a Department of Cardiology, DRK-Kliniken Westend, Medizinische Klinik II, Spandauer Damm 130,14050 Berlin, Germany
b Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum, Berlin, Germany
c Department of Chemistry, Humboldt University, Berlin, Germany
Received February 11, 2002;
accepted April 17, 2002
* Corresponding author. Tel.: +49-30-3035-4305; fax: +49-30-3035-4309
c.opitz{at}drk-kliniken-bln.de
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Abstract |
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Methods and results Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2±3.4ngkg1min1) reduced pulmonary (1772±844 vs 1325±615dynscm5, ) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813±827 vs 1323±614dynscm5,
) and systemic vascular resistance, and pulmonary artery (58±12 vs 50±12mmHg,
) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2±0.5ngkg1min1,
) a decrease in pulmonary (2202±529 vs 1515±356dynscm5,
) and systemic vascular resistance and right atrialpressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4°C) of its active drug concentration.
Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure withoutsystemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.
Key Words: Pulmonary hypertension Prostaglandin Prostacyclin Inhaled iloprost
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1. Introduction |
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The administration of inhaled iloprost, which is a more stable prostacyclin analogue, has been shown to have comparable haemodynamic effects on the pulmonary vascular resistance in these patients.6 Furthermore, significant improvements in functional capacity and ventilatory efficiency have been observed following inhalation of iloprost.7 Although evidence of its effectiveness in terms of improved survival is still lacking there are datathat strengthen the role of iloprost inhalation asan alternative treatment in patients with primary pulmonary hypertension.8 In a few cases iloprost has also been used for continuous intravenous treatment, primarily because of the high cost or even unavailability of prostacyclin.2 The intravenous application of iloprost has the advantage of a longer half-life (23min) compared to prostacyclin, which can be important in case of accidental interruption of the infusion. There are preliminary data suggesting that iloprost, when compared to prostacyclin, may be equally effective for intravenous treatment in pulmonary hypertension.911
However, only one small study directly compared both substances with respect to their acute haemodynamic effects,11 and data describing the differential effects of inhaled vs intravenouslyadministered prostaglandins in patients withprimary pulmonary hypertension are rare.
In this study we compared the acute haemodynamic effects of intravenous iloprost and prostacyclin in patients with primary pulmonaryhypertension. We also compared the acute haemodynamic effects of inhaled iloprost with those of intravenous prostacyclin. The latter was primarily done to differentiate between inhalation-matched selective pulmonary vasodilation and direct systemic vasodilation with increasing cardiac output following intravenous administration. Furthermore, we analysed the stability of iloprost in a solution that is used for chronic intravenoustreatment.
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2. Methods |
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Patients were in median New York Heart Association class III and the 6-min walk test (in 19/21 patients) showed a mean distance of 331±134m. Chronic stable medication consisted of diuretics , oral anticoagulation
, digitalis
, and calcium channel blockers
and was not changed during the study.
2.2. Haemodynamic measurements
Patients underwent right heart catheterization. This was performed via the right internal jugularor the right subclavian veins and an 8 FrenchSwanGanz catheter (Baxter®Swan Ganz IntelliCath) was used. Monitoring of arterial blood pressure and arterial blood gases was undertaken via an arterial line (Vygon leader cath 20G) inserted into the radial artery. Cardiac output (Fick method, estimated oxygen consumption), mean arterial blood pressure, mean pulmonary artery pressure, mean right atrial pressure and pulmonary capillary wedge pressure were measured at baseline and following each of the interventions. Cardiac index, systemic vascular resistance and pulmonary vascular resistance were calculated by the standardformula. In the patients with a patent foramen ovale the pulmonary blood flow was calculated by the Fick method, assuming a pulmonary venous oxygen saturation of 98% at room air and 100% during oxygen supplementation. Accordingly, for the calculation of pulmonary vascular resistance the pulmonary blood flow was used and the ratio of pulmonary blood flow (Qp) to systemic blood flow (Qs) calculated.
2.3. Study protocol
Measurements were started in a quiet atmosphere 1h after the catheters had been inserted. After baseline measurements had been performedpatients were given oxygen via nasal prongs. The minimal dose of oxygen was 3lmin1and was increased up to 8lmin1until an arterial oxygen saturation of 93% was reached. Measurements were performed after the patient had been on a stable dose of oxygen for 10min. Oxygen was then stopped unless the initial arterial oxygen saturation at room air was below 93%; in that case oxygen was continuously administered throughout the remaining study protocol. In the patients in whom oxygen was discontinued, a further baseline measurement was performed 30min after oxygen was discontinued. Intravenous prostacyclin was then started at a dose of 2ngkg1min1. The dose was increased by 2ngkg1min1every 10min until either a fall of mean arterial pressure below 50mmHg or symptomatic side effects (headache, thoracic oppression, severe flush) occurred.
