Pulmonary Hypertension

Key Clinical Questions

How does the classification system for pulmonary hypertension (PH) aid in understanding the pathophysiology, diagnostic evaluation, and treatments for this condition?
What signs and symptoms might increase the suspicion for elevated pulmonary arterial pressures?
What is a rational diagnostic approach to suspected PH?
What is the meaning of an elevated pulmonary pressure determined by echocardiography?
When should right heart catheterization be considered in the evaluation of suspected PH?
What are the key steps in the evaluation and management of acute right heart failure secondary to elevated pulmonary arterial pressure?
What are the common side effects of the medications used to treat PH?

Introduction

Pulmonary hypertension (PH) is simply defined as a mean pulmonary arterial pressure > 25 mm Hg at rest. However, this deceptively simple definition encompasses a broad spectrum of clinical entities. In this chapter, we will present an evidence-based approach to the care of the patient with elevated pulmonary arterial pressures. Table 244-1 lists landmark studies supporting the approach presented in this chapter.

Table 244-1 Evidence-Based Key References: Pulmonary Hypertension

Topic	Supporting Literature
Epidemiology	Humbert M, Sitbon O, Chaaouat A, et al. Pulmonary hypertension in France: results from a national registry. Am J Resp Crit Care Med. 2006;173:1023–1030.
	Lam CSP, Roger VL, Rodeheffer RJ, et al. Pulmonary hypertension in patients with preserved ejection fraction: a community based study. J Am Coll Card. 2009;53:1119–1126.
	Badesch DB, Raskob G, Elliott G, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry. Chest. 2010;137(2):376–387.
Classification and pathophysiology	Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351:1655–1665.
	Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–S54.
	Overbeek MJ, Vonk MC, Boonstra A, et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J. 2009;34(2):371–379.
Diagnosis: examination, laboratory	Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med. 1987;107:216–223.
	Dahlstrom U. Can natriuretic peptides be used for the diagnosis of diastolic heart failure? Eur J Heart Fail. 2004;6:281–287.
	Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865–870.
Diagnosis: echocardiography, imaging	Aurigemma GP, Zile MR, Gaasch WH. Lack of relationship between Doppler indices of diastolic function and left ventricular pressure transients in patients with definite diastolic heart failure. Am Heart J. 2004;148:E12.
	Fisher MR, Forfia PR, Chamera E, et al. Accuracy of doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179:615–621.
	Chetty KG, Brown SE, Light RW. Identification of pulmonary hypertension in chronic obstructive pulmonary disease from routine chest radiographs. Am Rev Respir Dis. 1982;126:338–341.
	Tunariu N, Gibbs SJ, Win Z, et al. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med. 2007;48:680–684.
Treatment	Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296–302.
	Jais X, D’Armini AM, Jansa P, et al. Bosentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFit. J Am Coll Cardiol. 2008;52:2127–2134.
	Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157.
Complications	Belenkie I, Dani R, Smith ER, Tyberg JV. Effects of volume loading during experimental acute pulmonary embolism. Circulation. 1989;80:178–188.
	Kallen AJ, Lederman E, Balaji A, et al. Incidence of central line infection in pulmonary hypertension patients receiving prostanoids. Infect Control Hosp Epidemiol. 2008;29:332–339.

Disease Classification, Epidemiology, and Pathophysiology

The first step in understanding the myriad presentations of pulmonary hypertension is to comprehend the pathophysiologic differences that divide the major groups of this disorder. These groups, as defined by the 2008 Fourth World Symposium on Pulmonary Arterial Hypertension, are shown in Table 244-2. Group I disease is defined as pulmonary arterial hypertension (PAH). PAH is characterized histologically by plexiform lesions occluding the pulmonary vasculature, in situ thrombosis, intimal proliferation and medial thickness, all resulting in decreased pulmonary vascular surface area, increased pulmonary vascular resistance, and functional disruptions of normal endothelial homeostasis. These perturbations are most notable in the prostacyclin, endothelin, nitric oxide, and serotonergic pathways regulating endothelial function. It is these pathways that are the targets of current PAH therapy. Group I PAH is most commonly associated with other conditions, including collagen vascular disease (most notably, systemic sclerosis), portal hypertension and HIV infection. Idiopathic pulmonary arterial hypertension (IPAH, formerly, “primary pulmonary hypertension”) is rare, but life-threatening, with a prevalence of approximately 15 cases/million, an incidence of 2.4 cases/million/year, and a median survival of only 2.8 years without treatment. Group I disease also includes the distinct entity of pulmonary venoocculsive disease (PVOD), which is generally less amenable to vasodilator treatment. Recent evidence suggests that PAH in systemic sclerosis may be more similar to PVOD than IPAH, suggesting a mechanism for the poor response of SSc-associated PAH to current treatment.

