Acute hemodynamic response to vasodilators in primary pulmonary hypertension.HH Kulkarni, AA Srinivas, AA Vora, PP Kerkar, BB Dalvi
Dept. of Cardiology, KEM Hospital, Parel, Mumbai.
Acute hemodynamic effects of high flow oxygen (O2) inhalation, sublingual isosorbide dinitrate (ISDN), intravenous aminophylline (AMN) and sublingual nifedipine (NIF) were studied in 32 patients with primary pulmonary hypertension (PPH). In 30 out of 32 patients the basal ratio of pulmonary to systemic vascular resistance (Rp/Rs) was > 0.5 (mean = 0.77 +/- 0.20). Oxygen caused significant decrease in the mean resistance ratio to 0.68 +/- 0.20 (p = 0.005). ISDN, AMN and NIF caused increase in the resistance ratio to 0.79 +/- 0.26; 0.78 +/- 0.26; and 0.80 +/- 0.23 respectively. O2, ISDN, AMN and NIF caused a fall of Rp/Rs in 21 (65.6%), 10 (31.2%), 10(31.2%) and 9(28.1%) patients respectively. Thus, of the four drugs tested high flow O2 inhalation resulted in fall of Rp/Rs in two thirds of patients whereas ISDN, AMN and NIF caused a mean rise in Rp/Rs. One third of patients did respond acutely to the latter three drugs. Acute hemodynamic studies are useful before prescribing vasodilators in patients with PPH since more of the commonly used drugs like ISDN, AMN, NIF could have detrimental hemodynamic responses in some patients. However, great caution should be exercised before performing hemodynamic study as the procedure has definite mortality and morbidity.
Keywords: Administration, Sublingual, Adolescent, Adult, Aged, Aminophylline, pharmacology,Bronchodilator Agents, pharmacology,Child, Comparative Study, Female, Human, Hypertension, Pulmonary, drug therapy,etiology,physiopathology,Infusions, Intravenous, Isosorbide Dinitrate, pharmacology,Male, Middle Age, Nifedipine, pharmacology,Oxygen Inhalation Therapy, Pulmonary Circulation, drug effects,Vascular Resistance, drug effects,Vasodilator Agents, pharmacology,
Over the last two decades several studies have shown beneficial effects of various vasodilators in patients with PPH,,,,. Inhalation of O2’ oral theophylline and nitrites have long been known to reduce pulmonary vascular resistance,. Recently isoproterenol, hydralazine, diazoxide and calcium channel blockers also have been used with varying success,,. However, there are many reports with deleterious effects of these drugs in PPH,,. Lack of clinically controlled studies and non-uniformity of drug response prompted us to evaluate acute hemodynamic response to vasodilators in patients with PPH. Unlike in other studies,, which have used pulmonary artery pressure (PAP) or pulmonary vascular resistance (PVR) as parameters for assessing the effects of drug treatment, we have used ratio of pulmonary and systemic vascular resistances. This ratio has an advantage over the other two indices since it takes into consideration effects of these interventions on cardiac output and systemic vascular response, both of which have obvious implications in clinical management.
Study group: Thirty-two patients, 18 women and 14 men, with PPH were studied for acute hemodynamic responses to O2, ISDN, AMN and NIF Their ages ranged from 6 to 65 with a mean of 25.59 years. Fourteen of these patients were in NYHA class II, 17 in class III and 1 in class IV. Diagnosis of PPH was established after ruling out intracardiac shunts, left sided heart diseases and pulmonary parenchymal diseases. This was done with the help of clinical history, ECG, X-ray chest and lung function tests. Pulmonary thrombo-embolism was ruled out using ventilation-perfusion scans. Mild impairment of diffusion capacity was detected in 8 out of 32 patients, which in itself could not explain the severity of pulmonary hypertension. Two dimensional echocardiography, Doppler studies were performed to rule out intracardiac shunts. All were tree from inter current medical illness at the time of acute hemodynamic drug testing.
