|
Robert Schilz, DO, PhD
Director of Pulmonary Vascular Disease
and Lung Transplantation
University Hospitals of Cleveland
Case University
Cleveland, Ohio
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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:
- The magnitude of pulmonary pressure elevation is
typically modest.
- Resting cardiac index is not usually affected.
- The sensation of dyspnea if present in these groups
of patients is usually not due primarily to circulatory
limitation.
- Supplemental oxygen and/or restoration of adequate
ventilation will often provide substantial clinical
improvement and in many cases improvement in the observed
pulmonary arterial pressure elevations.
- Treatment of the pulmonary hypertension per se may
not lead to clinical improvement or change the disease
course.
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.
Table
1. Agents for Treatment
of Pulmonary |
Arterial Hypertension.
Calcium channel antagonists
Prostanoids
Sildenafil
Nitric oxide
Endothelin antagonists
|
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.
Chronic Obstructive Pulmonary Disease
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)1,2 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.
Oxygen
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.
Calcium Channel Antagonists
Several studies report calcium channel antagonist treatment
of chronic obstructive pulmonary disease patients with
pulmonary hypertension.11-13 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.
Prostaglandins
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
Nitric Oxide
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 oxygenation18-20 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.
Endothelin Receptor Antagonists
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.2
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 Disease
| Table
2. Partial List of Interstitial Lung Diseases. |
Idiopathic
Usual interstitial pneumonitis/pulmonary fibrosis
Hypersensitivity pneumonitis
Diffuse interstitial pneumonitis
Nonspecific interstitial pneumonitis
Occupational and environmental exposure
Inorganic dust (silica, hard metal dusts)
Organic dust (bacteria, animal proteins)
Gases, fumes, drugs, and poisons
Drugs and poisons
Chemotherapeutic agents
Antibiotics (rare)
Radiation
Infections—residue of active infection
of any type
Connective tissue disease
|
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.22 In another study,
mean pulmonary pressure in 64 patients with severe disease
referred for lung transplantation was 28 mm Hg.23 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.
Calcium Channel Antagonists
Evaluation of both acute and short term administration
of these agents has been evaluated in a limited number
of patients24-27 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 ffects in
some patients.
Nitric Oxide
Short-term administration of nitric oxide has been shown
to improve oxygenation and mean pulmonary pressures.19,28,29
Olchewski and colleagues28 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 reported30 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.
Sildenafil
A single open-label study of acute administration of
sildenafil for treatment of pulmonary hypertension in
the setting of pulmonary fibrosis has been reported.31
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.
Prostaglandins
Investigations of acute administrations of intravenous26,31
and inhaled26 prostacyclin analogs as well as chronic
administration of inhaled iloprost26 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.26
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
Endothelin Receptor Antagonists
Increased levels of endothelin-1 have been reported
in patients with idiopathic pulmonary fibrosis.32 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.
Sleep Disordered Breathing
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)34 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 hese patients for pulmonary arterial hypertension.
Chronic Hypoventilation Syndromes
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 hypertension35-37
High Altitude Exposure
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 level38 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,6 suggesting
a significant impact in some cases.39 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.40
Calcium Channel Antagonists
Nifedipine has been shown reduce pulmonary pressures
in long-term inhabitants of altitude with echocardiographic
evidence of pulmonary hypertension41 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 edema42 as well in prophylaxis in susceptible
individuals.43
Sildenafil
Both acute and short term44 administration of sildenafil
has shown to blunt the rise in pulmonary artery pressures
with exercise associated with direct exposure to altitude44,45
or simulated hypobaric oxygen conditions46 of 4500 m
to 5400 m. Endothelin Antagonists Although increased
levels of endothelin-1 have been demonstrated in normal
subjects moving from low altitude to high altitude,
47 no published reports of the use of these agents in
altitude-induced pulmonary hypertension currently exist.
Summary
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.
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