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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 225-229

Effectiveness of sildenafil in pulmonary hypertension secondary to mitral valve disease


Department of CTVS, Medical College and Hospital, Kolkata, West Bengal, India

Date of Submission28-Apr-2020
Date of Decision04-Jun-2020
Date of Acceptance27-Jun-2020
Date of Web Publication23-Dec-2020

Correspondence Address:
Dr. Tinni Mitra
Flat No: GR 3B Samadrita Apartment, 142 Kendua Main Road, Kolkata - 700 084, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_72_20

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  Abstract 


Background and Aim: Pulmonary arterial hypertension almost always accompanies long-standing mitral valvular heart disease. The objective of this study is to study the effectiveness of sildenafil in reducing pulmonary hypertension in the peroperative and perioperative period. Materials and Methods: Fourteen patients were randomized into two groups test and control. Patients with mitral valvular disease with Pulmonary Artery Systolic Pressure (PASP) >50 were selected from the outpatient department and echo was done before the admission. Patients in the test group and control group were administered oral sildenafil 25 mg and placebo, respectively, three times a day in the preoperative period in the same fashion for 2 weeks. Preoperative echo was repeated thereafter. After induction of anesthesia and with all aseptic and antiseptic precautions, pulmonary artery catheter was inserted in the right internal jugular vein. PASP was calculated ½ hour after the induction of anesthesia. After operation, patients were monitored by transthoracic echo after 1 week. After discharge, patients were monitored by transthoracic echo at 1 month and at 3 months. Patients' data were analyzed using the statistical tools such as mean, Chi-square test for independence, and paired t-test. Results: There was a statistically significant reduction in PASP in the sildenafil group in the preoperative period (P < 0.05). In this study, PASP was significantly lower (P < 0.0001) after the induction of anesthesia and in the immediate postoperative period in the sildenafil group as compared with the control group. However, there was a marked lowering of PASP in both the control and sildenafil group following the surgical correction of mitral valve disease. Conclusion: In our study, oral sildenafil selectively reduced pulmonary hypertension without any adverse systemic effects.

Keywords: Mitral valve, phosphodiesterase type 5 inhibitor, pulmonary hypertension, valvular heart disease


How to cite this article:
Mitra T, Baksi KD, Mukherjee P, Pal MS, Halder S. Effectiveness of sildenafil in pulmonary hypertension secondary to mitral valve disease. Arch Med Health Sci 2020;8:225-9

How to cite this URL:
Mitra T, Baksi KD, Mukherjee P, Pal MS, Halder S. Effectiveness of sildenafil in pulmonary hypertension secondary to mitral valve disease. Arch Med Health Sci [serial online] 2020 [cited 2021 Apr 11];8:225-9. Available from: https://www.amhsjournal.org/text.asp?2020/8/2/225/304729




  Introduction Top


Pulmonary arterial hypertension almost always accompanies long-standing mitral valvular heart disease. Pulmonary arterial hypertension describes a group of pulmonary hypertension patients with precapillary pulmonary hypertension defined by pulmonary artery wedge pressure =15 mm Hg and pulmonary vascular resistance >3 wood units.[1] The rise in the pulmonary vascular resistance secondary to mitral valvular disease adversely affects the postoperative mortality rates. Pulmonary hypertension can be treated by calcium-channel blockers, endothelin receptor antagonists, phosphodiesterase inhibitors, and prostacyclin analogs.[2],[3] Sildenafil is an orally active, selective phosphodiesterase type 5 inhibitor (PDE5). PDE5 degrades cyclic guanosine monophosphate. Sildenafil thus sustains cAMP concentration and causes vasodilatation through NO/cGMP pathway.[4],[5],[6],[7] Studies have shown that sildenafil can be used to manage secondary pulmonary hypertension in the perioperative period in patients undergoing cardiac surgeries.[4],[5],[7],[8] This is a prospective, randomized, double-blind study aimed at studying the effect of sildenafil in secondary pulmonary artery hypertension due to mitral valvular disease.


  Materials and Methods Top


The patients were enrolled for the study after approval from the Institutional Ethics Committee after obtaining written consent. Fourteen patients with moderate-to-severe tricuspid regurgitation were enrolled. They were randomized into two groups. Randomization was done using the computer-generated random number table. Allocation concealment was done by the SNOSE technique. Patient blinding was done by dispensing of encapsulated drug (active drug/sugar). Observer blinding was done by dispenser and observer not being the same person.

The calculated sample size is 6 in each treatment group obtained by the pairwise comparison of sildenafil versus placebo using the parameter pulmonary artery systolic pressure (PASP) with the previously documented study by Gandhi et al.,[8] with the difference of mean being (59.30–47.65) =11.65 and the standard deviation (SD) 7.5 in the control group and 5.90 in the sildenafil group. With an expected dropout rate of 10%, this translates to seven cases in each group, i.e., a total of 14 patients.

