**7. Sleep disordered breathing and PH**

**6.4. Endothelin receptor antagonists (ERA)**

**6.5. Phosphodiesterase-5 (PDE-5) inhibitors**

as a treatment during ongoing hypoxia-induced PH [61].

with no beneficial effect on exercise capacity [66].

**6.6. Calcium channel blockers**

hepatotoxicity [57].

28 Pulmonary Hypertension

in functional capacity.

to hypoxia.

Bosentan, an oral endothelin-1 receptor antagonist is registered for use in patients with PAH in World Health Organisation (WHO) functional classes (FC) II-IV. It has been shown to reduce pulmonary vascular resistance and moderately improve exercise tolerance in people with mildly symptomatic disease. Hepatotoxicity and teratogenicity are potential toxicities [56]. Ambrisentan has been approved for PAH in WHO FC II-IV and has been shown to delay disease progression and improve exercise tolerance in patients with PAH with lower levels of

Trials with endothelin receptor antagonists in patients with COPD and PH have suffered from poor study design and the general trend was worsening gas exchange without improvement

Sildenafil is a selective inhibitor of PDE-5, an enzyme that is specific for both lung and penile vasculature. Although originally developed for treatment of erectile dysfunction, sildenafil is an effective pulmonary vasodilator [58-60]. PDE-5 is found throughout the muscularized pulmonary vascular tree, including in newly muscularized distal pulmonary arteries exposed

Sildenafil may be preferred to other vasodilator agents, particularly in patients with severe COPD, PH and poor RV function, because hemodynamic effects are likely to be selective on the pulmonary circulation. PDE-5 inhibition with sildenafil attenuates the rise in PAP and vascular remodelling when given before chronic exposure to hypoxia and when administered

Previous trials in patients with PAH (primary or associated with scleroderma) showed that sildenafil-induced pulmonary vasodilatation is well tolerated, increased exercise capacity, decreased Borg dyspnoea index and WHO functional class and improved haemodynamics [62,63]. Therefore, it has been proposed to consider the use of this medication in selected

A recent randomized trial in 20 patients with COPD-associated PH demonstrated that sildenafil improved pulmonary haemodynamics both at rest and during exercise, with mild to moderate worsening of gas exchange at rest due to worsening V/Q mismatch [64]. A longer duration of 3 months treatment with sildenafil did not significantly alter hemodynamic or functional capacity [65]. A more recent cross-over trial of sildenafil and placebo in COPDrelated PH showed significant worsening of gas exchange at rest and quality of life indices

Theadministrationofvasodilatordrugshasbeenproposedasanalternativeoradjuncttooxygen supplementationinthe treatmentofPHinCOPDforanumberofyears.However,there remains considerable controversy regarding the likely benefits of non-selective vasodilators [67-69].

patients with COPD-related PH, although clinical trials in this group are limited.

True prevalence of PH in OSA is unknown and ranges from 17 - 52% [86]. In our study of 27 patients with OSA 11 (41%) had mildly elevated PA pressures, mean PAP = 26 mmHg, in the absence of cardiac or pulmonary disease [14].

OSA patients maintain normal daytime oxygenation but experience episodic hypoxic events during sleep. Acute rises in PAP with sleep-disordered breathing have an inverse relationship with the degree of oxygen desaturation. Pulmonary artery pressure is influenced by an obstructive sleep apnoea cycle associated with changes to intra-thoracic pressure with the changes most marked in REM sleep [87]. Three main mechanisms have been proposed including hypoxia, mechanical factors and reflex mechanisms [16]. However, there are conflicting data to support these proposed mechanisms. It has been observed that changes in PA pressure were inversely correlated with the degree of arterial hypoxia [88, 89] while in another study supplemental oxygen did not affect pulmonary artery pressures [90].

Our understanding of the relationship between OSA and PH is evolving following recent studies. Twenty patients with OSA were treated for 4 months with CPAP and a decrease in the mean PAP by 13.9 mmHg was observed for all patients although only five had PH [19]. This reduction of PAP and hypoxic pulmonary vascular reactivity in OSA following CPAP treatment was associated with improved pulmonary endothelial function due to the elimina‐ tion of intermittent hypoxemia [19]. A randomised controlled cross-over trial using sham and effective CPAP in 23 patients with OSA (AHI = 44 ± 29.3/h) and 10 normal controls concluded that severe OSA was independently associated with PH [86]. The clinical impact of PH in sleepdisordered breathing remains under investigation. PH in OSA patients may lead to dyspnoea and reduction in 6MWD, suggesting functional impairment [91]. In a study of 296 OSA patients (AHI ≥ 20/hr) using nasal CPAP, pulmonary haemodynamics were not independently associated with mortality [42]. There are no consensus guidelines to recommend routine screening for PH in OSA. Although current data suggest improvement in PH when OSA is treated with CPAP therapy, the significance of this improvement in the clinical context remains unclear, particularly with mild to moderate PH observed in most patients with OSA.

more hypoxaemic than those without PH. A small number of patients (4) had more marked

Pulmonary Hypertension in Chronic Lung Diseases and/or Hypoxia

http://dx.doi.org/10.5772/55681

31

PH develops as a consequence of alveolar hypoxemia and progressive destruction of the lung parenchyma and pulmonary vascular bed. However, other mechanisms may also be involved. An early study of the prevalence and impact of PH in adult patients with CF reported PH in 7 of 17 patients (41%) with stable but severe lung disease. PH correlated with declining FEV1, diurnal and nocturnal oxygen saturation [4]. However, Doppler echocardiography, although used routinely as an initial screening test to estimate PAP, may frequently be inaccurate and some studies report poor correlation with right heart catheter measures [99]. The clinical impact of PH in most CF patients' management is unclear, although a trend towards worsening

There are no systematic studies to determine true prevalence of PH in bronchiectasis, which is defined as a progressive and permanent dilatation of predominantly medium and small airways. Bronchiectasis is often accompanied with significant airway obstruction and airflow

In a recent study of 94 patients with bronchiectasis, 31 patients (32.9%) had PH, defined as systolic PAP of ≥40 mmHg on Doppler echocardiography [100]. Significant correlation was observed between right ventricular dimensions and systolic PAP (r = 0.74) while RV dimen‐ sions were inversely related to PaO2 values (r = - 0.37) suggesting a role for hypoxemia in the

CT scan-derived measurements of the pulmonary artery have been shown to correlate favourably with the mean PAP derived from right heart catheterization [101-104]. In a study of 91 patients with bronchiectasis, increasing PH as characterised by CT measurements of PA

Interstitial lung diseases (ILD) are characterized by restrictive lung physiology with progres‐ sive impairment of gas exchange resulting in alveolar hypoxemia and PH. Mortality in these conditions is predicted by the degree of hypoxemia, spirometry and functional capacity as

The prevalence of PH in IPF is high and varies between 32 - 85%. PH is mostly of moderate severity although in a few patients pulmonary pressures may approximate systemic levels

As with CF patients, there is lack of data in managing PH in this group of patients.

No properly conducted studies of PH management in CF have been reported.

limitation, and is associated with considerable morbidity but low mortality.

dimensions was found to be an important prognostic marker [104].

PH with mean PAP ≥40 mmHg [99].

mortality has been observed in some small studies.

**10. PH in non-CF Bronchiectasis**

**11. PH in interstitial lung diseases**

defined by 6MWD and presence of PH [105-108].

development of PH [100].
