James K. Stoller

The hepatopulmonary syndrome

Interactions between the lung and the liver have been studied since 1884, when Fluckiger [1] first saw a woman with cirrhosis, cyanosis, and digital clubbing. This hypoxemia of cirrhosis was further clarified in 1935 by Snell [2], who recognized a decreased arterial saturation in three patients with cirrhosis and described what is currently called the hepatopulmonary syndrome. This term, first suggested in 1977 by Kennedy and Knudson [3], aptly characterizes the association of severe hypoxemia with intrapulmonary vascular dilatations in the setting of hepatic dysfunction. In the current era, successful liver transplantation has renewed interest in the pathophysiology of lung and liver interactions [4]. We review the clinical features and current pathophysiologic understanding of the hepatopulmonary syndrome. Specifically, we present the definition and clinical manifestations of the hepatopulmonary syndrome; diagnostic methods for detecting intrapulmonary vascular dilatations; the putative mechanisms underlying the vascular changes seen in patients with the hepatopulmonary syndrome; the efficacy of treatments, including liver transplantation, to reverse the hypoxemia associated with the syndrome; and currently unresolved questions needing further investigation. The studies we cite were identified by a MEDLINE search and from the bibliographies of eligible studies. We reviewed English-language articles found under the keyword hepatopulmonary that were published between January 1986 and December 1993, inclusive. Because only one study addressed an animal model of the hepatopulmonary syndrome, all studies selected examined humans. Case reports, case series, and observational cohort studies were included, but no randomized, controlled trials of treatments for the hepatopulmonary syndrome were identified. Bibliographies of articles identified in the MEDLINE search were reviewed for early descriptions (before 1986) of the hepatopulmonary syndrome; discussions of treatment of the hepatopulmonary syndrome, including organ transplantation; or descriptive series not found in the MEDLINE search. Definition and Clinical Manifestations of the Hepatopulmonary Syndrome The hepatopulmonary syndrome is defined as the triad of liver disease, an increased alveolar-arterial gradient while breathing room air, and evidence of intrapulmonary vascular dilatations [5]. Other cardiopulmonary abnormalities (such as pleural effusions or decreased lung volumes) are common and may coexist in patients with the hepatopulmonary syndrome. Several clinical signs and symptoms characterize this syndrome; most persons will present with the signs and symptoms of liver disease, including gastrointestinal bleeding, esophageal varices, ascites, palmar erythema, and splenomegaly [6]. Pulmonary features include digital clubbing, cyanosis, dyspnea, platypnea, and orthodeoxia. Dyspnea is a common symptom; it was the presenting symptom in 18% of patients in the series by Krowka and colleagues [6]; the mean duration of respiratory symptoms in these patients was 4.8 years. Platypnea, defined as dyspnea induced by the upright position and relieved by recumbency [7], and orthodeoxia, defined as arterial deoxygenation accentuated in the upright position and relieved by recumbency [8], are seen in as many as 5% of patients with cirrhosis [9, 10]. However, platypnea and orthodeoxia are more prevalent in patients with the severe hypoxemia characteristic of the hepatopulmonary syndrome. Krowka and colleagues [6] observed orthodeoxia in 14 of 16 patients (88%) with the syndrome, and Edell and colleagues [11] found orthodeoxia in all of 6 patients with cirrhosis and severe hypoxemia. Andrivet and colleagues [12] observed orthodeoxia in 9 patients with cirrhosis and hypoxemia [mean PaO].2, <45 mm Hg) while the patients were breathing 100% oxygen. Although orthodeoxia is not pathognomonic of the hepatopulmonary syndrome, it strongly suggests this diagnosis in the setting of liver dysfunction. Spider nevi are another common clinical feature of patients with the hepatopulmonary syndrome [13]. Rodriguez-Roisin and colleagues [9, 14] noted that patients with cutaneous spider nevi had more systemic and pulmonary vasodilatation, more profound gas exchange abnormalities, and less hypoxic pulmonary vasoconstriction, suggesting that spider nevi might be a cutaneous marker of intrapulmonary vascular dilatations. Similarly, Andrivet and colleagues [12] observed spider nevi in 7 of 9 patients with cirrhosis and hypoxemia (mean Pao 2, 64 mm Hg). Other than orthodeoxia, common cardiopulmonary features of chronic liver disease manifested by patients with the hepatopulmonary syndrome include alveolar hyperventilation with hypocapnia and a hyperdynamic circulation characterized by systemic vasodilatation and elevated cardiac output. The magnitude of the systemic hemodynamic changes is related to both the development of portal hypertension and the degree of