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`Inhaled Prostacyclin and Iloprost in Severe Pulmonary
`Hypertension Secondary to Lung Fibrosis
`HORST OLSCHEWSKI, H. ARDESCHIR GHOFRANI, DIETER WALMRATH, RALPH SCHERMULY,
`BETTINA TEMMESFELD-WOLLBRÜCK, FRIEDRICH GRIMMINGER, and WERNER SEEGER
`
`Depatment of Internal Medicine II, Justus-Liebig-University, Giessen, Germany
`
`Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is dif-
`ficult 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)I
` caused
`2
`⫾
`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 (R
`) from 810
` 226 to 386
` 69 dyn
`s
`L
`⫺
`5
`⬍
`cm
` (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. In-
`⫾
`haled NO similarly resulted in selective pulmonary vasodilatation, with R
` decreasing from 726
` 217
`L
`⫺
`5
`⫾
` ⭈
`⭈
`to 458
` 81 dyn
`s
`cm
`. In contrast, both intravenous PGI
` and CAAs were not pulmonary selective,
`2
`resulting in a significant drop in arterial pressure. In addition, PGI
` infusion caused a marked increase
`2
`in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI
` analog) resulted in un-
`2
`equivocal clinical improvement from a state of immobilization and severe resting dyspnea in a pa-
`tient with decompensated right heart failure. We concluded that, in pulmonary hypertension second-
`ary to lung fibrosis, aerosolization of PGI
` or iloprost causes marked pulmonary vasodilatation with
`2
`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.
`Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld-Wollbrück B,
`Grimminger F, Seeger W. Inhaled prostacyclin and iloprost in severe pulmonary hypertension
`secondary to lung fibrosis.
`AM J RESPIR CRIT CARE MED 1999;160:600–607.
`
`severe systemic hypotension in these patients if cardiac output
`) Any systemic administration
`is not adequately increased. (
`2
`of vasodilators may increase the blood flow to low or nonven-
`tilated lung areas by interfering with the physiological hypoxic
`vasoconstrictor mechanism, thereby worsening preexistent
`·Q
`ventilation (
`)/perfusion (
`) mismatch and shunt (5), result-
`ing in arterial hypoxia and wasting of the small ventilatory re-
`serve of these patients.
`Selective pulmonary vasodilatation by inhalation of the va-
`sorelaxant agent is an appealing concept to circumvent some
`of the hazards inherent in systemic vasodilator therapy in pul-
`monary hypertension. The feasibility of this concept was dem-
`onstrated 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 hyperten-
`sion that is characterized by severe pulmonary hypertension
`without interstitial lung disease (11). By employing an aerosol
`technique, our group demonstrated that the concept of pulmo-
`nary selectivity may be extended to inhalation of aerosolized
`, PGI
`) (12, 13): in patients with
`prostacylin (prostaglandin I
`2
`2
` caused pulmo-
`ARDS both intravenous and aerosolized PGI
`2
`nary vasodilatation; however, the former deteriorated whereas
`the latter improved shunt flow and gas exchange. This corre-
`sponds to studies of experimental pulmonary hypertension,
`
`V·
`
`Lung fibrosis of various etiologies is often associated with pul-
`monary 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 pa-
`tients (2–4). However, in the presence of lung fibrosis, any sys-
`temic vasodilator therapy may be hampered by two draw-
`) The percentage of increased pulmonary vascular
`backs. (
`1
`resistance that is due to fibrotic and thus “fixed” remodeling
`processes, compared with the percentage caused by vasocon-
`striction, is unknown. Systemic vasodilatation due to medica-
`tions in the absence of pulmonary vasodilatation may provoke
`
`)
`Received in original form October 2, 1998 and in revised form March 15, 1999
`(
`This study was supported by the Deutsche Forschungsgemeinschaft, Klinische
`Forschergruppe Respiratorische Insuffizienz.
`Correspondence and requests for reprints should be addressed to Dr. Horst Ols-
`chewski, Department of Internal Medicine II, Justus-Liebig-University, Klinikstr.
