(Circulation. 2000;101:2388.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Iloprost Inhalation on Exercise Capacity and Ventilatory Efficiency in Patients With Primary Pulmonary Hypertension
From Humboldt University Berlin (C.F.O., L.B., F.X.K.) and Deutsches Herzzentrum Berlin (R.W., R.E.), Germany.
Correspondence to Franz X. Kleber, MD, Humboldt University Berlin, Department of Internal Medicine, Unfall-Krankenhaus Berlin, Warener Straße 7, 12683 Berlin, Germany. E-mail franz-xaverk{at}ukb.de
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Abstract |
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Background—The continuous infusion of prostacyclin has been shown to improve exercise capacity and survival in patients with primary pulmonary hypertension (PPH). Inhalation of iloprost, a stable analog of prostacyclin, might be an alternative therapy for PPH, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug. We investigated the short-term effects of iloprost inhalation on exercise capacity and gas exchange in patients with PPH.
Methods and Results—In 11 patients with PPH, we performed 2
consecutive cardiopulmonary exercise tests before and after the
inhalation of 17 µg of iloprost. Patients had marked
pulmonary hypertension (mean pulmonary artery pressure
65 mm Hg), and inhalation resulted in a decrease in
pulmonary vascular resistance (1509 versus 1175 dyne ·
s-1 · cm-5, P<0.05).
Arterial blood gases remained unchanged
(PaO2 69.3 versus 66.8 mm Hg;
PaCO2 29.6 versus 28.8 mm Hg). Iloprost
significantly (P<0.05) improved exercise duration (379
versus 438 seconds), peak oxygen uptake (12.8 versus 14.2 mL ·
kg-1 · min-1), and
E-versus-CO2 slope
(58 versus 51.4).
Conclusions—The present data show that iloprost inhalation exerts pulmonary vasodilatation and improves symptoms and exercise capacity in patients with PPH. The data also suggest that iloprost inhalation is a suitable treatment for PPH. Whether these effects are maintained during long-term treatment and are paralleled by improvement in prognosis remains to be determined.
Key Words: iloprost • pulmonary heart disease • hypertension, pulmonary • exercise • lung
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Primary pulmonary hypertension (PPH) is a rapidly progressive disease of the pulmonary vasculature with consequent right heart failure.1 2 3 Because pulmonary vasoconstriction is a major pathogenic component in the disease process, pulmonary vasodilatation is a major aim in the treatment of these patients.3 4 5 Unfortunately, only a few vasodilator agents sufficiently lower pulmonary vascular resistance without the side effects of systemic hypotension or negative inotropic activity.6 7 8 9
The continuous infusion of prostacyclin has been shown to decrease pulmonary vascular resistance and to significantly reduce mortality rates from PPH, an effect thought to arise not only from pulmonary vasodilatation but also potentially from its antiproliferative activity.9 10 11 12 In addition to reduced mortality rates, significant improvements in symptoms and exercise tolerance have been reported.
However, the side effects of intravenous prostacyclin, which include catheter infection, flush, jaw pain, arterial hypoxemia, and systemic hypotension, can limit sufficient dose adjustment of the drug.9 10 Furthermore, pharmacological tolerance with the need for steady dose increments during long-term treatment is commonly observed.11
The inhalative application of prostacyclin causes pulmonary
vasodilatation without the negative side effects on gas exchange and
systemic blood pressure that result from ventilation-matched deposition
of the drug in the alveoli, thereby causing pulmonary
vasodilatation matched to ventilated areas.13 14 15 A steady
concentration gradient from the site of deposition to downstream
resistance vessels accounts for marked pulmonary vasodilatation
without pronounced systemic vasodilatation. However, the short
half-life of prostacyclin limits its use to monitored short-term
treatment, as in adult respiratory distress syndrome. Olschewski et
al16 showed that the inhalation of iloprost, a more stable
analog of prostacyclin, exerts equivalent effects that last for 
60
to 120 minutes, which makes outpatient treatment feasible.
In addition to death, exercise capacity is an important clinical parameter in the evaluation of the effectiveness of this therapy in PPH. Continuous prostacyclin therapy improved exercise tolerance in the 6-minute-walk test in patients with PPH.10
Cardiopulmonary exercise testing allows a reproducible and less
subjective assessment of exercise capacity and provides valuable
information on gas exchange and oxygen consumption
(O2). To determine the
short-term effects of inhaled iloprost on exercise capacity and
pulmonary gas exchange, we performed serial
cardiopulmonary exercise tests on patients with PPH before and
after the inhalation of iloprost.
