Hepatopulmonary Syndrome With Progressive Hypoxemia as an Indication for Liver Transplantation: Case Reports and Literature Review

Subspecialty Clinics: Pulmonary and Critical Care Medicine Hepatopulmonary Syndrome With Progressive Hypoxemia as an Indication for Liver Transplantation: Case Reports and Literature Review MICHAEL J. KROWKA, M.D., MICHAEL K. PORAYKO, M.D., DAVID J. PLEVAK, M.D., S. CHRIS PAPPAS, M.D., JEFFREY

L. STEERS,

M.D., RUUD

A. F.

KROM, M.D., AND RUSSELL

In the hepatopulmonary syndrome (HPS), a pulmonary vascular complication of liver disease, severe hypoxemia due to pulmonary vascular dilatation can be extremely debilitating. Determining whether patients with advanced liver disease and HPS should be considered for liver transplantation is difficult. We describe three patients with progressive and severe hypoxemia who underwent successful liver transplantation and had resolution of their arterial hypoxemia. In these patients, the progressive pulmonary deterioration accelerated the need and was considered an indication for liver transplantation rather than being considered an absolute or relative contraindication. In addition, we review the literature on 81 pediatric and adult patients with HPS who underwent liver transplantation and specifically highlight mortality,

morbidity, syndrome resolution, and prognostic factors. Posttransplantation mortality (16%) was associated with the severity of hypoxemia (mean arterial oxygen tension [Pao z] in 68 survivors was 54.2 ± 13.2 mm Hg and in 13 nonsurvivors was 44.7 ± 7.7 mm Hg; P<0.03). Patients with a pretransplantation Pao, of SO mm Hg or lower had significantly more frequent mortality (30%) in comparison with those with a Pao, greater than SO mm Hg (4%; P<0.02). Pulmonary recommendations that address the severity of hypoxemia and candidacy for liver transplantation are discussed. (Mayo Clin Proc 1997; 72:44-53) HPS =hepatopulmonary syndrome; Pao, =arterial oxygen tension; 99mTcMAA =99mTc macroaggregated albumin

The hepatopulmonary syndrome (HPS) is characterized as a triad: liver disease, intrapulmonary vascular dilatation, and arterial hypoxemia.t-' Although HPS is an infrequent cause of hypoxemia in adults or children with hepatic dysfunction (5 to 29% of patients studied), the syndrome can result in debilitating, severe hypoxemia (arterial oxygen tension [Pa0 2 ], 50 mm Hg or lower with the patient breathing room air) that necessitates 24-hour continuous oxygen supplementation." The pulmonary pathophysiologic feature (that is, hypoxemia as a consequence of pulmonary vascular dilatation and possible proliferation) involves ventilation-perfu-

sion mismatching, oxygen diffusing limitation, and intrapulmonary shunting in varying degrees."? The oxygen abnormality may worsen as the patient moves from the supine to the standing position (orthodeoxia), and the response to 100% inspired oxygen varies considerably? Pulmonary angiography has demonstrated diffuse (type I) and discrete (type II) vascular lesions associated with hypoxemia in HPS. 3 The natural history of HPS is poorly understood to date, but progressive hypoxemia has been well described in the setting of clinically stable hepatic dysfunction. Significant mortality, despite medical therapeutic approaches to correct the hypoxemia, has been reported.v' Of recent interest is the diagnosis of HPS in patients with end-stage liver disease in whom liver transplantation is the only viable therapeutic option for the hepatic dysfunction. Initially, severe hypoxemia (Pao., 50 mm Hg or lower) due to HPS was considered an absolute contraindication to transplantation due to the perioperative deaths associated with hypoxemia." Over time, liver transplantations were successful for various end-stage liver disorders in patients who also

From the Division of Pulmonary and Critical Care Medicine and Internal Medicine (M,J,K.), Division of Gastroenterology and Internal Medicine (M.K,P., RH.W.), Department of Anesthesiology (D.J.P,), and Division of Transplantation Surgery (J.L.S., R.A.F.K.), Mayo Clinic Rochester, Rochester, Minnesota; and Department of Gastroenterology (S.c.P,), Methodist Hospital, Indianapolis, Indiana. Address reprint requests to Dr. M. J. Krowka, Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1997; 72:44-53

H. WIESNER, M.D.

44

© 1997 Mayo Foundationfor Medical Education and Research

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HEPATOPULMONARY SYNDROME AND PROGRESSIVE HYPOXEMIA

had varying degrees of HPS. Subsequently, severe hypoxemia due to HPS became a relative contraindication to transplantation." A recent survey of 52 medical centers that performed 2,656 transplantations in 1992 indicated that 33% excluded patients with HPS from consideration for liver transplantation. IO Herein we describe three adult patients with advanced liver disease, HPS, and progressively severe hypoxemia who underwent liver transplantation in an attempt to correct the hepatic and associated pulmonary dysfunction. In all three patients, successful transplantation resulted in the resolution of arterial hypoxemia. In addition, we review the literature on patients with HPS who underwent liver transplantation, with particular reference to mortality, morbidity, syndrome resolution, and possible prognostic factors. REPORT OF CASES Case 1.-A 28-year-old woman was referred to the Mayo Clinic Rochester liver transplant service in April 1993 for consideration for transplantation. In 1975, esophageal variceal bleeding had developed, which was managed by splenectomy and a splenorenal vascular shunt. A liver biopsy was also done in 1975, and findings were compatible with a diagnosis of autoimmune chronic active hepatitis. She was treated periodically with corticosteroids between 1975 and 1986. The patient was first examined at the Mayo Clinic in 1989, and baseline arterial blood gas studies were done. She experienced progressive shortness of breath, and HPS was diagnosed in 1990 (pulmonary vascular dilatation suggested

Pa0 2 (mm Hg)