`36, D-35392 Giessen, Germany. E-mail: horst.olschewski@innere.med. unigiessen.de
`Am J Respir Crit Care Med Vol 160. pp 600–607, 1999
`Internet address: www.atsjournals.org
`
`
`
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`Olschewski, Ghofrani, Walmrath, et al.: Inhaled Prostanoids in Secondary Pulmonary Hypertension
`
`
`
`601
`
`) of 26% rel-
`tal capacity (VC) of 48% and CO-diffusing capacity (D
`CO
`ative 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 re-
`ceived low-dose diltiazem for several years, but validation of this ap-
`proach had never been performed. None of the patients were antico-
`agulated or treated with other vasodilatory agents. Underlying causes
`for pulmonary hypertension other than parenchymal lung diseases
`were excluded by transthoracic and transesophageal echocardio-
`⫽
` 8), ventilation and perfusion pulmonary nuclear scintig-
`graphy (n
`⫽
` 8), and pulmonary angiogram (patient F).
`raphy (n
`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 de-
`compensating 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 vascu-
`lar disease resulting in progressive lung fibrosis with continuous re-
`. Exercise tolerance had been declining more
`duction of VC and D
`CO
`rapidly in the previous 12 mo. She had been treated with high-dose
`corticosteroids and azathioprine, and subsequently with bolus applica-
`2
`, 4 wk apart) with-
`tion of cyclophosphamide (two boluses with 1 g/m
`out clinical benefit. Current therapy included high-dose corticoste-
`roids, 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 Health-
`care, Irvine, CA) was inserted to measure central venous pressure (Pcv),
`pulmonary artery pressure (Ppa), pulmonary artery wedge pressure
`(Ppa,we), cardiac output ( ; thermodilution technique), right ventric-
`ular ejection fraction (RVEF), and central venous oxygen saturation
`). A femoral artery catheter was used to assess mean arterial
`(Sv
`O
`2
`pressure (
`) and to draw arterial blood samples. The pulmonary
`Pa
`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, hal-
`othane, diethyl ether, and acetone were used to determine the pattern
`of ventilation and perfusion distributions (multiple inert gas elimina-
`tion technique, MIGET) as described in detail by Wagner and co-
`
`Q.
`
`wherein selective vasodilatation in the pulmonary vascular
` (14). Subsequent stud-
`bed was achieved by aerosolized PGI
`2
`ies in patients with ARDS and severe pneumonia demon-
` resulted in
`strated that inhalation of NO and aerosolized PGI
`2
`comparable hemodynamic and gas exchange effects (15, 16).
`By employing this approach in patients with PPH and ex-
`cessive pulmonary hypertension, we found that aerosolization
` or its stable analog, iloprost, effected equipotent pul-
`of PGI
`2
`monary vasodilatation to the maximum tolerable dose of in-
`travenous prostacyclin, but induced fewer systemic side effects
`(17). In these patients, prostacyclin appeared to be more po-
`tent than NO in decreasing pulmonary resistance, correspond-
`ing 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 pul-
`monary 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 sys-
`temic and inhalative vasodilators, NO and intravenous and in-
` and systemic calcium
`haled prostacyclin, in comparison with O
`2
`antagonists in patients with severe pulmonary hypertension
`associated with interstitial lung diseases of differing etiologies.
