Abstract
Rationale: Sildenafil, a phosphodiesterase-5 inhibitor, could be useful for treating pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). However, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange in this condition.
Objectives: To assess the acute hemodynamic and gas exchange effects of sildenafil in patients with COPD-associated PH.
Methods: We conducted a randomized, dose comparison trial in 20 patients with COPD-associated PH. Eleven patients were assigned to 20 mg, and 9 patients to 40 mg, of sildenafil. Pulmonary hemodynamics and gas exchange, including ventilation–perfusion () relationships, were assessed at rest and during constant-work rate exercise, before and 1 hour after sildenafil administration.
Measurements and Main Results: Both sildenafil doses reduced the mean pulmonary arterial pressure (PAP) at rest and during exercise, without differences between them. Overall, PAP decreased −6 mm Hg (95% confidence interval [95% CI], −7 to −4) at rest and −11 mm Hg (95% CI, −14 to −8) during exercise. After sildenafil, PaO2 decreased −6 mm Hg (95% CI, −8 to –4) at rest because of increased perfusion in units with low ratio, without differences between doses. No change in PaO2 (95% CI, −3 to 0.2 mm Hg) or relationships occurred during exercise after sildenafil. Changes induced by sildenafil in PaO2 and distributions at rest correlated with their respective values at baseline.
Conclusions: In patients with COPD-associated PH, sildenafil improves pulmonary hemodynamics at rest and during exercise. This effect is accompanied by the inhibition of hypoxic vasoconstriction, which impairs arterial oxygenation at rest. The use of sildenafil in COPD should be done cautiously and under close monitoring of blood gases.
Clinical trial registered with www.clinicaltrials.gov (NCT00491803).
Sildenafil, a phosphodiesterase-5 inhibitor, is currently used to treat pulmonary arterial hypertension. It could be also useful to treat pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD). However, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange in this condition.
In patients with COPD-associated pulmonary hypertension, sildenafil improves pulmonary hemodynamics at rest and during exercise, but it also entails the risk of worsening arterial oxygenation due the inhibition of hypoxic pulmonary vasoconstriction, especially at rest. Accordingly, assessment of the long-term effects of this type of drugs in this condition should be done with caution and under close monitoring of arterial oxygenation, to detect patients that would require supplementary oxygen to counteract its potential detrimental effect on gas exchange.
To date the treatment of PH in COPD has been disappointing (5). Long-term oxygen therapy aimed at correcting hypoxemia is the only treatment that has proved to slow or reverse its progression, although it does not reverse it completely (6). Vasodilators reduce pulmonary arterial pressure (PAP), but in COPD they may also worsen arterial oxygenation as a result of greater ventilation–perfusion () imbalance, due to the inhibition of hypoxic pulmonary vasoconstriction (7–9).
Endothelial dysfunction of pulmonary arteries is at the origin of PH in COPD (10, 11). It results from changes in the synthesis and balanced release of endothelium-derived mediators with vasodilator or vasoconstrictive properties (12). Nitric oxide (NO) is the main endogenous vasodilator synthesized by the endothelium (13). In COPD, pulmonary endothelial dysfunction is associated with reduced expression of endothelial NO synthase (14), a change likely involved in the pathogenesis of PH.
Drugs that modulate the endothelium-derived vasoactive mediator imbalance conform the current strategy for the treatment of severe forms of PH (15, 16). Sildenafil, a phosphodiesterase-5 inhibitor, enhances the vasodilator and antiremodeling effects of endogenous NO (13). In patients with pulmonary arterial hypertension (PAH), sildenafil reduces pulmonary vascular resistance, increases exercise tolerance, and has beneficial effects on survival (17, 18).
Considering that in COPD the endogenous synthesis and availability of NO are impaired (12, 14), it is conceivable that sildenafil might be of clinical benefit in patients with COPD-associated PH. However, in the case of COPD, one major limitation of agents with vasodilator properties, such as sildenafil, is their potential risk of gas exchange impairment, due to hypoxic vasoconstriction inhibition (8). Indeed, sildenafil inhibits hypoxic vasoconstriction in healthy subjects (19). Accordingly, the effects of sildenafil on pulmonary hemodynamics and gas exchange should be carefully evaluated in COPD before considering the assessment of its long-term efficacy (20).
