Resolution of right-to-left shunt after primary pulmonary hypertension treatment with sildenafil

Abstracts

Primary pulmonary hypertension is a rare, progressive disease with high mortality rates. The treatment of primary pulmonary hypertension is still based on high-cost drugs, not yet available in developing countries. Recently, the use of sildenafil as an alternative drug for primary pulmonary hypertension treatment has been reported. It is reported a case of a 21 year-old female patient with primary pulmonary hypertension, who presented an acute worsening of symptoms and decrease of oxygen saturation. The investigation revealed the existence of a patent oval foramen not previously seen, with right-to-left shunt. Sildenafil treatment was instituted in escalating doses. After 40 days of treatment, the echocardiogram showed resolution of the shunt, concomitant to oxygenation improvement. The authors believe that sildenafil is a feasible alternative for primary pulmonary hypertension treatment, although larger clinical trials are necessary to determine its clinical safety and efficacy.

Pulmonary hypertension; Vasodilator agents

Hipertensão pulmonar primária é uma doença rara, progressiva e com alta mortalidade, cujo tratamento baseia-se em medicações de alto custo e pouco disponíveis em nosso meio. O sildenafil é um vasodilatador de fácil administração por via oral, com indicação primária para disfunção erétil e que recentemente tem sido descrito como opção terapêutica para a hipertensão pulmonar primária. Relata-se o caso de uma paciente de 21 anos com diagnóstico de hipertensão pulmonar primária, que apresentou piora abrupta da saturação de oxigênio, com abertura do forame oval e shunt direita-esquerda, evidenciados ao ecocardiograma. Foi introduzido sildenafil na dose de 225mg/dia com melhora progressiva da oxigenação e reversão do shunt após 40 dias. Os autores acreditam que o sildenafil seja uma opção no tratamento da hipertensão pulmonar primária, embora estudos clínicos que comprovem sua segurança e eficácia ainda sejam necessários.

Hipertensão pulmonar; Vasodilatadores

CASE REPORT

Resolution of right-to-left shunt after treatment of primary pulmonary hypertension with sildenafil^*

Sérgio Marques da Silva^I; Carla Bastos Valeri^I; Humberto Bassit Bogossian^II (te sbpt); Carlos Jardim^I; Sérgio Eduardo Demarzo^III (te sbpt); Rogério Souza^IV (te sbpt)

^{Correspondence}

ABSTRACT

Primary pulmonary hypertension (PPH) is a rare and progressive disease with high mortality rates. The treatment of PPH is still based on high-cost drugs, not yet available in developing countries. Recently, the use of sildenafil as an alternative for PPH treatment has been reported. We report a case of a 21-year-old female patient with PPH who presented acute worsening of symptoms and a decrease in oxygen saturation. The investigation revealed the existence of a patent oval foramen not previously present, with right-to-left shunt. Sildenafil treatment was instituted in escalating doses. After 40 days of treatment, the echocardiogram showed resolution of the shunt, concomitant to oxygenation improvement. We believe that sildenafil is a feasible alternative for PPH treatment, although larger clinical trials are necessary to determine its clinical safety and efficacy.

Key words: Primary Pulmonary Hypertension. Treatment, Sildenafil

Abbreviations:

cGMP – Cyclic guanosine monophosphate

PH – Pulmonary hypertension

PPH – Primary pulmonary hypertension

PaO₂ – Arterial oxygen tension

PAP – Pulmonary artery pressure

PDE-5 – Phosphodiesterase-5

Introduction

Primary Pulmonary Hypertension (PPH) is a rare disease that affects lung blood vessels, causing constriction, remodeling of the vessel walls and in situ thrombosis and resulting in increased right-ventricular afterload and progressive heart failure. This disease has a high mortality rate and affects mainly young adults in their 30s and 40s, predominantly females.⁽¹⁾

The treatment of PPH is based mainly on the use of oral anticoagulant agents⁽²⁾ in combination with vasodilators.^(3,4) É mandatória aPerforming a hemodynamic test with short acting vasodilators (prostacyclin, adenosine or nitric oxide) in order to choose which vasodilator to use is mandatory. This test is performed through catheterization of the right ventricle, as there are no proven, noninvasive methods for this evaluation. Approximately 25% of patients respond favorably, with decreased pulmonary vascular resistance and increased cardiac output. For these patients, vasodilator therapy with calcium channel blockers is indicated. For the remaining 75% of patients, the use of drugs such as epoprostenol (a prostacyclin analog for intravenous use), iloprost (also a prostacyclin analog, but for inhalation) or bosentan (a nonselective endothelin receptor antagonist for oral use) is indicated.⁽⁵⁾ However, access to these drugs is limited due to their high cost and scarcity, especially in countries such as Brazil, where per-capita income is low.

Recently, sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, has been shown to be effective in the management of PPH. It is easy to use, with lower cost and good market availability. Here we report the case of a patient who, after a significant worsening of symptoms (with the onset of interatrial communication), was started on sildenafil as therapy for her PPH.

Case Report

An 18-year-old patient came to the hospital complaining of dyspnea after moderate exertion and of lightheadedness, both of which had been occurring for one year. Upon physical examination, she presented only an accentuated second cardiac sound and no murmurs. Transthoracic echocardiography showed right chamber enlargement with a systolic pulmonary artery pressure (PAP) of 116 mmHg (estimated through tricuspid regurgitation) and left chambers of normal size and function.

Angiotomography of the chest showed no thrombi or interstitial changes revealing only alterations consistent with pulmonary hypertension (Figure 1). The patient tested negative for hepatitis and HIV, as well as for autoantibodies. After the diagnosis of PPH had been established, oral anticoagulants were started and an acute test with vasodilator was scheduled.