`
`METHODS
`Patients
`Eight patients with lung fibrosis and pulmonary hypertension, who
`were referred to the Division of Pulmonary and Critical Care (De-
`partment 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 pulmo-
`⬎
` 30 mm Hg as measured by catheter investiga-
`nary mean pressure
`tion, 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, postradia-
`tion lung fibrosis, and idiopathic pulmonary fibrosis (Table 1). The di-
`agnosis of these diseases was based on history, lung function testing,
`chest X-ray, and high-resolution computed tomography, which dem-
`onstrated at least medium-grade bilateral interstitial fibrosis in all pa-
`tients. Flexible bronchoscopy with biopsy and bronchoalveolar lavage
`was performed in five patients. All suffered from significant lung re-
`striction or severe restriction in gas exchange capacity, with a mean vi-
`
`TABLE 1
`BASELINE CHARACTERISTICS AND LUNG FUNCTION
`
`Underlying
`Disease
`
`Sex
`
`EAA
`SS
`CREST
`EAA
`BPD
`CVOL
`PRT
`IPF
`
`F
`M
`M
`M
`F
`F
`F
`M
`
`Patient
`
`A
`B
`C
`D
`E
`F
`G
`H
`Mean
`
`Age
`(
`yr
`)
`
`30
`54
`59
`59
`38
`27
`25
`75
`45.9
`
`Height
`
`
`(cm)
`
`Weight
`
`
`(kg)
`
`VC
`
`Liters
`
`% pred
`
`156
`170
`174
`172
`160
`164
`162
`180
`167.3
`
`78
`51
`70
`76
`40
`65
`74
`79
`66.6
`
`1.25
`2.17
`3.19
`1.69
`0.68
`1.21
`1.52
`3.92
`2.0
`
`37.1
`51.5
`71.9
`40.2
`20.8
`32.3
`41.5
`87.6
`47.9
`
`1
`
`FEV
`
`(L
`)
`
`1.04
`1.68
`1.96
`1.52
`0.66
`1.16
`1.12
`2.27
`1.4
`
`c
`D
`CO
`(
`
`%)
`
`25.3
`17.1
`27.5
`13
`ND
`28.2
`61.6
`11.8
`26.4
`
`P
`O2
`(mm Hg
`
`
`
`)
`
`P
`CO2
`(mm Hg
`
`
`
`)
`
`59
`60
`58
`47.9
`45
`49.7
`75.4
`42
`54.6
`
`37.2
`31.1
`36.3
`37.6
`51.6
`28
`42.6
`36.7
`37.6
`
`⫽
`⫽
` bronchopulmonary dysplasia after premature birth and long-term ventilation; CREST
`Definition of abbreviations: BPD
`
` calcinosis, the
`⫽
`Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia; CVOL
` collagen vascular overlap syndrome (
`
`see text);
`D
`c, diffusion capacity for CO gas, corrected for the actual hemoglobin concentration, given as a percentage of predicted values, cor-
`CO
`⬎
` ⬍
`rected 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; FEV
`
` forced expiratory volume within 1 s; IPF
` idiopathic pulmonary fibrosis; M
`1
`⫽
`⫽
`⫽
`male; ND
` not determined; P
`and P
`
` resting arterial oxygen and carbon dioxide partial pressure during oxygen pause; PRT
` post-
`O
`CO
`2
`2
`radiation 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.
`
`
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`AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 160 1999
`
`R
`/Rva
`L
`
`Shunt
`
`
`(%)
`
`TABLE 2
`BASELINE HEMODYNAMICS
`
`Q·
`
`
`
`(L/min)
`
`Ppa
`
`
`(mm Hg)
`
`Ppa,we
`
`(mm Hg
`)
`
`R
`L
`5
`⭈
`s)/cm
`[(dyn
`]
`
`
`
`A
`B
`C
`D
`E
`F
`G
`H
`Mean
`
`4.6
`3.5
`3.4
`7.5
`4.7
`2.7
`4.4
`7.4
`4.8
`
`36
`30
`51
`32
`50
`55
`38
`30
`40.2
`
`10
`4
`12
`5
`3
`6
`11
`5
`7.0
`
`457
`570
`931
`288
`800
`1,468
`488
`285
`660
`
`RVEF
`
`
`(%)
`
`31
`9
`8
`22
`30
`7
`30
`26
`20.4
`
`Pcv
`(mm Hg
`
`
`
`)
`
`HR
`⫺
`1
`(min
`)
`
`
`
`Pa
`
`
`(mm Hg)
`
`5
`5
`11
`3
`⫺
`3
`16
`5
`⫺
`1
`5.1
`
`55
`100
`82
`84
`96
`108
`103
`112
`92.5
`
`94
`68
`114
`115
`114
`117
`91
`60
`96.6
`
`0.292
`0.397
`0.379
`0.241
`0.402
`0.485
`0.314
`0.410
`0.365
`
`0.32
`4.8
`3.6
`26.4
`ND
`3.6
`ND
`9.9
`8.1
`
`⫽
`⫽
`⫽
`⫽
`Ppa
` central venous pressure;
` mean systemic arterial pressure; Pcv
`
` heart rate;
`Definition of abbreviations: HR
`
`
` mean pulmonary
`Pa
`Q·
`⫽
`⫽
`⫽
`⫽
`artery pressure; Ppa,we
` pulmonary artery wedge pressure;
`
` cardiac output; R
`
` pulmonary vascular resistance; R
`/Rva
` R
`/Rva (sys-
`L
`L
`L
`⫽
`⫽
`temic 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.