The objective of the present study was to assess the acute effects of a single dose of sildenafil on pulmonary hemodynamics and gas exchange in patients with COPD-associated PH both at rest and during submaximal exercise. We were particularly interested in evaluating the effects of sildenafil on relationships, to analyze the effects of the drug on hypoxic pulmonary vasoconstriction.
Some of the results of the study have been previously reported in abstract form (21, 22).
Fifty-six patients previously diagnosed of COPD (23, 24) with clinical suspicion of PH were screened by Doppler echocardiography. Those with an estimated systolic PAP greater than 40 mm Hg were asked to participate in the study (Figure 1). Data from the 20 patients entering in the study are shown in Table 1.
Figure 1. Trial profile. Population screened and included in the study. PAP = pulmonary artery pressure.
[More] [Minimize]All Patients | Patients Assigned to 20 mg of Sildenafil | Patients Assigned to 40 mg of Sildenafil | |
|---|---|---|---|
| N | 20 | 11 | 9 |
| Sex, men/women | 17/3 | 9/2 | 8/1 |
| Age, yr | 64 ± 7 | 66 ± 7 | 62 ± 6 |
| FVC, % predicted | 65 ± 20 | 68 ± 23 | 62 ± 17 |
| FEV1, % predicted | 35 ± 11 | 35 ± 12 | 34 ± 11 |
| FEV1/FVC | 0.39 ± 0.11 | 0.38 ± 0.11 | 0.42 ± 0.12 |
| TLC, % predicted | 114 ± 19 | 119 ± 14 | 109 ± 23 |
| DlCO, % predicted | 44 ± 17 | 48 ± 18 | 41 ± 17 |
| PaO2, mm Hg | 64 ± 11 | 69 ± 11 | 58 ± 8* |
| PaCO2, mm Hg | 42 ± 6 | 39 ± 5 | 46 ± 6* |
| P(a–a)O2, mm Hg | 32 ± 9 | 31 ± 9 | 35 ± 10 |
| mPAP, mm Hg | 27 ± 10 | 25 ± 6 | 30 ± 13 |
| PCWP, mm Hg | 7 ± 3 | 7 ± 3 | 7 ± 3 |
| CI, L·min−1·m2 | 2.72 ± 0.44 | 2.59 ± 0.47 | 2.87 ± 0.38 |
| PVR, dyn·s·cm−5 | 339 ± 165 | 321 ± 92 | 362 ± 229 |
| Wmax, % predicted | 35 ± 15 | 36 ± 14 | 34 ± 19 |
| V̇o2max, % predicted | 53 ± 20 | 55 ± 18 | 51 ± 23 |
The study was approved by the internal review board of Hospital Clínic (Barcelona, Spain) and written informed consent was obtained from each participant.
Before the study, the highest workload that each patient could tolerate was determined by an incremental exercise test. The day of the study, a Swan-Ganz catheter and an arterial line were placed in the pulmonary and radial arteries, respectively. Pulmonary vascular pressures were measured at end-expiration. Cardiac output (CO) was determined by the thermodilution technique.
Ventilation and respiratory gas measurements in arterial and mixed venous blood and mixed expired air were performed as previously described (25). Tissue oxygen delivery was calculated by multiplying the oxygen content in arterial blood by CO.
Ventilation–perfusion distributions were estimated by the inert gas elimination technique (26). The dispersion of perfusion and ventilation distributions on a logarithmic scale (LogSDQ and LogSDV, respectively) were used as indices of mismatch (upper normal limit: LogSDQ, 0.60; LogSDV, 0.65) (27). The difference among retentions and excretions of inert gases, corrected for dead space (DISP R–E, normal < 3.0), was used as an overall descriptor of inequality (27).
