Pulmonary hypertension (PH) is a complex, multidisciplinary disorder, characterized by abnormal high pulmonary vascular pressure. It is defined by a mean pulmonary artery pressure (PAP) >25 mmHg at rest. If untreated, right heart dysfunction or even death will ultimately occur. Pulmonary arterial hypertension (PAH) is the first classification of PH and has always been the focus of PH. PAH is a panvasculopathy predominantly affecting small pulmonary arteries and is characterized by a variety of arterial abnormalities, including intimal hyperplasia, medial hypertrophy, adventitial proliferation, thrombosis in situ, varying degrees of inflammation, and plexiform arteriopathy.1
In line with the international expert consensus and guidelines,1–3 acute vasoreactivity was tested in order to identify PAH patients with a better prognosis and more likely to have a sustained beneficial response to oral calcium channel blockers. Such responders could be treated with less expensive calcium channel blockers rather than prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors. Therefore, acute vasoreactivity testing is especially important in developing countries such as China. For acute vasodilator testing, the guidelines recommend inhaled nitric oxide, intravenous epoprostenol, or adenosine. Of these three, only adenosine is available in China. However, based on our and others' experiences, intravenous adenosine often causes severe systemic hypotension and other intolerable adverse effects when dosage is increased to higher levels.4,5 The tolerated dose of adenosine is much lower than the dose recommended elsewhere, especially in Chinese patients.5
Prostacyclin synthase is reduced in lungs of PAH patients, resulting in inadequate production of the vasodilator prostacyclin-I2.6 Administering prostanoids has been a mainstay of PAH therapy for many years. Iloprost is a stable, short-acting carbacyclin analog of prostacyclin with a plasma half-life of 20-30 minutes.7 It has been widely used for acute pulmonary vasoreactivity testing in many medical centers.5,8 Since most tests have been performed in idiopathic PAH, little was known of the responses in PH due to other etiologies. Therefore, we investigated the acute hemodynamic and oxygenation responses and tolerability to inhaled Iloprost in Chinese patients with various types of PH and whether the responses to Iloprost were dependent on the specific causes of PH.
Between March 2005 and May 2010, PH patients who agreed to undergo acute vasoreactivity testing with inhalation of aerosolized Iloprost (Ventavis, Bayer-Schering Pharma, Madrid, Spain) were consecutively enrolled in this study. Patients with PH due to left heart disease or with a pulmonary capillary wedge pressure >15 mmHg were not included. PH was confirmed at rest by right heart catheterization. To find the etiology of PH, the following were obtained in every patient: thorough individual and family histories, physical examinations, electrocardiography, serological tests for connective tissue disease, HIV infection or hepatitis, echocardiography for congenital heart disease or left heart disease, chest radiography, computed tomography and pulmonary function test for lung disease, pulmonary scintigraphy and computed tomography for chronic thromboembolic PH, and comprehensive thyroid and liver function test for thyroid and liver diseases. This study was approved by the institutional review board of Fuwai Hospital (Beijing, China).
Hemodynamic measurements and blood gas analyses
All patients were hospitalized and provided written informed consents. Oral anticoagulant was stopped until international normalized ratio of prothrombin time was below 1.5. Patients were routinely given 5 mg diazepam on the night before vasoreactivity testing and were taken to the catheterization lab half an hour in advance for adaptation. With local anesthesia under continuous electrocardiographic monitoring, a 6 French pigtail catheter or 7 French Swan-Ganz catheter (Edwards Lifesciences World Trade Co. Ltd, Irvine, CA, USA) was advanced into the pulmonary artery through the right femoral vein or right internal jugular vein by placement of a 6 or 7 French vascular sheath. The catheter was flushed with heparinized normal saline. Correct catheter positioning was verified by fluoroscopy. Transducers were positioned at the midaxillary line and zeroed at the atmospheric pressure. The patients were equilibrated for about 10 minutes before the following hemodynamic measurements and blood gas analyses were made: cardiac output, stroke volume, total pulmonary resistance, systemic vascular resistance, mixed venous blood oxygen saturation (SvO2), and systemic arterial blood oxygen saturation (SaO2). Cardiac index and stroke volume index were calculated by dividing the cardiac output and stroke volume by body surface area. These measurements were obtained twice: at baseline and again after inhalation completion. To determine the time courses of the effects of inhaled Iloprost on hemodynamic parameters, heart rate, systolic, diastolic and mean PAP, and noninvasive systolic, diastolic and mean systemic blood pressure (SBP) were recorded at baseline and 1, 3, 5, 10, and 15 minutes after initiation of inhalation.