impairment of liver function [15, 16]. Although patients with the hepatopulmonary syndrome show pulmonary vasodilatation accompanying intrapulmonary shunt, their systemic hemodynamics resemble those of patients who have cirrhosis without the hepatopulmonary syndrome. Specifically, cardiac output often exceeds 7 L/min, systemic and pulmonary vascular resistances decrease, and the difference between the arterial and the mixed-venous oxygen content narrows [12, 17-21]. Low pulmonary vascular resistance and low pulmonary artery pressures are characteristic of the hepatopulmonary syndrome because the intrapulmonary vascular dilatations further decompress the vascular bed [11, 18, 22]. Restoration of this hyperdynamic cardiovascular state to normal after liver transplantation has been documented in some patients with cirrhosis, some of whom have and some of whom do not have the hepatopulmonary syndrome [18, 19, 21, 23]. Other reports have refuted this observation, showing persistently increased cardiac output and increased splanchnic blood flow after transplantation, presumably because of a persistently elevated, undefined mediator [24-26]. End-stage liver disease may be characterized by various other derangements of pulmonary function, including a restrictive pattern of lung function characterized by decreased total lung capacity, air flow obstruction, impairment of diffusing capacity, and a widened alveolar-arterial oxygen gradient [27-32]. In describing pulmonary function abnormalities in 116 candidates for liver transplantation, Hourani and colleagues [29] reported that the most common abnormality was a reduction in diffusing capacity for carbon monoxide, seen in 52% of patients. Diffusion impairment was accompanied by a restrictive defect in only 35% of persons with impaired diffusing capacity. A restrictive pattern was noted in 25% of patients and airflow obstruction in 3% of patients. Krowka and colleagues [28] studied 159 consecutive patients before liver transplantation and found diffusing capacity values of less than 80% predicted in 55% of patients. Although patients with the hepatopulmonary syndrome also often have low values for diffusing capacity, their lung volumes and expiratory flow rates may remain normal [33-35]. Patients with the hepatopulmonary syndrome may manifest on a chest radiograph the abnormalities that generally occur in patients with cirrhosis, including decreased lung volumes (57%), pleural effusions (19.3%), increased interstitial markings (13.8%), and increased pulmonary vascular markings (3.7%) [29]. More specifically, however, the hepatopulmonary syndrome may be accompanied by characteristically increased basilar interstitial and pulmonary vascular markings. For example, Stanley and Woodgate [27] were the first to describe a mottled shadowing on chest radiographs associated with finger clubbing, hypoxemia, and cyanosis in 6% of 170 patients with chronic liver disease. Krowka and colleagues [33] observed bilateral interstitial markings in 8 of 11 patients with severe hypoxemia; these markings are thought to be due to intrapulmonary vascular dilatations [36]. Although these markings may be caused by intrapulmonary vascular dilatations, the possibility of other causes precludes diagnosis of the hepatopulmonary syndrome by chest radiograph alone. Krowka and colleagues [6] have proposed two radiographic patterns for the hepatopulmonary syndrome on the basis of pulmonary angiographic features in seven patients with this syndrome. Type 1, or minimal pattern, is characterized by a pattern of finely diffuse, spidery infiltrates, and type 2 is characterized by discrete, localized arteriovenous communications. As Krowka and colleagues have speculated, the type 1 pattern may be associated with severe hypoxemia, orthodeoxia, and a good oxygenation response to 100% inspired oxygen, and the type 2 pattern may respond poorly to supplemental oxygen. Additionally, the type 1 minimal pattern may evolve into a type 1 advanced pattern, which Krowka and colleagues [6] describe as having a diffuse spongy or blotchy angiographic appearance and which may be less responsive to 100% oxygen. Although these patterns are appealing, their description is based on only a few patients with the hepatopulmonary syndrome, and further study is needed before their significance in terms of severity, prognosis, or the prospect of reversibility can be confirmed. Hypoxemia associated with the Hepatopulmonary Syndrome Impaired arterial oxygenation is a hallmark of the hepatopulmonary syndrome. Mild hypoxemia is a frequent feature of chronic liver disease; it occurs in approximately one third of all patients [13, 17, 37, 38] and is multifactorial. In contrast, severe hypoxemia (Pao2 < 60 mm Hg) is less common with cirrhosis alone and is unusual without associated cardiopulmonary disease. In the absence of independent lung disease (obstructive or restrictive), severe hypoxemia in the setting of liver disease suggests the possibility of the hepatopulm