This was a randomized, open-label with blind evaluation, dose comparison trial in two parallel groups. All patients were studied while breathing room air. Forced spirometry was performed at the beginning of the study. Hemodynamic and gas exchange measurements were performed at rest and during constant-work rate exercise on a cyclo-ergometer, at a workload equivalent to 50% of the maximal tolerated in the previous incremental test. All measurements were taken under steady state conditions, defined by stable minute ventilation, breathing frequency, heart rate, and systemic blood pressure, which is a requirement for the assessment of distributions by the inert gas elimination technique (28). After completing baseline measurements at rest and during exercise, a randomized single dose of 20 or 40 mg of sildenafil was administered. The medication was administered by a nurse not involved in the study. Neither the patient nor the investigators were informed about the administered dose. After 1 hour, spirometric, hemodynamic, and gas exchange measurements were repeated in both conditions. We took special care to ensure that exercise measurements were obtained at the same workload, cycling rate, and exercise time than at baseline.
The sample size was calculated by estimated standard deviation from previously published data with a similar study design (25, 29). The sildenafil dose was unblinded after the preestablished number of 20 patients completed the study. Data are expressed as means ± SD and estimated effects as 95% confidence interval (95% CI). The decrease in PAP and PaO2 were the prespecified measures of efficacy and safety, respectively. The effects of sildenafil and exercise (intrasubject), and of sildenafil dose (intersubject), were initially assessed by a general linear model for repeated measures ANOVA (MANOVA). No effects related to the sildenafil dose were observed in PAP, CO, total pulmonary resistance (TPR), PaO2 and LogSDQ by means of the MANOVA test. Accordingly, subsequent analyses were performed by pooling the two doses and assessing the effects of sildenafil in the two study conditions, and on the change from rest to exercise, by means of two-sided t tests. P < 0.05 was considered significant in all cases.
Twenty patients (17 men, 3 women) were included in the study (Figure 1). They suffered from severe or very severe COPD, air trapping with a residual volume of 208 ± 58% of predicted, severe reduction of carbon monoxide diffusing capacity, and moderate to severe hypoxemia (Table 1). Ten patients were under long-term oxygen therapy. The incremental exercise test revealed moderate to severe impairment of exercise tolerance (Table 1).
Eleven patients were assigned to 20 mg of sildenafil and 9 to 40 mg. Both groups had similar characteristics, except for the PaO2 and PaCO2, which were significantly lower and higher, respectively, in the group assigned to 40 mg of sildenafil (Table 1).
Seventeen patients showed PH at rest, considered as a mean PAP (mPAP) greater than 20 mm Hg (30, 31). Only one had severe PH with an mPAP of 61 mm Hg; whereas in the remaining 16, mPAP ranged from 21 to 34 mm Hg. On average, mPAP was moderately increased at rest. The cardiac index was within the normal range in the majority of patients (Tables 1 and 2).
Rest | Exercise | |||||
|---|---|---|---|---|---|---|
| Before Sildenafil (Mean ± SD) | Change after Sildenafil [Mean (95% CI)] | Before Sildenafil (Mean ± SD) | Change after Sildenafil [Mean (95% CI)] | |||
| mPAP, mm Hg | 27 ± 10 | −6 (−7 to −4)* | 56 ± 14† | −11 (−14 to −8)*‡ | ||
| CO, L·min−1 | 4.90 ± 0.95 | 0.13 (−0.09 to 0.34) | 9.00 ± 2.29† | 0.32 (0.05 to 0.60)* | ||
| SV, ml | 59 ± 16 | 0.75 (−4.98 to 3.49) | 84 ± 24† | 4.55 (1.03 to 8.07)* | ||
| PCWP, mm Hg | 7 ± 3 | −1.5 (−2.6 to −0.3)* | 22 ± 8† | −4.4 (−8.1 to −0.6)* | ||
| TPG, mm Hg | 20 ± 9 | −4 (−3 to −5)* | 35 ± 13† | −6 (−3 to −10)* | ||
| TPVR, dyn·s·cm−5 | 456 ± 191 | −110 (−148 to −72)* | 537 ± 220† | −136 (−194 to −79)* | ||
| RAP, mm Hg | 3 ± 2 | −1.1 (−2.0 to −0.2)* | 13 ± 5† | −0.4 (−2.8 to 2.0) | ||
| mSAP, mm Hg | 97 ± 15 | −14 (−18 to −9)* | 123 ± 21† | −13 (−19 to −8)* | ||
At baseline, PaO2 was abnormal (<80 mm Hg) in all but two patients, and in nine it was lower than 60 mm Hg. Arterial PCO2 was within the normal range in the majority of patients, except in five who had increased values (Table 1). Gas exchange abnormalities were the result of a moderate degree of mismatch. In all but one patient, ventilation and blood flow distributions had a broad unimodal shape (Figure 2). One patient had a bimodal distribution of blood flow, reflecting substantial perfusion in areas with low ratio. On average, values of LogSDQ, LogSDV, and DISP R–E were moderately increased (Table 3), in keeping with previous observations in patients with this degree of COPD severity (32). Intrapulmonary shunt was less than 5% in the majority of cases.
