Hepatopulmonary Syndrome in Patients With Hypoxic Hepatitis

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Hepatopulmonary Syndrome in Patients With Hypoxic Hepatitis VALENTIN FUHRMANN,* CHRISTIAN MADL,* CHRISTIAN MUELLER,‡ ULRIKE HOLZINGER,* REINHARD KITZBERGER,* GEORG–CHRISTIAN FUNK,§ and PETER SCHENK* *Intensive Care Unit 13H1; ‡Division of Gastroenterology and Hepatology; §Pulmonary Division, Department of Internal Medicine IV, Medical University Vienna, Vienna, Austria

Background & Aims: The hepatopulmonary syndrome (HPS) is defined as the triad of liver disease, arterial deoxygenation, and widespread pulmonary vasodilatation. Hypoxic hepatitis, also known as ischemic hepatitis, is the leading cause of acute liver impairment in hospitals. It is unknown whether HPS occurs in hypoxic hepatitis. We assessed the prevalence and clinical consequences of HPS in patients with hypoxic hepatitis. Methods: Forty-four patients with hypoxic hepatitis were screened prospectively for HPS using established criteria: (1) presence of hepatic disease, (2) increased alveolar-arterial difference for the partial pressure of oxygen greater than the age-related threshold, and (3) intrapulmonary vasodilatation detected via contrast-enhanced echocardiography. Sixty-two critically ill patients with different cardiopulmonary diseases but without hepatic disease were screened for prevalence of intrapulmonary vasodilatation as a control group. Results: Criteria of HPS were fulfilled in 18 patients with hypoxic hepatitis. HPS-positive patients had a significantly decreased partial pressure of arterial oxygen (P ⴝ .001) and partial pressure of arterial oxygen/fraction of inspired oxygen ratio (P ⴝ .034) at the time of diagnosis of HPS, a significant decreased area under the curve of the partial pressure of arterial oxygen/fraction of inspired oxygen ratio during the first 48 hours after diagnosis of hypoxic hepatitis (P ⴝ .009), and a significantly increased peak serum aspartate transaminase level (P ⴝ .028), compared with patients without HPS. Complete resolution of intrapulmonary vasodilatation was observed during follow-up evaluation. Contrast-enhanced echocardiography was negative for intrapulmonary vasodilatation in all 62 control patients. Conclusions: Intrapulmonary vasodilatation indicating HPS frequently occurs in patients with hypoxic hepatitis. It is reversible after normalization of the hepatic dysfunction. Clinicians should consider intrapulmonary vasodilatation and HPS in patients with hypoxic hepatitis.

he hepatopulmonary syndrome (HPS) is defined as the triad of liver disease, arterial deoxygenation, and widespread intrapulmonary vasodilatation (IPVD). The hallmarks of pulmonary vascular changes in HPS are dilated vessels at the precapillary and capillary level and

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direct arteriovenous communications. This causes rightto-left shunting of blood flow, mismatch between ventilation and perfusion, and diffusion limitation. Clinical consequences are impaired arterial oxygenation, respiratory insufficiency, and increased mortality in patients with cirrhosis and HPS.1,2 There are few case reports of HPS in patients without cirrhosis.3–9 A histopathologic study described widespread pulmonary vasodilatation in patients who died of fulminant hepatic failure, indicating a high frequency of HPS in these patients.10 Hypoxic hepatitis (HH), also known as ischemic hepatitis, is characterized by centrilobular liver cell necrosis caused by passive congestion, ischemia, and arterial hypoxemia of the liver.11,12 The disorder usually is identified by an acute marked and reversible increase in serum transaminase levels in the absence of other causes. HH is caused mainly by cardiac failure.11,13 Although HH is the most common cause of massive increase of serum transaminase levels in the hospital, there are no data concerning the prevalence of HPS in these patients.14,15 The aim of this study was to investigate the prevalence and clinical consequences of HPS in patients with hypoxic hepatitis. Furthermore, critically ill patients with several cardiopulmonary diseases but without HH or other kinds of hepatic disease were screened for the presence of IPVD via contrast-enhanced echocardiography (CEE) as a control group.

