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Sildenafil e Hipertensión pulmonar neonatal
Junio 2007
Estimados Colegas Neonatólogos :
Respecto a la dosificación de Sildenafil se maneja vía oral dado que no hay presentación IV , la dosis es de 1-2 miligramos VO cada 6 horas. Debemos recordar que este inhibidor de fosfodiesterasas tiene poco efecto sobre la vasodilatación sistémica a diferencia del sulfato de magnesio el cual es un hipotensor sistémico (recordemos que los obstetras lo llegan a manejar en las preeclampsias severas) . Es verdad que lo hemos manejado en momentos donde no teníamos otra terapéutica al alcance pero los resultados son diversos y tambien dependerá a que tipo de HPPRN nos estemos enfrentando. Volviendo a Sildenafil existen estudios realizados en Colombia con el Dr. Vaquero (Pediatrics 2007 Enero) y algunos aquí en México con buenos resultados. Se empiezan a realizar estudios de Sildenafil inhalado al parecer con resultados prometedores.
En relación del uso de Bicarbonato hay evidencia (revisión Cochrane 2006) sobre que el uso de Bicarbonato en infusión continua no es tan útil como suponíamos hace algunos años, inclusive actualmente se cuestiona su uso en neonatos para corrección de acidosis inclusive se vuelve controversial en el paciente en paro cardiorespiratorio.
A continuación pongo a su consideración lo que normalmente manejamos como medidas generales en estos casos de pacientes con HPPRN :
1.- Acceso vascular y Monitoreo
El acceso venoso adecuado es esencial.
Un catéter venoso umbilical aporta acceso venoso central fácil y seguro, el cual es particularmente importante si el uso de inótropicos llega a ser necesario; si es posible debe usarse un catéter multilumen.
El acceso arterial es útil para proveer monitoreo de presión arterial invasiva y muestras de gases sanguíneos.
Monitoreo ECG y de SaO2 deberían ser continuos y es útil monitorear saturaciones de oxígeno pre y postductales como índice del grado de shunt.
Debe monitorearse la temperatura corporal ajustando adecuadamente la temperatura ambiental.
2.- Manipulación
Los niños con hipertensión pulmonar son extremadamente inestables.
La manipulación es pobremente tolerada y puede resultar en rápido deterioro.
Por tanto, estos niños debieran ser manipulados lo menos posible.
Los procedimientos deben mantenerse al mínimo y la aspiración endotraqueal y orofaríngea debe se realizada solo cuando es clínicamente necesario.
3.- Líquidos, electrolitos y nutrición
El líquido de mantenimiento debe mantenerse al mínimo requerido para mantener hidratación y niveles de glicemia.
Puede administrarse líquido adicional cuando está clínicamente indicado.
Debe realizarse evaluación frecuente de los electrolitos y corregir los desbalances electrolíticos , particularmente en relación a calcio, potasio y magnesio.
Pueden requerirse concentraciones aumentadas de glucosa para mantener niveles sanguíneos normales.
La alimentación enteral debe ser cuidadosamente introducida cuando se ha alcanzado un nivel de estabilidad clínica.
La alimentación parenteral es requerida a menudo y lo más temprano posible.
Debe alentarse a las madres a extraer y almacenar leche materna para su uso cuando sea iniciada la alimentación.
4.- Estado hemodinámico
La presión arterial sistémica media debe mantenerse en el rango normal alto (usando edad gestacional como guía) con el uso de expansión de volumen e inótropos.
Deben corregirse anemia, trombocitopenia y coágulopatías con transfusiones de sangre, plaquetas y plasma respectivamente.
Debe mantenerse un hematocrito normal (mayor 40%) y si hay policitemia significativa (mayor a 65%) puede ser necesaria una exsanguíneotransfusión dilucional.
5.- Ventilación
El objetivo de la ventilación en hipertensión pulmonar es corregir hipoxia (hasta donde sea posible) y evitar situaciones que puedan agravar la hipoxia: ej; neumotórax, extubación accidental , bloqueo del tubo traqueal y respiración asincrónica.
Es por tanto importante que el niño sea adecuadamente sedado y se use un relajante muscular apropiado.
Se requiere cuidado cuando se introduce un opiáceo o benzodiazepina para evitar una respuesta hipotensora, la cual puede llevar a empeorar la hipoxia.
Se prefiere infusiones continuas a administración de bolos para asegurar una sedación constante.
