Sildenafil in the management of idiopathic pulmonary arterial hypertension in children and adolescents

Abstracts

OBJECTIVE: This study aims to provide data on the use of oral sildenafil in patients in New York Heart Association functional class III or IV with severe idiopathic pulmonary arterial hypertension unresponsive to conventional therapy. METHOD: In this series, six patients with idiopathic pulmonary arterial hypertension were prospectively treated with 2 to 8 mg of oral sildenafil in four to six doses a day. All pa-tients were submitted to physical examination, electrocardiogram and echocardiogram, chest computed tomography, ventilation and pulmonary perfusion scintigraphy, coagulation studies, and tests for collagen vascular disease, acquired immune deficiency syndrome and schisto-somiasis in order to rule out secondary causes of pulmonary arterial hypertension. All patients underwent cardiac catheterization for vasoreactivity tests using nitric oxide, O2 at 100% and oral nifedipine, and a 6-minute walking test was performed in those patients who were con-sidered able to exercise. RESULTS: All patients achieved a good therapeutic response, with improvement by at least one functional class, and presented an increase in systemic arterial oxygen saturation. Five patients showed a decrease in the pulmonary systolic pressure to systemic systolic pres-sure ratio and improvement in the six-minute walking test. No major side effects were ob-served at 4 to 36 months of follow-up. One patient had sudden death after sildenafil had been withdrawn by mistake. CONCLUSIONS: These data suggest that sildenafil may be useful in the manage-ment of idiopathic pulmonary arterial hypertension. Patients should be advised against the withdrawal of sidenafil without medical supervision.

Pulmonary arterial hypertension; phosphodiesterase inhibitors

OBJETIVO: Este artigo tem por objetivo relatar a experiência com o uso do sildenafil oral no tratamento de pacientes com hipertensão arterial pulmonar idiopática grave em classe funcional III e IV, sem resposta à terapia convencional e às provas de reatividade pulmonar. MÉTODO: Trata-se de estudo prospectivo, tipo de série de casos em que seis pacientes com diagnóstico de hipertensão arterial pulmonar idiopática foram tratados com sildenafil oral, com doses de 2 a 8 mg/kg/dia, divididas em quatro a seis vezes. Os pacientes foram submetidos a exame clínico, eletrocardiograma, ecocardiograma, tomografia do tórax, cintilografia de perfusão e ventilação pulmonar, estudos da coagulação, pesquisa de esquistossomose, doença do colágeno e de síndrome de imunodeficiência adquirida para afastar causas secundárias de hipertensão pulmonar. Todos os pacientes foram submetidos a cateterismo cardíaco para a realização das provas de reatividade pulmonar com óxido nítrico, O2 a 100% e nifedipina oral e ao teste de caminhada de 6 minutos nos pacientes em condições de realizá-lo. RESULTADOS: Todos eles apresentaram boa resposta, traduzida por melhora de, pelo menos, uma classe funcional, aumento da saturação sistêmica. Cinco pacientes apresentaram diminuição da relação da pressão sistólica pulmonar/pressão sistólica sistêmica e aumento da distância percorrida no teste de caminhada nos que a realizaram. Não foram observados efeitos colaterais em um tempo de seguimento de 4 a 36 meses. Um paciente apresentou morte súbita após a suspensão do medicamento. CONCLUSÕES: Os resultados sugerem que o sildenafil possa ser uma droga promissora no tratamento dos pacientes com hipertensão pulmonar idiopática, os quais devem ser conscientizados do risco da suspensão da medicação sem orientação médica.

