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Introduction*: Diagnosis and Management of Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Lewis J. Rubin, MD, FCCP
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*From the Division of Pulmonary and Critical Care Medicine University of California, San Diego School of Medicine, La Jolla, CA.

Correspondence to: Lewis J. Rubin, MD, FCCP, Professor of Pulmonary and Critical Care Medicine, UCSD Medical Center/Thornton, 9300 Campus Point Dr/MC 7372, La Jolla, CA 92037-1300; e-mail: ljrubin@ucsd.edu



Chest. 2004;126(1_suppl):7S-10S. doi:10.1378/chest.126.1_suppl.7S
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Interposed between the two sides of the heart and embedded within the matrix of the lung, the pulmonary circulation plays a pivotal role in the cardiopulmonary functions of gas exchange and oxygen transport. Its central position, however, renders the pulmonary circulation vulnerable to injury as a result of developmental or acquired disorders affecting the heart or lungs, as well as conditions that may also affect the systemic vasculature. Accordingly, pulmonary vascular disease is not the exclusive domain of any medical discipline: specialists in respiratory medicine, cardiology, rheumatology, infectious diseases, hematology, and pediatrics, among others, must all provide care for patients with these conditions. The most serious and potentially devastating chronic disorder of the pulmonary circulation is pulmonary hypertension (PH), a hemodynamic abnormality of diverse etiology and pathogenesis that challenges physicians with both its diagnosis and treatment. This document, developed by a multidisciplinary panel of experts, is intended to provide physicians with comprehensive, evidence-based guidelines for the approach to patients with pulmonary arterial hypertension (PAH).

Initially described by Romberg1as “sclerosis of the pulmonary arteries” > 100 years ago, idiopathic PAH (IPAH) has been the subject of great interest, particularly over the past decade, and has recently undergone several name changes. The term primary pulmonary hypertension (PPH) was coined by Dresdale et al2 50 years ago to characterize a condition in which hypertensive vasculopathy existed exclusively in the pulmonary circulation without a demonstrable cause. Observing a reduction in pulmonary arterial pressure in response to IV-administered acetylcholine, Wood3postulated that a “vasoconstrictive factor” may be responsible for its pathogenesis; however, clinical experience with vasodilator therapy proved largely disappointing, and the landmark pathologic studies by Wagenvoort and Wagenvoort4 suggested that more extensive vascular injury and remodeling were fundamental components of the disease process.

The early focus on the pathologic features of IPAH was reflected in the report by the first international working group on PPH5 that met in Geneva in 1973 and was supported by the World Health Organization. The classification of disease developed by this expert committee was based primarily on histopathologic features, and distinguished arteriopathy from both pulmonary venous hypertension and thromboembolic disease.

The subsequent 20 years witnessed several seminal events in the story of this disease: an epidemic associated with the use of aminorex, a diet-suppressant medication available in several Western European countries6; the use of a variety of vasodilator agents and heart-lung transplantation to treat the disease7; and the recognition that other conditions, including connective tissue disease, liver disease with portal hypertension, and HIV infection, to name a few, may be associated with pulmonary vascular disease that shared pathologic and clinical features with PPH. These conditions were commonly grouped as secondary pulmonary hypertension, differentiating them from the idiopathic, or primary, forms.

Recognizing the emerging clinical interest in PPH, the American College of Chest Physicians (ACCP) convened a multidisciplinary panel in 1993 to develop consensus guidelines for the diagnosis and treatment of PPH.8 Our task was relatively easy back then, since the published literature was fairly limited. Accordingly, our guidelines were largely driven by expert opinion.

Much has happened over the past 10 years, prompting the ACCP to commission a new working group and charging it with a more ambitious task: To create a more detailed, extensive, evidence-based guideline that addresses PAH more broadly and comprehensively. The recent advances have been quite remarkable, ranging from the identification of a gene responsible for inherited forms of the disease and the application of molecular biological techniques to explore its pathogenesis, to the development and commercialization of medical therapies and the refinement of surgical techniques for lung transplantation and pulmonary thromboendarterectomy.

The quickening pace of advancement resulted in two international meetings of experts during the past 5 years, the first since the original working group meeting in Geneva in 1973. In the first of these recent meetings, held in Evian, France in 1998, a revised classification for PH was adopted (Table 1 ). This classification separated conditions that directly affect the pulmonary arterial tree (PAH) from disorders that either predominantly affect the venous circulation or conditions that affect the pulmonary circulation by altering respiratory structure or function. Thus, while the term secondary pulmonary hypertension was abandoned, PPH remained the term of choice to define familial or sporadic disease of undetermined cause. In addition, the Evian meeting emphasized the role of functional assessment of patients with PH, and a functional assessment classification, modified from the New York Heart Association functional classification, was also adopted (Table 2 ). The impact of these classifications is perhaps best reflected by the regulatory approval of several new drugs for PAH, recognizing the common features shared by patients with these disease processes.

Shortcomings in the Evian classification, however, became clear with its application in the clinical setting, coupled with further developments in the elucidation of the pathogenesis of PH. A revision of this classification was proposed at the third World Conference on Pulmonary Hypertension, held in Venice in 2003 (Table 3 ): PPH has been replaced with IPAH or, when supported by genetic investigation, familial PAH (FPAH). The experts believed that these terms more accurately and appropriately describe our contemporary understanding and clinical perspective. This ACCP committee agrees with this view; accordingly, our document uses the terms IPAH and FPAH in lieu of PPH, and applies the newly modified Venice classification to other forms of pulmonary vascular disease that are addressed in this document. We use the term pulmonary hypertension to describe the hemodynamic state that is shared by many conditions. While there is no uniformly accepted definition for PAH, most specialists in this field accept the hemodynamic criteria used in the National Institutes of Health Registry on Primary Pulmonary Hypertension9: a mean pulmonary artery pressure > 25 mm Hg with a pulmonary capillary or left atrial pressure < 15 mm Hg. These criteria have also been used in most of the therapeutic clinical trials discussed in these Guidelines, which lends additional support for their general acceptance. By adopting the Venice Symposium nomenclature and the National Institutes of Health Registry hemodynamic definition of PAH, we hope to encourage their wider use.

