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Medical Management of Primary Pulmonary Hypertension

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Medical Management of Primary Pulmonary Hypertension Eur Respir J, 1996, 9, 2401–2409 Copyright ERS Journals Ltd 1996 DOI: 10.1183/09031936.96.09112401 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 SERIES 'UPDATE ON PULMONARY HYPERTENSION' Edited by E. Weitzenblum and T. Higenbottam Medical management of primary pulmonary hypertension M.P. Kneussl*, I.M. Lang**, †F.P. Brenot+ Medical management of primary pulmonary hypertension. M.P. Kneussl, I.M. Lang, Depts of *Internal Medicine IV (Pulmonary †F.P. Brenot. ERS Journals Ltd 1996. Medicine), and **Internal Medicine II ABSTRACT: Primary pulmonary hypertension (PPH) is a poorly understood, pro- (Cardiology), Pulmonary Hypertension gressive disease that is characterized by elevation of pulmonary artery pressure Clinic of the Vienna General Hospital, University of Vienna, Vienna, Austria. and vascular resistance, leading to right ventricular failure and death within 2–3 +Service de Pneumologie et Reanimation, yrs after diagnosis. Hopital Antoine Beclere, University of Based upon the concept that vasoconstriction and thrombotic occlusion of resis- Paris School of Medicine, Clamart, France. tance vessels precipitate this process, vasodilator therapy and anticoagulation have Correspondence: M.P. Kneussl become the main strategies for improving survival in these patients. Whereas, a Klinische Abteilung für Pulmologie few years ago, medical therapy of primary pulmonary hypertension was perceived Universitätsklinik für Innere Medizin IV as a bridging therapy to lung or heart lung transplantation, modes of therapy are Allgemeines Krankenhaus der Stadt Wien being clinically tested at this time to offer an alternative to the surgical treatment Wühringer Gürtel 18-20 of this disease. However, no selective pulmonary vasodilator is yet available. A-1090 Vienna Therefore, and because of the potential hazards of vasodilator treatment, stan- Austria dardized haemodynamic testing is performed prior to initiation of vasodilator treat- Keywords: Anticoagulation, calcium chan- ment. nel blockers, nitric oxide, primary pulmo- In this update, the currently available compounds both for haemodynamic test- nary hypertension, prostacyclin, standardized ing and chronic therapy, their mode of action, method of administration and effi- haemodynamic testing cacy are reviewed. Received: June 1 1996 Eur Respir J., 1996, 9, 2401–2409. Accepted after revision July 24 1996 Primary pulmonary hypertension (PPH) is an uncom- Table 1. – Diagnostic entities resulting in pulmonary mon disease characterized by increased pulmonary artery hypertension Ppa pressure ( ) and pulmonary vascular resistance (PVR), Primary (1% of autopsy and catheter cases) including spe- without an obvious cause [1–5]. A careful diagnostic cial forms such as: evaluation, based on the exclusion of all other causes Atrial septal defect (10%) of pulmonary hypertension (table 1), is a requirement AIDS (0.5%) [6, 7] for appropriate management of this disease and alter- Exogenous substance and drug-induced (e.g. toxic oil, amino- ation of its otherwise progressive course, which ends rex fumarate, fenfluramine) [8–11] with right ventricular failure (RVF) and death of the Pulmonary capillary haemangiomatosis [12] patient [4]. Veno-occlusive disease [13] Platelet delta storage disease [14] Familial PPH (7–10% of PPH, autosomal dominant with in- Haemodynamic testing complete penetrance) [15] Secondary: Based on the concept that vasoconstriction contributes to heart disease with elevated left atrial and end-diastolic left to the pulmonary hypertension of most patients with ventricular pressures (valvular, congenital [16, 17]) PPH at some stage in the course of their disease, vasodila- to systemic connective tissue diseases (e.g. CREST syndrome tors offer a logical approach to therapy. Although little [18, 19]) is known about the pathogeny of PPH and data now to persistent foetal circulation [20] to parenchymal lung disease (e.g. interstitial, obstructive, para- exist indicating that the elevation of Ppa is a common sitic, granulomatous, kyphoscoliotic [21]) endpoint of a variety of disorders, it appears from a to pulmonary artery abnormalities (e.g. vasculitis, stenoses) number of studies that the acute response to vasodila- to alveolar hypoventilation syndromes (e.g. sleep apnoea syn- tors gives an indication of the underlying pulmonary drome [22]) vascular morphology, and, thus, a clue to severity and to haemoglobinopathias [23] (e.g. sickle cell disease) prognosis of the disease. to chronic liver disease [24] Morphometric studies have suggested that pulmonary to pulmonary thromboemboli (CTEPH, ∼0.1% of survived vascular reactivity to vasodilators is lost as concentric pulmonary emboli) [25] medial hypertrophy gives way to intimal fibrosis and AIDS: acquired immune deficiency syndrome; CREST: calci- plexiform lesions. Therefore, various strategies have nosis, Raynaud's phenomenon, oesophageal dysfunction, scle- been developed for the evaluation of acute pulmonary rodactyly and telangiectasia; CTEPH: chronic thromboembolic vascular reactivity [26, 27]. A number of agents have pulmonary hypertension. 