American Journal of Respiratory and Critical Care Medicine

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation–perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 ± 4.2 to 31.6 ± 3.1 mm Hg, and pulmonary vascular resistance (Rl) from 810 ± 226 to 386 ± 69 dyn · s · cm 5 (p < 0.05, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with Rl decreasing from 726 ± 217 to 458 ± 81 dyn · s · cm 5. In contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition, PGI2 infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI2 analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.

Lung fibrosis of various etiologies is often associated with pulmonary hypertension, which may become a major contributor to morbidity and mortality, or may even represent the major cause of death as in systemic sclerosis (1). In patients suffering from primary pulmonary hypertension (PPH), intravenous prostacyclin has been demonstrated to be a potent pulmonary vasodilator, and long-term infusion of the prostanoid was found to improve exercise tolerance and survival in these patients (2-4). However, in the presence of lung fibrosis, any systemic vasodilator therapy may be hampered by two drawbacks. (1) The percentage of increased pulmonary vascular resistance that is due to fibrotic and thus “fixed” remodeling processes, compared with the percentage caused by vasoconstriction, is unknown. Systemic vasodilatation due to medications in the absence of pulmonary vasodilatation may provoke severe systemic hypotension in these patients if cardiac output is not adequately increased. (2) Any systemic administration of vasodilators may increase the blood flow to low or nonventilated lung areas by interfering with the physiological hypoxic vasoconstrictor mechanism, thereby worsening preexistent ventilation (V˙)/perfusion (Q˙) mismatch and shunt (5), resulting in arterial hypoxia and wasting of the small ventilatory reserve of these patients.

Selective pulmonary vasodilatation by inhalation of the vasorelaxant agent is an appealing concept to circumvent some of the hazards inherent in systemic vasodilator therapy in pulmonary hypertension. The feasibility of this concept was demonstrated for inhalation of nitric oxide (NO) by children with persistent pulmonary hypertension of the newborn (6-9), in the adult respiratory distress syndrome (ARDS) (10), and also in scleroderma patients with “isolated” pulmonary hypertension that is characterized by severe pulmonary hypertension without interstitial lung disease (11). By employing an aerosol technique, our group demonstrated that the concept of pulmonary selectivity may be extended to inhalation of aerosolized prostacylin (prostaglandin I2, PGI2) (12, 13): in patients with ARDS both intravenous and aerosolized PGI2 caused pulmonary vasodilatation; however, the former deteriorated whereas the latter improved shunt flow and gas exchange. This corresponds to studies of experimental pulmonary hypertension, wherein selective vasodilatation in the pulmonary vascular bed was achieved by aerosolized PGI2 (14). Subsequent studies in patients with ARDS and severe pneumonia demonstrated that inhalation of NO and aerosolized PGI2 resulted in comparable hemodynamic and gas exchange effects (15, 16).

By employing this approach in patients with PPH and excessive pulmonary hypertension, we found that aerosolization of PGI2 or its stable analog, iloprost, effected equipotent pulmonary vasodilatation to the maximum tolerable dose of intravenous prostacyclin, but induced fewer systemic side effects (17). In these patients, prostacyclin appeared to be more potent than NO in decreasing pulmonary resistance, corresponding to other data (18, 19). On the other hand, inhaled NO, owing to its immediate inactivation by hemoglobin binding on entering the intravascular space, is strictly selective to the pulmonary vessels, whereas inhaled prostacyclin will have some systemic effects due to overspill into the systemic circulation. In this study, we examined the effects of the most important systemic and inhalative vasodilators, NO and intravenous and inhaled prostacyclin, in comparison with O2 and systemic calcium antagonists in patients with severe pulmonary hypertension associated with interstitial lung diseases of differing etiologies.