Figure 2. Ventilation–perfusion distributions at rest and during exercise, before and after sildenafil administration, in one of the study patients. The amount of ventilation (open circles) and blood flow (solid circles) in units with a different ventilation–perfusion () ratio in each study condition is shown. At rest (top) sildenafil diverted blood flow to units with low ratio with the development of a second mode in the blood flow distribution. The dispersion of perfusion distribution (LogSDQ) increased from 0.76 to 1.19. During exercise (bottom) no change in distributions was observed after sildenafil administration, as shown by similar values of LogSDQ (0.67 and 0.74, before and after sildenafil, respectively).
[More] [Minimize]Rest | Exercise | |||||
|---|---|---|---|---|---|---|
| Before Sildenafil (Mean ± SD) | Change after Sildenafil [Mean (95% CI)] | Before Sildenafil (Mean ± SD) | Change after Sildenafil [Mean (95% CI)] | |||
| PaO2, mm Hg | 64 ± 11 | −6 (−8 to −4)* | 57 ± 12† | −1 (−3 to 0.2)‡ | ||
| PaCO2, mm Hg | 42 ± 6 | −2 (−3 to −1)* | 46 ± 6† | −2 (−3 to −0.5)* | ||
| P(a–a)O2, mm Hg | 32 ± 9 | 7 (5 to 9)* | 36 ± 11 | 2 (0 to 4)‡ | ||
| , mm Hg | 34 ± 2 | −1.1 (−1.8 to −0.4)* | 26 ± 3† | −0.01 (−0.5 to 0.4)‡ | ||
| Ve, L | 8.0 ± 1.2 | 0.6 (−0.1 to 1.2) | 22.9 ± 6.6† | −0.5 (−1.9 to 0.9) | ||
| O2 delivery, ml/min | 861 ± 170 | 4 (−82 to 91) | 1521 ± 410† | −8 (−67 to 51) | ||
| Shunt, %QT | 3.9 ± 2.0 | −0.1 (−0.8 to 0.7) | 2.9 ± 1.5† | −0.1 (−0.6 to 0.4) | ||
| Low , %QT | 1.4 ± 2.8 | 1.0 (−0.6 to 2.6) | 0.5 ± 1.0 | 0.0 (−0.3 to 0.3) | ||
| LogSDQa | 0.88 ± 0.17 | 0.13 (0.07 to 0.20)* | 0.82 ± 0.21 | 0.04 (−0.01 to 0.10)‡ | ||
| Dead space, % Va | 28.6 ± 8.9 | 4.1 (0.3 to 7.8)* | 24.0 ± 10.6 | 2.0 (−2.0 to 6.1) | ||
| High , % Va | 2.3 ± 3.6 | −0.1 (−1.3 to 1.1) | 6.4 ± 7.0† | 0.4 (−1.9 to 2.7) | ||
| LogSDV§ | 0.97 ± 0.17 | 0.01 (−0.05 to 0.06) | 0.88 ± 0.19 | 0.04 (−0.05 to 0.14) | ||
| DISP R–E | 12.8 ± 3.3 | 1.7 (0.4 to 3.0)* | 10.4 ± 3.0† | 0.7 (−0.3 to 1.6) | ||
Exercise measurements were performed at a constant workload (26 ± 8 W), which was equivalent to 50% of the maximum that patients tolerated and to 19 ± 7% of the predicted maximum. Exercise lasted 6–7 minutes. At its end, oxygen uptake, minute ventilation, and heart rate were close to the values achieved at peak exercise in the incremental test.
