As part of an ongoing series of articles on the evaluation and management of pulmonary hypertension, this article will address issues in the treatment of pulmonary hypertension related to hypoxemia.
The current WHO consensus diagnostic classification scheme for pulmonary hypertension groups disorders of the respiratory system and/or hypoxemia into category 3, which includes the following: chronic obstructive pulmonary disease, interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, and chronic exposure to high altitude.
As discussed in the previous article by Dr Girgis, persistent hypoxemia with accompanying vasoconstriction plays an important role in the pathogenesis of these disease states. Although hypoxemia may be seen in all forms of pulmonary hypertension, it largely defines these conditions, which typically differ from pulmonary arterial hypertension in the following important ways:
A small subset of patients may present with severe pulmonary hypertension “out of proportion” to what is typically seen with these diseases.1 2 Whether these patients have an exaggerated pulmonary vascular response to their underlying respiratory disease or concomitant pulmonary arterial hypertension is not clear.
Current treatment has not traditionally targeted the pulmonary hypertensive component of these diseases, but rather the derangements in oxygenation and/or ventilation. In fact, the presence of significant underlying respiratory disease has been an exclusion criterion for most of the recent drug trials in pulmonary arterial hypertension.
However, because many of the vascular pathobiologic changes seen in patients with pulmonary arterial hypertension are also seen in patients with pulmonary hypertension and respiratory disease, there is a rationale for considering medical therapy in this group (Table 1). Existing data and recommendations for approach to therapy will be outlined for each disease state within category 3.
As discussed in the previous article, pulmonary hypertension can be associated with chronic obstructive pulmonary disease. Studies of well-characterized populations even with advanced obstruction have generally shown mild to moderate elevations in pulmonary artery pressure, although occasionally chronic obstructive pulmonary disease patients may present with very high pulmonary arterial pressures (mean PAP >50 mm Hg)3 4 Overt right ventricular failure with depression of resting cardiac index is not typically seen.5 6 Despite the generally “mild” nature of pulmonary hypertension in chronic obstructive pulmonary disease, its presence in this group is clearly a poor prognostic factor7 Although associated with increased mortality, it is still unclear whether the pulmonary hypertension seen in patients with chronic obstructive pulmonary disease is a distinct entity requiring specific therapy or simply a marker of severe disease. Symptomatic dyspnea in chronic obstructive pulmonary disease patients is usually associated with air trapping and dynamic hyperinflation of the lung that manifests as ventilatory limitation rather than circulatory limitation in formal cardiopulmonary exercise testing.
Long-term oxygen therapy improves survival in patients with pulmonary hypertension due to chronic obstructive pulmonary disease8 9 and reduces their pulmonary vascular resistance10 These trials formed the basis of current practice for oxygen supplementation in chronic obstructive pulmonary disease and remain the only medical therapy clearly able to improve survival in patients with chronic obstructive pulmonary disease and hypoxemia.
Several studies report calcium channel antagonist treatment of chronic obstructive pulmonary disease patients with pulmonary hypertension.11 12 13 Statistically significant but small decreases (10% to 20%) in pulmonary pressures are typically seen in relative modest mean pulmonary pressures. These drugs lower both pulmonary and systemic vascular resistance and can cause systemic hypotension and worsen the mismatch between ventilation and perfusion in the lung14 Mortality has not been shown to be effected.