90 85 80 75 70 65 60 55 50 45 40 35 30

by delayed, abnormal contrast echocardiographic findings with arterial hypoxemia'), During follow-up examinations, sequential arterial blood gas studies were conducted and are summarized in Figure 1. Her liver function was clinically stable and remained unchanged until November 1992, when she sought medical assessment because of substantially increased jaundice, pruritus, edema, and ascites. At that time, the total and direct bilirubin levels were 11.0 and 5.1 mg/dL, respectively; platelet count was 294 X 109JL; prothrombin time was 15 seconds (normal, 8.4 to 12); and albumin level was 1.3 g/dL. Hepatitis Band C serologies were negative. The smooth muscle antibody was positive at a titer of 1:80. During the ensuing 4 months, her condition continued to deteriorate despite medical management. In April 1993, her prothrombin time was 15.8 seconds; total and direct bilirubin levels were 14.3 and 7.9 mg/dL, respectively; and albumin level was 1.1 g/dL. In addition, her oxygenation status had further deteriorated (Fig. 1), which was accompanied by progressive dyspnea and fatigue. On physical examination, the patient appeared ill; jaundice and diffuse spider angiomas over the thorax were evident. Clubbing and cyanosis were noted. Pulmonary function testing showed a single-breath diffusing capacity of 38% of the predicted value, with normal expiratory airflow and lung volumes. Chest roentgenographic findings were normal. Pulmonary angiography was not done because of the patient's excellent response to 100% inspired oxygen. At that time, she was advised to undergo liver transplantation to address the hepatic dysfunction and reverse the oxygenation deterioration in a definitive manner.

87.5

41.0

0 '

45

42.9

49.5*

",0»>.><}~'%~4"" 38 • 0

Room air ' '<1> standing exercise 3/89 7/89 1/90

Liver transplant 11/90 Time

5/91

6/94 4/93 6/93

Fig. 1 (case 1). Diagram showing 4-year progressive deterioration in oxygenation. Liver transplantation resulted in normalization of arterial oxygen tension (Pao) while patient was breathing room air.

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HEPATOPULMONARY SYNDROME AND PROGRESSIVE HYPOXEMIA

The patient received a liver transplant at the Mayo Clinic in June 1993, and no difficulty was encountered. Four hours postoperatively, however, she experienced a worsening of her Pao., from 303 mm Hg to 65 mm Hg, while intubated and receiving mechanical ventilation (100% oxygen). Chest roentgenography suggested no etiologic factor. Despite trials of positional changes, ventilator alterations, and intravenous somatostatin infusion, the patient had hypoxemia for 72 hours, with a documented Pao 2 nadir of 44 mm Hg. She then experienced a gradual resolution of the severe hypoxemia and was extubated 96 hours after transplantation; the resultant Pao2 was 114 mm Hg while she received 100% oxygen through a close-fitting mask. One year postoperatively, follow-up arterial blood gas studies performed with the patient sitting and breathing room air indicated a Pao, of 87.5 mm Hg. The patient had no pulmonary symptoms. A repeated contrast echocardiogram obtained in May 1995 showed no evidence of pulmonary vascular dilatation. Case 2.-A 47-year-old woman with a 20-year history of cryptogenic liver disease sought medical assessment. At age 27, she had pancytopenia, portal hypertension, and splenomegaly of unknown origin. Multiple episodes of esophageal bleeding had occurred. Splenectomy with a splenorenal shunt was done in 1986. In 1988, exertional dyspnea, arterial hypoxemia, and clubbing developed. Chest roentgenographic findings were unremarkable. Single-breath diffusing capacity was 52% of the predicted value, with a normal ratio of forced expiratory volume in 1 second to forced vital capacity (FEV/FVC) and a shunt fraction of 13% calculated by the 100% inspired oxygen method. Findings on a pulmonary angiogram showed no pulmonary emboli or pulmonary hypertension. Supplemental oxygen was ordered. In mid1990, she was assessed for consideration for orthotopic liver transplantation due to the hepatic history and pulmonary dysfunction. At that time, synthetic liver function showed a mild abnormality; the prothrombin time was 15 seconds (international normalized ratio, 1.5), and the albumin level was 3.3 g/dL. No ascites or edema was evident. No spider nevi were noted. In December 1990, the patient was examined at Mayo Clinic Jacksonville because of progressive dyspnea and for a second opinion about the cause of stable hepatic dysfunction with worsening dyspnea and arterial hypoxemia. Chest roentgenographic findings were normal. Pulmonary function testing showed a single-breath diffusing capacity of 53% of the predicted value with an FEV /FVC ratio of 80%, FVC of 99% of the predicted value, and total lung capacity of 120% of the predicted value. While the patient was standing, the Pao, was 44 mm Hg. A transthoracic contrast echocardiogram was diagnostic for intrapulmonary vascular dilatation with left atrial opacification noted 5 to 6 cardiac cycles

Mayo Clin Proc, January 1997, Vol 72

after appearance of microbubbles in the right ventricle. Color flow Doppler echocardiography and contrast studies demonstrated no evidence of intracardiac right-to-left shunt. Right ventricular systolic pressure was estimated to be 30 mm Hg (tricuspid peak velocity was 2.3 m per second). The pulmonary angiogram obtained in 1988 was reviewed and suggested a subtle spongy-diffuse arterial phase with no discrete arteriovenous communication evident. HPS (type I) was diagnosed. Liver function testing at that time indicated total and direct bilirubin levels of 1.6 and 0.4 mg/dL, respectively, and the albumin level was 2.8 mg/dL. A 4-day trial of subcutaneous somatostatin analogue therapy"!' resulted in no improvement in the Pao., Liver transplantation was suggested as a therapeutic option for the HPS; however, the patient wished to use supplemental oxygen and continue a conservative course. In 1992, she returned with worsening dyspnea and now needed 4 to 5 L/min of oxygen (by nasal cannula) 24 hours a day. Her quality of life was deteriorating. The Pao, deteriorated to 44 mm Hg while she was standing and breathing room air; it increased to 465 mm Hg while she was breathing 100%11 oxygen. At that time, she was advised, again, to undergo liver transplantation primarily for the HPS. Results of liver function testing remained stable; the prothrombin time was 15.5 seconds, the albumin level was 3.1 g/dL, and the total and direct bilirubin levels were 1.5 and 0.3 mg/dL, respectively. The patient declined the transplantation option and chose to continue supplemental oxygen use. Approximately 1 year later, a trial of prednisone was initiated in an attempt to improve the oxygenation, but the Pao z did not improve. Approximately 1 to 2 months later, substantial pneumonitis developed in conjunction with respiratory failure that necessitated mechanical ventilation. Adult respiratory distress syndrome was diagnosed; an open-lung biopsy was nondiagnostic for infection. The patient was in the intensive-care unit for 20 days. Again, after further consultation, the patient was encouraged to undergo liver transplantation because of the lack of other therapeutic options to correct her severe hypoxemia. In January 1994, uncomplicated liver transplantation was successfully accomplished at another institution (per S.C.P.). Six months after the transplantation, the hemoglobin saturation determined by finger oximetry was 99% while the patient was breathing room air. Approval for a follow-up contrast echocardiogram was denied by the patient's health maintenance organization (HMO). The patient has required no further supplemental oxygen. Case 3.-A 23-year-old woman with Child's class A micronodular cirrhosis with fatty infiltration was referred to the Mayo liver transplant clinic because of severe hypoxemia and for transplantation assessment. A diagnosis compatible with nonalcoholic steatohepatitis was made based on the history and a liver biopsy done in December 1990, when