After baseline hemodynamic measurements and blood gas analyses, 20 μg of Iloprost were delivered by a PARI LC STAR nebulizer (PARI GmbH, Starnberg, Germany) driven by a PARI TurboBOY-N compressor (PARI GmbH). This combination produced aerosolized particles with a mass median aerodynamic diameter of 2.2 μm with 89% of the mass fraction <5 μm.5 The patients were asked to breathe slowly and more deeply than usual when inhaling Iloprost. The inhalation lasted for 10-15 minutes, during which time PAP, SBP, and electrocardiography were monitored. All adverse events that occurred during inhalation and within 24 hours after inhalation requiring medical care or which caused termination of inhalation were recorded.
Continual variables were expressed as mean ± standard deviation (SD); category variables were usually shown in number and percent unless indicated otherwise. SPSS 13.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The individual pre-inhalation and post-inhalation variables and the global changes from baseline during repeated measurements over 15 minutes after inhalation were compared by analyses of variance for repeated measures. When comparing patients with increased, unchanged, or decreased mean PAP after inhaled Iloprost, analysis of variance was used for continuous variables and LSD-t test was used for multiple comparisons; χ2 tests or Fisher's exact tests for category variables. All tests were two-sided. Values of P <0.05 were considered statistically significant.
There were 71 male (33%) and 141 female (67%) PH patients included in the study, with a mean age of (34.1±12.4) years and mean body surface area of (1.6±0.2) m2. PH was idiopathic PAH in 77 patients (36%), associated with congenital heart disease in 78 (37%), connective tissue disease in 28 (13%), thromboembolism in 21 (10%), and other causes (chronic obstructive pulmonary disease in 3, hereditary hemorrhagic telangiectasia in 2, interstitial lung disease in 1, obstructive sleep apnea in 1, and portal hypertension in 1) in eight (4%). Baseline hemodynamic status demonstrated significant PH since mean PAP was (68.7±21.0) mmHg and total pulmonary resistance was (1747±918) dyn·s·cm-5.
Acute hemodynamic and oxygenation effects of inhalation of Iloprost
The hemodynamic parameters and the oxygenation status at baseline and at the end of Iloprost inhalation are shown in Table 1. Compared to baseline, total pulmonary resistance decreased strikingly (P <0.001), whereas systemic vascular resistance did not change significantly after inhalation of Iloprost (P=0.29). Concurrently, stroke volume, stroke volume index, cardiac output, and cardiac index increased mildly (P=0.002, 0.002, 0.009 and 0.012 respectively). Unexpectedly, SaO2 dropped by (0.7±3.2)% (P=0.002) and SvO2 did not rise significantly (P=0.47).
Over time changes of heart rate, PAP, and SBP
The time courses of heart rate, PAP, and SBP during inhalation of Iloprost are shown in Table 2 and Figure 1. Heart rate was minimally influenced (P=0.29), but systolic, diastolic, mean PAP, and SBP all decreased significantly (P <0.001 for all variables). Compared to baseline, PAP and SBP started to decrease within 1-3 minutes, and decreased rapidly within 5 minutes after starting inhalation, then slowly decreased further. The mean PAP was minimal at 15 minutes, whereas mean SBP was minimal at 10 minutes and mean PAP decreased more significantly than mean SBP. No evident hypotension occurred.