Con Ventilación mecánica convencional es importante mantener presiones inspiratorias máximas tan bajas como sea posible para reducir fuerzas que puedan provocar daño pulmonar y por consiguiente evitar la estimulación inadvertida de la musculatura lisa vascular pulmonar.
Se han sugerido varias estrategias usando presiones positivas de fin de espiración (PEEP) bajas o altas y tiempos inspiratorios (Ti) cortos y largos. La naturaleza de la enfermedad de base dictará cuales métodos de ventilación serán más efectivos, los cuales debieran apuntar al óptimo reclutamiento alveolar sin sobredistensión.
Presiones ventilatorias más altas no resultarán en una PaO2 aumentada si los alvélolos distendidos no están siendo perfundidos y de hecho pueden ser deletéreas al disminuir el retorno venoso al corazón y causar barotrauma.
Si es posible, el uso de FiO2 100 % debiera evitarse para disminuir el riesgo de atelectasia y el daño por radicales libres de oxígeno. Debido a la alteración en la relación V–Q una leve disminución de la FiO2 no afectará la PaO2.
La ventilación debe apuntar a disminuir la PaCO2 (30–35 mmHg) y aumentar el pH arterial hacia valores alcalóticos usando alto volumen minuto (aumentando ciclado). A menudo la administración de cristaloides ayuda a mejor la acidosis metabólica al igual que mejorar la oxigenación.
La hiperventilación y alcalosis respiratoria son efectivas en disminuir PAP pero debe evitarse una hipocapnia mantenida (PaCO2 < 20 mmHg) debido a su efecto vasoconstrictor cerebral y depresor miocárdico.
La posición prona es útil para superar en parte la alteración V–Q.
La ventilación de alta frecuencia oscilatoria (HFO) es una forma efectiva de ventilación en hipertensión pulmonar y es fácilmente combinada con terapia con óxido nítrico.
La HFO es efectiva en bajar las presiones máximas de la vía aérea y maximizar la expansión pulmonar y reclutamiento alveolar. Además es una modalidad efectiva para disminuir el CO2.
Una estrategia de alto - volumen es útil para el reclutamiento alveolar, pero altas presiones medias de vía aérea deben ser usadas con cuidado dado que el retorno venoso puede deteriorar más la hipoperfusión pulmonar.
6.- Apoyo inotrópico
Por diversas razones hay a menudo bajo débito ventricular en los niños con hipertensión pulmonar.
La perfusión pulmonar disminuída lleva a retorno venoso pulmonar más bajo y por consiguiente a una precarga ventricular izquierda disminuída. Por contraste, el ventrículo derecho está luchando contra una alta postcarga.
La función miocárdica puede estar disminuída debido a la hipoxia, hipercarbia o acidosis. Puede haber un efecto directo sobre la función cardíaca y perfusión periférica debido a la causa subyacente, por ejemplo, sepsis.
No es sorprendente por tanto que estos niños requieran frecuentemente apoyo inotrópico, particularmente dado que los vasodilatadores frecuentemente usados en el tratamiento de hipertensión pulmonar resultan en hipotensión sistémica.
La Dobutamina es el fármaco de elección una vez que el volumen circulante se ha optimizado con infusiones de líquidos.
La Dobutamina causa la menor vasoconstricción pulmonar pero no es siempre efectiva en elevar la presión sanguínea.
Dopamina en altas dosis produce vasoconstricción de vasos sistémicos y pulmonares. A menudo hay una compensación entre el uso de inótropos y vasodilatadores pulmonares , la mayoría de los cuales causa hipotensión sistémica.
Debe mantenerse la presión arterial media en valores normales altos para tratar de aumentar el flujo en la vasculatura pulmonar.
Quedo a sus órdenes para cualquier comentario
Dr. Moisés Quiles Corona Pediatra Neonatólogo
UCIN Hospital Juan I. Menchaca y Hospital Real San José Guadalajara , Jalisco, México.