Eight patients with lung fibrosis and pulmonary hypertension, who were referred to the Division of Pulmonary and Critical Care (Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany) between June 1995 and October 1996, were included in the study. Criteria for entry included a peak systolic pulmonary pressure > 50 mm Hg, as suggested by echocardiography or a resting pulmonary mean pressure > 30 mm Hg as measured by catheter investigation, and the diagnosis of chronic fibrotic lung disease. The underlying diseases included extrinsic allergic alveolitis (two patients), systemic sclerosis, CREST syndrome (calcinosis, the Raynaud phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia), collagen vascular overlap syndrome, bronchopulmonary dysplasia, postradiation lung fibrosis, and idiopathic pulmonary fibrosis (Table 1). The diagnosis of these diseases was based on history, lung function testing, chest X-ray, and high-resolution computed tomography, which demonstrated at least medium-grade bilateral interstitial fibrosis in all patients. Flexible bronchoscopy with biopsy and bronchoalveolar lavage was performed in five patients. All suffered from significant lung restriction or severe restriction in gas exchange capacity, with a mean vital capacity (VC) of 48% and CO-diffusing capacity (Dco) of 26% relative to unaffected control patients. Significant arterial hypoxia under resting conditions was noted in seven patients, and these received long-term oxygen therapy. Seven patients were treated with steroids (mean dose, 21 mg of methylprednisolone per day). Two patients were treated with low-dose calcium antagonists (CAAs): patient B had received felodipine because of a right heart catheterization 7 mo before this study, and had subsequently recovered from a period of right heart decompensation. The other patient (patient H) had received low-dose diltiazem for several years, but validation of this approach had never been performed. None of the patients were anticoagulated or treated with other vasodilatory agents. Underlying causes for pulmonary hypertension other than parenchymal lung diseases were excluded by transthoracic and transesophageal echocardiography (n = 8), ventilation and perfusion pulmonary nuclear scintigraphy (n = 8), and pulmonary angiogram (patient F).


PatientUnderlying DiseaseSexAge (yr)Height (cm)Weight (kg)VCFEV1(L)Dcoc (%)Po 2(mm Hg)Pco 2(mm Hg)
Liters% pred

Definition of abbreviations: BPD = bronchopulmonary dysplasia after premature birth and long-term ventilation; CREST = calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia; CVOL = collagen vascular overlap syndrome (see text); Dcoc, diffusion capacity for CO gas, corrected for the actual hemoglobin concentration, given as a percentage of predicted values, corrected for age, sex, and body surface area (single-breath method in patients with VC > 1.5 L and steady state in patients with VC < 1.5 L); EAA = chronic extrinsic allergic alveolitis; F = female; FEV1 = forced expiratory volume within 1 s; IPF = idiopathic pulmonary fibrosis; M = male; ND = not determined; Po 2 and Pco 2 = resting arterial oxygen and carbon dioxide partial pressure during oxygen pause; PRT = postradiation therapy presenting with lung fibrosis and kyphoscoliosis occurring after thoracic radiation during the first year of life and due to malignant neuroblastoma; SS = systemic sclerosis; VC = inspiratory vital capacity in liters and as a percentage of predicted values.

Seven patients were classified as stage III according to the New York Heart Association (NYHA) system of classification. Patient F, who later received long-term iloprost inhalation, presented with decompensating right heart failure, unable to walk despite continuous nasal oxygen. This patient was a 27-yr-old woman with a history of dry cough and intermittent pleurisy for 4 yr. High-titer anti-nuclear, anti-DNA, and anti-skin-sensitizing antibodies, suggested collagen vascular disease resulting in progressive lung fibrosis with continuous reduction of VC and Dco. Exercise tolerance had been declining more rapidly in the previous 12 mo. She had been treated with high-dose corticosteroids and azathioprine, and subsequently with bolus application of cyclophosphamide (two boluses with 1 g/m2, 4 wk apart) without clinical benefit. Current therapy included high-dose corticosteroids, continuous nasal oxygen, and diuretics.

Study Protocol

All patients gave informed written consent to participate in the test protocol, which was approved by the institutional ethics committee of the Justus-Liebig-University. A fiberoptic thermodilution pulmonary artery catheter (Edwards Swan-Ganz, 93A-754H-7.5F; Baxter Healthcare, Irvine, CA) was inserted to measure central venous pressure (Pcv), pulmonary artery pressure (Ppa), pulmonary artery wedge pressure (Ppa,we), cardiac output (Q˙; thermodilution technique), right ventricular ejection fraction (RVEF), and central venous oxygen saturation (SvO2 ). A femoral artery catheter was used to assess mean arterial pressure (Pa) and to draw arterial blood samples. The pulmonary shunt flow was measured by determining the retention and excretion values of sulfur hexafluoride (20) in all patients. In addition, in patient F, the retention and excretion values for ethane, cyclopropane, halothane, diethyl ether, and acetone were used to determine the pattern of ventilation and perfusion distributions (multiple inert gas elimination technique, MIGET) as described in detail by Wagner and co-workers (20). Concerning the patients with long-term CAA therapy, the agent was discontinued 48 h before the test in patient H and continued in patient B, who had suffered from right ventricular decompensation before therapy with felodipine.