In the analysis of responses among different etiologies of PH, eight patients due to other causes were not included because the sample size was too small. Using absolute change of mean PAP from baseline, we found that patients with idiopathic PAH responded more significantly than patients with congenital heart disease, chronic thromboembolic PH, and connective tissue disease (F=34.52, P <0.001; F=7.14, P=0.001; F=8.08, P <0.001 respectively); and patients with congenital heart disease responded more significantly than patients with chronic thromboembolic PH and connective tissue disease (F=8.29, P <0.001; F=9.03, P <0.001, Figure 2A). The significance remained unchanged using percent change of mean PAP from baseline (Figure 2B).
Response of mean PAP to Iloprost
Patients were divided into three groups according to the response of mean PAP to Iloprost: increased mean PAP (percentage of absolute change of mean PAP >10%), unchanged mean PAP (percentage of absolute change of mean PAP from -10% to 10%), and decreased mean PAP (percentage of absolute change of mean PAP <-10%). Baseline variables of these three groups are shown in Table 3. Patients with increased mean PAP had the highest right atrial pressure (P=0.009 vs. unchanged mean PAP; P=0.001 vs. decreased mean PAP) and the lowest SvO2 (P=0.026 vs. unchanged mean PAP; P <0.001 vs. decreased mean PAP). Patients with decreased mean PAP had lower total pulmonary resistance and systemic vascular resistance and higher cardiac output, cardiac index, stroke volume, and stroke volume index than increased mean PAP (P=0.036 for total pulmonary resistance; P=0.027 for systemic vascular resistance; P=0.001 for cardiac output and cardiac index; P=0.003 for stroke volume and stroke volume index respectively) and unchanged PAP (P <0.001 for total pulmonary resistance; P=0.032 for systemic vascular resistance; P=0.001 for cardiac output and cardiac index; P=0.002 for stroke volume and stroke volume index respectively). Patients with unchanged mean PAP had higher systolic, diastolic, and mean PAP than patients with increased mean PAP (P=0.02, P=0.022, and P=0.005 respectively) and decreased mean PAP (P=0.014, P=0.004, and P=0.005 respectively). And SvO2 and SaO2 were lower in patients with unchanged mean PAP than decreased mean PAP (P=0.005 and 0.014).
Acute vasoreactivity responses
The international guidelines define a positive response as a decrease in mean PAP by at least 10 mmHg to an absolute level of ≤40 mmHg without a decrease in cardiac output.2,3 Only four patients (2%) met these criteria: three females and one male of the age group 28-50 years, all with idiopathic PAH (5% of patients with idiopathic PAH). Mean PAP decreased by more than 10 mmHg in 53 patients, while mean PAP declined to ≤40 mmHg in 12 patients and cardiac output decreased in 28 of these 53 patients. According to the traditional definition of a positive response as more than 20% fall in both mean PAP and pulmonary vascular resistance9–12 (we used total pulmonary resistance instead in this study), only 19 patients (9%) were responders: 4 men and 15 women of the age group 17-60 years, 16 of whom had idiopathic PAH (21% of idiopathic PAH patients) and three had congenital heart disease. In these patients, mean PAP dropped by (40.3±13.5)% and total pulmonary resistance dropped by (38.4±13.0)%, but mean PAP was decreased by less than 10 mmHg in one, mean PAP did not drop below 40 mmHg in eight, and cardiac output decreased in nine.
No adverse events requiring medical care or leading to termination of inhalation occurred during inhalation and within 24 hours after inhalation.
In this study, we investigated the acute effects and tolerability of inhalation of 20 μg Iloprost in Chinese patients with PH, and which categories of PH had more favorable responses. Iloprost significantly decreased PAP and SBP within 1-3 minutes after the beginning of inhalation and reached the maximal effect in the pulmonary artery within 15 minutes and in systemic circulation within 10 minutes. Iloprost preferentially decreased total pulmonary resistance and elevated stroke volume and cardiac output. Patients with idiopathic PAH responded more favorably to Iloprost than PH due to other etiologies. PH patients tolerated inhalation of 20 μg Iloprost well, but marked responses were infrequent.
