm Hg on an FiO2 of 0.95 (by face mask; P/F ratio 5 62). He underwent a tracheotomy on POD8 and required an FiO2 between 0.7 and 0.9 until POD67 (discussed later). Throughout this period, oxygen requirements were out of keeping with parenchymal disease on computed tomography (CT). Contrast echocardiography on POD25 confirmed persistent intrapulmonary shunting with no pulmonary hypertension or other

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abnormalities. The patient developed episodes of VAP on POD36 and POD60, and each was treated with antibiotics. CT scans on POD42, POD56, and POD65 showed progressively worsening diffuse peripheral and peribronchovascular ground glass opacities with new, evolving interstitial changes. On POD67, the patient was started on inhaled epoprostenol (50 ng/kg/minute). Within 1 hour, his PaO2 improved from 58 to 69 mm Hg on an FiO2 of 0.9 (P/ F ratio improved from 64 to 77). However, his FiO2 requirements gradually increased again, and the patient was switched from inhaled epoprostenol to iNO at 40 ppm on POD71. His PaO2 increased from 55 to 64 mm Hg within 1 hour (P/F ratio improved from 55 to 64) and to 76 mm Hg (P/F ratio 5 76) after 3 hours (FiO2 5 1.0). However, his gas exchange deteriorated after this, and he continued to require an FiO2 of 1.0 to maintain a saturation  85% between POD71 and POD74. On POD74, he developed new hypotension requiring norepinephrine, and he began to develop hypercapnia [partial pressure of carbon dioxide (PCO2) 5 53 mm Hg]. APRV was then initiated but had no effect on gas exchange and was abandoned. HFOV was initiated on POD75 (6 Hz, mean airway pressure 5 30 cm H2O) with an increase in his PaO2 from 47 mm Hg on an FiO2 of 0.8 to 92 mm Hg on an FiO2 of 0.9 within 1 hour (P/F ratio improved from 59 to 102), but he experienced a concurrent increase in his PCO2 from 47 to 76 mm Hg and a decrease in his pH from 7.36 to 7.20. Three hours later, his PaO2 had decreased to 68 mm Hg on an FiO2 of 0.9 (P/F ratio 5 76) with a partial pressure of arterial carbon dioxide of 92 mm Hg and a pH of 7.16. Despite several HFOV setting changes, the patient had progressive hypercapnia and acidemia and died on POD77 after the withdrawal of life support. A postmortem examination suggested that the cause of death was a diffuse alveolar injury secondary to pneumonia.

Patient 3 A 58-year-old woman with cryptogenic cirrhosis– related HPS (baseline PaO2 5 41 mm Hg) was assessed in November 2009 and underwent uneventful living donor LT in March 2010. Her gas exchange was stable in the immediate post-LT period, but she developed progressive hypoxemia on POD1 with a transient requirement for an FiO2 of 1.0, and her PaO2 settled at 55 mm Hg on an FiO2 of 0.65 (P/F ratio 5 85). Accordingly, iNO at 20 ppm was attempted, but this did not improve oxygenation during a 2-hour trial. She was then switched to inhaled epoprostenol (50 ng/kg/minute; FiO2 5 0.65), and there was an improvement in her PaO2 from 38 to 52 mm Hg (P/F ratio improved from 58 to 80) within 10 minutes, to 65 mm Hg (P/F ratio 5 100) within 3 hours, and to 69 mm Hg (P/F ratio 5 106) by POD2. On POD3, the patient developed VAP. Despite this, her gas exchange gradually improved. She was weaned off epoprostenol by POD5, at which point her PaO2 was 95 mm Hg on an FiO2 of 0.5 (P/F ratio 5 190). The patient was extu-

NAYYAR ET AL. 187

bated on POD10, and she was eventually weaned off oxygen as an outpatient, 12 weeks after LT.