Table 244-2 2008 Fourth World Symposium on Pulmonary Arterial Hypertension: Classification

Group I. Pulmonary arterial hypertension
- Idiopathic (formerly “primary pulmonary hypertension”)
- Heritable
- Drug or toxin-induced (eg, anorexigens, rapeseed oil, l-tryptophan, methamphetamine, and cocaine)
- Associated conditions: collagen vascular disease, congenital heart disease, portal hypertension, HIV infection, schistosomiasis, chronic hemolytic anemias
- Associated with significant venous or capillary involvement
  - Pulmonary venoocclusive disease
  - Pulmonary-capillary hemangiomatosis
Group II. Pulmonary venous hypertension
- Left-sided systolic, diastolic, or valvular heart disease
Group III. Pulmonary hypertension associated with lung disease and/or chronic hypoxemia
- Chronic obstructive pulmonary disease
- Interstitial lung disease
- Mixed restrictive and obstructive lung diseases
- Sleep-disordered breathing
- Alveolar hypoventilation disorders
- Chronic exposure to high altitude
- Developmental abnormalities
Group IV. Chronic thromboembolic pulmonary hypertension
Group V. Pulmonary hypertension of unclear or multifactorial mechanisms
- Hematologic disorders: splenectomy, myeloproliferative disorders
- Systemic disorders: sarcoidosis, pulmonary Langerhans’ cell histiocytosis, lymphangiomatosis, vasculitis, neurofibromatosis
- Metabolic disorders: Gaucher’s, glycogen storage disease, thyroid disease
- Other: tumoral compression of pulmonary vessels, fibrosing mediastinitis, chronic hemodialysis.

Group II disease constitutes the most common cause of elevated pulmonary pressures: pulmonary venous hypertension. Pulmonary venous hypertension results from elevated left atrial pressures due to left ventricular systolic, diastolic (heart failure with preserved ejection fraction), or valvular disease. Due to the low sensitivity of traditional echocardiographic measures (eg, E/A ratio) for the diagnosis of left ventricular diastolic dysfunction, this disorder may be confused with IPAH in the absence of right heart catheterization showing an elevated pulmonary capillary occlusion pressure. Although treatment of underlying cardiac disease and diuresis are the mainstays of group II disease therapy, a small proportion of patients with long-standing pulmonary venous hypertension may develop physiology and histology consistent with group I disease; this is usually poorly responsive to traditional cardiac risk factor modification. Initial treatment of patients with pulmonary venous hypertension with pulmonary vasodilators may result in flash pulmonary edema from sudden reduction of pulmonary vascular resistance and acutely increased preload overwhelming the compromised left ventricle. This underscores the importance of right heart catheterization to correctly characterize the etiology of pulmonary hypertension prior to starting therapy.

Group III disease describes pulmonary hypertension due to chronic lung disease and hypoxic vasoconstriction. This group most commonly presents with known pulmonary diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), obstructive sleep apnea (OSA), and/or obesity hypoventilation syndromes. Treatment of the underlying lung disease and use of supplemental oxygen are the foundations of care for pulmonary hypertension associated with chronic hypoxemia. Because pulmonary vasodilators may elicit significant ventilation/perfusion mismatch and severe hypoxemia with in patients with underlying structural lung disease, these medications are currently investigational in this patient population.

Group IV disease is caused by embolic disease to the pulmonary circulation. Most commonly, the source of emboli are thrombi, generating chronic thromboembolic pulmonary hypertension (CTEPH). However, any source of emboli (tumor, parasite, foreign body) can generate group IV disease. Definitive treatment of group IV disease due to thrombotic pulmonary emboli involves pulmonary arterial thromboenderterectomy.

Group V disease is best described as a catch-all of miscellaneous causes of PH. These include diseases with multifactorial mechanisms (ie, hematologic disorders, metabolic disorders, sarcoidosis, etc) or disease states associated with external compression of pulmonary arteries, such as tumor, lymphadenopathy, or fibrosing mediastinitis (most commonly caused by radiation therapy for Hodgkin disease).

There may be overlap of disease classification in of any individual case of PH. Given the potential complications associated with improper use of pulmonary vasodilators in patients with group II–V disease, initiation of these agents (prostacyclins, phosphodiesterase inhibitors, endothelin receptor antagonists) should be restricted to specialists with experience in their use, only after a diagnostic group has been established for a particular patient.