The acute hemodynamic effects of aerosolized Iloprost on PAP, pulmonary vascular resistance, and cardiac output in our patients were quite similar to previous studies.5,7,13,14 As the plasma half-life of Iloprost is 20-30 minutes,7 it also affects the systemic circulation.15,16 While in our study, systemic vascular resistance did not significantly change and no patient experienced lightheadedness, intolerable hypotension, or significant changes in heart rate. The mechanism of increased stroke volume and cardiac output by prostanoids is not clear. Iloprost may have a direct positive inotropic action,17–19 or may activate the baroreceptor reflex due to systemic vasodilation resulting in an indirect positive inotropic effect.7,20 But it has also been reported that prostanoids could inhibit the sympathetic nerve or blunt its effect.21,22 Treprostinil (one prostanoid) was found to augment the positive inotropic effects of catecholamines, but had no positive inotropic effects of its own.23 This may also apply to Iloprost.
In a few studies, Iloprost inhalation increased SaO2 and SvO2 in PAH patients.5,7 However, we found that SaO2 fell slightly after inhalation perhaps due to increased perfusion of poorly ventilated airspaces just as what was found in healthy volunteers.24 Our findings agree with those of Krug et al's study in chronic thromboembolic PH,25 although they postulated that Iloprost-induced increased right to left shunting might be the reason.
Others have also reported that inhalation of Iloprost reached maximal effect in pulmonary arteries within 12-15 minutes,7 which was in accordance with our study. We did not record the PAP after 15 minutes' inhalation time. According to the published literatures, the effect could last for about 1-2 hours.26 This study appears to be the first to demonstrate that patients with idiopathic PAH respond more significantly than those with congenital heart disease and both more significantly than those with chronic thromboembolic PH and connective tissue disease.
In the present study, patients with increased mean PAP after inhalation had the highest right atrial pressure and the lowest SvO2, and patients in whom mean PAP decreased after inhalation had the highest cardiac output and the lowest total pulmonary resistance and systemic vascular resistance. This indicates that patients with less severe PH have better acute pulmonary hemodynamic responses to inhalation of Iloprost. Cardiac index, SvO2, and right atrial pressure could predict the prognosis of PAH patients1 and may also be used as a predictor for the response to Iloprost.
The definition of a positive response is still controversial. According to the definition of the international guidelines,2,3 only four (2%) PH patients met their criteria of responders, all with idiopathic PAH. In our 77 patients with idiopathic PAH, the rate of 5% responders was lower than that reported elsewhere.5,27,28 Based on the traditional definition (more than 20% fall in both mean PAP and pulmonary vascular resistance9–12), 19 of our patients (9%) were responders and 16 had idiopathic PAH. Twenty-one percent of responders in idiopathic PAH is comparable to the rate of 12.6%-55% in other series.9–11 Evidence in other studies of responders to vasodilators are rare among PH groups than idiopathic PAH and is further verified in our study.29–31
Our study showed that inhalation of Iloprost is well-tolerated and safe. In one study of Chinese patients with idiopathic PAH, 2.7% patients experienced increased cough and hypotension, but none of them were intolerable.5 In Hoeper et al's study,7 five of 35 patients with primary PAH developed minor headache and facial flush and one patient complained of mild jaw pain.
There were limitations in our study. First, PH patients other than idiopathic PAH, PAH due to congenital heart disease and connective tissue disease, and PH due to thromboembolism were rarely or not included, so that the findings of this study may not be applicable to PH due to other causes. Second, we recorded the changes of hemodynamic variables for only 15 minutes, so we do not know how long these hemodynamic changes persisted. But according to our prior experiences and the findings of others, adverse effects after 15 minutes are unlikely.
Inhalation of 20 μg Iloprost showed potent and selective pulmonary hemodynamic effects in Chinese PH patients. Patients with idiopathic PAH and less severe PH responded more favorably to inhalation of Iloprost. And PH patients tolerated inhalation of 20 μg Iloprost well, but the rate of marked responses to inhaled Iloprost is low.
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