α1-antitrypsin deficiency

Summary α1-antitrypsin deficiency is a genetic disorder that affects about one in 2000–5000 individuals. It is clinically characterised by liver disease and early-onset emphysema. Although α1 antitrypsin is mainly produced in the liver, its main function is to protect the lung against proteolytic damage from neutrophil elastase. The most frequent mutation that causes severe α1-antitrypsin deficiency arises in the SERPINA 1 gene and gives rise to the Z allele. This mutation reduces concentrations in serum of α1 antitrypsin by retaining polymerised molecules within hepatocytes: an amount below the serum protective threshold of 11 μmol/L increases risk for emphysema. In addition to the usual treatments for emphysema, infusion of purified α1 antitrypsin from pooled human plasma represents a specific treatment and raises the concentrations in serum and epithelial-lining fluid above the protective threshold. Evidence suggests that this approach is safe, slows the decline of lung function, could reduce infection rates, and might enhance survival. However, uncertainty about the cost-effectiveness of this expensive treatment remains.

A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations: A Randomized, Controlled Trial

BACKGROUND Improving a patients ability to self-monitor and manage changes in chronic obstructive pulmonary disease (COPD) symptoms may improve outcomes. OBJECTIVE To determine the efficacy of a comprehensive care management program (CCMP) in reducing the risk for COPD hospitalization. DESIGN A randomized, controlled trial comparing CCMP with guideline-based usual care. (ClinicalTrials.gov registration number: NCT00395083) SETTING: 20 Veterans Affairs hospital-based outpatient clinics. PARTICIPANTS Patients hospitalized for COPD in the past year. INTERVENTION The CCMP included COPD education during 4 individual sessions and 1 group session, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. Patients in both the intervention and usual care groups received a COPD informational booklet; their primary care providers received a copy of COPD guidelines and were advised to manage their patients according to these guidelines. Patients were randomly assigned, stratifying by site based on random, permuted blocks of variable size. MEASUREMENTS The primary outcome was time to first COPD hospitalization. Staff blinded to study group performed telephone-based assessment of COPD exacerbations and hospitalizations, and all hospitalizations were blindly adjudicated. Secondary outcomes included non-COPD health care use, all-cause mortality, health-related quality of life, patient satisfaction, disease knowledge, and self-efficacy. RESULTS Of the eligible patients, 209 were randomly assigned to the intervention group and 217 to the usual care group. Citing serious safety concerns, the data monitoring committee terminated the intervention before the trials planned completion after 426 (44%) of the planned total of 960 patients were enrolled. Mean follow-up was 250 days. When the study was stopped, the 1-year cumulative incidence of COPD-related hospitalization was 27% in the intervention group and 24% in the usual care group (hazard ratio, 1.13 [95% CI, 0.70 to 1.80]; P= 0.62). There were 28 deaths from all causes in the intervention group versus 10 in the usual care group (hazard ratio, 3.00 [CI, 1.46 to 6.17]; P= 0.003). Cause could be assigned in 27 (71%) deaths. Deaths due to COPD accounted for the largest difference: 10 in the intervention group versus 3 in the usual care group (hazard ratio, 3.60 [CI, 0.99 to 13.08]; P= 0.053). LIMITATIONS Available data could not fully explain the excess mortality in the intervention group. Ability to assess the quality of the educational sessions provided by the case managers was limited. CONCLUSION A CCMP in patients with severe COPD had not decreased COPD-related hospitalizations when the trial was stopped prematurely. The CCMP was associated with unanticipated excess mortality, results that differ markedly from similar previous trials. A data monitoring committee should be considered in the design of clinical trials involving behavioral interventions.