Materials and Methods Patients A total of 646 patients were admitted to our intensive care unit (ICU) between October 2003 and May 2005. FortyAbbreviations used in this paper: CEE, contrast-enhanced echocardiography; HH, hypoxic hepatitis; HPS, hepatopulmonary syndrome; ICU, intensive care unit; INR, international normalized ratio; IPVD, intrapulmonary vasodilatation. © 2006 by the American Gastroenterological Association Institute 0016-5085/06/$32.00 doi:10.1053/j.gastro.2006.04.014

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four patients fulfilled the criteria of HH and were screened for the presence of HPS. The control group consisted of all the remaining 602 patients, who fulfilled the following criteria: (1) presence of cardiogenic pulmonary edema, pneumonia, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pleural effusion, atelectasis, or pulmonary embolism; (2) no sign of severe liver dysfunction (defined as serum transaminase levels reaching maximum 3-fold the upper limit of normal and serum bilirubin levels ⬍1.5 mg/dL), viral or drug-induced hepatitis, or cirrhosis; and (3) necessity of routine CEE (detection of intracardiac shunting, evaluation of right ventricular function, and enhancement of tricuspid regurgitation Doppler signals).16 –19 Sixty-two patients fulfilled these criteria and were assigned to the control group. The study was approved by the local ethical committee of the Medical University of Vienna, Austria. Conscious patients gave written informed consent and unconscious patients, who were not able to give written informed consent, received written patient information after regaining consciousness according to Austrian law.

Definition of HH HH was defined according to 3 widely accepted criteria11: (1) clinical setting of cardiac, circulatory, or respiratory failure; (2) acute but transient increase in serum transaminase levels reaching at least 20-fold the upper limit of normal (normal range in the University Hospital of Vienna: serum aspartate transaminase [AST] ⬍ 35 U/L, serum alanine transaminase [ALT] ⬍ 45 U/L); and (3) exclusion of other putative causes of liver cell necrosis, particularly viral or druginduced hepatitis. Liver biopsy examination was not required for the diagnosis of HH, in agreement with other studies showing that a histologic confirmation is unwarranted and even inadvisable when all criteria listed previously are met.11,20 –22 Exclusion criteria were the presence of cirrhosis, high level of serum transaminases after liver surgery, and viral, autoimmune, or drug-induced hepatitis.

Definition of HPS HPS was defined by the following: (1) presence of hepatic disease, (2) increased alveolar-arterial difference for the partial pressure of oxygen above the age-related threshold, and (3) IPVD detected via 2-dimensional CEE. The alveolar-arterial difference for the partial pressure of oxygen was not included in the analysis in patients who required oxygen support via face mask because the fraction of inspired oxygen is indeterminable in these patients. However, the alveolararterial difference for the partial pressure of oxygen was considered as increased in these patients because they required oxygen support.

CEE Agitated saline was used as a contrast medium, which creates a stream of microbubbles after intravenous injection. In

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healthy individuals, these microbubbles, greater than 15 ␮m in diameter, opacify the right heart chambers only because they are filtered in the pulmonary capillary bed and do not appear in the left heart chambers. In intracardiac shunt, the microbubbles generally appear within 3 heartbeats after their appearance in the right heart chambers. In IPVD, they appear 4 – 6 heartbeats after the initial appearance in the right side of the heart. CEE was performed after a median of 1 day (range, 0 – 4 days) after diagnosis of HH in patients with IPVD and after a median of 1 day (range, 0 – 4 days) after the diagnosis of HH in patients without IPVD (P ⫽ NS).

Arterial Blood Gas Analysis Arterial blood gas samples were obtained via an arterial catheter that was inserted as clinically indicated. Samples were analyzed with a fully automated blood gas analyzer (Radiometer ABL 700; Radiometer Medical ApS, Brønshøj, Denmark). The alveolar-arterial difference for the partial pressure of oxygen was calculated via the alveolar gas equation.23,24 The age-related threshold for the alveolar-arterial difference for the partial pressure of oxygen was calculated according to the standards of the Austrian Thoracic Society, as reported previously.2

Chest Radiograph A chest radiograph performed on the day of screening for HPS via CEE revealed pleural effusion in 5 patients (3 HPS positive), pulmonary infiltrate in 6 patients (2 HPS positive), and congestion in 7 patients (4 HPS positive).