Test Procedure

In patients receiving long-term oxygen therapy (seven patients), catheterization was performed with ongoing nasal oxygen. Oxygen delivery was then stopped for 20 min, and baseline values were determined. Next, high-dose oxygen was administered (4–8 L/min) in order to increase arterial oxygen saturation above 95%, and measurements were performed. Subsequently, oxygen supply was titrated to maintain baseline arterial oxygen saturation above 85% (0–4 L/min). This oxygen flow was kept constant throughout the following tests, which were performed in randomized order. Inhaled nitric oxide (15 to 80 ppm; mean, 40 ppm) was titrated to achieve a maximum response of pulmonary artery pressure decrease without decline of arterial oxygen saturation, as assessed by fingertip oximetry. After 5 min on a constant dose, a complete set of hemodynamic measurements was performed. Intravenous prostacyclin (epoprostenol sodium; Wellcome Research Laboratories, Beckenham, Kent, UK) was increased in increments of 2 (ng/kg)/min until patients experienced discomfort (thoracic oppression, heat, headache) or until mean arterial pressure decreased to less than 70 mm Hg. The highest tolerated doses ranged from 5 to 16 (ng/kg)/min, with a mean of 8.0 (ng/kg)/min. Fifteen minutes after finding the highest tolerated dose, during continuous PGI2 infusion, a complete set of hemodynamic measurements was performed. Aerosolized prostacyclin, diluted in glycine buffer (50 μg/ml), was jet nebulized (Puritan-Bennett raindrop medication nebulizer) with room air at a pressure of 80 kPa (compressor from Pari Boy, Pari, Germany) (fluid flux, 0.09 ml/min; mass median aerodynamic diameter of particles, 3.5 μm; geometric SD of 2.6, ascertained by impactor technique) and delivered to a spacer connected to the afferent limb of a Y-valve mouthpiece. The total inhalation time was 12 to 15 min (total nebulized dose, 54 to 68 μg), depending on systemic pressure and fingertip oximetry. Hemodynamic measurements were performed every 3 min and arterial and central venous blood samples were drawn before and during the last minute of inhalation. After each test, 1 h was allowed to pass to achieve a new baseline. After termination of the randomized trial period, calcium antagonists were given to six patients. Nifedipine, 10 to 20 mg, was administered sublingually (patients A, C, D, E, and F) and hemodynamic measurements were then performed 30 min after ingestion of this dose. In one patient (patient H), instead of nifedipine, diltiazem was applied corresponding to the preceding therapy. Diltiazem, 40 mg, was applied intravenously during a 30-min infusion period. Measurements were performed 15 min after the end of infusion. Patient G refused to take calcium antagonists owing to intolerance during preceding episodes of treatment with these drugs, and patient B was not included owing to continuous felodipine therapy.


One-way analysis of variance (ANOVA) was employed to evaluate changes in parameters during exposure to the different agents (pre- and postexposure percent differences for Q˙, pulmonary vascular resistance [Rl], and systemic vascular resistance [Rva] and numerical differences for other parameters) and the Scheffé test was used as an a posteriori test for linear contrasts between these differences. The response to an agent was considered significant if the 95% confidence interval (p < 0.05) or the 99% confidence interval (p < 0.01) of the pre- and postexposure difference did not overlap with zero. The significance level for the Scheffé test was set at p = 0.05.

Baseline Data

Values of Ppa and Rl for all patients were significantly elevated and scattered over a wide range (Table 2). Ppa,we was in the normal range, excluding left heart failure as the underlying cause of the pulmonary hypertension. Q˙ values were in the normal or lower normal range in all patients, except in patient F, who presented with low-output syndrome and decompensated right heart failure, and had elevated Pcv (Table 3). The Rl/Rva ratio was increased and RVEF was decreased in all. Shunt flow was increased with great differences between individuals. Seven patients presented with significant arterial hypoxemia, whereas Pco 2 values were slightly elevated in only one patient.