Pediatrics Vol. 119 No. 1 January 2007, pp. 215-216
To the Editor
The interesting work of Baquero et al1 showed for the first time the beneficial effects of sildenafil in a series of newborn patients affected with severe persistent pulmonary hypertension (PPHN), improving survival and the oxygenation index after oral administration of 2 mg/kg per dose. Regarding this pathology, different therapeutic strategies have been used with the aim of improving blood oxygenation in the newborn severely affected by PPHN. The gold-standard therapy for this pathology is inhaled nitric oxide (iNO), although its high cost limits its widespread use in ICUs, especially in the developing world. Moreover, in countries where iNO is available, the need to send the patient to the iNO-equipped area and the fact that there are up to 60% of patients who do not improve their oxygenation index with iNO, depending of the series and the pathology involved,2 make it necessary to search for cheaper therapies, assuring quick effectiveness and stabilization of the patient going through a very high-risk situation. One of the latest explored drugs is the phosphodiesterase inhibitor type 5, sildenafil. From different works it can be concluded that the time of maximum action and duration of the effect varies depending on the dose, the route of administration, and the model or clinical situation in which sildenafil has been used.3–7 The most used route of administration has been oral, and the duration of the effect goes from 20 minutes to 6 hours afterward.6,7 Many other vasodilators such as prostacyclin (PGI2) or fentanyl have also been given in both intravenous and intratracheal forms to neonates with PPHN. Unfortunately, none of these agents are selective pulmonary vasodilators.
The selectivity of sildenafil in lung tissue makes it attractive as an anti-PPHN drug. In these sense, to obtain a quick response in pulmonary circulation and as an alternative procedure, our group has explored its effects in a model of PPHN induced by meconium aspiration in newborn piglets. Sildenafil (0.75 or 1.5 mg/kg per dose administered intratracheally) induced a rapid decrease in mean pulmonary arterial pressure (PAP), which occurred as soon as 2 minutes and lasted for 120 minutes. Both doses significantly decreased PAP compared with the pressure acquired at the point of more marked changes induced by meconium aspiration, and there was no significative difference between both doses. Moreover, the PAP after sildenafil administration was not significantly different compared with basal data, before the beginning of meconium instillation in the airway. However, in this model without inotropic support, there was also a significant decrease in mean systemic arterial pressure, a fact to take into account at the moment of managing a child with this therapeutic option. These data are summarized in Fig 1 (P < .01).
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These results show that sildenafil offers the possibility of quick action applied intratracheally, similar to the utility of prostacyclin, representing a cheaper solution, of particular value in any place where there is no other effective therapy available until the oral administration could provide effect or another therapy is administered.
References
Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117 :1077 –1083
Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr. 2000;136 :717 –726
Weimann J, Yllrich R, Hromi H, et al. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology. 2000;92 :1702 –1712
Shekerdemian L, Ravn HB, Penny KJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Respir Crit Care Med. 2002;165 :1098 –1102
Ichinose F, Erana-Garcia J, Hromi H, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med. 2001;29 :1000 –1005
Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension. Circulation. 2002;105 :2398 –2403
Fernández González N, Rodríguez Fernández A, Jerez Rojas J, Parrondo Garrido SM, Martínez Mengual L. Oral sildenafil as a treatment of a newborn with persistent pulmonary hypertension [in Spanish]. An Pediatr (Barc). 2004;61 :562 –568
Pediatrics Vol. 119 No. 1 January 2007, pp. 216
We thank Martell et al for their letter regarding our prospective randomized masked trial in human neonates on the effects of oral sildenafil.1 As they noted, Ichinose et al2 showed that nebulized (aerosolized) sildenafil was a selective pulmonary vasodilator with no effect on systemic arterial pressure that potentiated the effects of inhaled nitric oxide (iNO) just as when it was given orally or as an intravenous infusion.2 In that study, aerosols of 10 and 30 mg of sildenafil decreased pulmonary arterial pressure by 21% to 26%. When 10 mg of sildenafil were inhaled while simultaneously breathing 2 and 5 ppm of iNO, pulmonary arterial pressure decreased by 35% to 43%. Inhaled sildenafil did not impair systemic oxygenation, increase right-left intrapulmonary shunting, or impair the ability of iNO to reduce this shunting. Nebulized sildenafil also did not result in any apparent lung injury on microscopic examination.2 Very recently, nebulized sildenafil was proven effective in an in vitro model.3 The authors aimed to estimate pulmonary deposition of the drug from commonly used nebulizers using in vitro techniques and to create a mathematical model to predict inspired mass of aerosol. They found that the drug could be nebulized, but the expected pulmonary deposition varied depending on the nebulizer.3 This is an area of concern for incorporation of such treatment into clinical practice. In their letter, Martell et al described their findings in neonatal piglets but did not tell us how the sildenafil was prepared for intratracheal instillation or how it was instilled. We can only speculate on the pK (degree of dissociation or proton-binding affinity of this molecule), pH, dilution, solubility, particle size, and sterility of the solution prepared. All are potential inducers of severe airway and lung damage. As Martell et al mentioned, there are reports on intratracheal (nebulized) administration of prostacyclin and also of nitroprussiate and even tolazoline. The hope was to provide more selective effects and at the same time avoid systemic undesired consequences. However, these drugs were designed and approved for intravenous administration. It is worrisome to think of administering to human newborns a drug, such as sildenafil or any other, that was designed, studied, and approved for oral use only. Furthermore, the report of systemic hypotension induced by the intratracheal treatment is also intriguing and worrisome as a systemic undesired consequence. In our neonatal study and in many others in children and adults when the drug was administered orally, this known potential systemic undesired effect of sildenafil has been either nonexistent or minimal and infrequent. We agree with Martell et al about the need to find an effective and less costly option for the treatment of PPHN. Although there is still much to be learned about oral sildenafil use in neonates, at this time it seems that this alternative is much safer and efficacious than aiming for a potentially quicker action by administering sildenafil intratracheally. We believe that the research findings of this group reported in their letter should not be used at this time as support to justify instilling the oral preparation of sildenafil into the trachea of human neonates.
