Pulmonary hypertension-specific therapy in patients with chronic respiratory insufficiency

To the Editor:

We read with much interest the article by Held et al. [1] regarding pulmonary hypertension (PH) due to hypoventilation. In this retrospective study, the authors reported 18 patients with alveolar hypoventilation (due to obesity or chronic obstructive pulmonary disease (COPD)) and daytime PH associated with reduced exercise capacity. They showed that noninvasive positive-pressure ventilation (NIPPV) was followed by significant improvement in haemodynamics and exercise capacity; thus, strongly supporting the use of NIPPV in patients with hypoventilation and PH, and suggesting a major role for hypoxia and hypercapnia in PH [2].

As it is unknown whether PH-specific therapy targeting vasculopathy and remodelling of the pulmonary arteries may also have an impact in this setting, we retrospectively studied patients with chronic respiratory insufficiency and hypoventilation treated with long-term NIPPV who received off-label specific therapy for severe PH.

We extracted from the French registry, in which all consecutive adult patients with PH are prospectively included with written consent [3], incident cases from our centre seen between 2006 and 2013 with the following criteria. 1) Chronic respiratory insufficiency with alveolar hypoventilation (daytime arterial carbon dioxide tension >45 mmHg and hypoxaemia before NIPPV), receiving long-term NIPPV for at least 6 months. 2) Precapillary PH: defined by mean pulmonary artery pressure (PAP) ≥25 mmHg and pulmonary artery wedge pressure ≤15 mmHg at right heart catheterisation. 3) Severe PH: defined by mean PAP ≥35 mmHg and/or cardiac index <2 L·min⁻¹·m⁻². 4) Off-label PH-specific therapy. 5) Available follow-up for at least 6 months. 6) Absence of associated conditions: chronic thromboembolic PH, post-capillary PH or severe left heart conditions. 18 out of 626 patients with precapillary PH were identified with chronic respiratory insufficiency, of whom 11 had severe PH, including two treated with NIPPV for at least 6 months prior to initiation of PH-specific therapy and followed for at least 6 months (table 1).

Both patients (one female and one male) had COPD with a forced expiratory volume in 1 s (FEV₁)/forced vital capacity ratio of 49% and 43%, respectively, FEV₁ of 45% predicted and 36% pred, respectively, and a diffusing capacity of the lung for carbon monoxide of 27% pred and 41% pred, respectively. Body mass index was 24 kg·m⁻² and 35 kg·m⁻², respectively. Neither patient had associated sleep apnoea syndrome or obesity hypoventilation syndrome. Both patients were efficiently treated with NIPPV (with an inspiratory pressure of 15 mmHg and 20 mmHg, respectively) and 1.5 L·min⁻¹ supplemental oxygen overnight for 6 months before PH was diagnosed, with adequate correction of night-time and daytime hypoxaemia and hypercapnia (44 mmHg and 45 mmHg, respectively). The patients received a further 5 L·min⁻¹ and 3 L·min⁻¹, respectively, of oxygen continuously during the daytime. Routine echocardiography suggested presence of PH in both patients, and right heart catheterisation demonstrated severe precapillary PH with preserved cardiac index. After discussion, it was considered that severe PH may contribute to their functional limitation. Patients’ consent was obtained and off-label sildenafil therapy was initiated, with later combination with bosentan in one case and diuretics in both cases. In patient 1, no clinical or haemodynamic improvement was observed. Patient 2 had no clinical or functional improvement, despite long-term haemodynamic improvement with increase in cardiac index and decrease in mean PAP. Inhaled bronchodilators, NIPPV and supplemental oxygen were unchanged. No significant change was observed in arterial oxygen tension, or oxygen saturation at rest or during 6-min walking test over more than 1 year of follow-up. However, hypoxaemia worsened in patient 1 after 38 months of sildenafil treatment, with an increase in alveolar–arterial partial pressure of oxygen gradient, which partially corrected after sildenafil had been discontinued.

These observations of COPD hypoventilation with severe PH differ from the study of Held et al. [1], which predominantly included patients with obesity hypoventilation syndrome. This report emphasises that severe precapillary PH is rare in the setting of chronic respiratory insufficiency, even in a large Dept of Respiratory Medicine and referral centre for PH, further suggesting that PH-specific drug therapy is unlikely to be beneficial in this setting. As stated at a recent international conference on PH, PH-specific drugs are not recommended in patients with PH associated with chronic respiratory diseases (group 3), and treatment should focus on managing the underlying disease [4]. Oxygen supplementation may stabilise PH in patients with COPD [5], and NIPPV may improve haemodynamics in patients with alveolar hypoventilation [1]. Although off-label treatment is sometimes considered in individuals with severe PH when functional limitation is considered to be related to pulmonary vascular disease, there is currently little if any evidence that PH therapy may be beneficial in this setting, with further anecdotal evidence that treatment may increase hypoxaemia through ventilation/perfusion mismatch.

We therefore strongly agree with Held et al. [1] that correction of hypoventilation should be the main objective of management in chronic respiratory insufficiency, even in the presence of severe PH.

• Received March 21, 2014.
• Accepted April 16, 2014.

• ©ERS 2014