Tolazoline

In 53 patients with COPD and precapillary pulmonary hypertension, we investigated the effect of three typical calcium antagonists on hemodynamics at rest and during bicycle ergometer exercise. In the responders, the decrease in pulmonary vascular resistance following nifedipine was 23 percent at rest (p<0.0005) and 35 percent during exercise p<0.0005); following diltiazem, it was 10 percent at rest p<0.05) and 23 percent during exercise (p<0.025); following verapamil, it was 22 percent at rest (p<0.005) and 11 percent during exercise (p<0.025). The cardiac index rose significantly at rest and under exercise only after the administration of nifedipine (+ 16 percent and + 8 percent, resp). Nifedipine caused the most distinctive peripheral vasodilation. The heart rate increased slightly following nifedipine and decreased slightly following diltiazem and verapamil. After long-term therapy with nifedipine (13 [+ or -] 5 months), the decrease in pulmonary artery pressure and pulmonary vascular resistance was no longer significant. In our opinion, the different hemodynamic action profiles will have consequences for the differential therapy in patients with COPD and pulmonary hypertension.

PH = pulmonary hypertension; RA = right atrial mean pressure; PAs = systolic pulmonary artery pressure; PAd = diastolic pulmonary artery pressure; PAP = mean pulmonary artery pressure; PCP = pulmonary capillary wedge pressure; RR = mean arterial blood pressure; SVI = stroke volume; index; TPR = total peripheral resistance; PVR = pulmonary vascular resistance

Secondary pulmonary hypertension, and finally, chronic cor pulmonale are most frequently caused by COPD.[1] The degree of increase in pressure in the pulmonary circulation has an important influence on the life expectancy of those patients.[2] Thus, drug therapy was tried to lower the pulmonary artery pressure in order to prevent cor pulmonale, and as a consequence, right ventricular decompensation. Vasodilators with different modes of action, such as tolazoline,[3] phentolamine,[4] isoproterenol,[5] nitroglyzerin,[6] nitroprusside,[7] diazoxide,[8] hydralazine,[7,9] captopril,[10] and some calcium antagonists,[10-16] were used with quite different results. Calcium antagonists have a blocking action on the calcium ion entry into smooth vascular muscle cells and myocardial cells. Thus, they have a vasodilatory effect on the one hand and inhibitory effect on the other hand on the conduction in the sinoatrial node and on atrioventricular conduction.[17] The fact that the degree of active vasoconstriction may be different in patients with PH secondary to COPD[18] suggests that calcium antagonists might also be used successfully in this patient population.[12,15,16] Some calcium antagonists mainly have peripheral-vascular action (eg, nifedipine), others have the same action on heart and periphery (eg, verapamil), and still others have a range of action that lies in between (eg, diltiazem). These differences might be useful in differential therapy. Thus, we investigated whether calcium antagonists could effectively decrease pulmonary artery pressure and favorably influence right ventricular function in patients with PH secondary to COPD. Besides, we were interested to know whether specific differences in hemodynamic action could be useful in a well-founded differential therapy with calcium antagonists. In five patients, we could observe the long-term effects of nifedipine through recatheterization.

PATIENTS AND METHODS

In the course of diagnostic right ventricular catheterization, 53 patients with secondary precapillary PH and COPD were prospectively administered nifedipine (N = 21), diltiazem (N=20), and verapamil (N = 12) in the order of their admission. The average age and the severity of COPD were comparable in the groups (Table 1). COPD was diagnosed on the basis of history, clinical findings, and lung function. As pathologic lung function findings in the sense of an obstruction, we defined a ratio of forced expiratory volume in one second to inspiratory vital capacity of <75 percent of the vital capacity ([FEV.sub.1]/VC), a vital capacity of <100 percent, and a resistance (R) of >3 cm [H.sub.2O]/L/s; and in the sense of lung emphysema, a total lung capacity of >130 percent of the normal value, an intrathoracic gas volume of >70 percent of the total lung capacity, and a residual volume of >50 percent of the total lung capacity.[19] The VC and [FEV.sub.1]/VC were determined spirographically, and R was measured plethysmographically (whole-body plethysmograph).