Laboratory and Respiratory Features Laboratory parameters were collected during routine laboratory control. The individual respiratory support was performed as clinically indicated in all patients.

Data Analysis Results are expressed as mean ⫾ SD or median and range if appropriate. The area under the curve was calculated via GraphPad Prism 4.00 software program (GraphPad Software, Inc., San Diego, CA). Comparisons between groups were performed with the Mann–Whitney U test. For qualitative data, ␹2 analysis or Fisher exact test were used. Comparisons between peak value and follow-up value of the same parameter were performed via Wilcoxon test. Analysis was performed using statistical software (SPSS for Windows 12.0; SPSS, Chicago, IL). For all comparisons, statistical significance was defined as a P value of less than .05.

Results Study Population Data were collected and analyzed in a total of 44 critically ill patients with HH. Figure 1 shows the recruitment algorithm of the study patients.

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Figure 1. Overview algorithm of the recruitment of patients with HH fulfilling inclusion criteria in terms of presence or absence of HPS. PFO, patent foramen ovale.

The median age of the study patients was 62 years (range, 22– 83 years); 29 (66%) were men and 15 (34%) were women. The mean acute physiologic and chronic health evaluation III score was 82 ⫾ 31. Demographic data and patients’ characteristics are summarized in Table 1. Control Population The control group consisted of 62 critically ill patients without HH but several cardiopulmonary diseases causing hypoxemia. The median age was 62 years (range, 18 – 89 years), the mean acute physiologic and

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chronic health evaluation III score was 78 ⫾ 31, and there were 39 (63%) men and 23 (37%) women. Ten patients had chronic obstructive pulmonary disease (8 patients were ventilated mechanically), 10 patients were treated at the ICU for acute respiratory distress syndrome (all were ventilated mechanically), 9 patients had pneumonia (7 patients were ventilated mechanically), 9 patients had pleural effusion (8 patients were ventilated mechanically), 13 patients had congestion or cardiogenic pulmonary edema (12 patients were ventilated mechanically), 3 patients had pulmonary embolism (2 patients were ventilated mechanically), and 8 patients had atelectasis (7 patients were ventilated mechanically). None of these patients had HH, cirrhosis, or another cause of hepatic disease. Prevalence of HPS in Patients With HH Eighteen patients had IPVD detected via CEE and fulfilled the criteria of HPS. Of the remaining 26 patients, 21 patients had no IPVD and were HPS negative. Three patients had an intracardiac shunt owing to patent foramen ovale and 2 patients had inadequate echocardiographic image quality. These 5 patients were neither considered HPS positive nor HPS negative because the presence of IPVD could not be assessed sufficiently. Therefore, the prevalence of HPS in patients with HH was 46% (18 of 39 patients). CEE was negative for IPVD in all control patients. Intracardiac right to left shunting was diagnosed in 4 control patients via CEE (1 patient with cardiogenic

Table 1. Demographic and Clinical Data of Patients With HH Variable Median age, y (range) Men, n (%) Height, cm Weight, kg APACHE III score Mechanical ventilation, n (%) ICU survival, n (%) ICU length of stay, days (range)a Vasopressor therapy, n (%) Factors predisposing patients to HHb Cardiopulmonary resuscitation, n Acute myocardial infarction, n Cardiomyopathy, n Arrhythmia, n Septic shock, n Pulmonary embolism, n Valvular heart disease, n Pericardial effusion, n

HPS-positive patients (n ⫽ 18)

HPS-negative patients (n ⫽ 21)

P value

63 (22–78) 13 (72%) 175 ⫾ 8 77 ⫾ 15 87 ⫾ 33 13 (72%) 10 (56%) 5.5 (3–23) 11 (61%)

56 (29–83) 12 (57%) 172 ⫾ 11 82 ⫾ 28 78 ⫾ 31 17 (81%) 9 (43%) 6 (4–19) 17 (81%)

NS NS NS NS NS NS NS NS NS

7 5 5 5 3 3 1 0

7 7 3 1 4 2 5 1

NOTE. ⫾ values are mean ⫾ SD. APACHE III, acute physiologic and chronic health evaluation III score. aSolely ICU-surviving patients included. b20 patients (51%) had more than 1 predisposing event.