Q˙ (L/min) Ppa(mm Hg)Ppa,we (mm Hg)Rl [ (dyn · s)/cm5 ] RVEF (%)Pcv (mm Hg)HR (min 1) Pa(mm Hg)Rl /RvaShunt (%)
A4.6361045731 5 55 940.292 0.32
B3.530 4570 9 5100 680.397 4.8
C3.45112931 811 821140.379 3.6
D7.532 528822 3 841150.24126.4
E4.750 380030−3 961140.402ND
F2.755 61,468 7161081170.485 3.6
G4.4381148830 5103 910.314ND
H7.430 528526−1112 600.410 9.9
Mean4.840.2 7.066020.4 5.1 92.5 96.60.365 8.1

Definition of abbreviations: HR = heart rate; Pa = mean systemic arterial pressure; Pcv = central venous pressure; Ppa = mean pulmonary artery pressure; Ppa,we = pulmonary artery wedge pressure; Q˙ = cardiac output; Rl = pulmonary vascular resistance; Rl/Rva = Rl/Rva (systemic vascular resistance) ratio; RVEF = right ventricular ejection fraction, assessed by thermodilution; Shunt = right-to-left shunt blood flow as a percentage of total pulmonary blood flow, assessed by MIGET analysis.


Q˙( L/min) Ppa(mm Hg)Rl[(dyn · s)/cm5 ]RVEF (%)Pcv (mm Hg)HR (min−1 ) Pa(mm Hg)PaO2 (mm Hg)Shunt (%)
Before NO2.1652,243 71811311069.4 3.6
During NO5.0447741510 9012088.6 6.3
Before PGI2, intravenous2.4591,789 91911112171.9 5.1
During PGI2, intravenous6.04247020101021056223.1
Before PGI2, aerosolized2.5652,179 71811311274.6 2.4
During PGI2, aerosolized4.74564420.5 9.5 9311381.5 5.6
Before nifedipine2.1642,375 91910411870.7 3.4
After nifedipine3.3519551016108 9474.5 3.7
After 5 mo
 Before iloprost, aerosolized2.9571,452 912100 9166
 During iloprost, aerosolized5.34460424 3 90 8473
After 12 mo
 Before iloprost, aerosolized2.9531,31110 9 9310453
 During iloprost, aerosolized4.15088219 2 92 9758

Definition of abbreviations: see Tables 1 and 2.

*Response to NO, intravenous PGI2, aerosolized PGI2, and nifedipine during the first test trial and after 5 and 12 mo of iloprost inhalation in patient F. Measurements on the first day were performed during continuous oxygen flow (4 L/min); during subsequent trials, measurements were performed without nasal oxygen supply.


During high-dose oxygen inhalation, PaO2 increased to an average of 125 mm Hg (p < 0.01), with a corresponding increase in SaO2 (Figure 1). Heart rate decreased significantly from 92.5 ± 6.1 to 85.3 ± 6.3 min−1 (p < 0.05) and Ppa decreased from 40.1 ± 3.4 to 37.5 ± 3.9 mm Hg (p < 0.05; Figure 2). All other hemodynamic and gas exchange variables were not significantly altered. Continuous low-flow nasal oxygen was then administered to maintain baseline SaO2 values above 85% (see increased baseline SaO2 data in the following tests).


Inhaled NO significantly decreased Ppa from 39.8 ± 4.3 to 31.9 ± 3.2 mm Hg (p < 0.01), Rl from 726 ± 217 to 458 ± 81 dyn · s · cm−5 (p < 0.05), and the Rl/Rva ratio from 0.389 ± 0.026 to 0.289 ± 0.030 (p < 0.05). RVEF was increased from 20.5 ± 3.9 to 24.4 ± 4.4% (p < 0.05). All other hemodynamic and gas exchange variables were not significantly altered (see Figures 1 and 2).