Comorbidities, Patient Knowledge, and Disease Management in a National Sample of Patients with COPD

OBJECTIVE Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States but is often undertreated. COPD often overlaps with other conditions such as hypertension and osteoporosis, which are less morbid but may be treated more aggressively. We evaluated the prevalence of these comorbid conditions and compared testing, patient knowledge, and management in a national sample of patients with COPD. METHODS A survey was administered by telephone in 2006 to 1003 patients with COPD to evaluate the prevalence of comorbid conditions, diagnostic testing, knowledge, and management using standardized instruments. The completion rate was 87%. RESULTS Among 1003 patients with COPD, 61% reported moderate or severe dyspnea and 41% reported a prior hospitalization for COPD. The most prevalent comorbid diagnoses were hypertension (55%), hypercholesterolemia (52%), depression (37%), cataracts (31%), and osteoporosis (28%). Only 10% of respondents knew their forced expiratory volume in 1 second (95% confidence interval [CI], 8-12) compared with 79% who knew their blood pressure (95% CI, 76-83). Seventy-two percent (95% CI, 69-75) reported taking any medication for COPD, usually a short-acting bronchodilator, whereas 87% (95% CI, 84-90) of patients with COPD and hypertension were taking an antihypertensive medication and 72% (95% CI, 68-75) of patients with COPD and hypercholesterolemia were taking a statin. CONCLUSION Although most patients with COPD in this national sample were symptomatic and many had been hospitalized for COPD, COPD self-knowledge was low and COPD was undertreated compared with generally asymptomatic, less morbid conditions such as hypertension.

ROLE OF BRONCHOSCOPY IN MASSIVE HEMOPTYSIS

Massive hemoptysis accounts for a minority of all patients with hemoptysis but poses a major challenge for the acute and long-term treatment. Massive hemoptysis can lead to asphyxiation and airway obstruction, shock, and exsanguination. Bronchoscopy plays an integral part in managing massive hemoptysis in diagnosis and treatment (Table 5). Specifically, bronchoscopy allows lateralization and more specific localization of bleeding that is critically important for effective management. Furthermore, acute control of bleeding can sometimes be achieved with instruments and catheters placed through the bronchoscope or by agents instilled into the airways through the bronchoscope.

Oxygen therapy for patients with COPD: Current evidence and the long-term oxygen treatment trial

Long-term use of supplemental oxygen improves survival in patients with COPD and severe resting hypoxemia. However, the role of oxygen in symptomatic patients with COPD and more moderate hypoxemia at rest and desaturation with activity is unclear. The few long-term reports of supplemental oxygen in this group have been of small size and insufficient to demonstrate a survival benefit. Short-term trials have suggested beneficial effects other than survival in patients with COPD and moderate hypoxemia at rest. In addition, supplemental oxygen appeared to improve exercise performance in small short-term investigations of patients with COPD and moderate hypoxemia at rest and desaturation with exercise, but long-term trials evaluating patient-reported outcomes are lacking. This article reviews the evidence for long-term use of supplemental oxygen therapy and provides a rationale for the National Heart, Lung, and Blood Institute Long-term Oxygen Treatment Trial. The trial plans to enroll subjects with COPD with moderate hypoxemia at rest or desaturation with exercise and compare tailored oxygen therapy to no oxygen therapy.