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Table 2. Arterial Blood Gas Analysis and Respiratory Parameters During CEE in Patients With HH HPS-positive patients Arterial blood gas analysis during CEE pH 7.34 ⫾ .15 76 ⫾ 11 PaO2, mm Hg PaCO2, mm Hg 40 ⫾ 15 231 ⫾ 126 AaDO2, mm Hg Respiratory parameters in mechanically ventilated patients during CEE PEEP, mbar 7.5 ⫾ 2.8 P max insp, mbar 22.2 ⫾ 5.3 Tidal volume, mL 485 ⫾ 90 Respiratory rate per minute 18 ⫾ 5 PaO2/FiO2 152 ⫾ 61 266 ⫾ 102 AaDO2, mm Hg AUC48hr of PaO2/FiO2, mm Hg · h 7465 ⫾ 2409a

HPS-negative patients

P value

7.40 ⫾ .06 92 ⫾ 16 40 ⫾ 9 204 ⫾ 118

NS .001 NS NS

8.9 ⫾ 4.1 22.9 ⫾ 6.2 531 ⫾ 152 16 ⫾ 5 203 ⫾ 63 215 ⫾ 112 11,620 ⫾ 4281b

NS NS NS NS .034 NS .009

NOTE. ⫾ values are mean ⫾ SD. For the arterial blood gas analysis during CEE there were 18 HPS-positive patients and 21 HPS-negative patients. For the respiratory parameters in mechanically ventilated patients during CEE there were 11 HPS-positive patients and 18 HPS-negative patients. PaO2, partial pressure of arterial oxygen; PaCO2, partial pressure of arterial carbon dioxide; AaDO2, alveolar-arterial difference for the partial pressure of oxygen; PEEP, positive end expiratory pressure; P max insp, maximal inspiratory pressure; PaO2/FiO2, ratio of the arterial oxygen tension and the fraction of inspiratory oxygen in mechanically ventilated patients; AUC48hr, area under the curve during the first 48 hours after diagnosis of HH. aNumber of HPS-positive patients ventilated mechanically for at least 48 hours after HH ⫽ 10. bNumber of HPS-negative patients ventilated mechanically for at least 48 hours after HH ⫽ 14.

pulmonary edema, 1 patient with pulmonary embolism, 1 patient with pleural effusion, and 1 patient with atelectasis). Laboratory Features Admission laboratory parameters did not differ significantly in HPS-positive vs HPS-negative patients: the AST levels were 490 ⫾ 872 U/L vs 348 ⫾ 749 U/L (P ⫽ NS), ALT levels were 321 ⫾ 551 U/L vs 206 ⫾ 506 U/L (P ⫽ NS); serum lactate dehydrogenase levels were 683 ⫾ 699 U/L vs 642 ⫾ 624 U/L (P ⫽ NS); bilirubin levels were 1.29 ⫾ .73 mg/dL vs .86 ⫾ .40 mg/dL (P ⫽ NS); and the international normalized ratios (INRs) were 1.43 ⫾ .64 vs 1.19 ⫾ .15 (P ⫽ NS). The mean peak AST levels were significantly higher in HPSpositive patients compared with HPS-negative patients (6959 ⫾ 5267 U/L vs 3719 ⫾ 3964 U/L; P ⫽ .028). The mean peak ALT levels (2693 ⫾ 1938 U/L vs 1992 ⫾ 1838 U/L; P ⫽ NS) and the mean peak serum lactate dehydrogenase values (5226 ⫾ 4286 U/L vs 3955 ⫾ 3490 U/L; P ⫽ NS) were higher in HPS-positive patients, but this was not statistically significant. The mean peak bilirubin levels (2.06 ⫾ 1.38 mg/dL vs 1.93 ⫾ 1.47 mg/dL; P ⫽ NS) and the mean peak INRs (2.57 ⫾ 1.45 vs 1.78 ⫾ .45; P ⫽ NS) did not differ between HPSpositive and HPS-negative patients. In the control group the mean AST level was 51 ⫾ 26 U/L, mean ALT level was 41 ⫾ 31 U/L, mean serum lactate dehydrogenase level was 408 ⫾ 246 U/L, mean bilirubin level was .75 ⫾ .37 mg/dL, and mean INR was 1.41 ⫾ .81.