Measurements were obtained at the highesttolerable dose. After 1h (for reestablishment of baseline conditions) iloprost was administered by a jet nebulizer (Iloneb, Nebutec, Germany) at aconcentration of 10µgml1. With an average nebulization rate of 1.7mlmin1, after 10min a cumulative dose of 17µg iloprost had been administered. Measurements were performed within the last minute of inhalation. A cumulative dose of 17µg was chosen because it had been reported as 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 six inhalations.2,6,8 In eight patients intravenous iloprost was started at a dose of 0.5ngkg1min12h after the end of iloprost inhalation. Following this time interval, baseline conditions were re-established since the effects of inhaled iloprost typically last for less than 1h.14 The dose was increased by 0.25ngkg1min1at 90min intervals until either a fall of arterial pressure below 50mmHg or symptomatic side effects (headache, thoracic oppression, flush) occurred. Measurements were obtained at the highest tolerable dose.
The sequence in which these vasodilators were administered could not be randomized due to the contrasting pharmacological properties of the drugs and the resulting logistical constraints. However, each vasodilator application was followed by asufficient wash-out period in order to allow for re-establishment of baseline conditions.
2.4. Measurement of stability of iloprost in saline solution
Iloprost was diluted in 0.9% saline solution (20mg in 20ml) to reach a concentration of 1mgml1, which is the concentration used for chronic treatment in our departments. The iloprost solution was then deposited into commercially available bags (SIMS Deltec, St. Paul, USA) and stored at 4, 20 or 37°C for 4 weeks, respectively. From each solutionsamples were taken on days 0, 5, 15, 23 and 33. The iloprost concentration was determined by fiverepeated measurements using high-performance liquid chromatography (Knauer System, Germany) with UV detection at 205nm (SPD-10A VP,Shimadzy, Japan) and expressed as area under the curve.
2.5. Statistical analysis
Baseline data are expressed as mean±standarddeviation. Changes in haemodynamic parameters before and after each intervention were analysed by paired t-test. To compare the acute haemodynamic effects between the different interventions a paired t-test was used. Data are shown as mean±standard deviation. If data did not follow normal distribution the Wilcoxon signed rank test was used.
2.6. Ethics
The study was approved by the local ethics committee, and all patients gave written informedconsent.
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3. Results |
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3.2.2. Intravenous prostacyclin
Prostacyclin was uptitrated as described. The mean plateau dose was 7.2±3.4ngkg1min1. At this dose a decrease in pulmonary vascular resistance, systemic vascular resistance, arterial pressure and right atrial pressure was observed (Table 1). There was a marked increase in cardiac index and mixed venous oxygen saturation and a less pronounced effect on heart rate (Table 1). No significant changes in pulmonary artery pressure and arterial oxygen saturation occurred (Table 1). In the subgroup of patients with a patent foramen ovale prostacyclin caused a marked increase in pulmonary blood flow Qp (2.6±0.9 vs 3.4±1.2lmin1,) and systemic blood flow Qs (3.3±1 vs 4.6±1.6lmin1,
). There was a marginal decrease in the Qp/Qs ratio (0.8±0.1 vs 0.76±0.13,
). Arterial oxygen saturation did not change in the patients with a patent foramen ovale (91±6 vs 92±6%,
) nor in the patients without a patent foramen ovale (94±3 vs 94±2%,
).
3.3. Inhaled iloprost
The full dose of iloprost could be administered without severe symptomatic side effects in allpatients. Iloprost inhalation resulted in a decrease in pulmonary vascular resistance, systemic vascular resistance, pulmonary artery pressure and right atrial pressure (Table 1). Cardiac index, mixed venous oxygen saturation and arterial oxygen saturation increased significantly (Table 1). There were no significant changes in heart rate and arterial pressure (Table 1). In the 14 patients with a patent foramen ovale, pulmonary blood flow Qp increased from 2.3 to 2.8lmin1 and systemic blood flow Qs from 3.4±1.3 to 3.8±1.3lmin1
. There was no change in the Qp/Qs ratio (0.79±0.13 vs 0.82±0.1,
). In these patients, however, arterial oxygen saturation increased (90±8 vs 93±6%,
), whereas it did not change in those patients without a patent foramen ovale (95±2 vs 95±2.5%,
).