Intravenous PGI2

Prostacyclin infusion increased Q˙ from 4.9 ± 0.7 to 7.1 ± 1.0 L/min (p < 0.01) and significantly decreased both Ppa from 39.6 ± 4.9 to 33.6 ± 3.0 and Pa from 93.1 ± 7.3 to 81.6 ± 8.1 mm Hg (p < 0.05, respectively). Correspondingly, both Rl and Rva were decreased by an average of 40%, resulting in an unchanged Rl/Rva ratio. RVEF increased significantly from 18.2 ± 3.9 to 24.5 ± 4.2%. A more than 2.5-fold increase in pulmonary shunt flow occurred, from an average of 7.0 ± 1.9 to 18.4 ± 3.1% (see Figures 1 and 2). Owing to the increased central venous oxygen saturation (data not given), which reflected Q˙ increase, this marked augmentation of shunt flow resulted in only a moderate decrease in SaO2 .

Inhaled PGI2

Aerosolized PGI2 markedly decreased the pulmonary artery pressure from 44.1 ± 4.2 to 31.6 ± 3.1 mm Hg. This response was significantly greater than the response to intravenous PGI2 (Scheffé test). Most of the difference in these responses, however, resulted from increased preinhalation rather than decreased postinhalation pressures. In contrast, Pa values were not significantly reduced. Q˙ increased from 5.1 ± 0.8 to 6.4 ± 0.8 L/min. Correspondingly, the Rl values were reduced by about 50% (from 810 ± 226 to 386 ± 69) and the Rl/Rva ratio was significantly decreased (from 0.456 ± 0.034 to 0.319 ± 0.022). RVEF was increased from 18 ± 4.0 to 24.6 ± 4.6%, and Pcv was significantly lowered from 6.3 ± 2.6 to 3.4 ± 2.0 mm Hg. Shunt flow and heart rate did not change significantly.

Calcium Antagonists

Calcium antagonists significantly decreased Ppa and, more impressively, Pa values. Q˙ increased from 4.3 ± 0.8 to 5.4 ± 0.8 L/min and RVEF was increased from 18.6 ± 4.5 to 22.8 ± 5.9% on average (p < 0.05, respectively). Correspondingly, both Rl and Rva were significantly reduced, with unchanged Rl/Rva ratio. Shunt flow and arterial oxygenation were not significantly altered.

Long-term Therapy

On the basis of the results of the test trial, in three patients (A, C, and E), in whom nifedipine resulted in a substantial decrease in Ppa and Rl without systemic side effects, treatment with calcium antagonists was started and in patient H the CAA was withdrawn owing to decreased arterial oxygen pressure after the test dose. In the patient with immobilization due to decompensated right heart failure (patient F), calcium antagonists were not tolerated. This may be related to a negative inotropic effect of the calcium antagonist suggested by the moderate Pcv decrease from 19 to 16 mm Hg despite an afterload reduction > 50% (see Table 3) in this patient; long-term therapy with repetitive aerosolization of iloprost, the stable analog of prostacyclin, was started. This decision was based on the fact that both PGI2 infusion and PGI2 inhalation markedly decreased the excessively high Ppa and Rl values, with approximate doubling of Q˙, but intravenous PGI2 drastically increased the shunt flow in this patient (Figure 3), with concomitant drop in arterial oxygenation, and a sensation of dyspnea and anginal oppression (Table 3). In contrast, aerosolized PGI2, similar to NO, did not significantly increase shunt flow and increased PaO2 values. NO, however, was not employed owing to possible rebound pulmonary hypertensive crisis on abrupt cessation of the gas flow (21). Aerosolization of iloprost (13.5 μg within 15 min) exerted acute benefits on hemodynamics and gas exchange, comparable to those of inhaled PGI2 (Figure 4), but the effect lasted longer (≈ 90 min). A daily total dose of 135 μg of iloprost, divided in nine aerosol applications (15 μg each) with two 4-h nocturnal intervals, was then continuously administered for 21 mo. The patient was discharged home after 4 wk, and is now performing light housework. Recatheterization after 5 and 12 mo showed a tendency toward improvement of baseline hemodynamics (assessed in the morning after a 6-h interval without nebulization), as well as a maintained acute response to the aerosolization of iloprost without any increase in dosage (Table 3). Exercise tolerance increased, and after 12 mo she performed a 6-min walk of 240 m just before and 314 m just after inhalation of iloprost. Interestingly, lung fibrosis did not progress further as assessed by VC, Dco, and chest X-ray.