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HEPATOPULMONARY SYNDROME AND PROGRESSIVE HYPOXEMIA

she was scheduled to undergo tonsillectomy and was found to have abnormal results of coagulation studies, hepatosplenomegaly, and mild ascites. Assessment for hepatitis A, B, and C; (Xl-antitrypsin deficiency; hemochromatosis; and Wilson's disease revealed normal findings. Panhypopituitarism was also diagnosed and thought to be due to an intracranial hemorrhage of unknown cause during childhood. Right coronary catheterization, conducted in August 1993, showed a cardiac output of 12.5 L/min and a pulmonary artery systolic/diastolic pressure of 28/14 mm Hg with a pulmonary artery occlusion pressure of 12 mm Hg. A 99mTc macroaggregated albumin (99mTcMAA) lung scan showed substantial right-to-left shunt with pronounced activity over the brain and kidneys. Contrast echocardiography demonstrated no evidence of an intracardiac shunt; delayed opacification was noted in the left side of the heart. During the ensuing 12 months, the patient's condition deteriorated, and she experienced progressive fatigue, especially with exertion. Oxygen (by nasal cannula), 6 L/min, failed to maintain hemoglobin saturations higher than 90% during exertion. On physical examination of the patient, cyanosis of the nailbeds and clubbing were evident. Her skin had multiple telangiectases that blanched with compression; a prominent telangiectasia was present on the lower lip. Findings on the ear, nose, and throat examination were unremarkable, as were those on the chest examination. Hepatic evaluation yielded the following results: hemoglobin, 14.5 g/dL; platelet count, 79 X 109/L; serum albumin, 4.1 g/dL; total bilirubin, 1.2 mg/dL; aspartate aminotransferase, 41 U/L; alanine aminotransferase, 26 U/L; 'Yglutamyltransferase, 39 U/L; and prothrombin time, 14.4 seconds. Ultrasonography of the liver showed diffuse increase in homogeneity in echotexture, consistent with cirrhosis. Findings on roentgenography and computed tomography of the chest were normal. Doppler studies of the portal venous system, hepatic veins, splenic vein, and inferior vena cava showed patency with normal direction of flow. Splenomegaly was noted. Pulmonary studies included a review of the pulmonary angiogram obtained elsewhere, which showed no evidence of either diffuse or discrete arteriovenous communications. Transit through the pulmonary vascular bed seemed to be rapid with rapid venous filling. A 99mTcMAA study showed a shunt estimate of 22.5% (normal, less than 5%), as measured over the brain and adjusted for a blood flow of 13% to the brain. The Pao z deteriorated from 57 to 53 mm Hg while the patient was standing and breathing room air and further deteriorated to 42 mm Hg while she was exercising; the Pao, was 481 mm Hg while she was breathing 100% oxygen. Because of the patient's stable hepatic status but severe and debilitating pulmonary situation, liver transplantation

47

was done at Mayo Clinic Rochester on Jul. 15, 1995. The explanted liver confirmed the diagnosis of steatohepatitis with cirrhosis. The patient had an unremarkable postoperative course and was dismissed from the hospital on Aug. 5, 1995. At that time, arterial blood gas studies (while the patient was sitting and breathing room air) indicated a Pao z of 70 mm Hg and an alveolar-arterial oxygen difference gradient of 31 mm Hg. She required no supplemental oxygen. Four months posttransplantation, Pao, determinations with the patient breathing room air at rest were normal: 76 mm Hg (while supine) and 81 mm Hg (while standing). While the patient was standing and breathing 100% oxygen, the Pao z was 560 mm Hg. A repeated 99mTcMAA scan showed a shunt estimate of less than 3%. Contrast echocardiography still showed evidence of mild pulmonary vascular dilatation. DISCUSSION

Case Summaries.-In our three patients with liver disease, the severity of HPS was considered an indication for liver transplantation. Hypoxemia due to HPS was a major factor in the recommendation for liver transplantation because of concerns about the patients' ability to survive the procedure and postoperative course in light of the deterioration in pulmonary status. Preliminary experience suggests that liver transplantation can result in improved oxygenation in some patients with HPS. Our first patient (case 1) had a period of clinically stable hepatic dysfunction followed by a fairly rapid decline in synthetic function and quality of life during a minimum of 4 months before liver transplantation. The transplantation was advised for the concomitant indications of hepatic dysfunction and deteriorating arterial oxygenation due to HPS. In our second patient (case 2), liver transplantation was recommended throughout a 3-year period primarily because of debilitating, severe hypoxemia that necessitated increasing amounts of supplemental oxygen 24 hours per day in the setting of a stable hepatic abnormality. Despite the occurrence of the adult respiratory distress syndrome complicating HPS, the patient recovered and subsequently underwent a successful liver transplantation. Both patients experienced complete resolution of their arterial hypoxemia, and our first patient had normal findings on contrast echocardiography after liver transplantation. In our third patient (case 3), the predominant decision for transplantation was the severity of hypoxemia due to HPS; the degree of hepatic dysfunction seemed to be clinically minimal. Oxygenation was normal 4 months posttransplantation. Literature Review.-A critical literature review of 73 patients with HPS who underwent liver transplantation in combination with 8 patients assessed at the Mayo Clinic (including the 3 current patients) is summarized in Table 1.11-35 HPS was diagnosed by demonstration of pulmonary vascular

