Doppler echocardiographic assessment of the effects of inhaled long-acting β2-agonists on pulmonary artery pressure in COPD patients

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Abstract

Increase in pulmonary artery pressure (PAP), which is common in severe chronic obstructive pulmonary disease (COPD), is a predictor of mortality independent of airflow limitation. β-agonists might slightly attenuate this increase because they exert a vasodilating effect on pulmonary circulation when systematically administered. We have investigated the acute effects of salmeterol and formoterol on echocardiographic systolic pulmonary artery pressure (sPAP) in 20 patients with COPD and a sPAP greater than 20 mmHg at rest. Acute haemodynamic responses to inhaled formoterol or salmeterol were assessed in all patients, in a randomized, double-blind double-dummy fashion. On two consecutive days, patients received, in a randomized order, formoterol 12 μg via Turbuhaler plus placebo via Diskus or salmeterol 50 μg via Diskus plus placebo via Turbuhaler. Transthoracic Doppler echocardiography measurements of sPAP were made before and 15, 30, 60 and 180 min after bronchodilator inhalation. Lung function, pulse oximetry and heart rate were also monitored at the same times. Mean sPAP significantly (p<0.05) decreased in comparison with baseline at 15, 30, and 60 min post inhalation but returned towards control levels at 180 min after both salmeterol and formoterol. There was no correlation between the maximum increase in FEV1 and maximum decrease in sPAP either after inhalation of salmeterol (r2=0.071) or after that of formoterol (r2=0.0006). The increases in FEV1 in comparison with baseline were always significant (p<0.05) from 15 to 180 min post inhalation after either salmeterol or formoterol. Neither pulse oximetry nor heart rate changed in a significant manner (p>0.05). This study demonstrated that salmeterol and formoterol were equally beneficial for pulmonary haemodynamics in patients with COPD. A direct vasodilatation due to the activation of β-adrenoceptors that are present in pulmonary vessels is a likely mechanism of their action in inducing the decrease in sPAP.

Introduction

Elevated pulmonary artery pressure (PAP) is the main cardiovascular complication in severe chronic obstructive pulmonary disease (COPD). It is a predictor of mortality independent of airflow limitation [1], and the best independent predictor of hospitalization for acute exacerbation [2]. These findings suggest that patients with an abnormal pulmonary vascular bed might have fewer functional reserves to overcome the potential complications that occur during the evolution of the disease, hence needing hospital admissions more frequently [3].

Chronic hypoxic pulmonary vasoconstriction is generally assumed to be the cause of the increase in PAP in COPD [4], [5]. In patients with COPD, there is a negative correlation between PAP and oxygen saturation (SaO2) [6]. Chronic hypoxia leads to muscularization of a subset of arterioles in the lung, the so-called precapillary “resistance vessels,” which are particularly sensitive to the effects of hypoxia [7]. This structural alteration can explain why an increase in PAP following chronic hypoxia may occur even in the absence of vasoconstriction [7], although it progresses slowly, with an average annual raise of only 0.5 mmHg [4]. However, PAP can rise suddenly and markedly during episodes of acute respiratory failure [4]. This increase results mainly from vasoconstriction [7].

Many agents have been tried to reverse the elevated PAP, but consensus exists only on the use of oxygen therapy [3], although vasodilators may be useful in patients with acute exacerbation of COPD and cor pulmonale [3].

Although β-agonists generally produce trivial changes in PAP [3], some reports suggest that these agents decrease PAP when administered intravenously [8], [9], [10]. Unfortunately, these effects are frequently accompanied by worsening of arterial oxygenation, due to the inhibitory effect of β-agonists on hypoxic pulmonary vasoconstriction [11], [12]. Such a detrimental effect of these agents on gas exchange is not seen when they are administered by inhalation [12].

To our best knowledge, there has been no clinical study to address the effects of long-acting β2-agonists formoterol and salmeterol on PAP in COPD patients. Therefore, we have conducted a pilot trial to test the acute effects of salmeterol and formoterol on lung function and echocardiographic systolic pulmonary artery pressure (sPAP) in this type of patients. Previous studies have, in fact, demonstrated that sPAP can be determined non-invasively by Doppler echocardiography [13], [14], [15], [16], but apparently no study has investigated the effects of bronchodilators on this parameter using this technique.

Section snippets

Patients

This study was made up of 20 severe-to-very severe COPD patients with an echocardiographic sPAP>20 mmHg at rest. The diagnosis of COPD was consistent with the diagnostic standards of American Thoracic Society/European Respiratory Society for the management of COPD [17]. All the patients were smokers or ex-smokers with a history of smoking equivalent to at least 20 pack-years. None of the patients had a history of atopy or a significant reversibility of airflow obstruction (FEV1 increasing by

Results

Intra-observer variability of sPAP derived from echocardiographic tricuspid regurgitation had good precision. The mean difference between the values obtained by the same reader during two different days was close to zero (Fig. 1A). Also inter-observer variability of sPAP was close to zero. In fact, the second observer measured similar peak tricuspid regurgitation velocities in comparison to the first observer (Fig. 1B).

The inhalation of either salmeterol or formoterol led to a significant

Discussion

The present trial demonstrated that inhaled long-acting β2-agonists could have a significant short-term effect of sPAP in COPD patients. Salmeterol and formoterol were equally able in reducing sPAP in these patients. β2-Agonists have been suggested to induce a fall in pulmonary vascular resistance because of an increase in cardiac output [8], [23] and in right ventricular ejection [23], [24]. However, Eliasen et al. [10] documented that intravenous terbutaline did not modify mean PAP, at least

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    This study neither received external support nor was funded by any drug company.

    1

    Dr. Cazzola has received financial support for research and attending meetings and fees for speaking and consulting by AstraZeneca, Novartis, Chiesi and GSK.

    2

    up>Prof. Centanni has received financial support for research and attending meetings and fees for speaking by AstraZeneca and GSK.

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