Hipertensão arterial pulmonar; inibidores da fosfodiesterase

ORIGINAL ARTICLE

Sildenafil in the management of idiopathic pulmonary arterial hypertension in children and adolescents

Edmundo Clarindo Oliveira^I; Carlos Faria Santos Amaral^II

^IChief of the cardiology service, Hospital Vera Cruz. Chief of the pediatric cardiology service at Fundação Hospitalar de Minas Gerais. Pediatric hemodynamicist, Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil

^IIPhD. Professor, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil

^{Correspondence}

ABSTRACT

OBJECTIVE: This study aims to provide data on the use of oral sildenafil in patients in New York Heart Association functional class III or IV with severe idiopathic pulmonary arterial hypertension unresponsive to conventional therapy.

METHOD: In this series, six patients with idiopathic pulmonary arterial hypertension were prospectively treated with 2 to 8 mg of oral sildenafil in four to six doses a day. All patients were submitted to physical examination, electrocardiogram and echocardiogram, chest computed tomography, ventilation and pulmonary perfusion scintigraphy, coagulation studies, and tests for collagen vascular disease, acquired immune deficiency syndrome and schistosomiasis in order to rule out secondary causes of pulmonary arterial hypertension. All patients underwent cardiac catheterization for vasoreactivity tests using nitric oxide, O₂ at 100% and oral nifedipine, and a 6-minute walking test was performed in those patients who were considered able to exercise.

RESULTS: All patients achieved a good therapeutic response, with improvement by at least one functional class, and presented an increase in systemic arterial oxygen saturation. Five patients showed a decrease in the pulmonary systolic pressure to systemic systolic pressure ratio and improvement in the six-minute walking test. No major side effects were observed at 4 to 36 months of follow-up. One patient had sudden death after sildenafil had been withdrawn by mistake.

CONCLUSIONS: These data suggest that sildenafil may be useful in the management of idiopathic pulmonary arterial hypertension. Patients should be advised against the withdrawal of sildenafil without medical supervision.

Key words: Pulmonary arterial hypertension, phosphodiesterase inhibitors.

Introduction

Idiopathic pulmonary arterial hypertension (IPAH) is defined as a mean pulmonary artery pressure higher than 25 mmHg at rest or 30 mmHg on exercise, of unknown etiology, and with normal pulmonary capillary pressure.¹ It is a rare disease, with an incidence of one to two cases per one million inhabitants/year. IPAH may show familial predisposition in 10% of cases. Observations suggest that vasoconstriction plays a crucial role in the pathogenesis of this disease, which is characterized by pathological hypertrophy of the tunica media of pulmonary arterioles, reduction in the endothelial production of prostacyclin and nitric oxide, and increase in endothelin production.² Symptoms, such as fatigue, dizziness, chest pain, heart failure and hypoxemia often develop in the presence of severe hypertension. After its onset, the expectation is of 68, 48 and 34% in one, three and five years, respectively,³ in the absence of treatment to reduce pulmonary pressure (PP). The disease is incurable, and patients need lifelong treatment. Reducing PP is the most effective way to alleviate heart failure symptoms, to increase survival, and to improve the quality of life of these patients. Unfortunately, there is no ideal drug for this purpose.

Several drugs have been used in a continuous fashion, of which calcium antagonists, especially nifedipine, have been used for a longer time period. The pulmonary vasodilatory action of these antagonists is acknowledged, with reduction in PP and increase in the survival of IPAH patients.⁴ The necessary doses for PP reduction are usually greater than those used to treat systemic hypertension. It is common knowledge that most patients do not respond to calcium antagonists and may have severe side effects, which shows the importance to perform acute reactivity tests in order to select those patients who would definitely benefit from their use. Pulmonary reactivity tests employ oxygen at 100% and short half-life drugs with pulmonary vasodilatory action, such as adenosine,⁵ prostacyclin,⁶ acetylcholine and mainly nitric oxide,⁷ since it is a selective and short-acting pulmonary vasodilator.