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Methods |
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Patients
The present study consisted of 10 patients with PPH and 1 patient (patient 9) with pulmonary hypertension associated with Osler disease (mean age 41±12 years). The diagnosis of PPH was established on the basis of a mean pulmonary artery pressure of >30 mm Hg and the exclusion of secondary causes of pulmonary hypertension according to the diagnostic criteria reported by Rich et al.1 All patients had limitation of exercise capacity in accordance with New York Heart Association functional class III. In patient 3, a patent foramen ovale was diagnosed. Long-term medication, which included calcium channel blockers (n=5), oral anticoagulation (n=9), diuretics (n=11), and nasal oxygen therapy (n=3), was kept constant. The study was approved by the institutional ethics board, and written informed consent was given by each patient.
Hemodynamic Measurements
To characterize the hemodynamic response to
inhaled iloprost before the initiation of long-term inhalation therapy,
patients underwent right heart catheterization. This
was performed via the right internal jugular or right subclavian vein,
and an 8F Baxter Swan-Ganz catheter (IntelliCath) was used. Monitoring
of arterial blood pressure and arterial blood
gases was undertaken with an arterial
intravenous line (Leader 20-gauge catheter; Vygon) that was
inserted into the right radial artery. Cardiac output (Fick method),
arterial blood pressure, pulmonary artery pressure,
mean right atrial pressure, and pulmonary capillary wedge
pressure were measured at baseline and at the end of iloprost
inhalation. Iloprost was applied with a jet nebulizer at a
concentration of 10 µg/mL. According to an average nebulization rate
of 1.7 mL/min, after 10 minutes, a cumulative dose of 17 µg of
iloprost had been administered. Measurements were performed within the
final minute of inhalation. A cumulative dose of 17 µg was chosen
because it had been reported to be safe and effective for the long-term
treatment of pulmonary hypertension when used as a single
inhalation dose of a daily therapy regimen consisting of 6
inhalations.16 Patients were started on long-term
inhalation of 17 µg of iloprost 6 times daily on the day after
catheterization.
Cardiopulmonary Exercise Tests
Within the first week of the initiation of inhalation therapy,
patients underwent cardiopulmonary exercise testing. Tests were
performed on 2 consecutive days before iloprost inhalation and within
15 minutes after the inhalation of 17 µg of iloprost. The modified
Naughton protocol17 for treadmill exercise testing was
used. This is an incremental exercise test with stages of 2 minutes and
increments in both slope and velocity of the treadmill that simulate an
increment of 1 metabolic equivalent (3.5 mL
O2 · kg-1 ·
min-1) per stage. Exercise testing with the use
of a cycle ergometer (ER 900; Jäger) was started at 20 W with a
stepwise increment of 16 W/min. Patients were tested with the same
exercise protocol (either treadmill or cycle ergometer) for both tests.
A Medical Graphics cardiopulmonary exercise system (CPX/D) was
used, and gas was sampled through a Rudolph mask. For each type, dead
space as specified was corrected individually. The expiratory gas was
collected and conveyed to a spirometer as well as to an oxygen and a
carbon dioxide detector. O2,
carbon dioxide output (CO2),
instantaneous expiratory gas concentrations throughout the respiratory
cycle, and minute ventilation (E) were measured
continuously on a breath-by-breath basis.
Maximal oxygen uptake (O2 max)
was defined as the peak O2
that was measured, which always occurred well beyond the
anaerobic threshold. The
O2 at the gas exchange
anaerobic threshold was detected with the V-slope
method,18 19 supplemented by the simultaneous
observation of end-tidal gas concentrations.
Ventilatory efficiency on exercise was measured by plotting
E against
CO2. This plot revealed a
linear relationship (r=0.98 to 0.99). The ventilatory
efficiency on exercise is represented by the slope of all
E/CO2
values for 1 person during incremental exercise. The nonlinear portion
of this relationship after the onset of acidotic drive to
ventilation20 was excluded. The
parameters that we used to determine exercise capacity were
O2 max, oxygen uptake at the
ventilatory anaerobic threshold, and exercise duration.
Pulmonary gas exchange was assessed with the ratio of
E to CO2,
the slope of this ratio on exercise, the end-tidal partial pressure of
carbon dioxide (PETCO2) at rest, and
percutaneous oxygen saturation.
Statistical Analysis
Values are given as mean±SD. Changes in exercise
parameters before and after iloprost inhalation were
analyzed with the paired t test or Wilcoxon
signed rank test.