All patients with mitral valvular disease with PASP >50 were selected from the outpatient department, and Echo was done before admission patients in Group S (sildenafil, in routine hospital supply) and Group C (control group) were administered oral sildenafil 25 mg[9] (Penegra, Zydus Healthcare, India) and placebo, respectively, three times a day in the preoperative period in the same fashion for 2 weeks. Preoperative echo was repeated thereafter. The measurement of PASP was done by transthoracic echocardiography in apical four-chamber view by measuring TR jet velocity. After the induction of anesthesia and under all aseptic and antiseptic precautions, pulmonary artery catheter (PAC) (Edwards Lifescience, Irvine, CA, USA) was inserted in the right internal jugular vein. PASP was calculated ½ hour after the induction of anesthesia. After operation, patients were monitored by transthoracic echo after 1 week. After discharge, patients were monitored by transthoracic echo at 1 month and 3 months.

Patients' data were analyzed using the statistical tools such as mean, Chi-square test for independence, and paired t-test.

Data collection and analysis

PASP was measured 30 min after the insertion of PAC under anesthesia. The statistical analysis was performed using the MEDCAL Statistical Package. The values were expressed as mean ± SD. Paired and unpaired “t”-test were used to calculate the P values. A value of P < 0.05 was considered statistically significant.


  Results Top


A total of 14 patients were included in the study, seven patients in each group. Demographic characteristics were similar in both groups. The tabulation of results is given separately.

Patients' data were analyzed using the statistical tools such as mean, Chi-square test for independence, paired t-test, and regression analysis. The statistical analysis was performed using the MEDCAL Statistical Package. The values were expressed as mean ± SD. Paired and unpaired “t”-test were used to calculate the P values. A value of P < 0.05 was considered statistically significant.

A total of 14 patients were included in the study, seven patients in each group. Demographic characteristics were similar in both groups.


  Discussion Top


Pulmonary hypertension can be passive or reactive[9],[10],[11] depending on the absence or presence of elevation of transpulmonary gradient, i.e., the difference of mean pulmonary artery pressure and left atrial pressure. In passive PH, there is no significant histopathological[12],[13],[14] change in pulmonary vascular bed. This is characteristic of early stage of the development of pulmonary artery hypertension and is not associated with structural and functional changes. Reactive pulmonary hypertension is associated with the specific changes in pulmonary vascular bed and is of two possible types: reversible and irreversible. Reactive reversible Group 2 PH is defined by normalization of the TPG and PVR during vasodilator challenge, suggesting a predominance of functional over structural abnormalities of the pulmonary arterial vessels. This type of PH may represent the transition from passive to reactive PH.[13],[14] Reactive irreversible Group 2 PH is defined by a PVR which cannot be reduced to <3 WU after alleviation of the high downstream pressure. Structural over functional abnormalities of the pulmonary arterial vascular bed are presumed to exist. Histological changes of pulmonary vasculature bed appear to be the same as in precapillary forms of PH. Thus, this group may be considered as a target for therapy with a specific pulmonary artery vasodilator agent.

Studies have shown that pulmonary hypertension is present in 68% to 78%[12] patients with heart failure with reduced ejection fraction. In one study, PH was found to be present in 80% to 90% of patients with heart failure-more than 50% of patients with PH had reactive PH irrespective of the left ventricular ejection fraction. Ghio et al.[12] reported reactive PH >60% of their patients with heart failure.

The final messenger for vascular smooth muscle relaxation, cGMP, is metabolized by PDE5.[2],[5] Among the various phosphodiesterase, PDE5 is the predominant type in the normal pulmonary vasculature that may be upregulated after cardiopulmonary bypass (CPB).[15],[16] The inhibition of PDE5 is, therefore, a logical step to increase the bioavailability of cGMP and support endogenous vasodilation in patient with PAH. Phosphodiesterase type 5A inhibition may be a particularly attractive option in this setting because such agents are pulmonary arterial vasodilators and have been shown to attenuate hypertrophy and fibrosis in the animal models of severe heart failure. PDE5 is selectively inhibited by sildenafil, vardenafil, and tadalafil and less selectively by zaprinast and dipyridamole.

In this prospective, double-blind, randomized controlled study, oral sildenafil 25 mg[17] three times over 24 h before the surgery produced significant pulmonary vasodilatation without any significant systemic effects.

Oral sildenafil is widely used in the treatment of patients with erectile dysfunction[18] and shows an excellent cardiovascular safety profile. It is emerging as an effective and safe pulmonary vasodilator in primary pulmonary hypertension[18],[19],[20] as well as secondary pulmonary hypertension.[21],[22] PDE5 is abundant in lung tissue; hence, sildenafil selectively inhibits it and preferentially dilates pulmonary vascular beds.[23],[24] Oral sildenafil selectively reduced pulmonary hypertension without any adverse systemic effects.[24],[25],[26]

In the present study, 25 mg of oral sildenafil was administered three times a day for 24 h with the last dose administered 6 h before the surgery. Wilkens et al. demonstrated that the maximal hemodynamic effects of sildenafil on pulmonary circulation could be achieved with a dose as low as 25 mg. We used three doses over 24 h to reduce pulmonary hypertension. Sildenafil has a half-life of about 4 h; it is rapidly absorbed through the stomach and its plasma levels peaks within 30–120 min after ingestion.