`
`workers (20). Concerning the patients with long-term CAA therapy,
`the agent was discontinued 48 h before the test in patient H and con-
`tinued in patient B, who had suffered from right ventricular decom-
`pensation before therapy with felodipine.
`
`Test Procedure
`In patients receiving long-term oxygen therapy (seven patients), cath-
`eterization was performed with ongoing nasal oxygen. Oxygen deliv-
`ery was then stopped for 20 min, and baseline values were deter-
`mined. 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 main-
`tain 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 con-
`stant dose, a complete set of hemodynamic measurements was per-
`formed. Intravenous prostacyclin (epoprostenol sodium; Wellcome
`Research Laboratories, Beckenham, Kent, UK) was increased in in-
`crements of 2 (ng/kg)/min until patients experienced discomfort (tho-
`
`racic oppression, heat, headache) or until mean arterial pressure de-
`creased 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 min-
`utes after finding the highest tolerated dose, during continuous PGI
`2
`infusion, a complete set of hemodynamic measurements was per-
`␮
`g/ml),
`formed. Aerosolized prostacyclin, diluted in glycine buffer (50
`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 diame-
`␮
`m; geometric SD of 2.6, ascertained by impactor
`ter of particles, 3.5
`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 (to-
`␮
`g), depending on systemic pressure and
`tal nebulized dose, 54 to 68
`fingertip oximetry. Hemodynamic measurements were performed ev-
`ery 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 pa-
`tients. Nifedipine, 10 to 20 mg, was administered sublingually (pa-
`tients 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 dur-
`
`TABLE 3
`ACUTE RESPONSE OF A PATIENT WITH DECOMPENSATED RIGHT HEART
`FAILURE TO VASODILATORY THERAPY*
`
`Ppa
`
`mm Hg)
`
`(
`
`R
`L
`⭈
`s)/cm
`[(dyn
`
`
`5
`]
`
`RVEF
`(
`
`%)
`
`Pcv
`(mm Hg
`
`
`
`)
`
`HR
`⫺
`1
`min
`)
`
`(
`
`Pa
`(mm Hg
`
`
`)
`
`Pa
`O2
`
`
`mm Hg)
`
`(
`
`Shunt
`
`
`(%)
`
`Q·
`
`(
`
`L/min
`
`)
`
`Before NO
`During NO
`, intravenous
`Before PGI
`2
`, intravenous
`During PGI
`2
`Before PGI
`, aerosolized
`2
`, aerosolized
`During PGI
`2
`Before nifedipine
`After nifedipine
`After 5 mo
`Before iloprost, aerosolized
`During iloprost, aerosolized
`After 12 mo
`Before iloprost, aerosolized
`During iloprost, aerosolized
`
`2.1
`5.0
`2.4
`6.0
`2.5
`4.7
`2.1
`3.3
`
`2.9
`5.3
`
`2.9
`4.1
`
`65
`44
`59
`42
`65
`45
`64
`51
`
`57
`44
`
`53
`50
`
`2,243
`774
`1,789
`470
`2,179
`644
`2,375
`955
`
`1,452
`604
`
`1,311
`882
`
`7
`15
`9
`20
`7
`20.5
`9
`10
`
`9
`24
`
`10
`19
`
`18
`10
`19
`10
`18
`9.5
`19
`16
`
`12
`3
`
`9
`2
`
`113
`90
`111
`102
`113
`93
`104
`108
`
`100
`90
`
`93
`92
`
`110
`120
`121
`105
`112
`113
`118
`94
`
`91
`84
`
`104
`97
`
`69.4
`88.6
`71.9
`62
`74.6
`81.5
`70.7
`74.5
`
`66
`73
`
`53
`58
`
`3.6
`6.3
`5.1
`23.1
`2.4
`5.6
`3.4
`3.7
`
`—
`—
`
`—
`—
`
`Definition of abbreviations: see Tables 1 and 2.