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Results |
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Hemodynamics
Baseline hemodynamic profiles of the patients and the acute effects of inhaled Iloprost are shown in the Table
. All patients had marked
pulmonary hypertension, with increased right atrial pressure in
6 patients. The inhalation of 17 µg of iloprost led to a significant
decrease in pulmonary vascular resistance, which resulted in an
increase in cardiac output and decreased pulmonary artery and
right atrial pressures. No significant changes occurred in
arterial oxygen saturation (92.3% versus 92.7%),
arterial partial pressure of oxygen
(PaO2) (69.3 versus 66.8
mm Hg), and arterial partial pressure of carbon dioxide
(PaCO2) (29.6 versus 28.8
mm Hg).
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No serious side effects or adverse drug reactions were observed during short-term testing or on the next days.
Cardiopulmonary Exercise Tests
Exercise testing was performed with a treadmill (n=7) or a cycle
ergometer (n=4). All patients tested with treadmill exercise reported
dyspnea as the limiting symptom at the end of exercise, whereas 3 of 4
patients tested with the cycle ergometer reported both dyspnea and
muscular weakness. There was no change in these symptoms when exercise
testing was compared before and after the inhalation of iloprost.
The inhalation of iloprost resulted in a significant increase in
exercise duration (379 versus 438 seconds, P<0.05) and
O2 max (12.8 versus
14.2 mL · kg-1 ·
min-1, P<0.05, Figures 1 and 2).
Furthermore, we observed a significant improvement (ie, a decrease) in
the
E-versus-CO2
slope on exercise (58 versus 51.4, P<0.05, Figure 3), whereas resting
PETCO2 (24.5 versus
24.7 mm Hg), resting
E/CO2
(58.4 versus 56.3), percutaneous oxygen saturation at
rest (93.5% versus 94.4%), and peak exercise levels (88.5% versus
89.2%) remained unchanged.
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Discussion |
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PPH is a progressive and fatal disease with a median survival time of 2.8 years after diagnosis.21 Hemodynamically, it is characterized by increased pulmonary vascular resistance that leads to an elevation in pulmonary artery pressure and consequent right heart failure. Among the various pharmacological agents used to influence the clinical course of the disease, prostacyclin has shown the most promising results. In a randomized study, the continuous intravenous application resulted in long-term reduction in pulmonary vascular resistance and, more importantly, improved survival times.9 10 11 Furthermore, hemodynamic and prognostic improvement correlated with an increased exercise tolerance on the 6-minute-walk test.
Recently, Olschewski et al16 reported that the inhalation of prostacyclin can exert effects on the pulmonary vascular resistance that are the equivalent of intravenous application and that the prostacyclin analog iloprost can produce comparable acute effects that last from 60 to 120 minutes. Iloprost inhalation might therefore represent a long-term therapy for patients with PPH. However, the effects of iloprost inhalation on cardiopulmonary exercise capacity, which is one of the most sensitive and objective parameters to describe functional impairment from pulmonary hypertension, have not been described yet.
In the present study, we observed an increased exercise capacity
after iloprost inhalation as indicated by an increased exercise time
and O2 max on an incremental
exercise protocol. As an indicator of pulmonary vasodilatation,
the initial hemodynamic studies revealed a marked
decrease in pulmonary vascular resistance. Consequently, right
ventricular afterload decreased, which led to a reduction
in right atrial pressure and an increase in cardiac output. Due to the
heterogeneity of the pulmonary vasodilator
response of patients with PPH, the quantitative comparison of different
vasodilator strategies between patient groups is rather unreliable.
However, inhaled iloprost exerted effects similar to those of
intravenous iloprost, as described
previously.22
Although hemodynamics were not monitored during
exercise, we suggest that an increased cardiac output secondary to
decreased right ventricular afterload accounts for the
observed effects on exercise capacity. Iloprost affected neither
arterial oxygenation nor the pronounced
hyperventilation with decreased
PaCO2, as is usually observed in
patients with PPH. Interestingly, in patient 3, the
E-versus-CO2
slope increased steadily during exercise, which reflected the
ventilatory response to an increasing right-to-left shunt through the
patent foramen ovale secondary to a rise in right atrial pressure as
right ventricular backward failure deteriorates on
exercise. In the absence of an intracardiac right-to-left shunt,
hyperventilation mainly accounts for the increased
E-to-CO2
ratio observed in patients with PPH, because no major abnormalities in
pulmonary ventilation/perfusion matching have been
reported.23 24 25 Iloprost inhalation did not decrease the
E-to-CO2
ratio at rest; however, the
E-versus-CO2
slope on exercise did improve after inhalation. We did not measure
arterial blood gases on exercise and therefore cannot
define whether this effect results from a decreased
PaCO2 set point during exercise.