References
Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117 :1077 –1083
Ichinose F, Erana-Garcia J, Hromi H, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med. 2001;29 :1000 –1005
Katz SL, Adatia I, Louca E, et al. Nebulized therapies for childhood pulmonary hypertension: an in vitro model. Pediatr Pulmonol. 2006;41 :666 –673
Abstracts
1: Neonatology. 2007; 91(2):92-100.
Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension
Noori S, Friedlich P, Wong P, Garingo A, Seri I.
USC Division of Neonatal Medicine, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
BACKGROUND: Pulmonary hypertension is a common problem in patients with congenital diaphragmatic hernia (CDH). In a subset of these patients, pulmonary hypertension persists despite optimized ventilatory management and supportive care. Sildenafil, a phosphodiestrase V inhibitor, has been used in the treatment of pulmonary hypertension in adults and children. Cardiovascular effects of sildenafil in patients with CDH and pulmonary hypertension are not known. OBJECTIVE: To describe the changes in cardiovascular and respiratory parameters in newborn infants with CDH and persistent pulmonary hypertension refractory to inhaled nitric oxide (iNO) during the first 2 weeks of sildenafil administration. METHODS: Retrospective data analysis of seven patients with CDH (birth weight = 2,573 +/- 1,019 g; gestational age = 35.6 +/- 4.3 weeks) receiving oral sildenafil for pulmonary hypertension refractory to iNO. Findings of serial echocardiograms and data on cardiovascular and respiratory status were assessed. RESULTS: Right cardiac output increased and left cardiac output tended to increase 1.5-4 h after initiation of sildenafil and the increase was sustained throughout the study. Echocardiographic indices of pulmonary hypertension showed an apparent reduction in abnormally high pulmonary vascular resistance. Systemic blood pressure tended to decrease. Shortening fraction did not change. Ventilatory index and the need for iNO tended to decrease in the five surviving infants. CONCLUSIONS: These preliminary findings suggest that sildenafil may improve cardiac output by reducing pulmonary hypertension refractory to iNO in patients with CDH.
2: Vasc Health Risk Manag. 2006;2(4):411-22.
Sildenafil in the treatment of pulmonary hypertension.
Critical Care Medicine
Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
The therapy of pulmonary hypertension has evolved rapidly in the last 10 years from the use of non-selective vasodilators to drugs that specifically target pulmonary vasodilation, endothelial function, and vascular remodeling. Sildenafil is a phosphodiesterase type 5 inhibitor that has an expanding role in the treatment of pulmonary hypertension. Case series and small studies, as well as the first large randomized controlled trial, have demonstrated the safety and efficacy of sildenafil in improving mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and exercise tolerance in pulmonary arterial hypertension. It may be useful in adults, children, and neonates after cardiac surgery, with left heart failure, in fibrotic pulmonary disease, high altitude exposure, and thromboembolic disease, and in combination with other therapies for pulmonary hypertension, such as inhaled iloprost. The oral formulation and favorable adverse effect profile make sildenafil an attractive alternative in the treatment of selected patients with pulmonary hypertension.
3: Drugs. 2007;67(1):57-73.
Therapeutic applications of sildenafil citrate in the management of paediatric pulmonary hypertension.
Leibovitch L, Matok I, Paret G.