`
`
`
`* Response to NO, intravenous PGI
`, aerosolized PGI
`, and nifedipine during the first test trial and after 5 and 12 mo of iloprost inhala-
`2
`2
`tion in patient F. Measurements on the first day were performed during continuous oxygen flow (4 L/min); during subsequent trials, mea-
`surements were performed without nasal oxygen supply.
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`Olschewski, Ghofrani, Walmrath, et al.: Inhaled Prostanoids in Secondary Pulmonary Hypertension
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`603
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`Figure 1. Acute responses to oxygen, NO, intravenously administered and inhaled prostacyclin (PGI i.v.
`and PGI aero, respectively) in eight patients, and to calcium antagonists (CAAs) in six patients. Dark col-
`umns and light columns give mean values ⫾ SE before and after drug administration, respectively, for arte-
`rial oxygen saturation (SaO2), right-to-left shunt flow (as a percentage of pulmonary blood flow; SHUNT),
`right ventricular ejection fraction (RVEF), and central venous pressure (CVP). p ⫽ significance level for dif-
`ferences in the responses to the various agents (ANOVA for the intrapair differences); * ⫽ significant differ-
`ence pre- and postapplication, p ⬍ 0.05; ⫹ ⫽ significant linear contrast between responses to different
`agents (Scheffé test, p ⬍ 0.05).
`
`Oxygen
`During high-dose oxygen inhalation, PaO2 increased to an av-
`erage 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
` decreased from 40.1 ⫾
`Ppa
`3.4 to 37.5 ⫾ 3.9 mm Hg (p ⬍ 0.05; Figure 2). All other hemo-
`dynamic and gas exchange variables were not significantly al-
`tered. Continuous low-flow nasal oxygen was then administered
`to maintain baseline SaO2 values above 85% (see increased
`baseline SaO2 data in the following tests).
`NO
` from 39.8 ⫾ 4.3 to
`Ppa
`Inhaled NO significantly decreased
`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
`·Q
` from 4.9 ⫾ 0.7 to 7.1 ⫾ 1.0
`Prostacyclin infusion increased
`L/min (p ⬍ 0.01) and significantly decreased both
`Ppa
` from
`39.6 ⫾ 4.9 to 33.6 ⫾ 3.0 and
` from 93.1 ⫾ 7.3 to 81.6 ⫾ 8.1
`Pa
`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 re-
`·Q
`flected
` increase, this marked augmentation of shunt flow
`resulted in only a moderate decrease in SaO2.
`
`ing a 30-min infusion period. Measurements were performed 15 min
`after the end of infusion. Patient G refused to take calcium antago-
`nists owing to intolerance during preceding episodes of treatment
`with these drugs, and patient B was not included owing to continuous
`felodipine therapy.
`
`Statistics
`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
`, pulmonary vascular resis-
`tance [RL], and systemic vascular resistance [Rva] and numerical dif-
`ferences for other parameters) and the Scheffé test was used as an a
`posteriori test for linear contrasts between these differences. The re-
`sponse 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 sig-
`nificance level for the Scheffé test was set at p ⫽ 0.05.
`
`Q.
`
`RESULTS
`Baseline Data
`Ppa
` and RL for all patients were significantly ele-
`Values of
`vated and scattered over a wide range (Table 2). Ppa,we was
`in the normal range, excluding left heart failure as the under-
`·Q
`lying cause of the pulmonary hypertension.
` values were in
`the normal or lower normal range in all patients, except in pa-
`tient F, who presented with low-output syndrome and decom-
`pensated 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 PCO2 values were slightly elevated in only
`one patient.
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`Figure 2. Acute responses to oxygen, NO, intravenously administered and inhaled prostacyclin (PGI i.v.
`and PGI aero, respectively), and calcium antagonists (CAAs). Dark columns and light columns give mean
`values ⫾ SE before and after drug administration, respectively, for mean pulmonary artery pressure (
`),
`Ppa
`pulmonary vascular resistance (RL), ratio of pulmonary to systemic vascular resistance (RL/Rva), mean sys-
`Q·
`temic arterial pressure (
`), cardiac output (
`), and heart rate (HR). For statistics see Figure 1.