The approach to diagnosis and treatment of PAH has undergone a remarkable and successful evolution since the last ACCP document. It is my hope that the hard work by this committee in preparing this Guideline will translate into improved care of patients with PAH, and will promote further advances through increased awareness by physicians, third-party payors, and policy makers. While the committee strove to base their recommendations on the medical and scientific evidence whenever possible, some of the recommendations contained within the main body of this report are based on expert opinion when the evidence was not sufficiently complete or consistent for the recommendations to stand on the evidence alone.

I am indebted to my colleagues on this committee, who devoted many hours of work individually and as a working group, for their commitment to this project. I am also indebted to the leadership of the ACCP, both for their recognition of the importance of this effort and for their support, and to the ACCP staff directed by Sandy Lewis, for their masterful coordination and orchestration of this endeavor.

A final note: Dr. James Theodore, Professor of Medicine at Stanford University who served as a panel member of the initial ACCP Consensus Panel, died a few months before this project was completed. Jim Theodore was a gifted clinician, teacher, and investigator who pioneered the development of lung transplantation for pulmonary vascular and parenchymal diseases. His contributions influenced many of us, and touched the lives of many patients. It is fitting, therefore, that we dedicate this ACCP Guideline report to his memory.

Abbreviations: ACCP = American College of Chest Physicians; IPAH = idiopathic pulmonary arterial hypertension; FPAH = familial pulmonary arterial hypertension; PAH =pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PH = pulmonary hypertension

For financial disclosure information see page 1S.

Table Graphic Jump Location
Table 1. Evian Nomenclature and Classification of PH (1998) Diagnostic Classification

Table Graphic Jump Location
Table 2. Functional Assessment
* 

From Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis of the Heart and Great Blood Vessels. 6th ed. New York, NY: New York Heart Association/Little Brown, 1964.

Table Graphic Jump Location
Table 3. Revised Nomenclature and Classification of PH (2003)

References

Romberg, E (1891) Ueber sklerose der lungen arterie.Dsch Arch Klin Med48,197-206
 
Dresdale, DT, Schultz, M, Michtom, RJ Primary pulmonary hypertension: I. Clinical and hemodynamic study.Am J Med1951;11,686-705
 
Wood, P Pulmonary hypertension with special reference to the vasoconstrictive factor.Br Heart J1958;21,557-570
 
Wagenvoort, CA, Wagenvoort, H Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 classically diagnosed cases.Circulation1970;42,1163-1184
 
Hatano, S Strasser, T eds. Primary pulmonary hypertension. 1975; World Health Organization. Geneva, Switzerland:.
 
Gurtner, HP Pulmonary hypertension, “plexogenic pulmonary arteriopathy” and the appetite depressant drug aminorex: post or propter?Bull Eur Pathophysiol Respir1979;15,897-923
 
Rich, S Primary pulmonary hypertension.Prog Cardiovasc Dis1988;31,205-238
 
Rubin, LJ, Barst, RJ, Kaiser, LR, et al ACCP consensus statement: primary pulmonary hypertension.Chest1993;104,236-250
 
Rich, S, Dantzker, DR, Ayres, SM, et al Primary pulmonary hypertension: a national prospective study.Ann Intern Med1987;107,216-223
 

Figures

Tables

Table Graphic Jump Location
Table 1. Evian Nomenclature and Classification of PH (1998) Diagnostic Classification
Table Graphic Jump Location
Table 2. Functional Assessment
* 

From Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis of the Heart and Great Blood Vessels. 6th ed. New York, NY: New York Heart Association/Little Brown, 1964.

Table Graphic Jump Location
Table 3. Revised Nomenclature and Classification of PH (2003)

References

Romberg, E (1891) Ueber sklerose der lungen arterie.Dsch Arch Klin Med48,197-206
 
Dresdale, DT, Schultz, M, Michtom, RJ Primary pulmonary hypertension: I. Clinical and hemodynamic study.Am J Med1951;11,686-705
 
Wood, P Pulmonary hypertension with special reference to the vasoconstrictive factor.Br Heart J1958;21,557-570
 
Wagenvoort, CA, Wagenvoort, H Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 classically diagnosed cases.Circulation1970;42,1163-1184
 
Hatano, S Strasser, T eds. Primary pulmonary hypertension. 1975; World Health Organization. Geneva, Switzerland:.
 
Gurtner, HP Pulmonary hypertension, “plexogenic pulmonary arteriopathy” and the appetite depressant drug aminorex: post or propter?Bull Eur Pathophysiol Respir1979;15,897-923
 
Rich, S Primary pulmonary hypertension.Prog Cardiovasc Dis1988;31,205-238
 
Rubin, LJ, Barst, RJ, Kaiser, LR, et al ACCP consensus statement: primary pulmonary hypertension.Chest1993;104,236-250
 
Rich, S, Dantzker, DR, Ayres, SM, et al Primary pulmonary hypertension: a national prospective study.Ann Intern Med1987;107,216-223
 
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