Prostaglandins,⁸ in aerosol or continuous infusion pump, are promising drugs, but they have some disadvantages, such as the necessity of many applications a day, risk of complications (infection and thrombosis) when used in continuous infusion, and their high cost. Endothelin inhibitors⁹ have been investigated recently, but their cost is also high and they may cause severe side effects (e.g.: liver disorders). Other medication, such as home oxygen therapy and oral anticoagulants, are only palliative, and their impact on the improvement of survival of IPAH patients is still unclear. Atrial septostomy¹⁰ and lung transplantation¹¹ are extreme forms of treating IPAH and have a poor result in the medium run.

Quite recently, sildenafil (Viagra^®), used to treat erectile dysfunction and marketed with this purpose, has been used to treat IPAH. This drug is a selective and powerful phosphodiesterase 5 (PDE5) inhibitor specific to cyclic guanosine monophosphate (GMPc), abundant in the lungs. PDE5 inhibition prevents the degradation of GMPc, which is an intracellular messenger for nitric oxide, with consequent pulmonary vasodilation. The medical literature has shown more and more frequent reports on the use of sildenafil for the treatment of pulmonary hypertension (PH) of different etiologies.^12,13

The present study describes the results of oral sildenafil therapy in six patients with IPAH in functional class III and IV, despite the use of conventional therapeutic measures.

Patients and methods

This is a prospective case series including six patients diagnosed with severe idiopathic pulmonary hypertension, who did not respond to conventional treatment. The diagnosis of PH was suspected due to the increase in the intensity of the pulmonary valve component of the second heart sound on auscultation and due to the signs of right ventricle (RD) enlargement, assessed by chest x-ray and electrocardiogram. Echocardiographic findings for the diagnosis of PH included an increase in PP, using the right ventricle-right atrium (RV-RA) gradient, estimated by tricuspid regurgitation, with addition of 10 mmHg, value assumed as right atrium (RA) pressure. Secondary causes of PH were ruled out by means of chest computed tomography, ventilation and pulmonary perfusion scintigraphy, coagulation studies, investigation for schistosomiasis and acquired immunodeficiency syndrome, echocardiogram, and cardiac catheterization. For cardiac catheterization, all patients were sedated with midazolam and fentanyl.

PP was monitored using a Swan-Ganz 7F catheter for adult patients and 5F for children, whereas arterial blood pressure was monitored with a 3F catheter inserted into the femoral artery. During catheterization, pressure measurements were performed in the pulmonary artery, aorta, pulmonary capillary bed and RA. Cardiac output and pulmonary and systemic vascular resistance were determined. This was carried out while patients breathed room air, after oxygen therapy at 100% for 15 minutes and use of nitric oxide in an initial concentration of 10 ppm; in the absence of response, the concentration was increased every 10 minutes, up to 80 ppm.⁶ Oral nifedipine was initially given in the dose of 5 mg to patients weighing more than 30 kg and in the dose of 0.2 mg/kg to children, with a 50% increase in the dose every six hours in case of no response or of side effects. Pulmonary reactivity tests were defined as positive in the presence of a decrease greater than 20% in mean PP, without reduction of systemic output and with maintenance of the reduction in the pulmonary systolic pressure (PSP)/systolic arterial pressure (SAP) ratio greater than 20%. Decrease in systemic output, maintenance or increase in the PSP/SAP ratio, persistent tachycardia and reduction in systemic oxygen saturation were regarded as absence of response to the tests. The patients were observed at an ICU, with monitoring of PP and arterial blood pressure during 12 to 24 hours. The six-minute walking test was not performed in four patients, due to the fact that they were receiving vasoactive drugs at the ICU, with heart failure and severe hypoxemia, and/or because they were children. Ongoing medications were maintained. Oral sildenafil was initially used in the dose of 2 mg/kg/day, up to 100 mg/day given in four or six doses. The doses could be increased every 15 days up to 8 mg/kg/day, or until they reached 500 mg/day¹⁴ in the absence of response or in case of side effects.