In all patients, use of all medications was discontinued 48 hours prior to the respective studies (hemodynamics, lung function), except for treatment with cardiac glycosides (in four patients with cardiac arrhythmias) or corticosteroids (in 17 patients). None of the patients received long-term oxygen therapy. Patients with coronary heart disease, valvular heart disease, systemic arterial hypertension or right ventricular decompensation were excluded from the study A mean pulmonary artery pressure (PAP) of >20 mm Hg at rest[1] was considered as PH. The hemodynamic study was performed using a Swan Ganz thermodilution catheter with the patient in a supine position. First, the patient was at rest, then exposed to a load, which was increased by 25 W every two minutes. The test was discontinued at the occurrence of dyspnea. Pressure levels were recorded digitally as well as in a curve. The method of procedure for the hemodynamic recording corresponded to common criteria.[10] The following parameters were recorded: arterial blood pressure according to Riva Rocci, heart rate, right atrial mean pressure at rest; also pressures in the right ventricle, the systolic, diastolic, and the mean pulmonary artery pressure, the pulmonary capillary wedge pressure, and cardiac output by the thermodilution method. These directly measured data served for the calculation of mean arterial blood pressure, cardiac index, stroke volume index, total peripheral resistance, and pulmonary vascular resistance.[20] All data were recorded at rest and at each load level. The right atrial and pulmonary artery and/or pulmonary capillary wedge pressures were recorded simultaneously After a recovery phase of 20 minutes, the patient was either given 20 mg nifedipine sublingually or 20 mg diltiazem intravenously, or 5 mg verapamil intravenously. After another 20 minutes (nifedipine and diltiazem groups), or 10 minutes verapamil group), the hemodynamic test was repeated in the same way as described above. We evaluated the hemodynamic data at rest and at the identical maximum load level before and after the administration of calcium antagonists.

In addition, blood gas values were determined in all patients at rest and at the maximum load level from the capillary blood of the earlobe ([Po.sub.2] = arterial partial pressure of oxygen, [Pco.sub.2] = arterial partial pressure of carbon dioxide, pH value). We considered those patients to be responders who reacted to the medication by a fall in PAP or PVR of > 10 percent at rest or during exercise.

The paired Student's t-test was used for statistical analysis, the level of significance was fixed at p<0.05. All parameters are mean values [+ or -] standard deviation ([PSI] [+ or -] SD). The patients were informed about the purpose of the study and gave oral consent.

RESULTS

The data on hemodynamics and blood gas analysis are listed in Tables 2 to 4. The load level achieved on an average was comparable in the groups and amounted to 61 [+ or -] 24 W in the nifedipine group, to 62 [+ or -] 25, W in the diltiazem group, and to 60 [+ or -] 29 W in the verapamil group. The rate of responders was 81 percent (17 of 21) in the nifedipine group, 60 percent (12 of 20) in the diltiazem group, and 83 percent (10 of 12) in the verapamil group.

The HR changed significantly only after the administration of nifedipine at rest (+4 percent) as well as during exercise (+ 7 percent). The decrease in RR was most significant following nifedipine (-12 percent at rest, p<0.005) and -8 percent during exercise, p<0.001); following diltiazem and verapamil, the fall in blood pressure was moderate and only significant at rest. Following nifedipine, PAP fell by 16 percent (p<0.01) at rest and by 23 percent (p<0.0005) during exercise. Following diltiazem, PAP fell by 15 percent (p<0.001) at rest and by 12 percent (p<0.005) during exercise. Following verapamil, the fall in PAP by 17 percent at rest was not significant, yet during exercise it was 12 percent (p<0.005). CI, which was in the normal range in all patients, increased significantly at rest and during exercise only after the administration of nifedipine (+16 percent and +8 percent, respectively); in the two other groups the mean changes were only moderate.

At rest, PVR decreased significantly to the same extent following nifedipine and veraparnil,(-23 percent and -22 percent, respectively), and following diltiazem to a less degree. During exercise, the most significant fall in PVR was achieved by nifedipine (-35 percent, p<0.0005). Nifedipine also caused the most distinctive peripheral vasodilation (see TTR).

A significant decrease in A was observed only during exercise (-23 percent) following nifedipine. The product of systolic arterial pressure and heart rate changed significantly only at rest following diltiazem and verapamil. A significant change in blood gas analysis was observed in the nifedipine group with a 7 percent fall in [Po.sub.2], from 59 to 55 mm Hg on the average, during exercise.

Follow-up with nifedipine: In five patients who were given 3 x 1 capsules of nifedipine (30 mg) per os daily, hemodynamic investigations were repeated after 13 months on an average (Table 5). The decrease in PAP and PVR was no longer significant after this period of time, although a significant decrease was shown in a short-term test at rest as well as during exercise. Table 6 shows a slight deterioration of lung function in these five patients.

[TABULAR DATA OMITTED]

No adverse effects were observed, neither after short-term administration nor during long-term therapy.

DISCUSSION

The use of calcium antagonists in PH secondary to COPD is justified on the assumption that active pulmonary vasoconstriction is an essential factor for the increase in PVR.[12,18] Patients with COPD form the largest group, in which a decrease in PVR by vasodilator therapy would theoretically be advantageous.

In accordance with the reports of other authors,[21] we divided our patient population into responders and nonresponders, with the highest rate of responders being achieved with nifedipine and verapamil. Those patients in whom the calcium antagonists had no effect, showed similar mean pressure values in the pulmonary circulation and were also not different from the others in other respects (eg, eight nonresponders with a PAP of 24 [+ or -] 4 mm Hg in the diltiazam group, and 23 [+ or -] 4 mm Hg after the administration of diltiazem).