A few studies used prostaglandins in patients with chronic obstructive pulmonary disease. Naeije et al15 administered intravenous PGE1 to 26 patients hospitalized for decompensated chronic obstructive pulmonary disease. Archer and colleagues reported a group of 16 patients given a 48-hour infusion of prostacylin during acute respiratory failure requiring mechanical ventilation. Mean pulmonary pressures ranged from 33 to 37 mm Hg in treatment groups. Although pulmonary vascular resistance decreased acutely, the effect disappeared in 48 hours. PaO2 decreased in the treatment group. These authors concluded that “PGI2 proved to be a nonselective vasodilator that caused mild hypoxemia. Despite acute respiratory failure, pulmonary hypertension is mild in patients with severe COPD receiving mechanical ventilation and IV PGI2 is not beneficial in such patients.”16 Another related case report suggests successful lowering of pulmonary pressures and improvement in exercise tolerance in a patient awaiting lung transplantation for cystic fibrosis with associated severe pulmonary hypertension.17
Numerous studies have assessed the short term effects of the inhalation of nitric oxide on pulmonary hypertension, cardiac function and oxygenation in patients with chronic obstructive pulmonary disease. These studies typically demonstrate modest drops in pulmonary vascular resistance with variable effects on oxygenation18 19 20 At least one trial has carried this to a model of chronic administration. Vonbank et al21 randomly assigned 40 patients with pulmonary hypertension due to chronic obstructive pulmonary disease to receive either oxygen alone or “pulsed” inhalation of nitric oxide with oxygen over a period of 3 months. Compared with oxygen alone, the combined inhalation of nitric oxide and oxygen caused a significant decrease in mean pulmonary artery pressure from 27.6 mm Hg to 20.6 mm Hg, without decreasing arterial oxygenation. Mean cardiac output increased from 5.6 L/min to 6.1 L/min ( P= .025).21 It is unknown whether this therapeutic combination would produce long-term benefits or change the natural course of chronic obstructive pulmonary disease compared to oxygen alone.
Although several studies have shown increased endothelin levels in patients with chronic obstructive pulmonary disease, no studies have systematically studied the impact of endothelin receptor antagonists in chronic obstructive pulmonary disease. A single case report describes the use of bosentan in a patient with moderate chronic obstructive pulmonary disease (FEV1 = 68%) but severe resting pulmonary hypertension.22 It is unclear if this patient had one disease (chronic obstructive pulmonary disease) or two diseases (chronic obstructive pulmonary disease plus idiopathic pulmonary arterial hypertension).
Although targeted therapy of pulmonary hypertension associated with modest elevations of pulmonary pressures in patients with chronic obstructive pulmonary disease has been shown to produce statistically significant decreases in pulmonary pressures, it is unclear that these modest changes are clinically relevant. Not long-term survival, or exercise capacity, or disease progression has been shown to be clearly impacted by treatment other than oxygen. Identifying whether or not specific pulmonary arterial hypertension therapies will help a subset of chronic obstructive pulmonary disease patients needs further study.
Interstitial lung diseases are a heterogeneous group of pulmonary disorders characterized by parenchyma destruction and dysfunction, usually in the setting of abnormal immune function and inflammation (Table 2).
Pulmonary fibrosis (idiopathic pulmonary fibrosis, crytogenic fibrosing alveolitis, and usual interstitial pneumonitis) represents the most common member of this family of diseases characterized by progressive parenchymal destruction in the setting of abnormal inflammation. The incidence and magnitude of pulmonary hypertension in this disease is not well studied. Evaluation of elevated pulmonary pressures in referral populations with advanced disease suggests that pulmonary artery pressure >30 mm Hg was approximately 10%, with approximately 50% of patients having normal pressures.23 In another study, mean pulmonary pressure in 64 patients with severe disease referred for lung transplantation was 28 mm Hg.24 These limited studies suggest that, like chronic obstructive pulmonary disease or sleep apnea, elevations of pulmonary pressures in most patients with idiopathic pulmonary fibrosis are modest compared to patients with pulmonary arterial hypertension.
The potential parallels between the vascular endothelial dysfunction in some idiopathic pulmonary fibrosis patients and the vasculopathy seen in idiopathic pulmonary arterial hypertension suggest that some therapies used for idiopathic pulmonary arterial hypertension may have utility in the pulmonary hypertension seen in idiopathic pulmonary fibrosis. Specific treatments are discussed below.