3.3.1. Intravenous iloprost
In eight patients iloprost uptitration was performed. The mean plateau dose achieved was 1.2±0.5ngkg1min1. At the highest tolerable dose we observed a decrease in pulmonary vascular resistance, systemic vascular resistance and right atrial pressure (Table 1). Cardiac index and mixed venous oxygen saturation increased significantly (Table 1). There were no changes in pulmonary artery pressure, arterial pressure, arterial oxygen saturation and heart rate (Table 1). In the patients with a patent foramen ovale (6/8) pulmonary blood flow Qp (1.8±0.3 vs 2.5±0.5lmin1, ) and systemic blood flow Qs (2.7±0.84 vs 3.5±0.7lmin1,
) increased. In these patients the Qp/Qs ratio and arterial oxygen saturation did not change (0.69±0.13 vs 0.72±0.18,
and 88±7 vs 89±8%,
, respectively).
3.4. Comparison between intravenous prostacyclin and inhaled iloprost
The comparison between those parameters that did change significantly during intravenous prostacyclin and inhaled iloprost administration is shown in Table 2. Prostacyclin infusion resulted in significant changes in heart rate (6.5±11%) and arterial pressure (12±11%), whereas both parameters remained stable during iloprost inhalation (3±7 and 2±6%, respectively). Iloprost inhalation resulted in a significant decrease in pulmonary artery pressure (12±11%) and increase in arterial oxygen saturation (2±3%) whereas intravenous prostacyclin did not cause significant changes in either parameter (3±11 and 0.6±3%, respectively).
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4. Discussion |
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4.1. Oxygen
It is unclear whether oxygen should be supplemented in primary pulmonary hypertension in the absence of relevant hypoxia, mainly because there are few studies on acute haemodynamic or long-term effects. Our data show that oxygen has the potential to relieve pulmonary vasoconstriction in primary pulmonary hypertension, which is in agreement with the data of Cockrill et al., who described selective pulmonary vasodilation following oxygen administration in 13 patients with pulmonary hypertension.15 Since alveolar hypoxia is not usually encountered in primary pulmonary hypertension our data suggest that oxygen has vasodilatoryeffects even in the absence of a hypoxic vasoconstrictor stimulus.
The arterial hypoxia present at baseline in our patients can be explained by the rather large proportion of patients with a patent foramen ovale. Oxygen led to a marked increase in arterial oxygen saturation in these patients. In contrast, patients without a patent foramen ovale showed nosignificant increase in arterial oxygen saturation, suggesting that the improvement in arterial oxygenation in patients with a patent foramen ovale during oxygen supplementation results from the increase in pulmonary blood flow and decrease in cardiac right to left shunt, secondary to the decrease in right atrial pressure and pulmonary vascular resistance. This is confirmed by the increase in the Qp/Qs ratio. The indication for the supplementation of oxygen throughout our study was arterial hypoxia (i.e. arterial oxygen saturation <93%). Since therefore a considerable number of ourpatients received background oxygen during the application of the other vasodilatorsthe acute haemodynamic effects of oxygen alone have not been compared with those of the other vasodilators.
4.2. Intravenous prostacyclin vs inhaled iloprost
Despite its beneficial prognostic effects, chronic treatment with prostacyclin carries the risk of certain complications arising from the need for permanent venous access as well as from the systemic side effects of the drug. Inhaled iloprost, in our study, showed an equally pronounced pulmonary vasodilator effect when compared to intravenous prostacyclin. However, we found some differences between the haemodynamic profiles during the two treatments. The increase in cardiac output was much more prominent with prostacyclin than during inhaled iloprost, which has previously been shown for inhaled vs intravenous prostacyclin in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease. In contrast, only inhaled iloprost was able to reduce the pressure within the pulmonary circulation whereas pulmonary artery pressure remained unchanged during prostacyclin infusion (Fig. 1).
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Using selective pulmonary vasodilator treatment these side effects can readily be avoided and observational studies with inhaled iloprost confirm that it can be an alternative treatment for primary pulmonary hypertension.8
However, mortality data are not yet available for this new treatment and in our experience intravenous prostaglandin treatment still seems to be more effective in advanced stages of primary pulmonary hypertension.17 This might result from only intermittent pulmonary vasodilation achieved with iloprost inhalation. With haemodynamic effects lasting for 45 to 120min, theoretically a minimum of 12 inhalations per 24h would be required to achieve continuous haemodynamic efficacy, which is impractical. Despite these pharmacokinetic limitations, frequent iloprost inhalation (12 times per day) has been shown to be a successful rescue therapy in very sick patients with primary pulmonary hypertension.18,19
Another interesting finding of our study is that in patients with a patent foramen ovale the right to left shunt did not decrease during either treatment. This observation deserves some discussion since pulmonary blood flow could not be measured directly.