In this study, systemic and inhaled vasodilators were applied to patients with significantly increased pulmonary vascular resistance and reduced right ventricular function, partly resulting in reduced cardiac output. In contrast to previous investigations addressing pulmonary vasodilatation in pulmonary hypertension (2, 3, 11, 17, 18), all of our patients suffered from severe interstitial lung disease with severe gas exchange abnormalities (mean CO diffusion capacity, ≈ 26%). Seven of the eight patients were receiving long-term oxygen therapy (mostly 24 h/d). To the best of our knowledge, this is the first investigation to compare the effects of different vasodilators in a population of patients with interstitial fibrosis accompanied by pulmonary hypertension.

The contribution of increased right ventricular afterload to the reduction of exercise tolerance in the individual patient is difficult to assess, although pulmonary hypertension was found to be the most common cause of death in systemic sclerosis (1). In our patient with decompensated right ventricular failure due to a collagen vascular disease, it was evident that restriction of circulation was predominant over the restriction of ventilation. On persistent reduction of the pulmonary vascular resistance with concomitant increase in cardiac output, this patient improved from a state of being confined to bed to a 6-min walking distance of 314 m, although lung restriction (reduced vital capacity, FEV1) and gas exchange abnormalities (CO diffusion) were entirely unchanged. This finding impressively supports the concept that lowering of the pulmonary resistance is a worthwhile goal in secondary pulmonary hypertension as long as arterial oxygenation and systemic pressure are not compromised.

As anticipated for pulmonary hypertension secondary to lung parenchymal disease, nasal oxygen supply effected a moderate yet significant decrease in Ppa. A detailed analysis of the hemodynamic data did, however, disclose that this effect was only partially due to a relaxation of the pulmonary vasculature, with Rl values being only minimally lowered. More importantly, the relief of systemic hypoxia caused a significant decrease in heart rate, most probably reflecting reduced sympathetic tone, with slightly decreased cardiac output. An “oxygen challenge” is thus clearly insufficient to discriminate between the reversible (vasoconstriction related) and the “fixed” component of the secondary pulmonary hypertension in lung fibrosis.

Inhaled NO significantly reduced Rl by ≈ 25%, with a concomitant Ppa decrease and increase in RVEF as a consequence of reduced right ventricular load. Q˙ was slightly increased and Pa values were not significantly altered. This corresponds to a profile of selective pulmonary vasodilatation, as anticipated for NO, and this was also reflected by the significant decrease in the Rl/Rva ratio. The response to NO in these patients with secondary pulmonary hypertension is thus similar to that in PPH patients (17, 18, 22) and in scleroderma patients suffering from “isolated” pulmonary hypertension (11). As reported from these previous investigations, the NO-induced changes in hemodynamics returned to baseline values within 2–5 min after cessation of inhalation.

In contrast to NO, infused prostacyclin drastically reduced both Rl and Rva, resulting in an unchanged Rl/Rva ratio. Pa was significantly decreased, resulting in arterial baroreflex activation with heart rate elevation and overshooting Q˙ increase, which partially antagonized the Ppa decrease. Nevertheless, improved right ventricular function was demonstrated by increased RVEF. Most disadvantageously, however, systemic prostacyclin administration caused a substantial increase in shunt flow in these patients with fibrosis-related secondary pulmonary hypertension, with concomitant drop in PaO2 despite enhanced central venous oxygen saturation. As repetitive measurements to establish dose–effect curves for intravenous PGI2 were not undertaken, it may not be excluded that the ratio of beneficial to adverse effects of this approach might have been more favorable at a lower dose of infused PGI2. At the highest tolerated dose of intravenously administered PGI2, effecting an Rl decrease equivalent to that in response to inhaled prostacyclin, the more disadvantageous effect of the intravenous application on gas exchange was obvious, accompanied by a sensation of dyspnea and oppression in some patients. This does not exclude the possibility that long-term effects of prostacyclin, particularly at lower doses, may be beneficial to such patients. Nevertheless, in our patient with decompensated right heart failure, we were not able to establish a long-term treatment with PGI2 owing to severe worsening of gas exchange.