ICU Course All patients with HH received respiratory support at diagnosis of HH: 34 (77%) patients were ventilated mechanically and oxygen supply was given via face mask to 10 (23%) patients. During CEE, the partial pressure of arterial oxygen values and the partial pressure of arterial oxygen/fraction of inspired oxygen ratio were significantly lower in HPS-positive patients compared with HPS-negative patients. Table 2 shows arterial blood gas analysis and respiratory support during CEE. The partial pressure of arterial oxygen/fraction of inspired oxygen ratio was calculated 3 times daily in all mechanically ventilated patients. We found a significantly lower area under the curve of the partial pressure of arterial oxygen/fraction of inspired oxygen ratio over time in mechanically ventilated HPS-positive patients during the first 48 hours after diagnosis of HH (Table 2). The ICU survival rate and the overall length of ICU stay for patients surviving the ICU were comparable in both groups (Table 1). Follow-up Evaluation Follow-up examination was possible in 7 of the 10 HPS-positive patients surviving their ICU stay after a median time of 4 weeks (range, 1– 42 weeks). At the time of follow-up evaluation, all of these patients revealed a decrease in transaminase levels and an increase in INR compared with peak laboratory parameters (peak AST levels, 8685 ⫾ 7563 U/L vs 90 ⫾ 153 U/L during follow-up evaluation, P ⫽ .018; peak ALT levels, 3247

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Table 3. Reversibility of HPS in Seven Patients With HH Parameters at diagnosis of HPS

Patient

Sex

Age, y

APACHE III score

1 2 3 4 5 6 7 Mean ⫾ SD

M F M M M M M

59 63 63 62 61 78 51 62 ⫾ 8

52 112 108 92 55 105 68 85 ⫾ 26

MV No No Yes Yes No Yes No

O2 via face mask

PaO2, mm Hg

Yes Yes

69 78 70 75 83 89 70 76 ⫾ 8

Yes Yes

CEE Positive Positive Positive Positive Positive Positive Positive

Weeks between Parameters during follow-up diagnosis of evaluation HPS and O2 via PaO2, follow-up MV face mask mm Hg CEE evaluation 42 4 9 11 2 1 1 10 ⫾ 15

No No No No No No No

No Yesa No No No Yesb Yesb

99 116 79 96 67 79 75 87 ⫾ 17

Negative Negative Negative Negative Negative Negative Negative

APACHE III, acute physiologic and chronic health evaluation III; MV, mechanical ventilation; O2, oxygen support; CPR, cardiopulmonary resuscitation. aPatient required oxygen support after aspiration and CPR 2 weeks after discharge from the ICU; between ICU discharge and CPR she did not require oxygen support. bPatient required oxygen support because of nosocomial pneumonia.

⫾ 2464 U/L vs 199 ⫾ 419 U/L during follow-up evaluation, P ⫽ .018; peak INRs, 2.64 ⫾ 1.40 vs 1.21 ⫾ .33 during follow-up evaluation [INR only available in 5 patients during follow-up evaluation], P ⫽ .028). Three of these patients required oxygen support during follow-up evaluation (2 patients because of nosocomial pneumonia and 1 patient after aspiration and cardiopulmonary resuscitation). However, all patients were negative for IPVD during follow-up evaluation. Patients’ characteristics are shown in Table 3.