Hemodynamic measurements: All medications except digoxin, diuretics and potassium chloride were discontinued for a week before the study. After obtaining informed written consent, cardiac catheterization was performed tinder local anaesthesia in non-sedated, overnight tasting state. Right heart catheterization was performed to measure the mean right atrial pressure (MRAP) and mean pulmonary artery wedge pressure (MPAWP). Central aortic catheter was used for the measurement of mean systemic arterial pressure (MSAP). Cardiac output (CO) was determined by using the Fick principle. Pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) were expressed as Wood units.
Drug testing: Our experience in first 5 patients of PPH (not included in this report) helped to decide the time interval between 2 drugs depending upon the drug washout period and the maximum dosage of each drug to avoid systemic hypotension. All 4 drugs were tested in all 32 patients in a randomized fashion. Five L/min of 100% O2 was inhaled for 15 min through a moulded rubber mask, which delivered FiO2 of 30-5O%. ISDN 5 mg and NIF 10 mg were used sublingually to shorten the time to peak drug effect and washout period of the drug. Aminophylline was administered as intravenous infusion, 5 mg/kg over 2 min. The doses of last three drugs were doubled in absence of any fall in mean systemic arterial pressure, after 20 minutes of drug administration. The end point was 20 mmHg fall in MSAP (fall in > 20 mm Hg MSAP caused significant hypotension in pilot study). Right sided and MSAP were recorded every 5 minutes. Minimum MSAP and MPAP were used for calculation of PVR and SVR. The second and subsequent drug evaluation was not initiated until the pre-drug values of each hemodynamic variable was within 5% of the baseline readings. The drug washout period varied from 30 min to 6 hours (mean + SD for each drug).
Data analysis: Hemodynamic response viz. PVR. SVR. PAP, Rp/Rs to each of the vasodilator was compared with pre-drug baseline by one way analysis of variance. All results are expressed as the mean +/- standard deviation.
Basal Rp/Rs between 0.50 to 0.74 was classified as moderate pulmonary hypertension (PH) and resistance ratio equal to or more than 0.75 to be severe PH. In all but 2 patients, the Rp/Rs was more than 0.50. Basal hemodynamic data are shown in [Table - 1].
In a given patient, responses to 4 vasodilators tested were variable. While one drug decreased Rp/ Rs, another increased it [Table - 2]. The hemodynamic responses viz. MPAP, MSAP, PVR, and SVR also deferred with different drugs. Some of our patients interestingly had increase in the Rp/Rs but a fall in PVR [Figure:1]. By one way analysis of variance. Rp/ Rs [Table - 2] showed significant decrease after 02 inhalation (p=0.005); whereas ISDN, AMN and. NIF caused significant increase in Rp/Rs i.e. p=0.017, p=0.012 and p=0.012 respectively. Fall in the PVR after Q. inhalation was significant (p<0.002), while that after ISDN (p<0.3). AMN (p<0.2), and NIF (p<0.6) was not. There was no significant change in SVR after O2 (p<0.9); whereas the fail in the SVR after ISDN (p<0.01), AMN (p<0.004) and NIF (p<0.0001) was significant. The Rp/Rs increased with O2, ISDN. AMN, and NIF in 2, 9, 3 and 8 patients respectively [Figure:2]. Reduction in both the variables viz PVR and Rp/Rs occurred in 17, 10, 9 and 8 after O2’ ISDN, AMN, and NIF respectively.
Morbidity and mortality: Six out of 32 patients who were in NYHA class III and IV had worsening of right heart failure and or fall in blood pressure < 80 mm Hg requiring inotropic support, 2 to 6 hours following the study. Four recovered after intravenous fluid infusion, and/or positive inotropic agents (dopamine and dobutamine). One of the patients with moderate PH and MSAP < 60 mm Hg with ISDN and AMN, and another with moderate PH had similar response after NIF: however both of these patients responded to intravenous fluids. Two died (1 with moderate and 1 with severe PH) on the following day due to progressive hypotension and right-sided congestive failure.