The study protocol was approved by the Research Ethics Committee of Hospital Vera Cruz, Belo Horizonte, and by the Research Ethics Committee of Universidade Federal de Minas Gerais (UFMG). An informed consent form was signed by the patients and/or their surrogates, wherein it was stated that sildenafil was being tested for the treatment of IPAH and that it was not primarily marketed for this purpose. The contact of patients and their families with the assistant physician was facilitated and so was the treatment of intercurrent events.

Results

The clinical characteristics of the six patients are shown in Table 1. All of them were categorized into functional class III or IV even if they were receiving medication for heart failure, including dopamine in two patients. Tables 2 and 3 show the results of the complementary exams. The data shown in these tables reveal that all patients had normal pulmonary capillary wedge pressure. Five of six patients had suprasystemic pulmonary pressure and the other patient had systemic pressure. Systemic oxygen saturation was less than 90% in four of them and no patient showed response to the pulmonary reactivity tests. Table 4 describes the results and the clinical outcome after oral administration of sildenafil. In the follow-up period, there was improvement by at least one functional class in all patients, improvement in systemic oxygen saturation and increase in the distance achieved within six minutes in those patients submitted to the walking test. Five of six patients demonstrated a decrease in the PSP/SAP ratio, which characterizes an effective decrease in PP.

Discussion

The six patients included in this study showed clinical improvement after oral administration of sildenafil, characterized by the reduction in at least one NYHA (New York Heart Association) functional class, decrease in the PSP/SAP ratio, improvement in systemic saturation, and increase in the distance achieved on the six-minute walking test. Pulmonary systolic pressure is usually assessed by echocardiogram, and this is why the pulmonary systolic/systemic systolic pressure ratio was used for the comparison. Nevertheless, a 19-year-old female patient (case 4), in functional class IV, with an 88% systemic saturation, and severe heart failure, died after showing clinical improvement and increase in systemic saturation. The patient had sudden death 24 hours after abrupt withdrawal of the medication she had been receiving while in hospital. Therefore, all patients and the medical staff should be warned against the abrupt withdrawal of the medication. In the other patients, the use of sildenafil was safe, with no side effects, despite the high doses. Remarkable systemic unsaturation (< 90%) was detected in four patients, which is not common in IPAH. However, pulmonary arterial blood pressure levels were greater than the systemic pressure, and unsaturation may be explained by RA shunt to the left atrium through the patent foramen ovale, observed on the echocardiogram and cardiac catheterization.

The medical literature has described a growing number of case reports on the use of oral sildenafil in the treatment of PH of different etiologies. Such reports indicate that this drug brings benefits to the patients, as it potentiates or allows for the withdrawal of nitric oxide in cases of PH crises.¹⁵ When combined with other drugs, sildenafil can increase the efficiency of each one of them, allowing their doses to be reduced or the dose intervals to be improved.¹⁶ Sildenafil has proved equally efficient in the treatment of PH secondary to collagen diseases,¹⁴ of chronic pulmonary thromboembolism without surgical management¹⁵ and mainly of IPAH.^13,17

Despite the clearer understanding about its pathophysiology and about the new treatment options, IPAH is still a serious disease, without any cure, and with no ideal drug therapy. All the available therapies have restrictions and risks of complications and also have a very high cost. IPAH patients in functional class IV are a special group, since they are often young and have a life expectancy shorter than one year. In this study, despite the low number of patients, there was some improvement in the functional class, in the tolerance of exertion (assessed by the increase in the walking distance in the two patients who were able to exercise) and by the improvement in the quality of life, with social reinsertion and absence of hospital admissions during the follow-up period. These findings suggest that sildenafil may be an alternative to this special group of patients. However, studies with a larger patient population and longer follow-up are necessary so that long-term results can be assessed and the ideal doses and ideal interval between them can be established.

References

Manuscript received Feb 03 2005, accepted for publication May 11 2005.

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Publication Dates

• Publication in this collection
  12 Dec 2005
• Date of issue
  Oct 2005

History

• Received
  03 Feb 2005
• Accepted
  11 May 2005