Evaluation of both acute and short term administration of these agents has been evaluated in a limited number of patients25 26 27 28 Results vary from modest improvements to either no effect or deleterious effects. Potentials for systemic hypotension, intolerance in the setting of cor pulmonale, and worsening of oxygenation have all been cited. No long-term survival or improvement in exercise tolerance has been reported. There appears to be a significant potential for adverse effects in some patients.
Short-term administration of nitric oxide has been shown to improve oxygenation and mean pulmonary pressures.29 30 31 Olchewski and colleagues32 assessed the acute response to nitric oxide administration in a group of patients with severe pulmonary fibrosis (mean FVC = 47%) and significant pulmonary hypertension (mean pulmonary artery pressure = 40 mm Hg). Mean pulmonary pressures decreased from 39.8 mm Hg to 31.9 mm Hg with a statistically significant increase in right ventricular ejection fraction. Other measures of systemic hemodynamics or gas exchange were not altered. At least one report details the use of pulsed ambulatory nitric oxide in a patient with idiopathic pulmonary fibrosis awaiting lung transplantation. Three-month sustained improvements in pulmonary pressures, oxygenation, and exercise tolerance were reported33 These limited data suggest further investigation of long-term administration of nitric oxide in patients with significant pulmonary hypertension in the setting of pulmonary fibrosis.
A single open-label study of acute administration of sildenafil for treatment of pulmonary hypertension in the setting of pulmonary fibrosis has been reported.34 Eight patients receiving a single dose of 50 mg of sildenafil were compared with eight patients receiving intravenous epoprostenol. While the decrease in pulmonary vascular resistance index was comparable (- 32.5% vs -36.9%, respectively), intravenous epoprostenol significantly worsened V/Q mismatch and oxygenation while sildenafil maintained V/Q matching, with raised arterial partial pressure of oxygen an average of 14.3 mm Hg. This short-term study suggests an acute improvement in both oxygenation and pulmonary hemodynamics in patients with pulmonary hypertension and pulmonary fibrosis. Further studies are needed to establish clinical benefit from such a management strategy.
Investigations of acute administrations of intravenous26,31 and inhaled26 prostacyclin analogs as well as chronic administration of inhaled iloprost35 have been reported. Acute administration of intravenous prostacyclin as described above led to decreased pulmonary pressures but with associated V/Q mismatch and hypoxemia consistent with systemic pulmonary vasodilatation. In contrast, inhaled prostacyclin and iloprost demonstrated similar acute decreases in pulmonary artery pressures but maintained oxygenation. A single patient with severe pulmonary hypertension (mean pulmonary artery pressure = 65 mm Hg) was followed for at least 1 year on a regimen of inhaled iloprost. This patient demonstrated increased 6-minute walk distance and sustained decrease in pulmonary artery pressures.36
Limited data demonstrate a decrease in pulmonary hypertension associated with pulmonary fibrosis by administration of prostacyclins. Inhaled agents may have an advantage by preserving V/Q matching and oxygenation in the acute setting. Of interest, the effects of prostacyclin treatment in these studies appear to be independent of the cause of fibrosis. Clinical trials are needed to validate these observations and identify the clinical benefit of such management strategies before any recommendations can be made
Increased levels of endothelin-1 have been reported in patients with idiopathic pulmonary fibrosis.37 No trials of endothelin receptor antagonists have specifically addressed the effects of treatment of pulmonary hypertension associated with pulmonary fibrosis. Recent trials BILD-1 and BILD-2, although designed to examine the question of the utility of bosentan in the treatment of the parenchymal lung disease associated with pulmonary fibrosis, may provide some additional information regarding incidental effects on pulmonary hypertension.