Mean PAP rose markedly during exercise, exceeding 30 mm Hg in all subjects. Pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and the transpulmonary pressure gradient (the difference between mPAP and PCWP) all increased significantly during exercise (Table 2).
During exercise, PaO2 decreased and PaCO2 increased slightly but significantly. There was a minor, although nonsignificant, increase in the alveolar-to-arterial O2 gradient P(a–a)O2. Ventilation–perfusion distributions were more homogeneous during exercise, as shown by the decrease of the DISP R–E index (Table 3 and Figure 2).
The administration of sildenafil produced significant vasodilation in both the pulmonary and systemic circulation. One hour after its administration, the mPAP decreased by 21 ± 9% from the baseline value (P < 0.001), with no change in CO (P = 0.10) (Table 2 and Figure 3). Pulmonary vascular resistance also decreased significantly after sildenafil administration. No differences in the hemodynamic effects of the drug were observed between the 20- and 40-mg doses, although there was a trend to a greater increase in CO with the 40-mg dose (Figure 4). Sildenafil also had significant vasodilator effect in the systemic circulation, reducing mean systemic arterial pressure by 13 ± 9% and systemic vascular resistance by 14 ± 12% (P < 0.001, each). There were no differences on the effects of sildenafil on systemic arterial pressure or resistance between the two tested doses. The ratio between pulmonary and systemic resistance decreased from 0.22 ± 0.10 at baseline to 0.20 ± 0.10 after sildenafil (P < 0.001), suggesting a slightly greater effect of the drug on the pulmonary circulation.
Figure 3. Individual effects of sildenafil on mean pulmonary artery pressure (mPAP) and arterial oxygen tension (PaO2) at rest and during exercise. Solid circles correspond to patients assigned to 20 mg sildenafil and open circles to patients assigned to 40 mg.
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Figure 4. Effects of sildenafil on pulmonary hemodynamics. Top: Mean ± SD values before (open columns) and after (solid columns) sildenafil administration, at rest, and during constant-workload exercise, of mean pulmonary artery pressure (mPAP), cardiac output (CO), and total pulmonary resistance (TPR) of all pooled cases. Bottom: Magnitude of change induced by sildenafil in mPAP and CO, related to sildenafil dose. Gray columns correspond to patients assigned to 20 mg of sildenafil and dashed columns to patients assigned to 40 mg. *P < 0.05 compared with the respective value before sildenafil, and Δ indicates the change induced by sildenafil in each study condition.
[More] [Minimize]Gas exchange worsened after sildenafil, decreasing PaO2 by −9 ± 7% (P < 0.001), and increasing P(a–a)O2 by 27 ± 27% (P < 0.001) (Table 3, and Figures 3 and 5). There was a slight decrease in PaCO2 (−4 ± 4%) (P < 0.001) after sildenafil administration, which coincided with a slight increase in minute ventilation (Table 3). The most pronounced decrease in PaO2 was experienced by patients with higher values at baseline, as shown by a significant correlation between baseline PaO2 and its decrease after sildenafil at rest (r = −0.77) (Figure 6). There were no differences in the effects of sildenafil on blood gas measurements between the two tested doses (Figure 5), even when considering the effect on PaO2 either as absolute or as a percentage change from the baseline value.