`Pa
`
`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
`·Q
` increased from 5.1 ⫾ 0.8 to
`were not significantly reduced.
`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 im-
`·Q
` increased from 4.3 ⫾ 0.8 to 5.4 ⫾
`pressively, Pa values.
`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 de-
`crease in Ppa and RL without systemic side effects, treat-
`ment 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 nega-
`tive inotropic effect of the calcium antagonist suggested by the
`moderate Pcv decrease from 19 to 16 mm Hg despite an after-
`load 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 ap-
`·Q
`, but intravenous PGI2 drastically in-
`proximate doubling of
`creased the shunt flow in this patient (Figure 3), with concom-
`itant drop in arterial oxygenation, and a sensation of dyspnea
`
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`Olschewski, Ghofrani, Walmrath, et al.: Inhaled Prostanoids in Secondary Pulmonary Hypertension
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`605
`
`sistance and reduced right ventricular function, partly result-
`ing in reduced cardiac output. In contrast to previous investi-
`gations 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 ab-
`normalities (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 accompa-
`nied 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 scle-
`rosis (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 vas-
`cular 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 abnormali-
`ties (CO diffusion) were entirely unchanged. This finding im-
`pressively supports the concept that lowering of the pulmo-
`nary 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 ef-
`fect 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 sig-
`nificant decrease in heart rate, most probably reflecting re-
`duced sympathetic tone, with slightly decreased cardiac out-
`put. An “oxygen challenge” is thus clearly insufficient to
`discriminate between the reversible (vasoconstriction related)
`and the “fixed” component of the secondary pulmonary hy-
`pertension in lung fibrosis.
`Inhaled NO significantly reduced RL by ⬇ 25%, with a con-
`comitant Ppa decrease and increase in RVEF as a conse-
`·Q
`quence of reduced right ventricular load.
` was slightly in-
`creased and
` values were not significantly altered. This
`Pa
`corresponds to a profile of selective pulmonary vasodilatation,
`as anticipated for NO, and this was also reflected by the signif-
`icant 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 ac-
`·Q
`tivation with heart rate elevation and overshooting
` in-
`crease, which partially antagonized the Ppa decrease. Never-
`theless, improved right ventricular function was demonstrated
`by increased RVEF. Most disadvantageously, however, sys-
`temic prostacyclin administration caused a substantial in-
`crease in shunt flow in these patients with fibrosis-related sec-
`ondary pulmonary hypertension, with concomitant drop in
`PaO2 despite enhanced central venous oxygen saturation. As
`repetitive measurements to establish dose–effect curves for in-
`
`Figure 3. Dose–response curve of prostacyclin inhalation. PGI2 was
`continuously aerosolized at a rate of 4.5 ␮g/min. Hemodynamic
`measurements were performed before onset of nebulization and
`after 3, 6, and 9 min, i.e., at cumulative nebulized doses of 13.5,
`27, and 40.5 ␮g of PGI2. Aerosolization was terminated after 12–
`15 min, depending on individual side effects (mean arterial pres-
`sure and arterial oxygen saturation [fingertip oximetry] starting to
`decrease) and the final measurement was then immediately per-
`Q·
`formed. Mean values ⫾ SEM are given for eight patients for
`, RL,
`and
`.
`Ppa
`
`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 ilo-
`prost (13.5 ␮g within 15 min) exerted acute benefits on hemo-
`dynamics and gas exchange, comparable to those of inhaled
`PGI2 (Figure 4), but the effect lasted longer (⬇ 90 min). A
`daily total dose of 135 ␮g of iloprost, divided in nine aerosol
`applications (15 ␮g 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 ten-
`dency toward improvement of baseline hemodynamics (as-
`sessed in the morning after a 6-h interval without nebuliza-
`tion), 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.
`
`DISCUSSION
`In this study, systemic and inhaled vasodilators were applied
`to patients with significantly increased pulmonary vascular re-
`
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`Q·
`Figur