Patient 4 A 59-year-old woman with HCV cirrhosis–related HPS (baseline PaO2 5 41 mm Hg) was assessed in December 2009 and underwent deceased donor LT in April 2011. Immediately after LT, she had a PaO2 of 56 mm Hg on an FiO2 of 1.0 (P/F ratio 5 56), which decreased further to 44 mm Hg (P/F ratio 5 44) 1.5 hours later. HFOV was then initiated (6 Hz, mean airway pressure 5 33 cm H2O), but her PaO2 remained low at 43 mm Hg (P/F ratio 5 43), and this was abandoned after a 40-minute trial. The patient was then started on inhaled epoprostenol (50 ng/kg/minute) on POD1, and her PaO2 improved from 44 to 86 mm Hg (FiO2 5 1.0, P/F ratio improved from 44 to 86) within 45 minutes. The patient was then weaned from epoprostenol, and she remained stable until POD5, when her PaO2 rapidly dropped to 50 mm Hg on an FiO2 of 1.0 (P/F ratio 5 50). Epoprostenol was then restarted but was discontinued after 1 hour when her PaO2 increased to only 55 mm Hg (P/F ratio 5 55). Later that day, the patient also developed progressive hypercapnia with a PCO2 of 54 mm Hg (which previously had been consistently between 40 and 45 mm Hg) despite pressure control ventilation (pressure control 5 24 cm H2O, positive end-expiratory pressure 5 5 cm H2O). VAP was diagnosed on POD7, and the patient was treated with antibiotics. iNO at 20 ppm was started on POD5, and there was an increase in PaO2 from 48 to 60 mm Hg (FiO2 5 1.0, P/F ratio improved from 48 to 60) within 30 minutes. iNO was continued until POD14, at which point her PaO2 had gradually declined to 62 mm Hg (P/F ratio 5 62) and her PCO2 had increased to 86 mm Hg with new acidemia (pH 5 7.29, FiO2 5 1.0). By the next day (POD15), the patient’s PCO2 had increased to 110 mm Hg with a PaO2 of 62 mm Hg (P/F ratio 5 62) and a pH of 7.20; high-frequency jet ventilation (HFJV) was then initiated (settings: 12 psi, jet 5 100/minute, ventilation 5 5, and positive endexpiratory pressure 5 10 cm H2O), but there were only marginal improvements in PCO2 and pH to 94 mm Hg and 7.24, respectively, and a decline in PaO2 to 55 mm Hg after 40 minutes (P/F ratio 5 55). iNO was attempted again later that day, but it failed to improve her gas exchange during a 3.5-hour trial. Finally, a simultaneous trial of iNO and intravenous methylene blue (3 mg/ kg) was undertaken on POD17, but this resulted in no improvement over the course of 5 hours. Because of the lack of response to any therapeutic trials and progressive hypoxemia, hypercapnia, and acidemia, support was withdrawn, and the patient died on POD19. It should also be noted that none of these 4 patients exhibited signs of significant graft dysfunction at any time.

DISCUSSION We reviewed the existing literature and our own experience to define and characterize the complication of

188 NAYYAR ET AL.

severe postoperative hypoxemia in patients with HPS receiving LT. We did not find a standard definition for severe post-LT hypoxemia. On the basis of the most commonly applied definitions in published reports, we defined this as: hypoxemia requiring 100% FiO2 to maintain a saturation  85% and out of proportion to any other concurrent lung disease. The prevalence of this complication in reported literature ranged from 6% to 21% (mean 5 12%), and the associated mortality was highly variable because of small numbers (mean 5 45%). This can be compared to reported 1year post-LT mortality of only 17% for all comers with HPS and only 18% for patients with severe HPS.14 This complication was also associated with the majority (68%) of postoperative deaths in each reporting series, and it was reported in several additional smaller reports. We limited the prevalence and mortality calculations to series that included at least 10 consecutive patients to avoid a bias toward small series/ inexperienced centers that might be reporting this complication disproportionately. However, it should be noted that not all series describing post-LT outcomes in HPS patients could be included in these calculations because they did not describe the postoperative clinical course in sufficient detail for us to determine whether the complication occurred and/ or caused mortality. The advantage of the definition that we are proposing is that it captures the most commonly applied definition in the literature and appears to be associated with clinically relevant outcomes. Accordingly, it is also a severe enough definition to merit the use of salvage therapies such as those used in our described cases. A possible disadvantage is that it does not capture milder cases such as those requiring high-flow oxygen but not quite 100% and those whose saturation does not fall as low as 85%. We propose that authors apply this standard definition in future studies to better characterize both its clinical correlates and management strategies. Also, authors should report the occurrence and outcomes of this complication in future reports of LT outcomes for HPS patients. Severe hypoxemia was initially seen within 24 hours of LT in all 4 of our patients, although one did have an initial resolution before a recurrence. This early onset is consistent with reports by other authors. There was an increased risk for this complication among patients with very severe HPS (PaO2  50 mm Hg) and among patients with an elevated MAA shunt fraction (20%). Because hypoxemia has been shown to be progressive in HPS,6 this reinforces the importance of early LT and the use of Model for End-Stage Liver Disease (MELD) exception points for patients with a PaO2 < 60 mm Hg to minimize the chance of this complication.28 This finding suggests that this complication may at least in part be due to an exaggeration of the existing ventilation-perfusion (VQ) mismatch and diffusion-perfusion defect which are thought to be the underlying causes of hypoxemia in