Department of Pediatric Critical Care, Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Pulmonary hypertension is characterised by a progressive increase in pulmonary vascular resistance and a poor prognosis. The exact underlying mechanisms are still poorly understood; however, it is hypothesised that pulmonary medial hypertrophy and endothelial dysfunction lead to impaired production of vasodilators such as nitric oxide (NO) and prostacyclin, and increased expression of vasoconstrictors such as endothelin-1. The current treatment modalities for pulmonary hypertension include conventional supportive therapies and more specific pharmacological therapies that are targeted at abnormalities of endothelial function. NO and phosphodiesterase type 5 (PDE5) inhibitors induce pulmonary vasodilation by increasing intracellular cyclic guanosine monophosphate (cGMP) concentrations.Sildenafil citrate is a highly selective inhibitor of PDE5. Investigations in animal models and recent clinical case reports with some studies in the paediatric population suggest that sildenafil may be a promising agent in treating pulmonary hypertension. The effect of sildenafil on pulmonary vasculature appears to be independent of the underlying cause, thereby providing a role in idiopathic pulmonary arterial hypertension (PAH), PAH associated with congenital heart disease, pulmonary hypertension secondary to lung disease or persistent pulmonary hypertension of the newborn. It may also be beneficial in postoperative pulmonary hypertension and in neonates who are difficult to wean from inhaled NO. It is easily administered and effective, and has minimal systemic adverse effects. Although the reported results in children with pulmonary hypertension are promising, it is an experimental drug and large-scale randomised controlled studies are required to validate the safety, efficacy and dosage in the paediatric population.
4: Ann Thorac Surg. 2007 Jan;83(1):68-71; discussion 71.
Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices.
Klodell CT Jr, Morey TE, Lobato EB, Aranda JM Jr, Staples ED, Schofield RS, Hess PJ, Martin TD, Beaver TM.
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA.
BACKGROUND: Pulmonary artery hypertension can complicate the early postoperative care of patients with left ventricular assist devices (LVADs). Inhaled nitric oxide (INO) is frequently used to manipulate pulmonary resistance after LVADs have been placed. We evaluated the effect of oral sildenafil therapy on pulmonary artery pressure, systemic pressure, and nitric oxide utilization. METHODS: After Institutional Review Board approval, the records of 10 consecutive adult patients with LVADs and pulmonary hypertension who received sildenafil were reviewed. Demographics, surgical history, INO use, inotrope requirements, and hemodynamic response to oral sildenafil at multiple intervals were collected. Hemodynamic data were analyzed with a two-way analysis of variance of repeated measures with correction for multiple comparisons. RESULTS: There were 8 men and 2 women with 6 Heartmate XVE LVADs and 4 Thoratec LVADs (both, Thoratec, Pleasanton, California). When weaning was attempted, 8 patients who received INO demonstrated rebound pulmonary hypertension or increased right heart dysfunction. All patients were on inotropic therapy with dobutamine and milrinone. Sildenafil produced a significant reduction in pulmonary artery systolic pressure within 90 minutes of oral administration (p = 0.042). Significant changes in systolic blood pressure, mean arterial pressure, systemic vascular resistance, and heart rate were not observed. All 8 patients receiving INO were weaned within 12 hours without recurrent pulmonary hypertension. All 10 patients were weaned from inotropic support within 72 hours. No patient suffered right-side heart failure requiring intervention. CONCLUSIONS: Oral sildenafil represents a useful adjunctive therapy for patients with LVADs. In our series, it provided additional reduction of pulmonary artery pressure, and facilitated weaning from INO and inotropes without deleterious hemodynamic consequences.
5: Rev Med Chil. 2006 Jul;134(7):902-9.
Update in the diagnosis and therapy for pulmonary arterial hypertension
Zagolin B M, Wainstein G E, Uriarte G P.
Departamento de Cardiologia, Instituto Nacional del Torax, Chile.