2402 M.P. KNEUSSL ET AL. Table 2. – Haemodynamic testing Table 3. – Definition of response to pharmacological testing a) Current screening vasodilator agents to evaluate vasodila- tor reserve Responders: reduction of PVR >20% and reduction of mean Ppa >20% Nitric oxide (NO) [28] Nonresponders: no significant change of PVR Epoprostenol sodium (prostacyclin (PGI2)) [29–31] Unfavourable responders: symptomatic systemic hypotension Adenosine [32] with a reduction >20% of mean systemic blood pressure with Acetylcholine [31, 33, 34] no change or reduction of CI Resistance responders: reduction of PVR >20% without sig- b) Flow chart of haemodynamic testing nificant reduction of mean Ppa (resistance responders are being evaluated and treated like responders) Baseline haemodynamic testing PVR: pulmonary vascular resistance; Ppa: pulmonary artery 10 min NO breathing (10 ppm) pressure; CI: cardiac index. "fixed" structural pulmonary vascular changes; 2) prog- Haemodynamic testing nosis at the time of diagnosis; and 3) the haemodyna- mic safety of chronic vasodilator therapy. 10 min NO breathing (20 ppm) Following baseline haemodynamic measurements, the patients breathe 10 parts per million (ppm) NO via a Haemodynamic testing continuous positive airway mask (CPAP) mask, that they have already been wearing during the initial mea- ∼30% responders ∼70% nonresponders surements. After 10 min, a complete haemodynamic Calcium antagonist testing Anticoagulation, PGI2, HLT measurement is performed. Another 10 min period of Long-term Ca++ antagonist 20 ppm NO breathing follows, after which another complete haemodynamic measurement is performed. In Hourly haemodynamic Hourly haemodynamic "responders" (approximately 30% of adult and 60–70% testing testing of paediatric patients (table 3)) haemodynamic testing is continued with an oral dose of calcium antagonist PGI2: prostaglandin I2 (prostacyclin); HLT: heart lung trans- plantation. (e.g. 10 mg of nifedipine), and measurements are taken every hour thereafter, with administration of another been successfully employed for acute testing (table 2a). oral dose after each measurement, until the optimal At the present time, no selective intravenous or oral response is reached in the absence of side-effects. pulmonary vasodilator exists. The greatest and most "Nonresponders" (table 3) are candidates for contin- reproducible vasodilator effect is achieved with inhaled uous intravenous prostacyclin therapy as a bridging ther- nitric oxide (NO) and prostacyclin (table 2a), two agents apy until transplantation, or as primary therapy. In that also offer the advantage of a very short plasma instances when prostacyclin therapy cannot be admin- half-life. However, several groups have reported a hig- istered for other reasons, standard therapy is initiated her incidence of adverse haemodynamic response in (see below). prostacyclin testing of patients with severe PPH com- pared with NO testing (personal communications). Selected vasodilators used for haemodynamic testing Current practice of haemodynamic testing Nitric oxide. NO has been identified as the powerful endothelium-derived relaxing factor (EDRF) [35]. Iso- The flow chart in table 2b depicts the practice of lated pulmonary arteries of humans relax with NO, but vasodilator testing. Pharmacological testing at our in- investigation in vitro is difficult because the effects of stitution is carried out in the intensive care unit for a NO, e.g. binding to haemoglobin, occur within fractions number of reasons: of a second. NO reacts with oxyhaemoglobin to form 1. Haemodynamic monitoring is carried out using a methaemoglobin, nitrites and nitrates. Because NO is freshly implanted central venous line and involves mea- inactivated by haemoglobin, its vasorelaxant effects are surement of cardiac output, pulmonary pressures, includ- restricted to the abluminal surface of the endothelium. ing capillary wedge pressure, central venous saturation However, if NO is inhaled, this obstacle can be over- and peripheral arterial saturation. come. NO reaches the abluminal pulmonary arterioles, 2. Prior to the measurements, the patient is rested for which are closely associated with bronchioli and alveoli 2 h in a quiet environment. and are involved in rapid transfer across the alveolo- 3. Because of the lack of the normal gradient for myo- capillary barrier, in a similar way to carbon monoxide. cardial perfusion between the
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