LIVER TRANSPLANTATION, February 2014

HPS.8,29 This may occur through postoperative pulmonary blood flow redistribution.8,10,30 Because HPS likely results from an imbalance in vascular tone mediators, with increased vasodilatory substances and/or decreased vasoconstrictive substances affecting the pulmonary vasculature, authors have postulated that at the time of LT, an abrupt reversal of the process driving pulmonary vascular dilatation may result in a transient exaggeration of pulmonary vasoconstriction.20,30 Given possible remodeling of dilated HPS vessels31 and the resulting impairment of their vasoconstrictive reponses,32 this vasoconstrictive stimulus might have a stronger effect on normal vessels, and thereby transiently redirect more flow to dilated HPS vessels and worsen both the VQ mismatch and the diffusion-perfusion defect. This mechanism would explain both the observed rapidity of the onset of this complication and the possibly increased risk in patients with more severe pretransplant vascular dilatation (as measured by the MAA shunt fraction) and hypoxemia. Accordingly, such patients should be identified in the preoperative period as having a high risk of this complication, and they should be targeted for the special care required for its management. Knowledge of appropriate management strategies for this complication is limited. In our series, inhaled pulmonary vasodilators (iNO and/or inhaled epoprostenol) appeared to at least transiently benefit all 4 patients in whom they were tried. They were also  et al.8 employed successfully in 3 patients by Taille and in several other individually reported cases.5,20,22,26 These agents likely act by mitigating the postulated postoperative vasoconstriction of normal pulmonary vessels (described previously) and thereby minimizing the transient exacerbation of the VQ mismatch and diffusion-perfusion defect after LT. Because HPS vessels may already be maximally dilated, the vasodilatation of normal vessels also enables them to steal pulmonary blood flow from HPS vessels, and this may improve whole-lung VQ matching and, as a result, improve gas exchange.20,26 Although these lung units would experience greater perfusion for a given ventilation, increases in perfusion would be unlikely to exceed their ability to fully oxygenate this blood because of the physiological buffer for gas exchange in normal lungs.33 However, it should be noted that this strategy has not proven to be universally effective, with some reports noting no significant effect on gas exchange.24 Previous reports have also noted improvements in oxygenation with Trendelenburg positioning in these patients, and this also requires further study.21 The intravenous administration of methylene blue, a potent vasoconstrictor, improved gas exchange in a group of 7 stable (nontransplant) HPS patients.34 This agent might induce the vasoconstriction of some dilated HPS vessels (some nonremodeled vessels may still be capable of vasoconstriction) and thereby reduce both the diffusion-perfusion defect and VQ mismatch of HPS. Because dilated HPS vessels have

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been shown to have impaired pulmonary hypoxic vasoconstriction,32 methylene blue may be particularly effective at improving VQ matching by vasoconstricting vessels in areas of physiologically impaired ventilation. A previous case report noted a significant decrease in oxygen requirements after methylene blue administration in an HPS patient after LT.25 As a result of their different administration routes, intravenous methylene blue and inhaled vasodilators may also act synergistically, with the former preferentially vasoconstricting inappropriately dilated vessels in areas of impaired ventilation (due to impaired hypoxic vasoconstriction) and the latter preferentially reaching and vasodilating normal vessels in well-ventilated areas of the same lungs. We did add methylene blue to iNO for patient 4 in our series. However, this was late (POD17) and after an episode of VAP and the onset of hypercapnic respiratory failure with acidemia, and that might explain the observed lack of effect. Our patients had complicated and prolonged postoperative courses. This can be compared to a median duration of mechanical ventilation of only 1 to 2 days and a median intensive care unit stay of 4 days for all comers with HPS.6,14 Although, as noted, severe hypoxemia is out of proportion to concurrent lung pathologies by definition, a number of other pulmonary changes likely incrementally impair gas exchange in the postoperative period, particularly with prolonged intubation. These include atelectasis, simple ventilator-related changes such as increased dead space due to the overventilation of susceptible lung units, physiological shunting due to underventilation or heterogeneous gas distribution, and complications such as VAP, which was seen in all 4 of our patients (in contrast to approximately 25% of routine LT cases).35 All of these exacerbate VQ mismatch through a mechanism distinct from that of HPS by primarily affecting ventilation rather than perfusion. This might also explain why inhaled vasodilators were only transiently effective when they were used in patient 2 (who had VAP and resulting diffuse alveolar damage) and when they were used for the second time in patient 4 (who had VAP). In addition, any preexisting concurrent lung condition may contribute to both preoperative and postoperative hypoxemia, and its deleterious effects on gas exchange may also become exaggerated while a patient is on a ventilator (this may also have played a role in patient 4, who had preexisting parenchymal sarcoidosis). Alternative ventilatory strategies did not consistently improve gas exchange in our patients, with HFOV and APRV being effective in patient 1 but HFJV and APRV being ineffective in patient 2 and HFOV and HFJV being ineffective in patient 4. However, because these strategies aid in recruiting collapsed lung units, they may have an important role in managing superimposed pulmonary pathologies such as VAP. It should be noted that HFOV has recently been shown to be of possible harm in acute respiratory distress syndrome,36 whereas prone ventilation has been

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shown to be of benefit in acute respiratory distress syndrome37; these require further study in HPS. In conclusion, severe postoperative hypoxemia is a common complication after LT in patients with HPS, and it is the leading cause of postoperative death in this population. Patients with very severe preoperative hypoxemia and anatomic shunting may be at increased risk for this complication. Although data are limited, therapies that may mitigate its severity include inhaled vasodilators and intravenous methylene blue. Advanced preoperative planning to enable early postoperative use of these approaches in the event of this complication should be undertaken for high-risk patients. Further research will be required to outline the best overall management strategy for this complication, including a protocolized approach and new techniques and/or agents.

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