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HEPATOPULMONARY SYNDROME AND PROGRESSIVE HYPOXEMIA

Mayo Clio Proc, January 1997, Vol 72

Table I.-Summary of Reported Cases of Hepatopulmonary Syndrome and Results of Liver Transplantation*t Pao z (mm Hg) Reference

Age (yr)

100% oxygen

Diagnosis

Room air Hemoglobin saturationrange, 85-88% 43

80

All alive at 96, 86, and 49 mo after transplantation; shunt, <15%

Starzl et al"

19mo

Sang Oh et al'"

20mo 13 mo 18

Hepatic carcinoma BA BA ai-AT

Stoller et aI'5

39

PBC

62

290

Eriksson et al," patient 5 Mews et al'?

18 12

52 48

95

16 13 53 17 14 11

TYR Wilson's disease CRC Cirrhosis Cirrhosis PVT BA BA

40 44 46 61 53 51

115 194 455 217 340 127

Itasaka et aP'

13

CRC

42

417

Schwarzenberg et apz

18

ai-AT

35

69

Scott et aP3

Caldwell et al"

38 63 52 51 55 51 2 10 7 15

35 65 51 71 63 66 63 40 36 55

350 389 446 425 460 445 186 72 65

Hobeika et aP6

28mo

CRC CRC CRC CRC ETOH ETOH BA BA CRC Histiocytosis X BA

48

196

TYR

58

487

NHP BA

56 45

314

AIR

47

400

PSC BA ai-AT BA BA BA BA BA BA BA BA BA

75 65 78 60

300 375 275 197

McCloskey et al" Dimand et al'? Laberge et apo

Van Obbergh et aF4

Fewtrell et aP7

6mo 11 8.5 2.5mo 2.5 9.8 9mo 3.5

72

86% saturation 60 42 80% saturation 80% saturation 85% saturation 82% saturation

Posttransplantation comments

No changes in massive shunt after 3 transplantations; died 3 mo after transplantation as a result of intracerebral bleeding Wk 3-Paoz' 567 on 100% oxygen; wk 52-Paoz' 84 on room air Mo 2-shunt <1% Sustained, severe hypoxemia with multiorgan failure; MV, 10 days; died 10 days after transplantation Mo 9-Paoz' 79 on room air Wk 12-Pa02, 70 on room air and 305 on 100% oxygen Wk 12-Pa02 , 100 on room air Wk 12-Paoz' 69 on room air and 540 on 100% oxygen Mo 9-Pao z' 96 on room air Mo 5-no shunt; saturation, 98% on room air; MV, 17 days Day 36-transient deterioration; wk 23-hemoglobin saturation, 96%; shunt <1% Day 5-PVT developed and thus second transplantation was done; 15 days later, intracranial bleeding occurred; MV, 1 mo; Paoz-no change for 3 mo; mo 14-Pa02, 114 on room air and 561 on 100% oxygen MV,66days No oxygen needed after transplantation Shunt improved after transplantation; MV, 27 days No oxygen needed after transplantation Shunt improved after transplantation; MV, 77 days No oxygen needed after transplantation Wk 6-Paoz' 89 on room air and 436 on 100% oxygen Wk 64-Pa02, 121 on room air and 535 on 100% oxygen Wk 29-Paoz' 87 on room air and 443 on 100% oxygen Mo 6-Pao z' 71 on room air Worsening hypoxemia despite 100% oxygen; died 4 days after transplantation Worsening hypoxemia despite 100% oxygen; died 20 days after transplantation Mo 3-Paoz' 90 on room air; MV, 7 days Worsening hypoxemia despite 100% oxygen; died 35 days after transplantation Primary graft nonfunction; died 10 days after transplantation Mo 8-Pa02, 100 on room air Mo 3-Paoz' 95 on room air Mo 6-Paoz' 95 on room air; MV, 19 days Mo 3-Paoz' 90 on room air; MV, 4 days Alive 3 yr after transplantation Wk 13-shunt 37% Alive 4 yr after transplantation Wk 4-shunt, 2.7%; MV, 21 days Wk 32-shunt, 6%; MV, 48 days Wk 2a-shunt, 2% Wk 16-shunt, 2%; MV, 30 days MV, 11 days; di.ed2 days after second transplantation (6 mo after first)

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Table L-Continued*t Paoz (mm Hg) Age (yr)

Reference Stoller et aF8 Cremona et aF9 Riegler et al'" Rodriguez-Roisin & Krowka" Scott et al"

Diagnosis

5 52 39

CRC ETOH CAH

58

HEM

Room air 36 43 45 (on oxygen) 64 56

100% oxygen

Posttransplantation comments All improved within 1-8 mo; shunts, 3.5-5.0%

442

41 Range-29-86

Mo 3-normal oxygenation Pao z improved after TIPS; oxygenation normal after transplantation Oxygenation improved after transplantation Duration of hospitalization, 4-120 days; refractory hypoxemia; 1 patient died after transplantation I patient died 25 days after transplantation as a result of graft rejection and pulmonary sepsis Mo 7-Pao2, 87

41 16 adult patients 6 pediatric patients 47

ETOH

51

588

47:1:

PSC

53:1:

ETOH

65, supine 61, standing 44, supine 36, standing

535 458 301 211

Krowka et al, II patient 11

37:1:

ETOH

47, supine 33, standing

431 407

patient 18

27:1:

93

Only pretransplantation evaluation at Mayo; bilateral pulmonary infiltrates; died 2 mo after transplantation performed elsewhere; no autopsy done Subclinical HPS; mo 2-Pao z' 81