There was a statistically significant reduction in PASP in the sildenafil group in the preoperative period (P < 0.05) [Table 1]. In this study, PASP was significantly lower (P < 0.0001) after induction of anesthesia [Table 2], and in immediate postoperative period in sildenafil group as compared with the control group [Table 3]. However, there was a marked lowering of PASP in both the control and sildenafil group following surgical correction of mitral valve disease[Table 3] and [Table 4].[27] Of the 14 patients studied, 13 had mitral valve replacement with bileaflet prosthetic valve with at least one chordal preservation. One patient had a transventricular mitral commisurotomy. Crossclamp and bypass times were comparable in the two groups. Cross clamp time in the sildenafil and control group ranging from 92 to 156 min and 109–142 min. Bypass times in the two groups ranged from 125 to 191 min and 165–181 min, respectively. A marked reduction in left atrial size was noted in both groups in postoperative echocardiography. Left atrial size reduction was also noted in the sildenafil group before surgery. There was also a statistically significant reduction in PASP in control (P = 0.01) as well as in the sildenafil group (P = 0.02) in operated patients [Table 3]. There was no statistically significant reduction in PASP in the follow-up period up to 3 months in both groups [Table 5], [Table 6] and [Table 7].
Table 1: Comparison of pulmonary artery systolic pressure at the admission with preoperative pulmonary artery systolic pressure after 2 weeks of therapy

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Table 2: Comparison of immediate preoperative pulmonary artery systolic pressure with per op pulmonary artery systolic pressure

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Table 3: Comparison of preoperative pulmonary artery systolic pressure with immediate postoperative pulmonary artery systolic pressure

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Table 1: Comparison of pulmonary artery systolic pressure at the admission with preoperative pulmonary artery systolic pressure after 2 weeks of therapy

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Table 5: Comparison of immediate postoperative pulmonary artery systolic pressure with pulmonary artery systolic pressure after 1 month of discharge

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Table 6: Comparison of immediate postoperative pulmonary artery systolic pressure with pulmonary artery systolic pressure 3 months after discharge

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Table 7: Comparison of pulmonary artery systolic pressure at 1 month and at 3 months postoperative

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During weaning from CPB, we started GTN infusion, adrenaline, and dobutamine infusion in all patients. Dobutamine infusion (5–10 μg/kg/min) continued when MAP was lower than 60 mmHg and also norepinephrine infusion (0.05–0.1 μg/kg/min) was added whenever required. In sildenafil group, only three (42%) patients required dobutamine infusion till on the postoperative day 2. In the control group, all seven patients required dobutamine infusion and of these 4 patients required norepinephrine infusion. Adrenaline infusion was continued in all patients till day 2 post op. Sildenafil group had fewer requirements of inotropes than control. Incidentally two mortalities was recorded during the study period – one in control and one in sildenafil group, first occurred on the second postoperative day due to low output, second occurred preoperatively. Both these patients had to be excluded from the main study.


  Conclusion Top


Cardiac surgery in patients with valvular heart disease with moderate-to-severe PAH is often complicated with the failure of the right ventricle which compounds to aggravation of morbidity and mortality. This necessitates the perioperative strategy to manage PAH and RV dysfunction.

The final messenger for vascular smooth muscle relaxation, cGMP, is metabolized by PDE5. Among the various phosphodiesterase, PDE5 is the predominant type in the normal pulmonary vasculature that may be upregulated after CPB. The inhibition of PDE5 is, therefore, a logical step to increase the bioavailability of cGMP and support endogenous vasodilation in patient with PAH. PDE5 is selectively inhibited by sildenafil.

Oral sildenafil has proven to be an effective and safe pulmonary vasodilator in primary pulmonary hypertension. It can be of use as well in secondary pulmonary hypertension. PDE5 is abundant in lung tissue; hence, sildenafil selectively inhibits it and preferentially dilates pulmonary vascular beds. In our study, oral sildenafil selectively reduced pulmonary hypertension without any adverse systemic effects.

Preoperative oral sildenafil reduces pulmonary artery pressure in the perioperative period in patients with severe pulmonary hypertension secondary to mitral valve disease undergoing mitral valve replacement. Because of the predominant selective activity of sildenafil in the management of pulmonary hypertension and improvement of RV function without compromising the systemic blood pressure, the use of this drug in cardiac surgical patients should be considered. In postoperative patients, however, sildenafil does not cause any significant reduction in PASP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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