Developing Physician-Leaders: A Call to Action

The many challenges in health care today create a special need for great leadership. However, traditional criteria for physicians’ advancement to leadership positions often regard academic and/or clinical accomplishments rather than the distinctive competencies needed to lead. Furthermore, physicians’ training can handicap their developing leadership skills. In this context, an emerging trend is for health-care institutions to offer physician-leadership programs. This paper reviews the rationale for developing physician-leaders. Factors that underscore this need include: (1) physicians may lack inclinations to collaborate and to follow, (2) health-care organizations pose challenging environments in which to lead (e.g., because of silo-based structures, etc.), (3) traditional criteria for advancement in medicine regard clinical and/or academic skills rather than leadership competencies, and (4) little attention is currently given to training physicians regarding leadership competencies. Definition of these competencies of ideal physician-leaders will inform the curricula and format of emerging physician leadership development programs.BackgroundThe many challenges in health care today create a special need for great leadership. However, traditional criteria for physicians’ advancement to leadership positions often regard academic and/or clinical accomplishments rather than the distinctive competencies needed to lead. Furthermore, physicians’ training can handicap their developing leadership skills. In this context, an emerging trend is for health-care institutions to offer physician-leadership programs.Methods and ResultsThis paper reviews the rationale for developing physician-leaders. Factors that underscore this need include: (1) physicians may lack inclinations to collaborate and to follow, (2) health-care organizations pose challenging environments in which to lead (e.g., because of silo-based structures, etc.), (3) traditional criteria for advancement in medicine regard clinical and/or academic skills rather than leadership competencies, and (4) little attention is currently given to training physicians regarding leadership competencies.ConclusionDefinition of these competencies of ideal physician-leaders will inform the curricula and format of emerging physician leadership development programs.

An official American Thoracic Society/European Respiratory Society statement: research questions in COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes. ATS/ERS statement highlighting research areas that will have the greatest impact on patient-centred outcomes in COPD http://ow.ly/LXW2J

Augmentation Therapy With α1-Antitrypsin: Patterns of Use and Adverse Events

Study objectives: To describe patterns of prescribing augmentation therapy, and types and rates of adverse events in the National Heart, Lung, and Blood Institute Registry for Individuals with Severe Deficiency of Alpha 1 -Antitrypsin. Design: Observational cohort study with follow-up visits every 6 to 12 months for up to 7 years. Measurements: The rate and dosing frequency with which Registry participants were prescribed to receive augmentation therapy by their managing physicians, and the type and frequency of adverse events, classified in two ways: severity of self-reported symptoms, and actions taken as a consequence of the symptom. Results: Over the course of Registry follow-up, 66% (n = 747) of the participants received augmentation therapy at some time. In keeping with recommendations made in the 1989 American Thoracic Society (ATS) statement, 75% of participants with airflow obstruction at first visit (defined as FEV 1 1 ≥ 80% predicted (14%) also received augmentation therapy. Among those with COPD for whom augmentation therapy was not prescribed, financial constraints were the reported cause in 30%. Observed patterns also varied from approved practice, in that dosing frequencies other than the US Food and Drug Administration-approved, once-weekly regimen were frequently prescribed. The overall rate of reported adverse events was 0.02 per patient-month, with 83% of participants reporting no events. This overall rate was composed of 16% considered mild events, 76% moderate events, and 9% severe events. Conclusions: We conclude that augmentation therapy was generally well tolerated and, consistent with ATS guidelines, physicians generally did not prescribe augmentation therapy for subjects with FEV 1 ≥ 80% predicted. However, the large percentage of subjects with FEV 1

THE HEPATOPULMONARY SYNDROME: Effect of Liver Transplantation

The role of liver transplantation as a treatment for the hepatopulmonary syndrome (HPS) has had an evolving and controversial history. Although early experience was disappointing, more recent experience has documented resolution of HPS-associated hypoxemia after liver transplantation. This article reviews the history of liver transplantation for patients with the hepatopulmonary syndrome. In addition, we discuss the clinical features that have been considered to predict successful reversibility and the time frame over which reversal occurs. Despite this evolution of thought, many basic questions still remain.