The high percentage of patients with a patent foramen ovale in our series is probably due to a play of chance in a relatively small sample size. However, previous studies rarely performed routine transoesophageal echocardiography to rule out or confirm this condition.
To obtain accurate values of Qp the oxygen saturation in a pulmonary vein has to be measured, which has not been done in this study. In fact, we believe that this is impossible when a SwanGanz catheter is used in the setting of an intensive care unit, as in our study. Such an approach would require the study to be performed in a catheterization laboratory, which is generally not feasible considering the length of the study protocol. Instead, we used the arbitrary numbers of 98 and 100% for pulmonary venous oxygen saturation at room air and oxygen supplementation, respectively. Considering that the arterial oxygen saturation in our patients without a patent foramen ovale was 9495% this might be an overestimation and the calculated pulmonary blood flow Qp therefore might have been lower than the actual figure. This might explain why we did not observe an increase in the Qp/Qs ratio during iloprost inhalation, although the increase in arterial oxygen saturation suggests a reduction of the right to left shunt. The small decrease in the Qp/Qs ratio seen during prostacyclin administration may arise from the same problem and is even less substantial in view of the stable arterial oxygen saturation. A compensatory increase of pulmonary vein oxygen saturation as a cause of the stable arterial oxygen saturation is highly unlikely since in the patients without apatent foramen ovale arterial oxygen saturation did not improve and prostacyclin is known rather to cause a worsening in pulmonary gas exchange that can even lead to arterial hypoxemia.
4.3. Intravenous prostacyclin vs intravenous iloprost
Iloprost is an analogue of prostacyclin that is characterized by a longer plasma half life (2 vs 23min) and chemical stability in saline solution at room temperature. Although the longer half-life makes the uptitration rather time-consuming it carries the advantage that in case of accidental interruption of the infusion during long-term treatment rebound effects are encountered later. This provides invaluable time for reinstitution of the treatment before rebound occurs.
Higenbottam and colleagues treated eightpatients with pulmonary hypertension (primarypulmonary hypertension in five) intravenously with prostacyclin and iloprost for 3 to 6 weeks, respectively, in a study following a cross-over design. They found comparable effects of the two drugs on parameters of exercise capacity.911 According to our data iloprost matches the pulmonary vasodilation induced by prostacyclin when symptom-limited uptitration is performed in patients with primary pulmonary hypertension. Furthermore, there were no differences between the two drugs with respect to systemic vasodilation, cardiac output or right atrial pressure. This suggests that both drugs are pharmacodynamically almost identical and differ only in their equipotent dose (1.2±0.5 vs 7.2±3.4ngkg1min1, for iloprost and prostacyclin, respectively), which may result from the different half-lives. There were minor differences for changes in heart rate. Prostacyclin caused a significant increase in heart rate (6%), whereas the small increase seen during iloprost administration (4.5%) was non-significant. Similarly, prostacyclin caused a slight fall in aortic pressure whereasiloprost did not (14 vs 0.8%, ). However, for both drugs these effects were non-significant and the comparison is therefore arguable. We would suggest that these differences may well result from the much slower uptitration of iloprost, which is necessary to achieve plateau concentration with the longer half-life.
Our stability data confirm that the salinesolution of iloprost, which is used for chronic treatment, is reasonably stable at room temperature for 5 days and can be refrigerated for 33 days, which avoids the need to cool the infusion pump and allows storage of the solutions for about 1 month. Iloprost is readily available within the European Community and the annual costs of such treatment there are clearly lower than those of intravenous prostacyclin (annual cost: prostacyclin 7.2ngkg1min1, 148 000 Euro; iloprost 1.2ngkg1min1, 130 000 Euro), which is economically important considering the enormous cost of long-term intravenous treatment in primary pulmonary hypertension. In a group of 37 patients with severe primary pulmonary hypertension treated with chronic intravenous iloprost at our institution (unpublished data) we observed full haemodynamic efficacy with intravenous iloprost for up to6 months with a mean dose at follow-up of 1.8±0.6ngkg1min1. When compared to the published data for chronic epoprostenol treatment, these data indicate a stable (if not progressive) difference in potency over time.
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5. Conclusion |
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When directly compared to prostacyclin, intravenous iloprost has comparable haemodynamiceffects. Together with its longer half-life, which may improve the safety profile during chronic treatment, these findings support a role of iloprost as an alternative drug for continuous intravenous prostaglandin treatment in patients with primary pulmonary hypertension. In addition, this approach can have economic advantages in areas where it is available on the market.
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Footnotes |
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References |
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