However, stable PaCO2 and
PETCO2 values at rest make this
mechanism rather unlikely. Another mechanism that might explain the
change in the
E-versus-CO2
slope could be the reduction in functional intrapulmonary
right-to-left shunt due to an increased mixed venous oxygen content and
reduced carbon dioxide content secondary to an increased cardiac
output. Although the exact mechanism remains unclear, the improved
ventilatory efficiency reduces the respiratory burden during exercise,
and therefore dyspnea, in these patients with PPH. Furthermore, in
chronic congestive heart failure, a lower
E-versus-CO2
slope has been found to correlate with increased survival time, which
is an effect that might be relevant in PPH as
well.20 26 27 28
A major limitation of the present study was the lack of a control
group to exclude the placebo effect, which was due to the limited
number of patients available. This in particular applies to the effects
on exercise duration and O2
max. However, hemodynamic measurements and
ventilatory efficiency are more objective parameters that
should not affected by this phenomenon. Blood gases remained unchanged
after iloprost inhalation. A training effect that might have affected
our result can be widely ruled out with the short time interval between
both exercise tests. An improvement in exercise capacity in a placebo
group has been described only at a markedly longer follow-up
period.29 The observed improvements in exercise capacity
and ventilatory efficiency show that iloprost inhalation affects not
only pulmonary hemodynamics but also
symptomatology and possibly survival in these patients. Compared with
continuous intravenous prostacyclin therapy, inhalation
provides the advantage of noninvasive drug administration, thereby
avoiding rare but serious side effects, such as infection and catheter
thrombosis. Furthermore, no adverse symptoms were reported during
inhalation, which is a major advantage of selective iloprost use.
A potential disadvantage of this therapy is the discontinuous drug application. Despite a markedly prolonged half-life compared with prostacyclin, iloprost does not exert a continuous effect on the pulmonary circulation when administered in a regimen of 6 inhalations/d. Instead, fluctuating drug levels are present for only a few hours during the day with a long drug-free interval during the night. In addition, it is unknown whether the proposed antiproliferative effect of this type of treatment requires a steady dose profile during the day to become fully effective. Therefore, the role of iloprost inhalation in the treatment of patients with PPH and its long-term effects on exercise capacity and survival remain to be investigated in randomized controlled studies.
Received August 6, 1999; revision received December 3, 1999; accepted December 22, 1999.
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 H. A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R. T. Schermuly, N. Weissmann, W. Seeger, and F. Grimminger Combination Therapy with Oral Sildenafil and Inhaled Iloprost for Severe Pulmonary Hypertension Ann Intern Med, April 2, 2002; 136(7): 515 - 522. [Abstract] [Full Text] [PDF]
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 N Nagaya, Y Shimizu, T Satoh, H Oya, M Uematsu, S Kyotani, F Sakamaki, N Sato, N Nakanishi, and K Miyatake Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension Heart, April 1, 2002; 87(4): 340 - 345. [Abstract] [Full Text] [PDF]
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T Iwase, N Nagaya, M Ando, T Satoh, F Sakamaki, S Kyotani, H Takaki, Y Goto, Y Ohkita, M Uematsu, et al. Acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension Heart, August 1, 2001; 86(2): 188 - 192. [Abstract] [Full Text] [PDF]
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X.-G. Sun, J. E. Hansen, R. J. Oudiz, and K. Wasserman Exercise Pathophysiology in Patients With Primary Pulmonary Hypertension Circulation, July 24, 2001; 104(4): 429 - 435. [Abstract] [Full Text] [PDF]
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S.-K. Shyue, M.-J. Tsai, J.-Y. Liou, J. T. Willerson, and K. K. Wu Selective Augmentation of Prostacyclin Production by Combined Prostacyclin Synthase and Cyclooxygenase-1 Gene Transfer Circulation, April 24, 2001; 103(16): 2090 - 2095. [Abstract] [Full Text] [PDF]
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S. Machherndl, M. Kneussl, H. Baumgartner, B. Schneider, V. Petkov, P. Schenk, and I.M. Lang Long-term treatment of pulmonary hypertension with aerosolized iloprost Eur. Respir. J., January 1, 2001; 17(1): 8 - 13. [Abstract] [Full Text] [PDF]
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R. Ewert, R. Wensel, C. F. Opitz, M. M. Hoeper, E. Spiekerkoetter, and H. Fabel Aerosolized Iloprost for Primary Pulmonary Hypertension N. Engl. J. Med., November 9, 2000; 343(19): 1421 - 1422. [Full Text]
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