Pulmonary Arterial Hypertension includes a heterogeneous group of disorders with a common genetic, pathological and hemodinamyc origin. It is characterized by a high pulmonary artery pressure due to a primary vascular disease, as a consequence of genetic and environmental factors. The common pathway is a vascular imbalance towards vasoconstriction and proliferation inside the small vessels. According to the World Health Organization, 2003, Pulmonary Arterial Hypertension is classified as idiopathic, familiar or associated to connective tissue diseases, HIV, drugs, porto-pulmonary hypertension, congenital intracardiac shunts and others. The diagnosis is based in hemodynamics. Echocardiogram is a non invasive and right ventricular catheterization is an invasive diagnostic tool. Follow up is based on a clinical and functional assessment through functional class classification, dyspnea scores and 6-minute walking test. The prognosis is historically devastating but new therapies are changing the natural history of the disease. New treatments have demonstrated improvement in symptoms, hemodynamic profiles and survival. Intravenous, subcutaneous or inhaled prostanoids such as Epoprostenol, Treprostinil or Iloprost respectively have been approved for Pulmonary Arterial Hypertension treatment as well as oral endothelial receptor blockers. They are all considered first line treatments for arterial pulmonary hypertensive patients with even better benefits than lung transplantation. Phosphodiesterase inhibitors (Sildenafil), have been recently approved for the treatment of pulmonary arterial hypertension.
6: Tuberk Toraks. 2006;54(2):177-81.
Inhaled iloprost as a long-term additional therapy to oral sildenafil in severe idiopathic pulmonary arterial hypertension.
Onen ZP, Akkoca Yildiz O, Eris Gulbay B, Karabiyikoglu G.
Department of Chest Diseases, Faculty of Medicine, Ankara University, Ankara, Turkey.
Idiopathic pulmonary arterial hypertension (IPAH) is an uncommon and devastating disease which, if untreated, progresses rapidly and leads to right heart failure and death. The course of the disease has been altered by advances in medical therapies. However, the effects of long-term alternative therapies and responses to each treatment protocols are not definite. We want to define an IPAH case, which had long-term temporary responses to the conventional therapy plus calcium channel blockers treatment and moreover compared the long-term clinical and physiologic effects of oral sildenafil mono therapy and additional inhaled iloprost therapy. Patients with IPAH may have response to a short-term vasodilatation therapy but they have to follow for the long-term results and may be of benefit from combination treatments.
7: Eur J Clin Invest. 2006 Sep;36 Suppl 3:32-8.
First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension.
Lunze K, Gilbert N, Mebus S, Miera O, Fehske W, Uhlemann F, Muhler EG, Ewert P, Lange PE, Berger F, Schulze-Neick I.
Klinik fur angeborene Herzfehler/Kinderkardiologie, Deutsches Herzzentrum Berlin, Berlin, Germany.
BACKGROUND: New oral substances such as beraprost, bosentan and sildenafil have proven effective in different forms of pulmonary arterial hypertension (PAH), both alone and in combination with standard treatment such as intravenous and inhaled prostacyclins. However, there are few reports so far on the effect of a combination of exclusively oral substances. In this paper, we present our initial findings of treatment using a combination of these oral substances in a heterogeneous group of patients with different forms of PAH. MATERIALS AND METHODS: Eleven patients with a median age of 12.9 years (5.5-54.7 years) with both idiopathic PAH and forms associated with congenital cardiac defects (PAH-CHD) with a mean pulmonary arterial pressure > 25 mmHg were enrolled in an observational, open-label, prospective, single-centre study. Either combination treatment with bosentan and sildenafil was started initially, or an existing bosentan treatment was complemented with sildenafil given as an add-on therapy. Mean doses given were 2.3 +/- 0.6 mg kg(-1) for bosentan and 2.1 +/- 0.9 mg kg(-1) for sildenafil. Clinical status, exercise capacity, and haemodynamics were assessed at baseline and at the end of the observation period after a mean follow-up time of 1.1 years (0.5-2.5 years). RESULTS: No major side effects regarding liver function and blood pressure regulation were noted. One patient died of sudden death elsewhere. Most patients were in New York Heart Association (NYHA) functional class III. Clinical improvement was about one NYHA class (mean 2.8 +/- 0.4-1.6 +/- 0.8, P = 0.001), which was associated with an increase of transcutaneous oxygen saturation (89.9 +/- 9.9-92.3 +/- 7.1%; P = 0.037), maximum oxygen uptake (18.1 +/- 6.8-22.8 +/- 10.4 mL kg(-1) x min; P = 0.043), and 6-minute walking distance (351 +/- 58-451 +/- 119 m; P = 0.039). Mean pulmonary arterial pressure measured invasively decreased (62 +/- 12-46 +/- 18 mmHg; P = 0.041). CONCLUSIONS: In our patient group, a combination of oral bosentan and sildenafil proved to be safe and effective. Clearly, randomized, double-blind, placebo-controlled studies are warranted to define the role and type of combination therapies in PAH.