Figure 5. Effects of sildenafil on gas exchange and ventilation–perfusion distributions. Top: Mean ± SD before (open columns) and after (solid columns) sildenafil administration, at rest, and during constant-workload exercise, of partial pressure of arterial oxygen (PaO2), ventilation–perfusion inequality (dispersion of blood flow distribution, LogSDQ) and oxygen delivery (O2 delivery) of all pooled cases. Bottom: Magnitude of change induced by sildenafil related to sildenafil dose on PaO2 and LogSDQ. Gray columns correspond to patients assigned to 20 mg of sildenafil and dashed columns to patients assigned to 40 mg. *P < 0.05 compared with the respective value before sildenafil, and Δ indicates the change induced by sildenafil in each study condition.
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Figure 6. Relationship between the change induced by sildenafil on PaO2 and the degree of mismatch (dispersion of blood flow distributions, LogSDQ) and baseline values. Solid circles correspond to patients assigned to 20 mg of sildenafil and open circles to patients assigned to 40 mg.
[More] [Minimize]Worsening of arterial oxygenation induced by sildenafil was caused by increased mismatching. The global index DISP R–E increased by 17 ± 21% (P < 0.001), due to greater dispersion of the blood flow distribution (LogSDQ), which increased by 17 ± 18% (P < 0.001). In two patients the distribution of blood flow switched from a unimodal to bimodal shape, with an apparent amount of blood flow diverted to poorly ventilated alveolar units with low ratios (Figure 2). Perfusion to alveolar units with ratios between 0.001 and 0.1 increased from 1.4 ± 2.8% at baseline to 2.3 ± 4.1% after sildenafil administration (P = 0.22). Intrapulmonary shunt remained unaltered (Table 3). Contrasting with changes in blood flow distribution, no changes were observed in the distribution of ventilation after sildenafil administration (Table 3). The effects of the two sildenafil doses on distributions were similar (Figure 5).
In spite of the decrease in arterial oxygenation, oxygen delivery to the tissues did not change after sildenafil administration (Figure 5).
After the administration of sildenafil, forced spirometry showed a slight, albeit significant, increase in FEV1 and FVC (P < 0.05 each, compared with baseline), with no change in the FEV1/FVC ratio (Table 4).
Exercise measurements after sildenafil administration were taken at the same workload and exercise time than at baseline. As expected, O2 uptake and CO2 production were similar than before the drug. During exercise, sildenafil reduced mPAP by 19 ± 10% (P < 0.001) from the baseline value, with a slight increase in CO (4 ± 7%) (P < 0.001) (Table 2, and Figures 3 and 4). The decrease in PAP induced by sildenafil during exercise was significantly greater than at rest. Total pulmonary vascular resistance decreased by 22 ± 11% (P < 0.001), as a result of the concomitant reduction in both the transpulmonary pressure gradient (−14 ± 25%) (P < 0.001) and PCWP (−17 ± 33%) (P = 0.02) (Table 2).
After sildenafil administration, PaO2 did not decrease further during exercise (Figures 3 and 5). There was a slight reduction in Paco2, although the P(a–a)O2 remained unchanged (Table 3). In agreement with this, distributions did not vary after sildenafil administration, as compared with the values recorded during exercise at baseline (Table 3 and Figure 2). Accordingly, the effects of the drug on arterial oxygenation and distributions during exercise were significantly different from those observed at rest (Table 3 and Figure 5).
Oxygen delivery to the tissues during exercise after sildenafil administration did not vary from the baseline value (Figure 5). Mixed venous Po2 also remained unaltered (Table 3).
There were no differences between both doses of sildenafil in the magnitude of change of mPAP, CO, PaO2, and LogSDQ during exercise (Figures 4 and 5).
The present study is the first comprehensive assessment of the acute effects of phosphodiesterase-5 inhibitors in patients with COPD-associated PH both at rest and during exercise. Our results show that although there was a substantial improvement of pulmonary hemodynamics in both study conditions, the effects of the drug on gas exchange were different at rest than during exercise. Whereas at rest sildenafil worsened arterial oxygenation, due to greater inequality, no further deterioration occurred during exercise. This novel finding extends and complements previous studies using vasodilators in COPD (7, 8, 25).