Therapeutic approach to PPH has posed a challenge to clinicians despite availability of a large number of potent vasodilators. However, there has been no major randomised drug trial laying guidelines as to the most appropriate therapy. The lack of clinical trials is because of the rarity of disease, short symptomatic period, late presentation and early mortality. Few individual drug trials are unable to prove the benefits of any single drug unequivocally due to variability in protocols. Acute hemodynamic studies with vasodilators have shown variable results,, and so far no drug has caused reversal of the disease process. Almost all vasodilators tested so far in the treatment of PPH cause varying degree of systemic vasodilatation tachycardia and change in CO. If systemic vasodilatation is more than pulmonary without any concomitant rise in CO, it would result in reduction of PAP and PVR but at the cost of severe systemic hypotension. On the other hand, there would be an increase in the PAP and PVR if the drug increased the CO without pulmonary vasodilatation. This could aggravate right ventricular failure. Pulmonary vasodilatation with proportionate increase in CO would result in a decreased PVR with no significant change in the PAP, as shown in this study. Therefore, only reduction in PAP and or PVR are not suitable therapeutic endpoints. Fall in Rp/Rs is a more appropriate criterion in the acute hemodynamic response of vasodilators for PPH as seen in the present study.
All 4 drugs are known to have varying degrees of vasodilatory action on pulmonary and systemic circulation and thus may change the CO without any significant change in the resistance. Oxygen causes a fall in pulmonary artery pressure without change in the CO and the beneficial effects of prolonged inhalation of O2 has been demonstrated in patients with PPH. However, high flow O2 inhalation may prove detrimental if it produces systemic vasoconstriction with resultant reduction in CO. In our study only O2 caused significant decrease in Rp/Rs (p<0.0008) indicating a favourable hemodynamic response. Fall in PVR was significant (p <0.002) while increase in SVR was not significant. Rp/Rs, PVR and MPAP decreased in 21 (65.6%), 23 (71.9%) and 21 (65.6%) patients respectively. All these 3 variables decreased in 17 (53.1%) patients. Out of 23 patients who had reduction in PM 2(6.25%) had increase or no change in Rp/Rs and was due to disproportionate increase in SVR in these patients. Nitrates produce pulmonary vasodilatation in doses that exert little effect on systemic arterial resistance. Due to their action on systemic venous capacitance vessels, they may cause reduction in MPAP by reducing venous return to right heart which may aggravate symptoms of giddiness or syncope due to fall in CO. In the present study 10 to 20 mg of sublingual ISDN showed fall in PVR that was not significant (p=0.3). There was significant reduction in SVR (p=0.01) suggesting preferential systemic vasodilatation. Rp/Rs, PVR and MPAP decreased in 10 (31.2%), 19 (59.3%) and 18 (56.2%) respectively and all 3 variables decreased in 10 (31.2%) patients. Out of 19 patients who had reduction in the PVR, 9 (28.1%) showed increase in the Rp/Rs, again emphasizing the fact that fall in the SVR is more than the fall in the PVR in these patients. Dantzker reported beneficial effects of sublingual ISDN in 2 patients. Hermillar et als reported less than 22% reduction in both PVR and PAP in 10 women with PPH. He stresses the importance of Rp/Rs in evaluating vasodilator response in pulmonary hypertension. Aminophylline is both a pulmonary and systemic vasodilator. With AMN there was a fall in the PVR that was not significant (p<0.2); fall in the SVR was significant (p<0.004); Rp/Rs, PVR and MPAP decreased in 10 (312 %), 14 (43.3%) and 13 (40.6%) patients respectively. All 3 variables decreased in 9 (21.4%) patients. Out of 14 patients in whom PVR fell, 3 exhibited predominant systemic vasodilatation as they had increase in the Rp/Rs. In the remaining 11, there was a fall in SVR and PVR, hence the Rp/Rs did not change. Efficacy of nifedipine in the treatment of PPH remains controversial. Favourable acute hemodynamic response to sublingual NIF has been reported by Rubin et al in a series of 9 patients. They demonstrated significant fall in both PVR and SVR, however no patients had fall in the PAP. Using high dose oral NIF, Rich demonstrated long term reduction in the PAP and PVR and regression of right ventricular hypertrophy in 4 out of 13 patients. However, hypotension, flushing and tachycardia may require withdrawal of the drug. The most disturbing adverse reactions are seen in the patients with pre-existing right ventricular dysfunction,. In our study, NIF caused a significant fall in PVR (p<0.6) whereas fall in SVR did not reach statistical significance (p<0.0001), indicating preferential systemic vasodilatation. Rp/Rs, PVR and MPAP decreased in 9 (28.1%), 18 (56.2%) and 18 (56.2%) patients respectively. All 3 variables decreased in only 8 (25%) patients. Out of 18 patients in whom PVR decreased, 8 (44.4%) showed increase or no change in Rp/Rs suggesting predominant systemic vasodilatation in these patients.