The patient presented a sudden worsening of the dyspnea, together with severe headache and severe hypoxemia (a decrease in oxygen saturation from 95% to 65% while breathing room air). She was hospitalized for treatment and investigation into the cause of the worsening of her status. Another lung scintigraphy and a second angiotomography were used to rule out pulmonary thromboembolism. However, transthoracic echocardiography showed a right-to-left interatrial shunt due to a permeable oval foramen (which was not present previously) and the same pressure levels in the pulmonary artery observed in the previous tests. These findings were confirmed by transesophageal echocardiography (Figure 2).

Oxygen therapy was started at admission and, due to the significantly worsening patient condition, we introduced sildenafil at a dosage of 25 mg every 8 hours and increased each dose by 25 mg until a dose of 225 mg a day was reached. The patient presented progressive improvement of the tachypnea and a partial reversion of the hypoxemia on room air during the 12 days she was hospitalized (from oxygen saturation = 65% and PaO₂ = 37 mmHg to oxygen saturation = 88% and PaO₂ = 58 mmHg). The patient was discharged under oxygen therapy.

After one month of sildenafil use, transthoracic echocardiography showed that her PAP had not changed (109 mmHg) but that the shunt had disappeared, which characterized the closing of the oval foramen. During this period, her hypoxemia progressively decreased and she attained an oxygen saturation of 95% and a PaO₂ of 71 mmHg on room air, which verified the closure of the right-to-left atrial shunt (Figure 3). The levels of carbonic gas partial pressure were within the normal range throughout.

Case discussion

PPH is a rare disease with an annual incidence of 1 to 2 cases per million. The diagnosis is difficult, due to the slow onset of the disease and to the necessity of excluding all other causes of secondary pulmonary hypertension. Its etiology is unknown, but it seems to be a result of abnormal interactions between genetic and environmental factors that lead to vasculopathy.^(1,6) The prognosis is negative, with a median estimated survival of 2.8 years.

Several drugs have been used to decrease the vasoconstriction of the pulmonary microvessels, leading to lower vascular pulmonary resistance, improvement of right ventricle hypertrophy and a significant drop in PAP. Among these drugs, epoprostenol, iloprost and bosentan have been shown to produce significantly beneficial clinical results.⁽⁵⁾

However, the problem is the unavailability of these drugs. This is owing to several factors, such as the high cost and the difficulty of administration (in the case of the intravenous and inhaled forms of prostacyclin). Also, pulmonary hypertension is not recognized as a public health problem, since there are few diagnosed cases.

Sildenafil is an oral medication prescribed mainly for erectile dysfunction, with a potent effect on the selective inhibition of PDE-5. PDE-5 is found in higher concentrations on lung tissues and acts directly on the hydrolysis of cyclic guanosine monophosphate (cGMP), which is the intracellular mediator responsible for vasodilation and antimitogenic actions under alveolar hypoxia.⁽⁷⁾ The cGMP is activated by nitric oxide (NO) and natriuretic peptide binding. Thus, sildenafil, by reducing PDE-5 activity, causes cGMP to become elevated, thereby provoking pulmonary vasodilation.

In animal as in human experimental research, sildenafil has significantly reduced pressure levels in pulmonary circulation during hypoxia, in both acute and chronic situations.

Recent studies have shown that sildenafil is as effective in the reduction of pulmonary vascular resistance as is inhalation of nitric oxide (NO). In addition, sildenafil provides greater improvement in the cardiac index and a greater decrease in pulmonary artery wedge pressure. The addition of inhaled iloprost also showed a pronounced effect on pulmonary vasodilation in patients with PPH and chronic thromboembolic pulmonary hypertension.^(9,10)

The opening of the oval foramen in adult patients with PPH is a rare occurrence and usually indicates a sudden worsening in condition. It causes severe acute hypoxemia due to the right-to-left atrial shunt. Despite the fact that atrial septostomy has been shown to improve survival in patients with PPH⁽¹¹⁾, this procedure is performed in stages, with concomitant control of cardiac output, since the area of the foramen is enlarged. In this manner, the creation of an excessive right-to-left interatrial shunt is avoided. To date, there have been no reports regarding the behavior of patients with spontaneous opening of interatrial communication, since it typically occurs as a consequence of the worsening of the baseline condition.

In the case we are describing, echocardiography showed pressure levels in the pulmonary artery to have remained unchanged. However, the closure of the oval foramen after the introduction of oral sildenafil was probably secondary to the global increase in pulmonary circulation capacitance, which allowed relief of the final diastolic volume of the right ventricle. As a consequence, cardiac output was improved, although invasive direct measurement methods were not employed.

The significant improvement of the dyspnea and hypoxemia since the onset of treatment gave an early indication of the shunt reversal, which was later confirmed through echocardiography. This demonstrates the important role that sildenafil can play.

We believe that sildenafil is a feasible alternative for the treatment of patients with PPH. It must be noted, however, that more clinical trials are necessary to evaluate the safety and the long-term effects of this therapy. While these studies are still ongoing, the use of sildenafil must be reserved for extreme cases when no other safe and effective options are available.

References

Submitted: 17/04/2003. Accepted, after revision: 27/05/2003.

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*

Study conducted in the Pulmonology Department of the

Faculdade de Medicina da Universidade de São Paulo (Medical School of the University of São Paulo)

Publication Dates

• Publication in this collection
  02 Mar 2004
• Date of issue
  Oct 2003

History

• Received
  17 Apr 2003
• Accepted
  27 May 2003