Similar to intravenous PGI2, CAAs effected a nonselective decrease in both Rl and Rva, with an unchanged Rl/Rva ratio. As cardiac output was not as markedly increased as noted in response to prostacyclin infusion, the drop in systemic arterial pressure was more prominent for the CAAs as compared with all other vasodilatory regimens. Interestingly, however, there was only a minor, insignificant increase in shunt flow. The reason for this better conservation of the ventilation–perfusion matching in response to systemically applied CAAs as compared with intravenous prostacyclin in this group of patients with fibrosis is currently not known. One hypothesis is that shunt vessels are more sensitive to PGI2 than to calcium antagonists; an alternative explanation could be that with calcium antagonists the highest tolerated dose was not titrated in this study. Aerosol application of PGI2 caused the most pronounced decrease in Ppa among all vasodilator challenges investigated. Similar to NO inhalation, a marked drop in the Rl/ Rva ratio was noted, which indicated predominant, although not exclusive, selectivity of the vasodilator effect for the pulmonary circulation. In marked contrast to infused prostacyclin, shunt flow was not significantly increased. These findings are consistent with our previous suggestion that aerosolization of PGI2 allows targeting of the vasorelaxant properties to lung vessels in well-ventilated areas (12, 13, 15, 17). The increase in cardiac output, which surpasses that in response to NO, may be explained by a more marked relief of the right ventricular afterload, but also by a minor reduction in Rva, most probably owing to some spillover of the prostaglandin into the systemic circulation. Nevertheless, the marked pulmonary vasodilatation during PGI2 inhalation concomitant with significant hemodynamic differences between aerosolized and infused PGI2 suggests that an alveolar deposition of the drug along with marked regional vasodilatation was achieved, with only minor systemic drug effects. The notion that preferential pulmonary vasodilatation is achieved by the aerosolization technique is also supported by the absence of typical side effects attributed to infused prostacyclin, i.e., flushing, headache, jaw pain, and/ or diarrhea.

In the patient presenting with decompensated right heart failure, the difference between the efficacy profiles of infused and inhaled PGI2 was most prominent. Prostacylin infusion caused a drastic increase in shunt flow, which at the given ventilatory restriction resulted in dyspnea and thoracic oppression not tolerated by the patient, whereas PGI2 nebulization resulted in a reduction in Rl to about one-third of the baseline value and in near doubling of cardiac output while conserving ventilation–perfusion matching. The same hemodynamic and gas exchange profile was achieved by aerosolization of iloprost, however, with longer lasting effect. After termination of aerosol inhalation, PGI2-induced changes returned to baseline within 10–30 min and those in response to iloprost within 60– 120 min. In view of the poor clinical state of the patient and the favorable response to inhaled iloprost, long-term treatment with daily repetitive iloprost inhalation was started. The drug was well tolerated, and an impressive improvement in the clinical state over the subsequent 18-mo observation period was noted. Interestingly, in addition to some moderate baseline hemodynamics (preinhalation) the acute reactivity to the prostaglandin aerosolization was maintained, obviating any need to increase the dosage. Overshooting “rebound” pulmonary hypertension, as observed on cessation of continuous NO inhalation (21), was not observed during the nocturnal interruption of iloprost inhalation. However, more data on the chronic effect of iloprost are mandatory with regard to the fact that acute vasodilatory efficacy and benefit on chronic use may be correlated.

We conclude that in severe pulmonary hypertension secondary to lung fibrosis, a considerable percentage of the lung vascular resistance increase is apparently caused by persistent vasoconstriction, which may be acutely antagonized by CAAs, intravenous PGI2, inhaled NO, and inhaled PGI2. The most profitable profile of changes in terms of hemodynamics and gas exchange was achieved by aerosolization of PGI2 or its stable analog, iloprost. Daily repetitive iloprost administration may be considered as a new approach for long-term therapy in severe secondary pulmonary hypertension, particularly in those patients not tolerating systemic vasodilator therapy because of enhanced shunting and drop in systemic arterial pressure. Long-term studies addressing chronic effects of inhaled iloprost in those patients are requested.

The authors thank Jens Bier for excellent technical assistance in the MIGET laboratory, Wolfgang Pabst (Institute for Medical Statistics, Justus-Liebig-University, Giessen) for the statistics, and Mary Kay Steen-Mueller, M.D., for carefully reviewing the manuscript.

This study was supported by the Deutsche Forschungsgemeinschaft, Klinische Forschergruppe Respiratorische Insuffizienz.

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Correspondence and requests for reprints should be addressed to Dr. Horst Olschewski, Department of Internal Medicine II, Justus-Liebig-University, Klinikstr. 36, D-35392 Giessen, Germany. E-mail:


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