The responses to 4 drugs were not uniform and the same patient responded differently to different vasodilators. Only 5 (15.6%) patients, 3 with moderate and 2 with severe PH had fall in Rp/Rs with all 4 drugs and 7 (21.9%) had increase in Rp/Rs with all 4 agents. Seventy percent of patients had predominant systemic vasodilatation with at least one of the four drugs as reflected by increase in the resistance ratio, which may be deleterious if it results in profound system hypotension.
O2 inhalation does seem to be the most beneficial in our patient population as shown by reduction in the resistance ratio in 65.6% of patients. ISDN, NIF, AMN improved resistance ratio in 312%, 31.2%, 28.1% patients respectively. As demonstrated in this study, Rp/Rs may either increase or remain unchanged in patients with reduction in PVR. We suggest that patients in whom the fall in PVR exceeds that of the SVR are manifesting a drug-specific pulmonary vasodilatory effect and that PVR/SVR ratio should be used in deciding beneficial response to a given drug. Such a drug may be safer than the one, which dilates both circulations equally or reduces SVR more predominantly.
In the present study [Figure:2], 15 patients had moderate PH and 15 patients had severe PH. Reduction in the Rp/Rs occurred after at least 1 drug in 12 patients in each group. However, only 3 patients belonging to severe PH (PASP > 70 mm Hg) group had significant fall in PH, whereas 6 patients belonging to moderate PH had significant fall in PAP post treatment. This suggests that patients with moderate PH are more responsive than those with severe PH. However, whether acute hemodynamic response translate themselves into long term benefits with drug treatment needs to be evaluated.
Four patients had hemodynamic complications needing intravenous fluids and/or inotropic support and two died. All four patients had compromised right ventricular function and were in NYHA class Ill or more. We feel that every patient of PPH should be categorised as per the severity of disease based on clinical presentation. Patients with minima) symptoms who have no hemodynamic compromise, need not be studied for acute hemodynamic drug response and can be treated emperically with various vasodilators. Also patients presenting in low output failure or cyanosis or severe right ventricular dysfunction can be treated with oxygen and inotropic support. Any invasive study in this group is not without complications and if necessary should be performed with great caution. Acute hemodynamic studies would be most useful in patients with NYHA class II and III where a drug which causes a tall in the resistance ratio i.e. Rp/ Rs with a rise or no change in CO be selected for long term therapy. However, it remains to be seen whether acute hemodynamic drug testing results can guide chronic therapy in PPH. No single vasodilator was found effective in all patients of PPH in our series. Although majority of patients responded to high flow O2 some of the non-responders showed beneficial hemodynamic effects with other vasodilators like NIF, ISDN, AMN.
Limitations of the study: Our protocol involved administration of intravenous and sublingual drugs over several hours and although the baseline hemodynamic measurements were reproducible, the potential effects of drug-drug interaction cannot be ruled out. Evaluation of each drug was done with resting hemodynamic measurement and thus comparative effects during exercise when symptoms are most marked remain unknown. Our study did not have a controlled or blinded design and hence data interpretation has some drawbacks, which are inherent to such a design.
We sincerely thank Mrs Deshpande and Mr. Yadav for their painstaking efforts in preparing this manuscript.
[Table - 1], [Table - 2]