313 70 550 522 465 374 481 346

Mo 7---coil embolotherapy; mo 12-normal Pao 2; MV, 4 days See text for details

Bynon et al" Petruff et aP4 Mayo Clinic cases Unpublished

Range-39-64

Poterucha et aP5

38:1:

Wilson's disease AIR

Current cases

28

CAH

47

CRC

23

STE

63, supine 45, standing 60, supine 50, standing 50, supine 44, standing 60, supine 53, standing 42, exercising

Mo 12-Pao2, 81 while standing Only pretransplantation evaluation at Mayo; multiple intracerebral bleeding sites; oxygenation was satisfactory with tracheostomy; died 28 days after transplantation performed elsewhere

*In addition to these cases, Shaw et al" described two patients with refractory hypoxemia who died after transplantation. No other details were provided. t AIR =autoimmune hepatitis; a l cAT =ai-antitrypsin deficiency; BA =biliary atresia; CAH =chronic active hepatitis; CRC =cryptogenic cirrhosis; ETOH = alcoholic cirrhosis; HEM = hemochromatosis; HPS = hepatopulmonary syndrome; MV = mechanical ventilation; NHP = nodular hyperplasia; Pao z = arterial oxygen tension; PBC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis; PVT =portal vein thrombosis; STE =steatohepatitis-cirrhosis; TIPS =transjugular intrahepatic portosystemic shunt; TYR =tyrosinemia. :l:Patients underwent liver transplantation because of deteriorating hepatic dysfunction; HPS was not considered a contraindication to transplantation. dilatation by means of (l) contrast echocardiography, 99mTcMAA lung scanning, or pulmonary angiography (in 73 patients); (2) intrapulmonary shunt demonstrated with use of inert gas elimination techniques (in 4 patients) or oxygen technique in children (3 patients); or (3) evidence of pulmonary shunt-associated orthodeoxia (in 1 patient). I Subclinical HPS (Paoz greater than 70 mm Hg but abnormal findings on contrast echocardiography or 99mTcMAA lung scan) was noted in four patients. The other patients had hypoxemia, as defined by a Paoz of 70 mm Hg or lower or a hemoglobin saturation of less than 88% by means of oximetry.

Mortality.-Thirteen of 81 patients (16%) with HPS died (Table 1) within 3 months after liver transplantation, 10 of whom were 18 years of age or younger. Determining the primary cause of death based on the literature was difficult; only major clinical associations with death could be summarized. Refractory hypoxemia despite mechanical ventilation or supplemental oxygen was the most frequent cause (in eight patients) and contributed to multiorgan failure in two patients. Intracerebral hemorrhage has been reported as a primary cause of death" and observed by other investigators as an associated cause of death in patients with HPS after

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HEPATOPULMONARY SYNDROME AND PROGRESSIVE HYPOXEMIA

Mayo Clin Proc, January 1997, voln

tran splantation (Abrams G . Personal communication). (Stulbarg MS, Abrams G. Personal communication). The Graft nonfunction, rejection, and sep sis occurred in two frequenc y of such failures from a pulmonary perspective is cases in the setting of continued hypo xemia. The median unknown at thi s time ; at least one ca se was due to time to death after transplantation was 14 days (range , 2 to nonresolution of angio graphically pro ven direct arte rio90). venou s communication s, and that patient underwent sucAt least 16 of 81 patients (20%) underwent transplanta- cess ful pulmonary vascular embolization and had normaltion due to the severity of or deterioration in pulmonary ization of Pao.." status (including the 3 patients described herein).19.zo,z4,z6,z7 Prognostic Factors.-Incomplete or incompatible data Death occurred in 4 of these 16 patients (25%) within 35 comparisons limited the characterization of prognostic varidays after transplantation and was attributed directly to re- ables from the available data summarized in Table 1. Indifractory hypoxemia. All these posttransplantation deaths vidual pretransplantation Paa z mea surements while patients occurred in children; the Pao, ranged from 45 to 58 mm Hg were breathing room air were reported in only 49 of 81 before transplantation, and the response to 100% inspired patients with HPS who rece ived a transplant (61%). Mean oxygen ranged from 196 to 487 mm Hg.Z6 Pao, with patients breathing room air was significantly less Morbidity.-Overall, 14 of 68 survivors (21 %) required in thos e who died (44.7 ± 7.7 mm Hg) in comparison with prolonged mechanical ventilation (range, 4 to 77 days ) and those who survived (54.2 ± 13.2 mm Hg; P<0.03; [Fig. 2]). intensive care (range, 4 to 120 day s). Tran sient deterioration Seven of 23 patients (30%) with severe hypo xemia (Paa z, 50 in oxygenation immediately after liver transplantation was mm Hg or lower) died after liver transplantation. Onl y I of noted in our first patient (case 1). The cause was never 26 patients (4%) with a Pao, greater than 50 mm Hg died determined, but the condition did not seem to be due to after tran splantation. A Paaz of 50 mm Hg or lower was retained secretions, pulmonary edema, pneumonitis, or pleu - asso ciated with signific antly more frequent mortality ral effu sion . Reduced cardiac output and altered ventilation- (P<0.02) in comparison with Pao, cutoffs of 60 and 70 mm perfusion ratio due to pulmonary vasoconstriction may have Hg. occurred. Such a clinical course was described by Itasak a What prognostic conclusions can be made from the evaluation and subsequent resolution of hypoxemia in our three and associates." Are some posttransplantation morbidities associated with patients with severe pre transplantation hypoxemia (Pao., 50 HPS unique? The occurrence of posttransplantation intra- mm Hg or lower)? Each patient had at least a modest Pao, cerebral hemorrhage is of potential interest and was reported respon se (522, 374 , and 346 mm Hg) to 100% inspired by Wijdicks and colleagues." Central nervous system oxygen while standing and a better response while supine events are a well-documented complication of pulmonary (550 ,465, and 481 mm Hg), despite severe hypoxemia while vascular malformations that are presumably associated with breathing room air. On the basi s of the literature review, we the passage of emboli through dilated pulmonary vessels." were unable to provide an accurate comparison of Paa z Because dilated pulmonary vascular pathologic features oc- values obtained while patients were breathing 100% oxygen cur in HPS , central nervous system abnormalities may occur (or estimated shunt percentages) due to the variability of techniques described. Such technique variation included more frequently. Syndrome Resolution.-On the basis of the literature face mask versus mouthpiece administration of 100% oxyrev iew, improvement in or normalization of hypo xemia due gen , duration of administration, supine versus sittin g vers us to HPS occurred in 66 of 8 1 transplant recipients (82%) standing position , and use of radial artery catheters versus within 15 months after succe ssful liver tran splantation. The single needle stick s. A preliminary study of 27 patient s with three patients described herein had resolution of hypox- HPS showed a poor correlation (r = 0.35) between Paa z emi a within 12 months; none required ongoing po sttran s- determined while patients were breathing room air and Pao, plantation supplemental oxygen after the y were dismissed determined from inspiration of 100% oxygen. " In summary, from the hospital. Continued presence of mild pulmonary we sugges t that room air Pao, determinants ma y provide vasc ular dilatation was noted on contrast echocardiog- only a partial characterization of HPS severity and that 100% raph y in our third patient (cas e 3), but the existence of oxygen studi es may have an additional factor of prognostic subclinical pulmonary vasodilatation with normal oxygen- importance if they are done uniforml y. It is unknown ation has been described. Further follow-up is necessary whether such an approach is valid in the pediatric age-group because the syndrome may not completely resolve for (due to the difficulty of providing accurate 100% inspiration) and of importance regarding prognosis in those undergoing month s. Undoubtedly, some patients may not experience resolu- liver transplantation. Children with severe hypoxemia and tion of the pulmonary vascular dilatations, and hypoxemia extremely poor response to 100% inspired oxygen have had remains despite otherwise succe ssful liver transplantation - successful posttransplantation outcomes.P>' The number of