Treatment of obstructive sleep apnea consists mostly commonly of noninvasive positive pressure ventilation (either by continuous positive airway pressure or bilevel positive pressure ventilation) This treatment often decreases pulmonary pressures which are both normal and fit the definition of pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg)38 To date, there are no data to support treating these patients with pulmonary artery hypertension medications. However, if significant pulmonary hypertension is present despite adequate treatment for the sleep apnea (eg, 4 to 6 months of continuous positive airway pressure therapy), and if other processes are excluded, it seems reasonable to treat these patients for pulmonary arterial hypertension.
In addition to the intermittent hypoxemia observed in obstructive sleep apnea, additional syndromes of chronic hypoventilation, including obesity hyperventilation syndrome, neuromuscular disease, and kyphoscoliosis, have been associated with the development of pulmonary hypertension and cor pulmonale. Treatment of these disorders has traditionally consisted of mechanical ventilation, which has been shown to improve pulmonary hypertension39 40 [fn]Schonhofer B, Barchfeld T, Wenzel M, Kohler D. [Effect of intermittent ventilation on pulmonary hypertension in chronic respiratory failure]. Pneumologie. 1999;53 Suppl 2:S113-5.[/fn]
Although unusual in everyday life, exposure to high altitude has increasingly been studied, including both the incidence and magnitude of pulmonary hypertension in such groups of subjects either acutely or chronically exposed to high altitude. Ambient partial pressures of oxygen are directly related to atmospheric pressure, which declines logarithmically with altitude. Altitude exposure leads to diffuse hypoxic vasoconstriction and modest increases in pulmonary pressures. Studies have included long-term altitude dwellers as well as shorter term exposures in mountain climbers and generally show modest increases in resting pulmonary pressures that tend to decrease with acclimatization or return to sea level41
Maximal aerobic ability (VO2 max) is reduced by approximately 1% for every 100 meters (~300 feet) above 4500 feet in recreational athletes. This decreased ability to exercise is likely multifactorial. Significant exertion at altitude can lead to substantial echocardiographic abnormalities during exercise,42 suggesting a significant impact in some cases.43 However, the link between pulmonary hypertension associated with altitude and exercise limitation may not be so clearly defined, since additional factors related to altitude exposure, such as regional blood flow changes, heart rate limitations, or other consequences of low PO2, could also lead to exercise limitation at altitude.44
Nifedipine has been shown reduce pulmonary pressures in long-term inhabitants of altitude with echocardiographic evidence of pulmonary hypertension45 In that study, 66% of patients achieved a 20% or greater decrease in estimated pulmonary pressures after receiving a single dose of sublingual nifedipine. Calcium channel antagonists have been shown to be effective in the management of acute high altitude pulmonary edema46 as well in prophylaxis in susceptible individuals.47
Both acute and short term48 administration of sildenafil has shown to blunt the rise in pulmonary artery pressures with exercise associated with direct exposure to altitude49 Ghofrani HA, Reichenberger F, Kohstall MG, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med. 2004;141(3):169-77.[/fn] or simulated hypobaric oxygen conditions50 of 4500 m to 5400 m.
Although increased levels of endothelin-1 have been demonstrated in normal subjects moving from low altitude to high altitude,fn]Goerre S, Wenk M, Bartsch P, et al. Endothelin-1 in pulmonary hypertension associated with high-altitude exposure. Circulation. 1995;91(2):359-64.[/fn] no published reports of the use of these agents in altitude- induced pulmonary hypertension currently exist.
The cornerstone of treatment for the vast majority of patients with pulmonary hypertension related to hypoxemia remains the restoration of a more physiologic level of oxygenation and ventilation. Although targeted therapy of the usual mild pulmonary hypertension in these groups has been inadequately studied, such “specific” therapeutic approaches may be of some value, especially in acute exposures to altitude, patients with advanced pulmonary fibrosis, or patients with pulmonary hypertension “out of proportion” to the disease state. Given the expense, potential toxicity, and concerns for worsening oxygenation with some of these agents, significant further investigation in these areas is necessary before any recommendations for treatment can be made.