Nifedipine had the most distinctive effect on the pulmonary circulation. Whereas pulmonary and peripheral afterloads were lowered to almost the same degree at rest (PVR fell by 23 percent, TPR by 21 percent), the decrease during exercise was more distinct in PVR by -35 percent, than in TPR by -20 percent (Fig 1). During exercise, the right ventricular preload was also decreased due to the fall in RA. This led to an improvement in the right ventricular function, which is, in addition to the level of PAP, a decisive determinant in prognosticating the life expectancy of the patients.[22] The use of nifedipine as vasodilator for the diminution of vasoconstriction secondary to hypoxia in PH was proposed in 13 patients with COPD.[12] Similar results were also obtained in patients with cor pulmonale associated with COPD[14] and in a crossover double-blind study in six patients with COPD.[16] Contrary to our findings, however, no deterioration in the arterial oxygen tension was observed. The effect of nifedipine on pulmonary hemodynamics can mainly be explained by the active pulmonary vasodilation, which is quite distinctive during exercise. The administration of nifedipine appears effective in those patients with COPD who are normofrequent or bradycardic, or have systemic arterial hypertension in addition. Its considerable coronary-dilating properties would also have beneficial effects on a concomitant coronary heart disease (especially of the vasospastic type). Conduction disturbances represent no contraindication for nifedipine administration.

At rest, verapamil caused almost the same fall in pressure in the pulmonary circulation as nifedipine during exercise; however, it was lower. With this calcium antagonist as well, the decrease was more distinct in the right than in the left ventricular afterload (Fig 1). We believe that the fall in CI during exercise was caused by the direct negative inotropic effect of verapamil.[23] The fall in CI during exercise might prove unfavorable in patients with COPD and reduced CI, especially in the case of a reduced oxygen transport due to an additional [Po.sub.2]-fall. Verapamil was also adminstered in primary PH with different effects on PVR and CI; in most cases, however, a fall in CI was recorded.[11] The administration of verapamil in patients with COPD would be justified with concomitant supraventricular tachycardiac arrhythmias (eg, tachycardiac atrial fibrillation, sinus tachycardias, paroxysmal atrial tachycardias), which are to be expected in 18 percent of this patient population according to our own results.[10] Verapamil inhibits conduction in the sinoatrial node as well as atrioventricular conduction.[24]

At rest, the effects of dialtiazem on the pulmonary circulation were similar to those of nifedipine, during exercise; however, the fall in PAP and PVR was lower. The decrease in PVR was more distinctive than in TPR (Fig 1). Hemodynamics were improved rather by the prevalently vasodilatory effect on the pulmonary vessels than by the decrease in TPR or by an elevated cardiac output. We did not observe any negative inotropic effect. The heart rate decreased slightly, similar to verapamil. Other authors reported similar results; in-five patients with severe PH, a decrease in PAP was observed in three out of five; in one patient, however, PAP rose after the administration of diltiazem.[13] Since diltiazem has an antiarrhythmic and depressor effect on sinoatrial and AV-nodes similar to verapamil,[25] it might be successfully employed in patients with COPD and PH and tachyarrhythmias. Concomitant coronary heart disease equally benefits from diltiazem due to its relaxing effect on the coronary vessels. With regard to pulmonary hemodynamics, diltiazem may be considered an effective intermediate calcium antagonist, having a weaker effect on the pulmonary artery pressure than nifedipine and a less negative inotropic effect than verapamil.

Based on the assumption that despite progression of the primary disease (Table 6) the pulmonary hemodynamics e favorably influenced, we do not interpret our results on long-term therapy with nifedipine as unfavorable. After 13 months, both PVR and PAP were further reduced as compared to control subjects (especially during exercise), but this was no longer significant. We concluded that together with the decrease in RA, the right ventricular function was improved. In accordance with the work of other authors,[14] we also chose low daily doses of nifedipine for long-term therapy in order to avoid the risk of unfavorable systemic effects in this patient population. However, higher doses were administered in patients with primary PH,[26] who had higher pressure values in the pulmonary circulation. The question of dosage in long-term therapy with nifedipine is still controversial. For the time being, it cannot be answered, whether the weakening in effect of nifedipine in our patient population was due to the gradual deterioration from the basic disease, and thus, to the loss in reactivity of the pulmonary vessels, or due to the fact that it was a kind of tachyphylaxis,[27] or due to wrong dosage. On observation of the individual patient, it becomes evident that favorable long-term effects cannot be deduced from favorable short-term effects without hesitation. But we hope that the progression of pulmonary artery pressure rise was prevented, even though only a 0.39 mm PAP rise per year was stated.[28]

[TABULAR DATA OMITTED]

We believe that the decrease in the right ventricular afterload caused by calcium antagonists represents a useful concept in the therapy of PH secondary to hypoxia. Long-term follow-up of hemodynamics and well-controlled studies will be required in order to generally recommend a vasodilator therapy with calcium antagonists in PH secondary to COPD. In a second step, the differentiated use of calcium antagonists, taking into account their hemodynamic profile, might lead to improved therapeutic results. A hemodynamic study of the pulmonary circulation should be performed in order to find out the appropriate calcium antagonist for the individual patient.

REFERENCES

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