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Mayo Clin Proc, January 1997, Vol 72

HEPATOPULMONARY SYNDROME AND PROGRESSIVE HYPOXEMIA

51

10090-

aoPa02 mmHg

706050-

4030

• ••

•

.p.

b

54.2

~

• Survived

. • I

••

44.7* *P<.03

Died

Fig. 2. Pretransplantation determinants of arterial oxygen tension (Pao 2 ) while patients were breathing room air, categorized by liver transplantation outcome.

patients studied to date is small, and further observations are necessary for clarification of prognostic indexes. Our third patient (case 3) had an increased pulmonary shunt estimate (22.5% [normal, less than 5%]), as measured by 99mTcMAA lung and brain scanning, in association with a moderate response to 100% oxygen (Pao., 346 mm Hg). Preliminary data suggest that shunt estimation with use of the 99mTcMAA scanning method may be significantly greater than estimates obtained with use of 100% oxygen. 38,39 Importance of and reasons for such differences are unknown at this time. The optimal physiologic characterization of an oxygenation abnormality in HPS may be related to response to 100% oxygen; the degree of anatomic abnormality may be best described with the 99mTcMAA technique." Possibly, larger shunts, as measured by the 99mTcMAA scan, are associated with poor prognosis. Our third patient (case 3) had a mild to moderate shunt, as estimated by either method. Additional study is needed to clarify the prognostic value of such noninvasive quantification of HPS with use of 100% oxygen and 99mTcMAA shunt estimates in terms of resolution of posttransplantation HPS.

RECOMMENDAnONS Evaluation of Hypoxemia.-Our current approach to the oxygenation assessment of patients with HPS focuses on two issues. First, quantifying the severity of hypoxemia helps determine which patients require supplemental oxygen (usually 24 hours per day). A simple Paoz determination with the

patient breathing room air must take into account that the Pao z may be worse while the patient is standing (orthodeoxia), exercising, and, possibly, sleeping. Second, despite severe hypoxemia while breathing room air, some patients may have a dramatic improvement in Pao, with 100% inspired oxygen. In any patient with severe hypoxemia, we currently assess Pao, response to 100% inspired oxygen. II Clinical correlations between Pao, response to 100% inspired oxygen and the degree of pulmonary shunting, as determined by 99mTcMAA scanning, are being investigated." Pulmonary Angiography.-The primary goals of pulmonary angiography in patients with HPS are to detect and embolize distinct arteriovenous communications." One question that should be addressed is when should pulmonary angiography be undertaken in patients with HPS? Preliminary data from the Mayo Clinic suggest that, if the Pao, is 500 mm Hg or greater while an adult patient is breathing 100% oxygen, clinically important (treatable) vascular problems have not been detected, and pulmonary angiography is unnecessary." Our institutional guideline, which currently is based on response to 100% inspired oxygen, is that adult patients with a Paoz of less than 150 mm Hg while breathing 100% oxygen should undergo pulmonary angiography. Such patients have been shown to have discrete arteriovenous communications amenable to embolotherapy." Another question is what Pao, level necessitates pulmonary angiography? This question cannot be answered with the available data. Whether pulmonary angiography can be of

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Mayo Clin Proc, January 1997, Vol 72