Discussion HPS is a known complication of chronic liver disease associated with increased morbidity and mortality.1,2,25 Most of the clinical studies focused on patients with cirrhosis. There are only a few cases reporting the occurrence of HPS in patients without cirrhosis.3–9 A histopathologic study of the lungs in patients who died of fulminant hepatic failure revealed pleural spider nevi, diffuse dilatation of the pulmonary vascular bed affecting arteries, precapillary vessels, and veins of all structural types, and precapillary anastomoses.10 These findings indicate that HPS also may occur in patients with acute liver injury. We present results of a prospective clinical study investigating the prevalence, clinical presentation, and consequences of HPS in patients with HH, a frequent cause of severe acute hepatic impairment in hospital.14,15 The prevalence of IPVD in patients with HH was 46% in our study. Although the reported prevalence of IPVD in cirrhotic patients ranges from 13% to 47%,26 arterial deoxygenation and therefore HPS was observed only in about 20% of cirrhotic patients.1 Patients with HH and IPVD had significantly impaired oxygenation

indices compared with patients with HH but without IPVD. However, all of our patients with HH had severe gas exchange abnormalities owing to their underlying diseases that had caused HH. Other techniques such as macroaggregated albumin lung perfusion scanning would be helpful to quantify the impact of IPVD on the observed gas exchange abnormalities.27 This method was not feasible in our critically ill patients. Because all of our patients with HH and IPVD had arterial deoxygenation and therefore fulfilled the criteria of HPS, we defined them as HPS positive. IPVD was reversible after normalization of hepatic function in all 7 patients with HH who were available for follow-up examination after discharge from the ICU. In addition to 2 case reports,4,7 this prospective study shows the reversibility of IPVD in patients with acute hepatic impairment. A number of potential mechanisms contributing to IPVD like pulmonary nitric oxide overproduction, carbon monoxide, endothelin-1, transforming growth factor ␤, and tumor necrosis factor ␣ have been found in experimental and human HPS.1,28 –38 Independently of the pathophysiologic mechanism causing IPVD, our data suggest that acute liver injury is associated frequently with the development of IPVD and HPS. Further studies will need to clarify whether factors causing acute hepatic impairment in cirrhosis like infection and acute gastrointestinal bleeding also may trigger the development of HPS. Length of stay at the ICU and survival were comparable in HPS-positive and HPS-negative patients. In contrast to patients with cirrhosis, in whom the presence of HPS is associated with an increased mortality rate,2 the prognosis of patients with HH seems to depend

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mainly on the reversibility of the basic, HH-causing disease: if it is possible to stabilize the acute decompensated pulmonary and cardiocirculatory dysfunction, reversibility of HH and HPS are likely. IPVD appears to be a finding that is highly specific for patients with hepatic disease. It is well known that the combination of arterial deoxygenation, IPVD, and liver disease supports the diagnosis of HPS also in the presence of coexistent chronic cardiopulmonary diseases.1,39,40 We could not detect IPVD via CEE in any of the 62 critically ill patients in the control group without acute or chronic hepatic impairment but with severe cardiopulmonary diseases. However, we cannot exclude the presence of IPVD in selected individuals without hepatic disease in a larger cohort of critically ill patients. We acknowledge potential limitations in our study. First, the number of patients in our study was relatively small. However, this is one of the largest prospective studies in patients with HH.11 Second, because critically ill patients may suffer from many causes of respiratory impairment, the contribution of IPVD to the gas exchange abnormalities may vary as discussed previously. Third, because some patients with HH died early after the occurrence of HH—possibly before the development of IPVD—the number of HPS-positive patients probably would have been higher if a longer observation period had been possible. In conclusion, our study shows that HPS criteria are fulfilled frequently in patients with HH. IPVD was reversible after normalization of hepatic dysfunction. HPS-positive patients had severe arterial deoxygenation in the first days after evolvement of HH. IPVD was not detected in critically ill patients without HH. Clinicians should consider IPVD and HPS in patients with HH.

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Received October 15, 2005. Accepted April 7, 2006. Address request for reprints to: Valentin Fuhrmann, MD, Department of Internal Medicine 4, Intensive Care Unit, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. e-mail: [email protected]; fax: (43) 1-40400-4797.