The therapeutic strategy for PH has experienced an enormous change. Significant clinical improvement and prolonged survival have been achieved in its more severe forms (33). There is great interest in knowing whether new specific PH therapy (16) could also be beneficial in more prevalent forms of PH, such as that associated with COPD (20). Nevertheless, given the poor clinical results obtained with vasodilator treatment in this condition (34), as well as concerns about their safety in terms of gas exchange (35), the acute effects of new specific PH therapy must be thoroughly assessed in pilot studies before considering their long-term evaluation (20, 36). The use of sildenafil, which acts on the NO–cyclic guanosine monophosphate pathway (13, 16), could be a reasonable alternative for the treatment of COPD-associated PH, as this pathway is impaired in these patients (11, 14).
The acute vasodilating effects of sildenafil on pulmonary circulation in the present study were similar to those reported previously in PAH (37), in PH associated with idiopathic pulmonary fibrosis (29), and also in COPD-associated PH treated with inhaled NO (8). After sildenafil administration, half of the patients reached normal values of mPAP at rest. Sildenafil also reduced the marked increase in mPAP that took place during exercise. The latter change resulted from diminished resistance in intrapulmonary vessels and, to some extent, from the decrease in capillary pressure. A major factor influencing the increase in mPAP during exercise in COPD is air trapping, which is reflected by the increase in capillary pressure at end-expiration. Nevertheless, left ventricular diastolic dysfunction cannot be disregarded in these patients. In fact, the reduction in capillary pressure after sildenafil administration could be explained by improved left ventricular contractility, resulting from reduced systemic vascular resistance. The effects on CO were minimal, even though significant increases in CO and stroke volume were noticed during exercise after sildenafil administration. We did not find any significant difference in the hemodynamic effects of the two tested doses, although there was a trend to greater increase in CO with the 40-mg dose, in accordance with previous studies of PAH (17). The increase in CO is the major change explaining the improvement in exercise tolerance with specific PH therapy (33). Our study was not addressed to assess changes in exercise tolerance, but it is conceivable that sildenafil could improve it in COPD, as cardiac performance may partially account for exercise limitation in this condition (38), even though the most important limiting factor is reduced ventilatory capacity.
Arterial oxygenation worsened after sildenafil administration at rest, irrespective of the dose. Assessment of relationships by the inert gas technique revealed that gas exchange worsening was the result of greater mismatching, as shown by the increase in the dispersion of blood flow distribution, which reflects the diversion of blood flow to poorly ventilated alveolar units with lower ratios. This observation is consistent with the inhibition of hypoxic vasoconstriction, which in COPD contributes to match perfusion with ventilation, thus maintaining arterial oxygenation (39). Indeed, it has been shown that sildenafil inhibits hypoxic pulmonary vasoconstriction in healthy subjects (19). These findings concur with previous observations demonstrating that the administration of vasodilators such as calcium channel blockers (7, 40) or inhaled NO (8, 9) inhibits hypoxic vasoconstriction and induces arterial deoxygenation in COPD. Interestingly, the most pronounced decrease in PaO2 was experienced by patients who had higher values at baseline. This is consistent with the fact that patients with more active hypoxic vasoconstriction are those with a less altered pulmonary vasculature (39, 41) and hence more sensitive to the action of vasodilators. Accordingly, in patients with greater pulmonary vascular derangement, hypoxic vasoconstriction might play a minor role in matching pulmonary blood flow and alveolar ventilation, and hence they show lesser changes in arterial oxygenation with sildenafil—a change that may easily be corrected with supplementary oxygen.