prognostic importance is unknown at this time; however, the aspects of 100% inspired oxygenation, the anatomic implicabenefits of pulmonary angiography must be balanced against tions of 99mTcMAA lung shunt estimates, and other apthe potential morbidity in the setting of advanced liver dis- proaches is needed to refine risk stratification of patients ease. We experienced one case of femoral artery puncture with HPS being considered for liver transplantation. complicated by bleeding, encephalopathy, and subsequent We recommend that patients with severe hypoxemia surgical intervention to correct the vascular insult in the (Pao z' 50 mm Hg or lower) due to HPS and advanced liver setting of thrombocytopenia and an increased prothrombin disease be considered for liver transplantation as a combined treatment approach to hepatic and pulmonary vascular dystime. Liver Transplantation.-From a pulmonary perspective, function. At our institution, such consideration includes the the suggestion to consider HPS as an indication for liver aforementioned oxygenation assessments, pulmonary transplantation has been raised for several reasons. First, a angiography in selected patients, and ongoing investigaliterature review and an analysis of the experience at the tional studies to quantify the severity and prognostic factors Mayo Clinic with a total of 57 patients with HPS (most were of HPS. Currently, such patients with HPS who have a not candidates for transplantation) noted a significant mor- pronounced response to 100% inspired oxygen are advised tality (33 to 40%) during a fairly brief time span (2.5 to 4.0 to undergo liver transplantation with the expectation that the years ).11 The condition of many patients deteriorated despite HPS will resolve. Patients with HPS who have severe hyclinically stable hepatic dysfunction. Second, progressive poxemia and a poor response to 100% inspired oxygen are hypoxemia responds to supplemental oxygen for a certain considered individually, and we can make no definitive contime frame; thereafter, extreme debilitation and inability to clusions from our data. oxygenate by nasal cannula or face mask may occur. Third, pharmacologic therapies (other than supplemental oxygen) CONCLUSION have been ineffective in providing pronounced improvement HPS seems reversible after liver transplantation in many, but in oxygenation.i-' Selected patients with type II HPS (dis- not all, patients. From a pulmonary perspective, progressive crete angiographic lesions) may have improved oxygenation hypoxemia may be an indication for liver transplantation. after coil embolotherapy, but the subsequent history even in Identifying optimal methods and criteria for patient selection these patients is unknown. Fourth, the effect of progressive (for example, 100% inspired oxygen and 99mTcMAA lung hypoxemia on impaired hepatic function is unknown. Limi- scanning) necessitates ongoing study. Patients with a Pao, tations of oxygen delivery in combination with increasing of 50 mm Hg or lower due to HPS have significant mortality metabolic demands may lead to additional hepatocellular after liver transplantation. Selection criteria for children dysfunction and damage. In brief, the nontransplanta- may differ from those for adults. Long-term results after tion therapeutic options for patients with severe hypoxemia liver transplantation and resolution of HPS, however, are due to HPS seem limited in both children and adults. Z.3 unknown at this time. A multicenter prospective study is Of importance, many medical centers have demonstrated under way to determine hepatic and pulmonary factors that complete resolution of HPS after liver transplantation. may distinguish the favorable from the unfavorable progCurrently, no data support lung transplantation or com- noses before transplantation in both children and adults with bined liver-lung transplantation efforts for the treatment of HPS. HPS. On the basis of our literature review of patients with HPS who underwent liver transplantation, mortality was 30% REFERENCES within 3 months in those with a pretransplantation Pao z of 50 1. Krowka MJ, Cortese DA. Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation. Hepatology 1990; mm Hg or lower. As a corollary, 70% (16 of 23) had 11:138-142 successful transplantation (and resolution of hypoxemia). 2. Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann Intern Limitations of retrospective analysis do not allow us to conMed 1995; 122:521-529 3. Castro M, Krowka MJ. Hepatopulmonary syndrome: a pulmonary clude which patients (with a Pao, of 50 mm Hg or lower) had vascular complication of liver disease. Clin Chest Med 1996 Mar; the greatest risk for mortality or pronounced morbidity. We 17:35-48 can, however, demonstrate from our limited data that, de4. Wolfe JD, Tashkin DP, Holly FE, Brachman MB, Genovesi MG. Hypoxemia of cirrhosis: detection of abnormal small pulmonary spite severe and debilitating hypoxemia, successful transvascular channels by a quantitative radionuclide method. Am J Med plantation and resolution of HPS occurred, and morbidity 1977; 63:746-754 was minimal when the Pao, response to 100% inspired oxy5. Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis 1989; 140:1631-1635 gen was at least moderate (Pao., 400 mm Hg or higher; 6. Hedenstierna G, Soderman C, Eriksson LS, Wahren J. Ventilationnormal response, 600 mm Hg or higher) when the patient perfusion inequality in patients with non-alcoholic liver cirrhosis. was supine. Obviously, further study of the physiologic Eur RespirJ 1991; 4:711-717

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Mayo Clin Proc, January 1997, Vol 72

7. 8. 9. 10.

II. 12. 13. 14.

15.

16.

17. 18.

19. 20.

21.

22. 23. 24.

HEPATOPULMONARY SYNDROME AND PROGRESSIVE HYPOXEMIA

Rodriguez-Roisin R, Agusti AG, Roca J. The hepatopulmonary syndrome: new name, old complexities [editorial]. Thorax 1992; 47:897-902 Van Thiel DH, Schade RR, Gavaler JS, Shaw BW Jr, Iwatsuki S, Starzl TE. Medical aspects of liver transplantation. Hepatology 1984; 4(Suppll):79S-83S Maddrey WC, Van Thiel DH. Liver transplantation: an overview. Hepatology 1988; 8:948-959 Lake JR (Liver and Intestinal Subcommittee of the American Society of Transplant Physicians). A lack of consensus regarding contraindications to liver transplantation (OLT) in the U.S. [abstract]. Hepatology 1994; 20(Program Issue):120A Krowka MJ, Dickson ER, Cortese DA. Hepatopulmonary syndrome: clinical observations and lack of therapeutic response to somatostatin analogue. Chest 1993; 104:515-521 Shaw BW Jr, Wood RP, Kaufman SS, Williams L, Antonson DL, Vanderhoof J. Liver transplantation for children. Part 1. J Pediatr Gastroenterol Nutr 1988; 7:157-166 Starzl TE, Groth CG, Brettschneider L, Moon 18, Fulginiti VA, Cotton EK, et al. Extended survival in 3 cases of orthotopic homotransplantation of the human liver. Surgery 1968; 63:549-563 Sang Oh K, Bender TM, Bowen A, Ledesma-Medina J. Plain radiographic, nuclear medicine and angiographic observations of hepatogenic pulmonary angiodysplasia. Pediatr Radiol 1983; 13:111-115 Stoller JK, Moodie 0, Schiavone WA, Vogt 0, Broughan T, Winkelman E, et at. Reduction of intrapulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation. Hepatology 1990; 11:54-58 Eriksson LS, Soderman C, Ericzon BG, Eleborg L, Wahren J, Hedenstierna G. Normalization of ventilation/perfusion relationships after liver transplantation in patients with decompensated cirrhosis: evidence for a hepatopulmonary syndrome. Hepatology 1990; 12:1350-1357 Mews CF, Dorney SF, Sheil AG, Forbes DA, Hill RE. Failure of liver transplantation in Wilson's disease with pulmonary arteriovenous shunting. J Pediatr Gastroenterol Nutr 1990; 10:230-233 McCloskey JJ, Schleien C, Schwarz K, Klein A, Colombani P. Severe hypoxemia and intrapulmonary shunting resulting from cirrhosis reversed by liver transplantation in a pediatric patient. J Pediatr 1991; 118:902-904 Dimand RJ, Heyman MB, Lavine JE, Bass NM, Lake JR, Roberts JP, et at. Hepatopulmonary syndrome: response to hepatic transplantation [abstract]. Hepatology 1991; 14(Program Issue):55A Laberge JM, Brandt ML, Lebecque P, Moulin 0, Veykemans F, Paradis K, et al. Reversal of cirrhosis-related pulmonary shunting in two children by orthotopic liver transplantation. Transplantation 1992; 53: 1135-1138 Itasaka H, Hershon JJ, Cox KL, Tokunaga Y, Concepcion W, Nakazato P, et al. Transient deterioration of intrapulmonary shunting after pediatric liver transplantation. Transplantation 1993; 55:212214 Schwarzenberg SJ, Freese OK, Regelmann WE, Gores PF, Boudreau RJ, Payne WD. Resolution of severe intrapulmonary shunting after liver transplantation. Chest 1993; 103:1271-1273 Scott V, Miro A, Kang Y, DeWolf A, Bellary S, Martin M, et al. Reversibility of the hepatopulmonary syndrome by orthotopic liver transplantation. Transplant Proc 1993; 25: 1787-1788 Van Obbergh L, Carlier M, de Clety SC, Sokal E, Rennotte MT, Veyckemans F, et al. Liver transplantation and pulmonary gas exchanges in hypoxemic children. Am Rev Respir Dis 1993; 148:1408-1410

25.

26. 27.

28.

29.

30.

31. 32.

33. 34. 35.

36. 37.

38.

39. 40.

41.

53

Caldwell SH, Brantley K, Dent J, Keeley RC, Pruett T, Angle JF, et al. The hepatopulmonary syndrome masquerading as pulmonary Langerhans-cell histiocytosis. Ann Intern Med 1994; 121:3436 Hobeika J, Houssin 0, Bernard 0, Devictor 0, Grimon G, Chapuis Y. Orthotopic liver transplantation in children with chronic liver disease and severe hypoxemia. Transplantation 1994; 57:224-228 Fewtrell MS, Noble-Jamieson G, Revell S, Valente J, Friend P, Johnston P, et at. Intrapulmonary shunting in the biliary atresia/ polysplenia syndrome: reversal after liver transplantation. Arch Dis Child 1994; 70:501-504 Stoller JK, Lange PA, Westveer MK, Carey WD, Vogt 0, Henderson JM. Prevalence and reversibility of the hepatopulmonary syndrome after liver transplantation: the Cleveland Clinic experience. West J Med 1995; 163:133-138 Cremona G, Higenbottam TW, Mayoral V, Alexander G, Demoncheaux E, Borland C, et al. Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome. Eur Respir J 1995; 8:1883-1885 Riegler JL, Lang KA, Johnson SP, Westerman JH. Transjugular intrahepatic portosystemic shunt improves oxygenation in hepatopulmonary syndrome. Gastroenterology 1995; 109:978983 Rodriguez-Roisin R, Krowka MJ. Is severe arterial hypoxaemia due to hepatic disease an indication for liver transplantation? A new therapeutic approach [editorial]. Eur Respir J 1994; 7:839-842 Scott VL, Nelson F, DeWolf AM, Paradis I, Ziady G, Kang Y, et at. Hepatopulmonary syndrome: a reversible disease by orthotopic liver transplantation [abstract]. Gastroenterology 1995; 108(Suppl): A1165 Bynon JS, Langnas AN, Sorrell MS, Vanderhoof JA, Fox IJ, Heffron TG, et al. Hepatopulmonary syndrome and liver transplantation [abstract]. Hepatology 1994; 19:461 Petruff CA, Gordon FD, Chopra S, Dushay KM, Lewis WD, Jenkins RL. Hepatopulmonary syndrome reversed by orthotopic liver transplantation [abstract]. Gastroenterology 1996; llO(Suppl):AI295 Poterucha JJ, Krowka MJ, Dickson ER, Cortese DA, Stanson AW, Krom RAF. Failure of hepatopulmonary syndrome to resolve after liver transplantation and successful treatment with embolotherapy. Hepatology 1995; 21:96-100 Wijdicks EFM, de Groen PC, Wiesner RH, Krom RAF. Intracerebral hemorrhage in liver transplant recipients. Mayo Clin Proc 1995; 70:443-446 Ueki J, Hughes JMB, Peters AM, Bellingan GJ, Mohammed MAM, Dutton J, et at. Oxygen and 99mTc_MAA shunt estimations in patients with pulmonary arteriovenous malformations: effects of changes in posture and lung volume. Thorax 1994; 49:327-331 Krowka MJ, Burnett OL, Wiseman GA, Cortese DA, Spivey JR. Positional oxygenation, response to 100% inspired oxygen and 99mTc macroaggregated albumin lung scanning in hepatopulmonary syndrome (HPS) [abstract]. Am J Respir Crit Care Med 1996; 153(Suppl):A752 Whyte MKB, Hughes JMB, Bellingan GJ, Peters AM, Ueki J, Ussov W. Measurement of right to left shunt in patients with the hepatopulmonary syndrome [abstract]. Thorax 1994; 49:431P Abrams GA, Jaffe CC, Hoffer PB, Binder HJ, Fallon ME. Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome. Gastroenterology 1995; 109:1283-1288 Krowka MJ, Cortese DA. Hepatopulmonary syndrome: classification by arterial oxygenation and pulmonary angiographic appearances [abstract]. Chest 1992; 102(Suppl):124S

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