There was a clear difference between the effects of sildenafil on gas exchange during exercise and at rest. Interestingly, during exercise, sildenafil did not have the deleterious impact on gas exchange it had at rest. The values of PaO2 and P(a–a)O2 during exercise after sildenafil administration remained essentially the same as at rest, whereas the amount of oxygen delivered to the tissues was not affected by the drug. No further worsening of distributions occurred during exercise after sildenafil administration. Similar effects during exercise have been observed with inhaled NO (25). This different effect of sildenafil on exertion than at rest could be explained because the vasodilator effect of sildenafil was exerted in alveolar units that received more ventilation during exercise, where it improved the matching of perfusion to ventilation, in detriment of alveolar units with greater structural derangement that received less ventilation during exercise. This contention is consistent with the aforementioned suggestion that the vasodilator effect of sildenafil appears to be exerted mainly in less altered vessels, which are probably more active in regulating hypoxic vasoconstriction. The observation that patients with greater gas exchange impairment at baseline were those with lesser worsening after sildenafil also points out that these patients had less room to deteriorate.
Sildenafil also had a slight but significant effect on airflow rates. The spirometry performed after administering the drug revealed slight increases in FVC and FEV1, consistent with the reduction of air trapping. Despite the fact that spirometric improvement with sildenafil has been occasionally reported in patients with COPD (42), the potential bronchodilatory effect of sildenafil should be evaluated in a controlled study.
One of the limitations of the study was that it was performed in a small number of subjects. This was because we adjusted the population size on the basis of previous studies (25, 29) and tried to avoid unnecessary studies considering the invasiveness of the procedures. Another limitation was the difference in PaO2 and PaCO2 between the groups assigned to 20 or 40 mg of sildenafil. This was the result of the random assignment to each dose and because the dose assigned to each patient was not unblinded until the end of the study. It should be noted that there were no differences in P(a–a)O2 between the groups, and that the effects of sildenafil on the major outcome variables did not differ between the groups. A third limitation was that we did not assess a placebo control group as this was a requirement of the internal review board in view of the invasive nature of the study, and because each patient was their own control on the effects of the drug. The second set of measurements was taken after resting for more than 1 hour after finishing the first exercise test, and we took special care to ensure that postsildenafil measurements were taken under exactly the same steady state conditions as at baseline. A similar design has been used in previous studies assessing the effect of vasodilators in COPD (7, 25). Furthermore, it has been previously shown that hemodynamic and gas exchange measurements remain stable in a second exercise, performed after adequate resting time (43, 44). Finally, in the present study we considered PH when mPAP was greater than 20 mm Hg at rest or greater than 30 mm Hg during exercise, values that differ somewhat from the most recent definition of PH, which is a resting mPAP equal to or exceeding 25 mm Hg (45). Nevertheless, 20 mm Hg is the upper limit of normal mPAP in healthy subjects (31) and this cutoff value has been commonly used to define PH in COPD (30), because in this condition it has important prognostic implications, as mPAP above this value is associated with shorter survival and more frequent exacerbation episodes (3, 46). A study by Kovacs and colleagues (31) indicates that elderly healthy individuals may show mPAP values above 30 mm Hg during exercise. For this reason the value of mPAP during exercise is no longer considered in the definition of PH (45). In our series there were 12 patients with resting mPAP equal to or more than 25 mm Hg and 8 patients with mPAP below that value. The effects of sildenafil on PAP, arterial oxygenation, and indices of mismatch did not differ between these two groups. Accordingly, the criteria used to define PH did not affect the major findings of the present investigation.
In conclusion, results of the present acute study show that sildenafil improves pulmonary hemodynamics in patients with COPD and associated PH, but it also entails the risk of worsening arterial oxygenation due to the inhibition of hypoxic pulmonary vasoconstriction. The fact that this risk was less apparent during exercise might open the opportunity to assess whether its long-term use could improve exercise tolerance in COPD-associated PH. This question must be addressed in properly designed, randomized, controlled clinical trials. In any case, the use of sildenafil in COPD should be done with caution, by experienced physicians, and under close monitoring of arterial oxygenation, to detect patients who would require supplementary oxygen to counteract its potential detrimental effect on gas exchange.
The authors thank F. P. Gómez, F. Burgos, Y. Torralba, J. A. Rodríguez, and M. Simó for invaluable support and collaboration in the studies; M. Sitges for the echocardiographic assessment; and L. de Jover for statistical advice.
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